ORCID Profile
0000-0003-3894-5301
Current Organisations
The University of Queensland Diamantina Institute
,
University of South Australia
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Publisher: American Society for Microbiology
Date: 02-2016
DOI: 10.1128/AAC.02461-15
Abstract: The objective of the study was to describe the subcutaneous interstitial fluid (ISF) pharmacokinetics of fluconazole in critically ill patients with sepsis. This prospective observational study was conducted at two tertiary intensive care units in Australia. Serial fluconazole concentrations were measured over 24 h in plasma and subcutaneous ISF using microdialysis. The concentrations in plasma and microdialysate were measured using a validated high-performance liquid chromatography system with electrospray mass spectrometer detector method. Noncompartmental pharmacokinetic analysis was performed. Twelve critically ill patients with sepsis were enrolled. The mean in vivo fluconazole recovery rates ± standard deviation (SD) for microdialysis were 51.4% ± 16.1% with a mean (±SD) fluconazole ISF penetration ratio of 0.52 ± 0.30 (coefficient of variation, 58%). The median free plasma area under the concentration-time curve from 0 to 24 h (AUC 0–24 ) was significantly higher than the median ISF AUC 0–24 (340.4 versus 141.1 mg · h/liter P = 0.004). There was no statistical difference in median fluconazole ISF penetration between patients receiving and not receiving vasopressors (median, 0.28 versus 0.78 P = 0.106). Both minimum and the maximum concentrations of drug in serum ( C max and C min ) showed a significant correlation with the fluconazole plasma exposure ( C max , R 2 = 0.86, P 0.0001 C min , R 2 = 0.75, P 0.001). Our data suggest that fluconazole was distributed variably, but incompletely, from plasma into subcutaneous interstitial fluid in this cohort of critically ill patients with sepsis. Given the variability of fluconazole interstitial fluid exposures and lack of clinically identifiable factors by which to recognize patients with reduced distribution/exposure, we suggest higher than standard doses to ensure that drug exposure is adequate at the site of infection.
Publisher: Elsevier BV
Date: 06-1979
Publisher: SPIE-Intl Soc Optical Eng
Date: 26-02-2013
Publisher: Springer Science and Business Media LLC
Date: 2002
Abstract: The conventional convection-dispersion model is widely used to interrelate hepatic availability (F) and clearance (Cl) with the morphology and physiology of the liver and to predict effects such as changes in liver bloodflow on F and Cl. The extension of this model to include nonlinear kinetics and zonal heterogeneity of the liver is not straightforward and requires numerical solution of partial differential equation, which is not available in standard nonlinear regression analysis software. In this paper, we describe an alternative compartmental model representation of hepatic disposition (including elimination). The model allows the use of standard software for data analysis and accurately describes the outflow concentration-time profile for a vascular marker after bolus injection into the liver. In an evaluation of a number of different compartmental models, the most accurate model required eight vascular compartments, two of them with back mixing. In addition, the model includes two adjacent secondary vascular compartments to describe the tail section of the concentration-time profile for a reference marker. The model has the added flexibility of being easy to modify to model various enzyme distributions and nonlinear elimination. Model predictions of F, MTT, CV2, and concentration-time profile as well as parameter estimates for experimental data of an eliminated solute (palmitate) are comparable to those for the extended convection-dispersion model.
Publisher: S. Karger AG
Date: 2008
DOI: 10.1159/000131078
Abstract: Cosmetic formulations may contain nano-emulsions and microscopic vesicles consisting of traditional cosmetic materials, although it is uncertain whether they should be qualified as actual i nanomaterials. /i Vesicle materials do not penetrate into living human skin. Vesicle formulations may enhance or reduce skin absorption of ingredients, albeit at a limited scale. Sunscreens contain TiO sub /sub or ZnO nanoparticles (NP), which are efficient UV filters. A number of studies suggest that insoluble NP do not penetrate into or through human skin. The results of in vivo toxicity tests showed that TiO sub /sub and ZnO NP are non-toxic. In vitro and in vivo cytotoxicity, genotoxicity, photogenotoxicity, acute toxicity, sensitisation and ecotoxicology studies on TiO sub /sub NP found no difference in the safety profile of micro- or nano-sized materials, all of which were non-toxic. Although some in vitro investigations on TiO sub /sub particles reported cell uptake, oxidative cell damage or genotoxicity, these results may be secondary to phagocytosis of cells exposed to excessive particle concentrations. Studies on wear debris nano- and microparticles support the traditional view that toxicity of small particles is related to their chemistry, rather than their particle size. There is little evidence supporting a general rule that adverse effects of particles on the skin or other tissues increase with smaller particle size, or produce novel toxicities relative to those of larger particles. Overall, the current evidence suggests that nano-sized cosmetic or sunscreen ingredients pose no potential risk to human health, whereas their use in sunscreens has large benefits, such as the protection of human skin against skin cancer.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2001
DOI: 10.1097/00008390-200112000-00007
Abstract: Nude rats bearing melanomas on their hindlimbs were treated by isolated limb infusion (ILI) with increasing doses (7.5-400 microg/ml) of melphalan. The response of tumours to treatment at the end of the observation period was graded, according to diameter, as complete response (CR), partial response (PR), no change (NC) or progressive disease (PD). No linear relationship between the dose of melphalan and the tumour response was observed. All doses above a threshold of 15 microg/ml achieved a PR or CR. The achievement of CR was not related to increased dose. Two major implications arise from this work. Firstly, the typically two- to three-fold increase in cytotoxic drug concentration given in high dose chemotherapy compared with standard drug concentration may not be sufficient to produce the expected increase in tumour response and possibly survival, and the controversial results of high dose chemotherapy in different studies may thus be explained. Secondly, since an increase in melphalan dose above a certain threshold does not greatly increase tumour response, the use of combination therapies would seem to be more likely to be effective than increased chemotherapeutic drug doses in achieving better tumour responses.
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.IJANTIMICAG.2018.09.021
Abstract: Vancomycin is a commonly prescribed antibiotic in the intensive care unit. However, there are limited data describing its distribution into the interstitial fluid (ISF) of tissues. The aim of this study was to describe the plasma and tissue ISF population pharmacokinetics of vancomycin in critically ill patients with sepsis. Serial vancomycin blood and ISF s les were collected at pre-specified time intervals in critically ill patients with sepsis. ISF s ling occurred using a subcutaneously inserted microdialysis catheter. Bioanalysis was undertaken using a validated spectrometric assay method. Population pharmacokinetic analysis was performed using Pmetrics
Publisher: Springer Science and Business Media LLC
Date: 2003
Abstract: To develop a 'quality use of medicines' coding system for the assessment of pharmacists' medication reviews and to apply it to an appropriate cohort. A 'quality use of medicines' coding system was developed based on findings in the literature. These codes were then applied to 216 (111 intervention, 105 control) veterans' medication profiles by an independent clinical pharmacist who was supported by a clinical pharmacologist with the aim to assess the appropriateness of pharmacy interventions. The profiles were provided for veterans participating in a randomised, controlled trial in private hospitals evaluating the effect of medication review and discharge counselling. The reliability of the coding was tested by two independent clinical pharmacists in a random s le of 23 veterans from the study population. Interrater reliability was assessed by applying Cohen's kappa score on aggregated codes. The coding system based on the literature consisted of 19 codes. The results from the three clinical pharmacists suggested that the original coding system had two major problems: (a) a lack of discrimination for certain recommendations e.g. adverse drug reactions, toxicity and mortality may be seen as variations in degree of a single effect and (b) certain codes e.g. essential therapy were in low prevalence. The interrater reliability for an aggregation of all codes into positive, negative and clinically non-significant codes ranged from 0.49-0.58 (good to fair). The interrater reliability increased to 0.72-0.79 (excellent) when all negative codes were excluded. Analysis of the s le of 216 profiles showed that the most prevalent recommendations from the clinical pharmacists were a positive impact in reducing adverse responses (31.9%), an improvement in good clinical pharmacy practice (25.5%) and a positive impact in reducing drug toxicity (11.1%). Most medications were assigned the clinically non-significant code (96.6%). In fact, the interventions led to a statistically significant difference in pharmacist recommendations in the categories adverse response, toxicity and good clinical pharmacy practice measured by the quality use of medicine coding system. It was possible to use the quality use of medicine coding system to rate the quality and potential health impact of pharmacists' medication reviews, and the system did pick up differences between intervention and control patients. The interrater reliability for the summarised coding system was fair, but a larger s le of medication regimens is needed to assess the non-summarised quality use of medicines coding system.
Publisher: Wiley
Date: 08-1998
Publisher: Springer Science and Business Media LLC
Date: 02-2007
DOI: 10.1007/S11096-005-5618-9
Abstract: To determine the prevalence of inappropriate prescribing, defined by applying modified Beers' criteria, and to examine the influence of the Pharmaceutical Benefits Scheme (PBS), Australia's national scheme for subsidising medicines, on inappropriate prescribing. Cross-sectional survey of nursing home records, including 7-days data from medication charts. Fiveteen randomly selected nursing homes (998 residents) in Southeast Queensland and Northern New South Wales, Australia. The prevalence of inappropriate prescribing as defined by modified Beers' criteria and its correlation with PBS restrictions. 18.5% of residents were ordered one or more inappropriate medications, and 1.5% of residents were ordered two or more. The level of PBS restriction and the percentage of residents ordered a medication were highly correlated (p = -0.87, P < 0.001). Medications in Beers' criteria that were not listed (subsidised) on the PBS were not ordered for any resident. PBS medicines with subsidies restricted to certain populations or indications were ordered for 0% to 0.1% of residents. Dextropropoxyphene, diazepam, amitriptyline and methyldopa were the only medications in Beers' criteria prescribed to more than 0.5% of residents. Dextropropoxyphene was only subsidised for war veterans, with a caution warning of its potential to cause drug dependence, while diazepam, amitriptyline and methyldopa were listed on the PBS without any subsidy restrictions. Increases in the level of PBS restriction were associated with decreases in the prevalence of inappropriate prescribing, The targeting of drug subsidies to reduce inappropriate prescribing warrants further investigation.
Publisher: Springer Science and Business Media LLC
Date: 22-02-2011
Abstract: Surgical site infections are common, so effective antibiotic concentrations at the sites of infection are required. Surgery can lead to physiological changes influencing the pharmacokinetics of antibiotics. The aim of the study is to evaluate contemporary peri-operative prophylactic dosing of cefazolin by determining plasma and subcutaneous interstitial fluid concentrations in patients undergoing elective of semi-elective abdominal aortic aneurysm (AAA) open repair surgery. This is an observational pharmacokinetic study of patients undergoing AAA open repair surgery at the Royal Brisbane and Women's Hospital. All patients will be administered 2-g cefazolin by intravenous injection within 30-minutes of the procedure. Participants will have s les from blood and urine, collected at different intervals. Patients will also have a microdialysis catheter inserted into subcutaneous tissue to measure interstitial fluid penetration by cefazolin. Participants will be administered indocyanine green and sodium bromide as well as have cardiac output monitoring performed and tetrapolar bioimpedance to determine physiological changes occurring during surgery. Analysis of s les will be performed using validated liquid chromatography tandem mass-spectrometry. Pharmacokinetic analysis will be performed using non-linear mixed effects modeling to determine in idual and population pharmacokinetic parameters and the effect of peri-operative physiological changes on cefazolin disposition. The study will describe cefazolin levels in plasma and the interstitial fluid of tissues during AAA open repair surgery. The effect of physiological changes to the patient mediated by surgery will also be determined. The results of this study will guide clinicians and pharmacists to effectively dose cefazolin in order to maximize the concentration of antibiotics in the tissues which are the most common site of surgical site infections.
Publisher: Oxford University Press (OUP)
Date: 11-2005
Abstract: Some patients may have medication-related risk factors only identified by home visits, but the extent to which those risk factors are associated with poor health outcomes remains unclear. To determine the association between medication-related risk factors and poor patient health outcomes from observations in the patients' homes. Cross-sectional study. Patients' homes. 204 general practice patients living in their own homes and at risk of medication-related poor health outcomes. Medications and medication-related risk factors were identified in the patients' homes by community pharmacists and general practitioners (GPs). The medication-related risk factors were examined as determinants of patients' self-reported health related quality of life (SF-36) and their medication use, as well as physicians' impression of patient adverse drug events and health status. Key medication-related risk factors associated with poor health outcomes included: Lack of any medication administration routine, therapeutic duplication, hoarding, confusion between generic and trade names, multiple prescribers, discontinued medication repeats retained and multiple storage locations. Older age and female gender were associated with some poorer health outcomes. In addition, expired medication and poor adherence were also associated with poor health outcomes, however, not independently. The findings support the theory that polypharmacy and medication-related risk factors as a result of polypharmacy are correlated to poor health outcomes.
Publisher: American Geophysical Union (AGU)
Date: 07-1997
DOI: 10.1021/JS960523Y
Publisher: Springer Science and Business Media LLC
Date: 20-02-2011
Publisher: Springer Science and Business Media LLC
Date: 1985
DOI: 10.1007/BF00547417
Abstract: The minimum distance for which two points still can be separated from each other defines the resolving power of a visual system. In an echo-acoustic context, the resolving power is usually measured as the smallest perceivable distance of two reflecting surfaces on the range axis and is found to be around half a millimeter for bats employing frequency modulated (FM) echolocation calls. Only few studies measured such thresholds with physical objects, most often bats were trained on virtual echoes i.e., echoes generated and played back by a computer moreover, bats were sitting while they received the stimuli. In these studies differences in structure depth between 200 and 340 μm were found. However, these low thresholds were never verified for free-flying bats and real physical objects. Here, we show behavioral evidence that the echo-acoustic resolving power for surface structures in fact can be as low as measured for computer generated echoes and even lower, sometimes below 100 μm. We found this exceptional fine discrimination ability only when one of the targets showed spectral interferences in the frequency range of the bats' echolocation call while the other target did not. This result indicates that surface structure is likely to be perceived as a spectral quality rather than being perceived strictly in the time domain. Further, it points out that sonar resolving power directly depends on the highest frequency/shortest wavelength of the signal employed.
Publisher: Springer Science and Business Media LLC
Date: 02-1988
DOI: 10.1007/BF01061862
Publisher: Springer Science and Business Media LLC
Date: 24-11-2010
Publisher: Inderscience Publishers
Date: 2010
Publisher: Elsevier BV
Date: 08-2011
DOI: 10.1016/J.JCHROMB.2011.06.006
Abstract: Carbofuran (CFN), carbosulfan (CSN) and fenobucarb (FBC) are carbamate pesticides that are widely used in gardening and agriculture for the control of insects. Human poisoning due to occupational or self-poisoning exposures is also reported, so assays are required to quantify the plasma concentration of these insecticides. An LC-MS/MS method was developed and validated for the simultaneous quantification of these three carbamate insecticides in the plasma of patients with acute intentional self-poisoning. Plasma s les were pretreated by acetonitrile for protein precipitation. Chromatography was carried out on a Luna C18(2) analytical column with gradient elution using a mobile phase containing acetonitrile and water with 10mM ammonium acetate. Mass spectrometric analysis was performed by an Applied Biosystems MDS Sciex API 2000 triple quadrupole mass spectrometer coupled with electrospray ionization (ESI) source in the positive ion mode. The total run time was 7 min. The assay was validated over a concentration range from 10 to 1000 ng/ml for CSN and FBC and 20-2000 ng/ml for CFN. The precision and accuracy for both intra- and inter-day determination of all analytes were acceptable (<15%). No significant matrix effect was observed. Stability of compounds was established for short term bench and autos ler storage as well as freeze/thaw cycles. The method was effectively applied to 270 clinical s les from patients with a history of acute intentional carbamate self-poisoning.
Publisher: Oxford University Press (OUP)
Date: 27-04-2009
DOI: 10.1093/JAC/DKP139
Abstract: To compare the plasma and subcutaneous tissue concentration-time profiles of meropenem administered by intermittent bolus dosing or continuous infusion to critically ill patients with sepsis and without renal dysfunction, and to use population pharmacokinetic modelling and Monte Carlo simulations to assess the cumulative fraction of response (CFR) against Gram-negative pathogens likely to be encountered in critical care units. We randomized 10 patients with sepsis to receive meropenem by intermittent bolus administration (n = 5 1 g 8 hourly) or an equal dose administered by continuous infusion (n = 5). Serial subcutaneous tissue concentrations were determined using microdialysis and compared with plasma data for first-dose and steady-state pharmacokinetics. Population pharmacokinetic modelling of plasma data and Monte Carlo simulations were then undertaken with NONMEM. It was found that continuous infusion maintains higher median trough concentrations, in both plasma (intermittent bolus 0 versus infusion 7 mg/L) and subcutaneous tissue (0 versus 4 mg/L). All simulated intermittent bolus, extended and continuous infusion dosing achieved 100% of pharmacodynamic targets against most Gram-negative pathogens. Superior obtainment of pharmacodynamic targets was achieved using administration by extended or continuous infusion against less susceptible Pseudomonas aeruginosa and Acinetobacter species. This is the first study to compare the relative concentration-time data of bolus and continuous administration of meropenem at the subcutaneous tissue and plasma levels. We found that the administration of meropenem by continuous infusion maintains higher concentrations in subcutaneous tissue and plasma than by intermittent bolus dosing. Administration by extended or continuous infusion will achieve superior CFR against less-susceptible organisms in patients without renal dysfunction.
Publisher: Informa UK Limited
Date: 31-01-2020
DOI: 10.1080/17435390.2019.1692382
Abstract: Suspensions of the UV filter, zinc oxide nanoparticles (ZnO NP), are widely used in sunscreen products. This paper compared the relative disposition and local cytotoxicity of ZnO NP, and zinc ions formed on its dissolution, against keratinocyte cultures and in the human epidermis (
Publisher: SAGE Publications
Date: 10-2002
DOI: 10.1046/J.1440-1614.2002.01068.X
Abstract: Objective: To examine the knowledge and beliefs of doctors and nurses in inpatient psychiatric units about pro re nata (PRN) (as needed) medications for psychotic disorders. Methods: Medical (n = 44) and nursing (n = 80) staff in two metropolitan public hospital units completed a structured questionnaire about their use of PRN psychotropic medications on one occasion during the four months from March–June 1999. Results: Nurses selected more indications for PRN antipsychotics than doctors (3.49 vs 2.72, p 0.05), whereas doctors selected more indications for PRN benzodiazepines (3.77 vs 3.19, p 0.05). The groups did not differ in the number of selected indications for using anticholinergics. For agitation, the majority of nurses viewed both benzodiazepines (56%) and antipsychotics (86%) as effective, with 60% preferring an antipsychotic. For the acute control of psychotic symptoms, 99% of nurses believed antipsychotics were effective and 58% benzodiazepines, with 87% preferring an antipsychotic. A large majority of doctors viewed both PRN benzodiazepines, 94%, and antipsychotics, 81%, as effective for agitation, and 55% preferred to use a benzodiazepine. For psychotic symptoms, 80% believed PRN antipsychotics were effective, but only 32% viewed benzodiazepines as effective, and 64% preferred to use an antipsychotic. Nursing staff identified more non-pharmacological techniques for managing both agitation and psychotic symptoms and reported using these more often than doctors. Junior staff, both nursing and medical, had less knowledge of nonpharmacological alternatives to PRN medication than senior staff. Conclusions: Disparities existed between doctors and nurses views on the indications for PRN medication in the acute management of psychoses, thus it is important for doctors to specify indications when writing PRN prescriptions. Despite evidence for the safety and effectiveness of benzodiazepines, there was widespread reluctance to use them as PRN medication in acute psychoses. Beliefs of some staff about PRN medications were at odds with the known properties of these medicines. Educational interventions for both nurses and doctors are required to achieve best practice in PRN medication.
Publisher: American Society for Microbiology
Date: 08-2016
DOI: 10.1128/AAC.00531-16
Abstract: Severe pathophysiological changes in critical illness can lead to dramatically altered antimicrobial pharmacokinetics (PK). The additional effect of obesity on PK potentially increases the challenge for effective dosing. The aim of this prospective study was to describe the population PK of meropenem for a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients prescribed meropenem were recruited into the following three body mass index (BMI) groups: nonobese (18.5 to 29.9 kg/m 2 ), obese (30.0 to 39.9 kg/m 2 ), and morbidly obese (≥40 kg/m 2 ). Serial plasma s les were taken, and meropenem concentrations were determined using a validated chromatographic method. Population PK analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Nineteen critically ill patients with different BMI categories were enrolled. The patients' mean ± standard deviation (SD) age, weight, and BMI were 49 ± 15.9 years, 95 ± 22.0 kg, and 33 ± 7.0 kg/m 2 , respectively. A two-compartment model described the data adequately. The mean ± SD parameter estimates for the final covariate model were as follows: clearance (CL), 15.5 ± 6.0 liters/h volume of distribution in the central compartment ( V 1 ), 11.7 ± 5.8 liters intercompartmental clearance from the central compartment to the peripheral compartment, 25.6 ± 35.1 liters h −1 and intercompartmental clearance from the peripheral compartment to the central compartment, 8.32 ± 12.24 liters h −1 . Higher creatinine clearance (CL CR ) was associated with a lower probability of target attainment, with BMI having little effect. Although obesity was found to be associated with an increased V 1 , dose adjustment based on CL CR appears to be more important than patient BMI.
Publisher: Wiley
Date: 11-10-2012
DOI: 10.1111/ICS.12001
Abstract: Twenty products, containing a radiolabelled form of each active in typical cosmetic formulations, were made and applied to female human epidermal membranes mounted in Franz diffusion cells for 48 h under 'in use' conditions. The products consisted of combinations of five formulations (a hydro-alcoholic gel, an oil in water emulsion, a water in oil emulsion, a microemulsion and an oil) with four model drug actives (testosterone, hydrocortisone, 5-fluorouracil and ketoconazole). Steady-state flux appeared to be reached by 8 h and maintained for all products, other than for the microemulsions, consistent with the actives being present in the residual formulation on the skin at saturation. The recovery for each active at the end of the 48-h study (from a series of stratum corneum tape strips, the remaining skin, cumulative amount penetrating into the receptor solution, product washed from the skin and on the donor chamber cap) ranged from 86.5% to 100.6%. The rank order of the fluxes for the actives from the hydro-alcoholic gel is consistent with the known active molecular size and polarity determinants for maximum epidermal flux. Actives with similar steady-state (maximum) fluxes from a range of formulations had retention in the stratum corneum and similar transport rate constants through the stratum corneum. The microemulsion formulation significantly enhanced both the stratum corneum steady-state flux and transport rate constant for 5-fluorouracil, hydrocortisone and testosterone. The penetration flux of each active could be related to its size and polarity and appeared maximal when the actives in the different cosmetic formulations applied to the skin under 'in use' conditions were likely to remain in the residual product on the skin as a saturated solution after solvent evaporation. Enhanced penetration fluxes can be achieved by formulation selection and an appropriate choice/mix of emollients/adjuvants. The principles described here provide a framework for understanding the delivery of cosmetic ingredients from various formulations.
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.IJPHARM.2009.08.028
Abstract: This study compared the impact of two perfusates (A: 4.5% BSA-MOPS buffer and B: 4% dextran and 0.5% BSA-MOPS buffer) on the pharmacokinetics of the physiological markers [(3)H]-water, [(14)C]-sucrose, [(14)C]-antipyrine and Evans Blue-labelled albumin and the drugs atenolol and propranolol using an in-situ single pass perfusion model in the rat lung. The multiple indicator dilution approach was used to define disposition. Similar perfusion pressures (17.6+/-6.71 vs 17.7+/-8.87 cm H(2)O), lung wet/dry ratio (6.14+/-1.16 vs 5.16+/-0.87), physiological spaces, and permeability-surface area products were found for the two perfusates. However, the recovery of propranolol using perfusate A (49.3+/-10.1%) was significantly higher than that using perfusate B (38.9+/-9.91%). This difference was consistent with changes in perfusate oncotic pressure associated with water and albumin distribution between the vascular, interstitial and cellular volumes of the lung.
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.IJPHARM.2012.01.055
Abstract: Fluorescence recovery after photo-bleaching experiments were performed in human stratum corneum in vitro. Fluorescence multiphoton tomography was used, which allowed the dimensions of the photobleached volume to be at the micron scale and located fully within the lipid phase of the stratum corneum. Analysis of the fluorescence recovery data with simplified mathematical models yielded the diffusion coefficient of small molecular weight organic fluorescent dye Rhodamine B in the stratum corneum lipid phase of about (3-6) × 10(-9)cm(2) s(-1). It was concluded that the presented method can be used for detailed analysis of localised diffusion coefficients in the stratum corneum phases for various fluorescent probes.
Publisher: Springer Science and Business Media LLC
Date: 25-08-2012
DOI: 10.1007/S11095-012-0846-X
Abstract: In principle, maximum transepidermal fluxes of solutes should be similar for different vehicles, except when the solute or vehicle modifies the skin. Here we estimated maximum flux, stratum corneum solubility, diffusivity and permeability coefficient for a range of similarly sized phenolic compounds with varying lipophilicity from polar and lipophilic vehicles. Maximum flux and other skin transport parameters through human epidermis were obtained from lipophilic vehicles (mineral oil (MO) and isopropyl myristate (IPM)) and compared with values from water and propylene glycol (PG)-water solutions. Solvent uptake and changes in stratum corneum infrared spectroscopy and multiphoton microscopy imaging were also investigated. Maximum fluxes for MO and water were similar but IPM has a higher value for more polar phenols due to a higher diffusivity and PG-water had a higher flux due to higher solubility in the stratum corneum. Whereas maximum flux for various phenols was directly related to solubility in the stratum corneum independent of vehicle, increasing phenol lipophilicity increased and decreased permeability coefficient for aqueous solvents and lipophilic solvents, respectively. The maximum fluxes for phenols with a similar molecular size and varying lipophilicity were comparable between water and MO vehicles but higher for IPM and PG-water mixtures.
Publisher: Ivyspring International Publisher
Date: 2018
DOI: 10.7150/THNO.22872
Publisher: American Chemical Society (ACS)
Date: 21-01-2016
Abstract: Zinc oxide (ZnO) is frequently used in commercial sunscreen formulations to deliver their broad range of UV protection properties. Concern has been raised about the extent to which these ZnO particles (both micronized and nanoparticulate) penetrate the skin and their resultant toxicity. This work has explored the human epidermal skin penetration of zinc oxide and its labile zinc ion dissolution product that may potentially be formed after application of ZnO nanoparticles to human epidermis. Three ZnO nanoparticle formulations were used: a suspension in the oil, capric caprylic triglycerides (CCT), the base formulation commonly used in commercially available sunscreen products an aqueous ZnO suspension at pH 6, similar to the natural skin surface pH and an aqueous ZnO suspension at pH 9, a pH at which ZnO is stable and there is minimal pH-induced impairment of epidermal integrity. In each case, the ZnO in the formulations did not penetrate into the intact viable epidermis for any of the formulations but was associated with an enhanced increase in zinc ion fluorescence signal in both the stratum corneum and the viable epidermis. The highest labile zinc fluorescence was found for the ZnO suspension at pH 6. It is concluded that, while topically applied ZnO does not penetrate into the viable epidermis, these applications are associated with hydrolysis of ZnO on the skin surface, leading to an increase in zinc ion levels in the stratum corneum, thence in the viable epidermis and subsequently in the systemic circulation and the urine.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Elsevier BV
Date: 08-1995
Abstract: The relationship between solute distribution, physicochemical properties, and tissue physiology was determined by the impulse-response (IR) technique and statistical moment analysis in the isolated perfused rat hindlimb. The concentration of bovine serum albumin (BSA 2, 4.7, and 7%, w/v), perfusate flow rate (4 and 8 mL/min), and solute physicochemical properties (lipophilicity, P, fraction unbound to protein, fu fraction ionized, fi and molecular weight MW) were varied to better understand the underlying determinants of solute distribution. An apparent low availability was found for a number of the solutes as a consequence of tissue sequestration. This low availability precludes the estimation of an apparent volume of distribution (V) for these solutes. The V of solute and tissue (skin, fat, and muscle) blood flow increased with perfusion flow rate (p < 0.01). The unbound distribution volume (Vu) of basic solutes was significantly linear with respect to P. Multiple linear regression analysis showed that the distribution volume of solute in tissue was significantly related to fu (p < 0.01), but not improved by including relationships to P, MW, and fi. Data obtained with this IR technique yield results consistent with in vivo studies in terms of the importance of fu as a determinant of V. This work has shown that the estimations of solute V by the IR technique in a single-pass preparation are unreliable for solutes with a low availability due to apparent solute sequestration into tissue. The parameter V may also be affected by changes in the perfused limb physiology associated with the perfusion conditions used. The Vs for lidocaine and diazepam vary with fu in accordance with deductions based on the results of steady-state studies.
Publisher: Elsevier BV
Date: 08-2021
Publisher: The Optical Society
Date: 15-11-2011
DOI: 10.1364/BOE.2.003321
Publisher: Elsevier BV
Date: 1991
DOI: 10.1016/0024-3205(91)90210-3
Abstract: The effects of beta-blockers on maternal and fetal heart rates have been assessed by comparing isoprenaline concentration-heart rate relationships of hearts isolated from pregnant rats. The normal and maximal heart rates obtained for the maternal and fetal hearts were similar to published data. A slightly but significantly higher concentration of isoprenaline was required to produce 50% of the maximal response of fetal hearts than maternal hearts, suggesting that fetal hearts were less sensitive to isoprenaline than the maternal hearts. The beta-blockers used (propranolol, labetalol, metoprolol and atenolol) all showed a lower affinity to the beta-receptors of fetal hearts than those of maternal hearts, as indicated by significant differences in the pA2 values. Given the similar effects of the beta-blockers in the maternal and fetal hearts it is concluded that pharmacokinetic considerations and beta-blocker selectivity should be used as the basis of choice when treating maternal hypertension during pregnancy.
Publisher: Springer Science and Business Media LLC
Date: 28-03-2017
DOI: 10.1038/SREP45374
Abstract: Oxidative stress reflects an imbalance between reactive oxygen species (ROS) and antioxidants, which has been reported as an early unifying event in the development and progression of various diseases and as a direct and mechanistic indicator of treatment response. However, highly reactive and short-lived nature of ROS and antioxidant limited conventional detection agents, which are influenced by many interfering factors. Here, we present a two-photon sensing platform for in vivo dual imaging of oxidative stress at the single cell-level resolution. This sensing platform consists of three probes, which combine the turn-on fluorescent transition-metal complex with different specific responsive groups for glutathione (GSH), hydrogen peroxide (H 2 O 2 ) and hypochlorous acid (HOCl). By combining fluorescence intensity imaging and fluorescence lifetime imaging, these probes totally remove any possibility of crosstalk from in vivo environmental or instrumental factors, and enable accurate localization and measurement of the changes in ROS and GSH within the liver. This precedes changes in conventional biochemical and histological assessments in two distinct experimental murine models of liver injury. The ability to monitor real-time cellular oxidative stress with dual-modality imaging has significant implications for high-accurate, spatially configured and quantitative assessment of metabolic status and drug response.
Publisher: Elsevier BV
Date: 08-1997
DOI: 10.1016/S0140-6736(05)63324-7
Abstract: Single-step genomic predictions obtained from a breeding value model require calculating the inverse of the genomic relationship matrix [Formula: see text]. The Algorithm for Proven and Young (APY) creates a sparse representation of [Formula: see text] with a low computational cost. APY consists of selecting a group of core animals and expressing the breeding values of the remaining animals as a linear combination of those from the core animals plus an error term. The objectives of this study were to: (1) extend APY to marker effects models (2) derive equations for marker effect estimates when APY is used for breeding value models, and (3) show the implication of selecting a specific group of core animals in terms of a marker effects model. We derived a family of marker effects models called APY-SNP-BLUP. It differs from the classic marker effects model in that the row space of the genotype matrix is reduced and an error term is fitted for non-core animals. We derived formulas for marker effect estimates that take this error term in account. The prediction error variance (PEV) of the marker effect estimates depends on the PEV for core animals but not directly on the PEV of the non-core animals. We extended the APY-SNP-BLUP to include a residual polygenic effect and accommodate non-genotyped animals. We show that selecting a specific group of core animals is equivalent to select a subspace of the row space of the genotype matrix. As the number of core animals increases, subspaces corresponding to different sets of core animals tend to overlap, showing that random selection of core animals is algebraically justified. The APY-(ss)GBLUP models can be expressed in terms of marker effect models. When the number of core animals is equal to the rank of the genotype matrix, APY-SNP-BLUP is identical to the classic marker effects model. If the number of core animals is less than the rank of the genotype matrix, genotypes for non-core animals are imputed as a linear combination of the genotypes of the core animals. For estimating SNP effects, only relationships and estimated breeding values for core animals are needed.
Publisher: S. Karger AG
Date: 06-11-2015
DOI: 10.1159/000441040
Abstract: b i Background/Aims: /i /b A range of vesicles is now widely used to carry various solutes into and through the epidermis. These usually have the active solute encapsulated within and may be modified to confer flexibility and skin penetration enhancement. Here, we compared the ability of five different vesicle systems to deliver a model hydrophilic drug, caffeine, into and through excised human skin. b i Methods: /i /b In addition to lipids, the vesicle excipients included eucalyptol or oleic acid as penetration enhancers, and decyl polyglucoside as a non-ionic surfactant. Vesicle particle sizes ranged between 135 and 158 nm, and caffeine encapsulation efficiencies were between 46 and 66%. Caffeine penetration and permeation were measured using high-performance liquid chromatography. b i Results: /i /b We found that niosomes, which are liposomes containing a non-ionic surfactant, and transferosomes (ultraflexible vesicles) showed significantly greater penetration into the skin and permeation across the stratum corneum. Significant enhancement of caffeine penetration into hair follicles was found for transferosomes and those liposomes containing oleic acid. b i Conclusions: /i /b We conclude that targeted delivery of the hydrophilic drug caffeine into the skin compartments can be modified using optimized vesicular formulations.
Publisher: Elsevier BV
Date: 03-2008
DOI: 10.1016/J.IJANTIMICAG.2007.09.013
Abstract: Plasma exchange (PE) is a treatment modality frequently used for many autoimmune diseases and may cause extracorporeal elimination of antibiotics. No data currently exist on antibiotic concentrations in extracellular fluid during PE. The aim of this study is to describe the effect of PE on the serum and subcutaneous tissue pharmacokinetics of piperacillin administered as a continuous infusion in a critically ill 17-year-old patient with Guillain-Barré syndrome and ventilator-associated pneumonia on Days 1 and 4 of antibiotic therapy. The effect of PE on piperacillin concentrations appears to be small. On Day 1, an estimated 7% of total piperacillin eliminated during PE was attributable to PE. On Day 4 this was estimated to be 11%. Using the in vivo s ling technique microdialysis, we have been able to show that a small redistribution of piperacillin from tissue to serum occurs in response to the reducing serum concentrations caused by PE. In critically ill patients, we believe that administration of a beta-lactam antibiotic by continuous infusion should be considered to maintain serum and tissue concentrations of these time-dependent antibiotics.
Publisher: PeerJ
Date: 06-12-2018
DOI: 10.7717/PEERJ.6072
Abstract: Mesenchymal stem/stromal cells (MSCs) are a promising tool for cell-based therapies in the treatment of tissue injury. The stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis plays a significant role in directing MSC homing to sites of injury. However in vivo MSC distribution following intravenous transplantation remains poorly understood, potentially h ering the precise prediction and evaluation of therapeutic efficacy. A murine model of partial ischemia/reperfusion (I/R) is used to induce liver injury, increase the hepatic levels of SDF-1, and study in vivo MSC distribution. Hypoxia-preconditioning increases the expression of CXCR4 in human bone marrow-derived MSCs. Quantitative assays for human DNA using droplet digital PCR (ddPCR) allow us to examine the in vivo kinetics of intravenously infused human MSCs in mouse blood and liver. A mathematical model-based system is developed to characterize in vivo homing of human MSCs in mouse models with SDF-1 levels in liver and CXCR4 expression on the transfused MSCs. The model is calibrated to experimental data to provide novel estimates of relevant parameter values. Images of immunohistochemistry for SDF-1 in the mouse liver with I/R injury show a significantly higher SDF-1 level in the I/R injured liver than that in the control. Correspondingly, the ddPCR results illustrate a higher MSC concentration in the I/R injured liver than the normal liver. CXCR4 is overexpressed in hypoxia-preconditioned MSCs. An increased number of hypoxia-preconditioned MSCs in the I/R injured liver is observed from the ddPCR results. The model simulations align with the experimental data of control and hypoxia-preconditioned human MSC distribution in normal and injured mouse livers, and accurately predict the experimental outcomes with different MSC doses. The modelling results suggest that SDF-1 in organs is an effective in vivo attractant for MSCs through the SDF-1/CXCR4 axis and reveal the significance of the SDF-1/CXCR4 chemotaxis on in vivo homing of MSCs. This in vivo modelling approach allows qualitative characterization and prediction of the MSC homing to normal and injured organs on the basis of clinically accessible variables, such as the MSC dose and SDF-1 concentration in blood. This model could also be adapted to abnormal conditions and/or other types of circulating cells to predict in vivo homing patterns.
Publisher: Elsevier BV
Date: 06-1996
DOI: 10.1016/0378-4347(96)00063-1
Abstract: This paper reports the development of a reversed-phase high-performance liquid chromatographic assay for quantifying five of the most common sunscreen agents, namely 2-ethylhexyl-p-dimethyl aminobenzoate (Escalol 507), 2-ethylhexyl-p-methoxycinnamate (Parsol MCX) 4-tert.-butyl-4'-methoxydibenzoylmethane (Parsol 1789), 2-hydroxy-4-methoxybenzophenone-3 (oxybenzone) and 2-ethylhexyl-salicylate (octylsalicylate). The assay permits analysis of the sunscreen agents in formulations and in biological fluids, including bovine serum albumin (BSA) solution, a common additive to in vitro skin diffusion cell receptor fluids, as well as human plasma. Separation was achieved using an ODS C154 column with a methanol-water (88:12) mobile phase. The analytes were detected by ultraviolet light absorption at a wavelength of 315 nm. The assay was linear with minimum detectable limits, calculated as greater than 3-times the baseline noise level: for oxybenzone and Escalol 507, 0.05 microgram/ml for Parsol 1789 and Parsol MCX, 0.1 microgram/ml for octylsalicylate, 1 microgram/ml. Recoveries from both plasma and 2% BSA were within the range 89-107%. The inter- and intra-day coefficients of variation for the five agents were not more than 4% at the upper end of the linear range and not more than 10% at the lower end. Preliminary stability studies of the sunscreen agents in a commercial product and in two diffusion cell receptor fluids were also conducted.
Publisher: Oxford University Press (OUP)
Date: 16-01-2014
DOI: 10.1093/JAC/DKT523
Abstract: Emerging evidence supports the use of therapeutic drug monitoring (TDM) of β-lactams for intensive care unit (ICU) patients to optimize drug exposure, although limited detail is available on how sites run this service in practice. This multicentre survey study was performed to describe the various approaches used for β-lactam TDM in ICUs. A questionnaire survey was developed to describe various aspects relating to the conduct of β-lactam TDM in an ICU setting. Data sought included: β-lactams chosen for TDM, inclusion criteria for selecting patients, blood s ling strategy, analytical methods, pharmacokinetic (PK) harmacodynamic (PD) targets and dose adjustment strategies. Nine ICUs were included in this survey. Respondents were either ICU or infectious disease physicians, pharmacists or clinical pharmacologists. Piperacillin (co-formulated with tazobactam) and meropenem (100% of units surveyed) were the β-lactams most commonly subject to TDM, followed by ceftazidime (78%), ceftriaxone (43%) and cefazolin (43%). Different chromatographic and microbiological methods were used for assay of β-lactam concentrations in blood and other biological fluids (e.g. CSF). There was significant variation in the PK/PD targets (100% fT>MIC up to 100% fT>4×MIC) and dose adjustment strategies used by each of the sites. Large variations were found in the type of β-lactams tested, the patients selected for TDM and drug assay methods. Significant variation observed in the PK/PD targets and dose adjustment strategies used supports the need for further studies that robustly define PK/PD targets for ICU patients to ensure a greater consistency of practice for dose adjustment strategies for optimizing β-lactam dosing with TDM.
Publisher: Elsevier BV
Date: 04-2001
DOI: 10.1002/1520-6017(200104)90:4<504::AID-JPS1008>3.0.CO;2-H
Abstract: The diffusion model for percutaneous absorption is developed for the specific case of delivery to the skin being limited by the application of a finite amount of solute. Two cases are considered in the first, there is an application of a finite donor (vehicle) volume, and in the second, there are solvent-deposited solids and a thin vehicle with a high partition coefficient. In both cases, the potential effect of an interfacial resistance at the stratum corneum surface is also considered. As in the previous paper, which was concerned with the application of a constant donor concentration, clearance limitations due to the viable eqidermis, the in vitro s ling rate, or perfusion rate in vivo are included. Numerical inversion of the Laplace domain solutions was used for simulations of solute flux and cumulative amount absorbed and to model specific ex les of percutaneous absorption of solvent-deposited solids. It was concluded that numerical inversions of the Laplace domain solutions for a diffusion model of the percutaneous absorption, using standard scientific software (such as SCIENTIST, MicroMath Scientific software) on modern personal computers, is a practical alternative to computation of infinite series solutions. Limits of the Laplace domain solutions were used to define the moments of the flux-time profiles for finite donor volumes and the slope of the terminal log flux-time profile. The mean transit time could be related to the diffusion time through stratum corneum, viable epidermal, and donor diffusion layer resistances and clearance from the receptor phase. Approximate expressions for the time to reach maximum flux (peak time) and maximum flux were also derived. The model was then validated using reported amount-time and flux-time profiles for finite doses applied to the skin. It was concluded that for very small donor phase volume or for very large stratum corneum-vehicle partitioning coefficients (e.g., for solvent deposited solids), the flux and amount of solute absorbed are affected by receptor conditions to a lesser extent than is obvious for a constant donor constant donor concentrations.
Publisher: American Scientific Publishers
Date: 10-2010
Abstract: There are a growing number of commercial uses of nanoparticles which involve direct people contact with the potential for absorption through the skin. Nanoparticles are present in a range of consumer products including colloidal health drinks, carbon fibre sports equipment, sunscreens, cosmetics, electronic products and as antibacterial components of toys, cooking products and wound dressings. Environmental sources of ultra-fine nanoparticles have been present for millennia and anthropogenic sources of similar materials result from industrial processes. Recent technological advances have enabled improvements in both the manufacture of nanoparticles and in the study of their safety. With subcellular dimensions, the physical properties of a nanoparticle cannot be easily predicted from the properties of a microparticle with identical chemical composition. Recent studies in animals and humans have sought to document the safety of consumer nanomaterials. In this article, the safety of such materials is critically reviewed.
Publisher: Wiley
Date: 07-12-2011
Publisher: Elsevier BV
Date: 09-2001
DOI: 10.1016/S0169-409X(01)00158-2
Abstract: A range of topical products are used in veterinary medicine. The efficacy of many of these products has been enhanced by the addition of penetration enhancers. Evolution has led to not only a highly specialized skin in animals and humans, but also one whose anatomical structure and skin permeability differ between the various species. The skin provides an excellent barrier against the ingress of environmental contaminants, toxins, and microorganisms while performing a homeostatic role to permit terrestrial life. Over the past few years, major advances have been made in the field of transdermal drug delivery. An increasing number of drugs are being added to the list of therapeutic agents that can be delivered via the skin to the systemic circulation where clinically effective concentrations are reached. The therapeutic benefits of topically applied veterinary products is achieved in spite of the inherent protective functions of the stratum corneum (SC), one of which is to exclude foreign substances from entering the body. Much of the recent success in this field is attributable to the rapidly expanding knowledge of the SC barrier structure and function. The bilayer domains of the intercellular lipid matrices within the SC form an excellent penetration barrier, which must be breached if poorly penetrating drugs are to be administered at an appropriate rate. One generalized approach to overcoming the barrier properties of the skin for drugs and biomolecules is the incorporation of suitable vehicles or other chemical compounds into a transdermal delivery system. Indeed, the incorporation of such compounds has become more prevalent and is a growing trend in transdermal drug delivery. Substances that help promote drug diffusion through the SC and epidermis are referred to as penetration enhancers, accelerants, adjuvants, or sorption promoters. It is interesting to note that many pour-on and spot-on formulations used in veterinary medicine contain inert ingredients (e.g., alcohols, amides, ethers, glycols, and hydrocarbon oils) that will act as penetration enhancers. These substances have the potential to reduce the capacity for drug binding and interact with some components of the skin, thereby improving drug transport. However, their inclusion in veterinary products with a high-absorbed dose may result in adverse dermatological reactions (e.g., toxicological irritations) and concerns about tissue residues. These are important considerations when formulating a veterinary transdermal product when such compounds are added, either intentionally or otherwise, for their penetration enhancement ability.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2006
Publisher: American Scientific Publishers
Date: 10-2010
Abstract: In this review, we discuss the use of inorganic nanoparticles, mainly zinc oxide (ZnO) and titanium dioxide (TiO2), for sunscreen applications considering their intrinsic physical properties and the Mie theory. These properties cause, from one side, attenuation of the ultraviolet light by absorption and scattering (dependent on a particle size), which is the purpose sunscreens are designed for, and formation of free radicals (i.e., phototoxicity) during this process--from the other. Particle penetration into skin is also an important issue addressed in this review due to possible adverse effects associated with interaction between nanoparticles and skin living cells.
Publisher: The Endocrine Society
Date: 06-1996
DOI: 10.1210/JC.81.6.2247
Publisher: American Scientific Publishers
Date: 10-2010
Publisher: Oxford University Press (OUP)
Date: 20-04-2021
DOI: 10.1093/AOB/MCAB029
Abstract: Rhizosheaths are defined as the soil adhering to the root system after it is extracted from the ground. Root hairs and mucilage (root exudates) are key root traits involved in rhizosheath formation, but to better understand the mechanisms involved their relative contributions should be distinguished. The ability of three species [barley (Hordeum vulgare), maize (Zea mays) and Lotus japonicus (Gifu)] to form a rhizosheath in a sandy loam soil was compared with that of their root-hairless mutants [bald root barley (brb), maize root hairless 3 (rth3) and root hairless 1 (Ljrhl1)]. Root hair traits (length and density) of wild-type (WT) barley and maize were compared along with exudate adhesiveness of both barley and maize genotypes. Furthermore, root hair traits and exudate adhesiveness from different root types (axile versus lateral) were compared within the cereal species. Per unit root length, rhizosheath size diminished in the order of barley & L. japonicus & maize in WT plants. Root hairs significantly increased rhizosheath formation of all species (3.9-, 3.2- and 1.8-fold for barley, L. japonicus and maize, respectively) but there was no consistent genotypic effect on exudate adhesiveness in the cereals. While brb exudates were more and rth3 exudates were less adhesive than their respective WTs, maize rth3 bound more soil than barley brb. Although both maize genotypes produced significantly more adhesive exudate than the barley genotypes, root hair development of WT barley was more extensive than that of WT maize. Thus, the greater density of longer root hairs in WT barley bound more soil than WT maize. Root type did not seem to affect rhizosheath formation, unless these types differed in root length. When root hairs were present, greater root hair development better facilitated rhizosheath formation than root exudate adhesiveness. However, when root hairs were absent root exudate adhesiveness was a more dominant trait.
Publisher: Wiley
Date: 10-1999
DOI: 10.1046/J.1365-2125.1999.00056.X
Abstract: Topical sunscreens are routinely applied to the skin by a large percentage of the population. This study assessed the extent of absorption of a number of common chemical sunscreen agents into and through human skin following application of commercially available products. Sunscreen products were applied to excised human epidermis in Franz diffusion cells with the amount penetrating into and across the epidermis assessed by h.p.l.c. for 8 h following application. All sunscreen agents investigated penetrated into the skin (0.25 g m-2 or 14% of applied dose), but only benzophenone-3 passed through the skin in significant amounts (0.08 g m-2 or 10% of the applied dose). With one exception, suncreen agents in corresponding products marketed for adults and children had similar skin penetration profiles. Whilst limited absorption across the skin was observed for the majority of the sunscreens tested, benzophenone-3 demonstrated sufficiently high penetration to warrant further investigation of its continued application.
Publisher: Springer Science and Business Media LLC
Date: 02-1981
DOI: 10.1007/BF00561946
Publisher: Springer Science and Business Media LLC
Date: 25-01-2007
DOI: 10.1007/S11095-006-9167-2
Abstract: To set up and validate a viable perfused rat pancreas model suitable for pharmacokinetic studies. We setup and conducted multiple indicator dilution studies in the single pass perfused rat pancreas. The distribution of the reference markers [99mTc]-red blood cells (RBC), [14C]-sucrose, and [3H]-water, and tolbutamide were analysed using both non-parametric and parametric methods. The perfusion preparation was observed to be viable by oxygen consumption, outflow perfusate pH, lactate release and insulin release in response to glucose. Parametric analysis of the outflow profiles suggested that the transport of water and tolbutamide from the vascular space was permeability limited. Parametric and nonparametric estimates of Vd for RBC and sucrose were similar and were 0.14+/-0.01, 0.15 0.005 and 0.35+/-0.01 ml/g. The parametric estimate for water, 1.04+/-0.05 ml/g was greater than the nonparametric estimate, 0.89+/-0.02 ml/g. The multiple indicator dilution method Vd of tolbutamide of 0.75+0.08 ml/g was similar to the reported value of 0.73+/-0.04 ml/g estimated by tissue partitioning studies. A viable single pass pancreas perfusion model was established and applied to define distribution spaces of reference markers and the distribution kinetics of tolbutamide.
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.TOXLET.2013.12.009
Abstract: Accidental or intentional ingestion of glyphosate surfactant-based herbicides, like Roundup(®), leads to nephrotoxicity as well as death. In this study, a panel of kidney injury biomarkers was evaluated in terms of suitability to detect acute kidney injury and dysfunction. The Roundup(®) intoxication model involved oral administration of glyphosate to rats at dose levels of 250, 500, 1200 and 2500 mg/kg. Urinary and plasma biomarker patterns were investigated at 8, 24 and 48 h after dosing. Biomarkers were quantified by absolute concentration by normalising to urine creatinine and by calculating the excretion rate. The diagnostic performances of each method in predicting of acute kidney injury were compared. By Receiver Operating Characteristic (ROC) analysis of the selected biomarkers, only urinary kidney injury molecule-1 (KIM-1) best predicted histological changes at 8h (best cut-off point>0.00029 μg/ml). Plasma creatinine performed better than other biomarkers at 24 h (best cut-off point>0.21 mg/dl). Urinary KIM-1 was the best early biomarker of kidney injury in this glyphosate-induced nephrotoxicity model.
Publisher: Pharmaceutical Society of Japan
Date: 2005
DOI: 10.1248/BPB.28.682
Abstract: Intestinal chiral inversion of ibuprofen is still lacking direct evidence. In a preliminary experiment, ibuprofen was found to undergo inversion in Caco-2 cells. This investigation was thus conducted to determine the characteristics and influence of some biochemical factors on the chiral inversion of ibuprofen in Caco-2 cells. The effects of substrate concentration (2.5-40 microg/ml), cell density (0.5-2 x 10(6) cells/well), content of serum (0-20%), coexistence of S ibuprofen (corresponding doses), sodium azide (10 mM), exogenous Coenzyme A (CoA) (0.1-0.4 mM), and palmitic acid (5-25 microM) on inversion were examined. A stereoselective HPLC method based on the Chromasil-CHI-TBB column was developed for quantitative analysis of the drug in cell culture medium. The inversion ratio (F(i)) and elimination rate constant were calculated as the indexes of inversion extent. Inversion of ibuprofen in Caco-2 cells was found to be both dose and cell density dependent, indicating saturable characteristics. Addition of serum significantly inhibited the inversion, to an extent of 2.7 fold decrease at 20% content. Preexistence of S enantiomer exerted a significant inhibitory effect (p<0.01 for all tests). Sodium azide decreased the inversion ratio from 0.43 to 0.32 (p<0.01). Exogenous CoA and palmitic acid significantly promoted the inversion at all tested doses (p<0.01 for all tests). This research provided strong evidence to the capacity and capability of intestinal chiral inversion. Although long incubation times up to 120 h were required, Caco-2 cells should be a suitable model for chiral inversion research of 2-APAs considering the human-resourced and well-defined characteristics from the present study.
Publisher: Elsevier BV
Date: 04-2011
Publisher: Wiley
Date: 12-03-2012
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.EJPB.2018.07.015
Abstract: The primary objective of this study is to introduce a simple and flexible mathematical approach which models transport processes in skin using compartments. The main feature of the presented approach is that the rate constants for exchange between compartments are derived from physiologically relevant diffusional transport parameters. This allows for better physical interpretation of the rate constants, and limits the number of parameters for the compartmental model. The resulting compartmental solution is in good agreement with previously published solutions for the diffusion model of skin when ten or more compartments are used. It was found that the new compartmental model with three compartments provided a better fit of the previously publish water penetration data than the diffusion model. Two special cases for which it is difficult to implement the diffusion model were considered using our compartmental approach. In both cases the compartmental model predictions agreed well with the diffusion model.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2004
DOI: 10.1097/00001721-200408000-00006
Abstract: Platelet-derived microparticles that are produced during platelet activation are capable of adhesion and aggregation. Endothelial trauma that occurs during percutaneous transluminal coronary angioplasty (PTCA) may support platelet-derived microparticle adhesion and contribute to development of restenosis. We have previously reported an increase in platelet-derived microparticles in peripheral arterial blood with angioplasty. This finding raised concerns regarding the role of platelet-derived microparticles in restenosis, and therefore the aim of this study was to monitor levels in the coronary circulation. The study population consisted of 19 angioplasty patients. Paired coronary artery and sinus s les were obtained following heparinization, following contrast administration, and subsequent to all vessel manipulation. Platelet-derived microparticles were identified with an anti-CD61 (glycoprotein IIIa) fluorescence-conjugated antibody using flow cytometry. There was a significant decrease in arterial platelet-derived microparticles from heparinization to contrast administration (P = 0.001), followed by a significant increase to the end of angioplasty (P = 0.004). However, there was no significant change throughout the venous s les. These results indicate that the higher level of platelet-derived microparticles after angioplasty in arterial blood remained in the coronary circulation. Interestingly, levels of thrombin-antithrombin complexes did not rise during PTCA. This may have implications for the development of coronary restenosis post-PTCA, although this remains to be determined.
Publisher: Springer Science and Business Media LLC
Date: 28-07-2012
Abstract: The pharmacokinetics of beta-lactam antibiotics in intensive care patients may be profoundly altered due to the dynamic, unpredictable pathophysiological changes that occur in critical illness. For many drugs, significant increases in the volume of distribution and/or variability in drug clearance are common. When “standard” beta-lactam doses are used, such pharmacokinetic changes can result in subtherapeutic plasma concentrations, treatment failure, and the development of antibiotic resistance. Emerging data support the use of beta-lactam therapeutic drug monitoring (TDM) and in idualized dosing to ensure the achievement of pharmacodynamic targets associated with rapid bacterial killing and optimal clinical outcomes. The purpose of this work was to describe the pharmacokinetic variability of beta-lactams in the critically ill and to discuss the potential utility of TDM to optimize antibiotic therapy through a structured literature review of all relevant publications between 1946 and October 2011. Only a few studies have reported the utility of TDM as a tool to improve beta-lactam dosing in critically ill patients. Moreover, there is little agreement between studies on the pharmacodynamic targets required to optimize antibiotic therapy. The impact of TDM on important clinical outcomes also remains to be established. Whereas TDM may be theoretically rational, clinical studies to assess utility in the clinical setting are urgently required.
Publisher: Bentham Science Publishers Ltd.
Date: 03-2009
DOI: 10.2174/138920009787846350
Abstract: The skin is the major interface between the body and the environment. The cutaneous metabolic activity has been identified and widely studied in recent years. It is clear that active enzymes in viable skin tissues have a capacity for bio-transforming topically applied compounds, with a consequence of an altered pharmacological effect. Although the extent of cutaneous metabolism is modest compared to major metabolism in liver, it is important to consider the effect of inherent metabolic function on both local and systematic transdermal delivery. In this review, recent literatures concerning in vitro & in vivo models and techniques used in the study of skin metabolic processes were summarized. The potential influence from skin transporters, diseased conditions, and the chemicals used in skin absorption studies on cutaneous metabolic function, was then discussed. We also reviewed the prodrug design strategy and its applications in transdermal drug delivery.
Publisher: Springer Science and Business Media LLC
Date: 10-1991
DOI: 10.1007/BF01062964
Abstract: Ns (neuroserpin) is a member of the serpin (serine protease inhibitor) gene family that is primarily expressed within the central nervous system. Its principal target protease is tPA (tissue plasminogen activator), which is thought to contribute to synaptic plasticity and to be secreted in a stimulus-dependent manner. In the present study, we demonstrate in primary neuronal cultures that Ns co-localizes in LDCVs (large dense core vesicles) with the regulated secretory protein chromogranin B. We also show that Ns secretion is regulated and can be specifically induced 4-fold by secretagogue treatment. A novel 13-amino-acid sorting signal located at the C-terminus of Ns is identified that is both necessary and sufficient to target Ns to the regulated secretion pathway. Its deletion renders Ns no longer responsive to secretagogue stimulation, whereas PAI-Ns [Ns (neuroserpin)-PAI-1 (plasminogen activator inhibitor-1) chimaera appending the last 13 residues of Ns sequence to the C-terminus of PAI-1] shifts PAI-1 secretion into a regulated secretory pathway.
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.EJPB.2016.04.022
Abstract: Public health concerns continue to exist over the safety of zinc oxide nanoparticles that are commonly used in sunscreen formulations. In this work, we assessed the effects of two conditions which may be encountered in everyday sunscreen use, occlusion and a compromised skin barrier, on the penetration and local toxicity of two topically applied zinc oxide nanoparticle products. Caprylic/capric triglyceride (CCT) suspensions of commercially used zinc oxide nanoparticles, either uncoated or with a silane coating, were applied to intact and barrier impaired skin of volunteers, without and with occlusion for a period of six hours. The exposure time was chosen to simulate normal in-use conditions. Multiphoton tomography with fluorescence lifetime imaging was used to noninvasively assess zinc oxide penetration and cellular metabolic changes that could be indicative of toxicity. We found that zinc oxide nanoparticles did not penetrate into the viable epidermis of intact or barrier impaired skin of volunteers, without or with occlusion. We also observed no apparent toxicity in the viable epidermis below the application sites. These findings were validated by ex vivo human skin studies in which zinc penetration was assessed by multiphoton tomography with fluorescence lifetime imaging as well as Zinpyr-1 staining and toxicity was assessed by MTS assays in zinc oxide treated skin cryosections. In conclusion, applications of zinc oxide nanoparticles under occlusive in-use conditions to volunteers are not associated with any measurable zinc oxide penetration into, or local toxicity in the viable epidermis below the application site.
Publisher: Wiley
Date: 17-06-2017
Abstract: Multiphoton microscopy (MPM) has become increasingly popular and widely used in both basic and clinical liver studies over the past few years. This technology provides insights into deep live tissues with less photobleaching and phototoxicity, which helps us to better understand the cellular morphology, microenvironment, immune responses and spatiotemporal dynamics of drugs and therapeutic cells in the healthy and diseased liver. This review summarizes the principles, opportunities, applications and limitations of MPM in hepatology. A key emphasis is on the use of fluorescence lifetime imaging (FLIM) to add additional quantification and specificity to the detection of endogenous fluorescent species in the liver as well as exogenous molecules and nanoparticles that are applied to the liver in vivo. We anticipate that in the near future MPM-FLIM will advance our understanding of the cellular and molecular mechanisms of liver diseases, and will be evaluated from bench to bedside, leading to real-time histology of human liver diseases.
Publisher: Informa UK Limited
Date: 30-01-2018
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.ADDR.2011.01.012
Abstract: Skin is a widely used route of delivery for local and systemic drugs and is potentially a route for their delivery as nanoparticles. The skin provides a natural physical barrier against particle penetration, but there are opportunities to deliver therapeutic nanoparticles, especially in diseased skin and to the openings of hair follicles. Whilst nanoparticle drug delivery has been touted as an enabling technology, its potential in treating local skin and systemic diseases has yet to be realised. Most drug delivery particle technologies are based on lipid carriers, i.e. solid lipid nanoparticles and nanoemulsions of around 300 nm in diameter, which are now considered microparticles. Metal nanoparticles are now recognized for seemingly small drug-like characteristics, i.e. antimicrobial activity and skin cancer prevention. We present our unpublished clinical data on nanoparticle penetration and previously published reports that support the hypothesis that nanoparticles >10nm in diameter are unlikely to penetrate through the stratum corneum into viable human skin but will accumulate in the hair follicle openings, especially after massage. However, significant uptake does occur after damage and in certain diseased skin. Current chemistry limits both atom by atom construction of complex particulates and delineating their molecular interactions within biological systems. In this review we discuss the skin as a nanoparticle barrier, recent work in the field of nanoparticle drug delivery to the skin, and future directions currently being explored.
Publisher: Springer Science and Business Media LLC
Date: 23-01-2014
DOI: 10.1007/S11095-013-1256-4
Abstract: This study sought to understand the mechanism by which the steady state flux of nicotine across the human skin from aqueous solutions is markedly decreased at higher nicotine concentrations. Nicotine's steady state flux through human epidermis and its amount in the stratum corneum for a range of aqueous nicotine solutions was determined using Franz diffusion cells, with the nicotine analysed by high performance liquid chromatography (HPLC). Nicotine's thermodynamic activity in the various solutions was estimated from its partial vapour pressure and stratum corneum hydration was determined using a corneometer. The amount of nicotine retained in the stratum corneum was estimated from the nicotine amount found in in idual stratum corneum tape strips and a D-Squame determined weight for each strip. The observed steady state flux of nicotine across human epidermis was found to show a parabolic dependence on nicotine concentration, with the flux proportional to its thermodynamic activity up to a concentration of 48% w/w. The nicotine retention in the stratum corneum showed a similar dependency on concentration whereas the diffusivity of nicotine in the stratum corneum appeared to be concentration independent. This retention, in turn, could be estimated from the extent of stratum corneum hydration and the nicotine concentration in the applied solution and volume of water in the skin. Nonlinear dependency of nicotine skin flux on its concentration results from a dehydration induced decrease in its stratum corneum retention at higher concentration and not dehydration induced changes nicotine diffusivity in the stratum corneum.
Publisher: Elsevier BV
Date: 05-2020
Publisher: Informa UK Limited
Date: 13-11-2014
DOI: 10.3109/08941939.2014.971205
Abstract: Reperfusion injury (RI) is associated with high generation of reactive oxygen species (ROS), but the extent of involvement of these agents in the injury remains controversial. The present study aimed to examine the effectiveness of ROS scavengers against hepatic reperfusion injury in the rat. The RI was induced in the liver using an isolated slow-flow, reflow perfused rat liver in both anterograde and retrograde perfusion. The effects of gentisic acid, N-acetyl cysteine, and trolox C on the superoxide production, liver function, and morphological changes were examined using different biochemical and histological assays. The hepatic RI caused a significant (p < 0.05) increase in superoxide production and enzyme releases and a decrease in bile flow in both directions. Histological changes induced by RI include apoptosis, necrosis, pale cytoplasm, cell vacuolation, and attenuation of cell cords. Although the production of superoxide in retrograde direction was significantly less than the anterograde, the extent of the injury in the retrograde was greater than the anterograde direction. Pretreatment of the livers with each of the test compounds significantly reduced the release of lactate dehydrogenase and aspartate aminotransferase and improved bile flow in the liver exposed to hypoxia/reperfusion. However, they failed to protect the liver against the structural alterations induced by RI. ROS scavengers can reduce superoxide-induced damage and improve the liver function, but they are not able to prevent the structural changes. It shows that ROS are not the sole causative mechanism of hepatic RI and other mechanisms and mediators may be involved.
Publisher: Elsevier BV
Date: 06-2008
Publisher: Springer Science and Business Media LLC
Date: 1997
Abstract: Ipomoea cairica is a perennial creeper that has been widely introduced as a garden ornamental across tropical, subtropical, and temperate regions. Because it grows extremely fast and spreads easily, it has been listed as an invasive species in many countries. Here, we constructed the chromosome-level reference genome of Ipomoea cairica by Pacific Biosciences HiFi and Hi-C sequencing, with the assembly size of 733.0 Mb, the contig N50 of 43.8 Mb, the scaffold N50 of 45.7 Mb, and the Benchmarking Universal Single-Copy Orthologs complete rate of 98.0%. Hi-C scaffolding assigned 97.9% of the contigs to 15 pseudo-chromosomes. Telomeric repeat analysis reveals that 7 of the 15 pseudo-chromosomes are gapless and telomere to telomere. The transposable element content of Ipomoea cairica is 73.4%, obviously higher than that of other Ipomoea species. A total of 38,115 protein-coding genes were predicted, with the Benchmarking Universal Single-Copy Orthologs complete rate of 98.5%, comparable to that of the genome assembly, and 92.6% of genes were functional annotated. In addition, we identified 3,039 tRNA genes and 2,403 rRNA genes in the assembled genome. Phylogenetic analysis showed that Ipomoea cairica formed a clade with Ipomoea aquatica, and they erged from each other 8.1 million years ago. Through comparative genome analysis, we reconfirmed that a whole genome triplication event occurred specific to Convolvulaceae family and in the ancestor of the genus Ipomoea and Cuscuta. This high-quality reference genome of Ipomoea cairica will greatly facilitate the studies on the molecular mechanisms of its rapid growth and invasiveness.
Publisher: Elsevier BV
Date: 2016
DOI: 10.1002/JPS.24699
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.IJANTIMICAG.2014.08.013
Abstract: Fluconazole is a widely used antifungal agent in critically ill patients. It is predominantly (60-80%) excreted unchanged in urine. Sustained low-efficiency diafiltration (SLED-f) is increasingly being utilised in critically ill patients because of its practical advantages over continuous renal replacement therapy. To date, the effect of SLED-f on fluconazole pharmacokinetics and dosing has not been studied. The objective of this study was to describe the pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving SLED-f and to compare this with other forms of renal replacement therapy. Serial blood s les were collected at pre- and post-filter ports within the SLED-f circuit during SLED-f and from an arterial catheter before and after SLED-f from three patients during one session. Fluconazole concentrations were measured using a validated chromatography method. Median clearance (CL) and 24-h area under the concentration-time curve (AUC0-24) were 2.1L/h and 152 mg·h/L, respectively, whilst receiving SLED-f. Moreover, 72% of fluconazole was cleared by a single SLED-f session (6h) compared with previous reports of 33-38% clearance by a 4-h intermittent haemodialysis session. CL and AUC0-24 were comparable with previous observations in a pre-dilution mode of continuous venovenous haemodiafiltration. The observed rebound concentration of fluconazole post SLED-f was 200mg daily are likely to be required to achieve the PK/PD target for common pathogens because of significant fluconazole clearance by SLED-f.
Publisher: Springer Science and Business Media LLC
Date: 1998
Abstract: An integrated ionic mobility-pore model for epidermal iontophoresis is developed from theoretical considerations using both the free volume and pore restriction forms of the model for a range of solute radii (rj) approaching the pore radii (rp) as well as approximation of the pore restriction form for rj/rp < 0.4. In this model, we defined the determinants for iontophoresis as solute size (defined by MV, MW or radius), solute mobility, solute shape, solute charge, the Debye layer thickness, total current applied solute concentration, fraction ionized, presence of extraneous ions (defined by solvent conductivity), epidermal permselectivity, partitioning rates to account for interaction of unionized and ionized lipophilic solutes with the wall of the pore and electroosmosis. The ionic mobility-pore model was developed from theoretical considerations to include each of the determinants of iontophoretic transport. The model was then used to reexamine iontophoretic flux conductivity and iontophoretic flux-fraction ionized literature data on the determinants of iontophoretic flux. The ionic mobility-pore model was found to be consistent with existing experimental data and determinants defining iontophoretic transport. However, the predicted effects of solute size on iontophoresis are more consistent with the pore-restriction than free volume form of the model. A reanalysis of iontophoretic flux-conductivity data confirmed the model's prediction that, in the absence of significant electroosmosis, the reciprocal of flux is linearly related to either donor or receptor solution conductivity. Significant interaction with the pore walls, as described by the model, accounted for the reported pH dependence of the iontophoretic transport for a range of ionizable solutes. The ionic mobility-pore iontophoretic model developed enables a range of determinants of iontophoresis to be described in a single unifying equation which recognises a range of determinants of iontophoretic flux.
Publisher: Bentham Science Publishers Ltd.
Date: 12-2011
DOI: 10.2174/138920111798808239
Abstract: There is pressing need to better understand pharmacokinetics in critically ill patients. This will aid clinicians in selecting optimal dosing regimens. Pharmacokinetic studies are difficult in this population due to the heterogeneity of the patients and the practical issues of research involving critically ill patients. Therapeutic drug monitoring is routinely performed to guide dosing for aminoglycoside and glycopeptide antibiotics. Expanding its use to other drug classes could provide new therapeutic advantages. Plasma concentration may not always reflect tissue distribution in critically ill patients. Microdialysis is a technique that can be applied in the Intensive Care Unit to measure tissue concentrations and provide further insights to antimicrobial therapy for critically ill patients. Finally, the application of population pharmacokinetic analysis in studies in critically ill patients may identify factors affecting pharmacokinetics and enhance drug dosing regimens for varied patient groups.
Publisher: MDPI AG
Date: 08-09-2021
DOI: 10.3390/IJMS22189730
Abstract: Zinc pyrithione (ZnPT) is an anti-fungal drug delivered as a microparticle to skin epithelia. It is one of the most widely used ingredients worldwide in medicated sh oo for treating dandruff and seborrheic dermatitis (SD), a disorder with symptoms that include skin flaking, erythema and pruritus. SD is a multi-factorial disease driven by microbiol dysbiosis, primarily involving Malassezia yeast. Anti-fungal activity of ZnPT depends on the cutaneous availability of bioactive monomeric molecular species, occurring upon particle dissolution. The success of ZnPT as a topical therapeutic is underscored by the way it balances treatment efficacy with formulation safety. This review demonstrates how ZnPT achieves this balance, by integrating the current understanding of SD pathogenesis with an up-to-date analysis of ZnPT pharmacology, therapeutics and toxicology. ZnPT has anti-fungal activity with an average in vitro minimum inhibitory concentration of 10–15 ppm against the most abundant scalp skin Malassezia species (Malassezia globosa and Malassezia restrica). Efficacy is dependent on the targeted delivery of ZnPT to the skin sites where these yeasts reside, including the scalp surface and hair follicle infundibulum. Imaging and quantitative analysis tools have been fundamental for critically evaluating the therapeutic performance and safety of topical ZnPT formulations. Toxicologic investigations have focused on understanding the risk of local and systemic adverse effects following exposure from percutaneous penetration. Future research is expected to yield further advances in ZnPT formulations for SD and also include re-purposing towards a range of other dermatologic applications, which is likely to have significant clinical impact.
Publisher: Informa UK Limited
Date: 22-01-2016
DOI: 10.3109/15563650.2015.1115054
Abstract: To describe the cardiovascular toxicity and pharmacokinetics of levetiracetam in overdose. A 43-year-old female presented 8 h post ingestion of 60-80 g of levetiracetam with mild central nervous system depression, bradycardia, hypotension and oliguria. Her cardiovascular toxicity transiently responded to atropine and intravenous fluids. A bedside echocardiogram demonstrated normal left and right ventricular contractility. Despite her cardiovascular toxicity and oliguria, she had normal serial venous lactates and renal function and made a complete recovery over 48 h. Her levetiracetam concentration was 463 mcg/ml 8 h post ingestion (therapeutic range 10-40 mcg/ml) and her concentration-time data best fitted a one-compartment model with first-order input and an elimination half-life of 10.4 h. Levetiracetam in large ingestions appears to cause bradycardia and hypotension that is potentially responsive to atropine and intravenous fluids. Based on a normal echocardiogram, the mechanism for this effect may be levetiracetam acting at muscarinic receptors at high concentration. The pharmacokinetics of levetiracetam in overdose appeared to be similar to therapeutic levetiracetam dosing.
Publisher: Elsevier BV
Date: 09-1993
Abstract: Blood flow rates to skin and underlying tissues in rats were determined by the radioactive microsphere technique. The dermal and local tissue clearance of two polar solutes, tritiated water and 14C-labeled sucrose, was assessed in anesthetized and sacrificed rats. The dermal clearance of tritiated water in the presence of viable dermal blood supply (6.17 +/- 1.41 mL/min/100 g) was similar in magnitude but more variable than the blood flow to skin estimated by the microsphere technique (5.18 +/- 0.25 mL/min/100 g). The dermal clearance of sucrose (1.66 +/- 0.32 mL/min/100 g) was approximately one quarter the dermal clearance for water, the difference corresponding to the free diffusion coefficients of the two solutes. The permeability coefficients of tritiated water in various tissues were estimated by both a pseudo-steady-state mass balance approach and numerical integration of differential equations (for dermis only) with a "series compartmental" model, from the tissue concentrations obtained in sacrificed rats. The estimates from numerical integration were comparable to those obtained by mass balance, confirming the general structure of the model. The observed tissue concentrations of tritiated water and sucrose in the anesthetized animal compared well with values predicted from the model.
Publisher: Springer Science and Business Media LLC
Date: 1999
Abstract: The lateral iontophoretic transport of three solutes (sodium, ethanolamine, lidocaine) from an active electrode through skin and other tissues to an indifferent electrodes was investigated. Anodal epidermal iontophoresis was carried out on an in vivo rat model using constant direct current of 0.38 mA/cm2. Cells were fixed on the epidermis of anesthetized rats at distances of adjacent, 3 cm and 7 cm apart. After iontophoresis, tissues were dissected at I cm intervals between the electrodes. Concentrations of the radiolabelled solutes in tissues were determined by liquid scintillation counting or gamma counting. The concentration of each solutes in the epidermis, dermis and other tissues was found to decrease in an exponential manner with lateral distance from the active electrode to the indifferent electrode. The detectable lateral distance for ethanolamine and lidocaine was less than 2 cm from the donor sites, at which distance the concentrations were not significantly different to those found in the corresponding contralateral site. The lateral drift velocities for all solutes in the epidermis and dermis were consistent with diffusivities of the order of 10(-6) cm2/s. The drift velocity of sodium was greater than either lidocaine or ethanolamine. The decline in solute concentration with lateral distance is mainly due to clearance from the site of application by the skin's microcirculation and decreases with distance from the active electrode until a baseline concentration, similar to the contralateral tissue concentration is reached.
Publisher: Elsevier BV
Date: 08-2011
DOI: 10.1016/J.JCONREL.2011.04.018
Abstract: In principle, the maximum skin flux of solutes should be unaffected by the vehicle, unless that vehicle affects the skin. We recently showed that the maximum epidermal flux for 10 similarly sized phenolic compounds, with differing lipophilicities was defined by their solubility in the skin. Here, we extend these studies to examine how maximum fluxes are affected by cosolvents reported to enhance skin penetration. We compared in vitro human epidermal permeation and stratum corneum solubility for 10 phenols with similar molecular weights and hydrogen bonding but varying lipophilicity from 60% propylene glycol (PG)/water, 40% PG/water and water vehicles. We also measured solvent uptake into stratum corneum, investigated the changes in the attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy of stratum corneum and the multiphoton microscopy (MPM) images of β-naphthol for the various vehicles. We found that phenolic compounds maximum flux and stratum corneum solubilities generally increased with the percentage of PG in the binary solvent system but that the estimated diffusivities appeared to be vehicle independent. Maximum fluxes were related to vehicle-dependent stratum corneum solubilities. Theses solubilities, in turn, depended on the amount of vehicle absorbed into the stratum corneum and the amount of phenolic compounds dissolved in that absorbed vehicle. ATR-FTIR and MPM studies suggest that the vehicle-induced increased uptake of solutes into the stratum corneum occurred by an increased solubility in intercellular lipids of stratum corneum.
Publisher: SPIE-Intl Soc Optical Eng
Date: 08-09-2014
Publisher: De Gruyter
Date: 22-01-2018
Publisher: Springer Science and Business Media LLC
Date: 06-1986
DOI: 10.1007/BF01106706
Abstract: The composite abuse scale (CAS) is a comprehensive tool used to measure intimate partner violence (IPV). The aim of the present study is to translate the CAS from English to Arabic. The translation of the CAS was conducted in four stages using a multi-method approach: 1) preliminary forward translation, 2) discussion with a panel of bilingual experts, 3) focus groups discussion, and 4) back-translation of the CAS. The discussion included a linguistic validation by a comparison of the Arabic translation with the original English by assessing conceptual and content equivalence. In all the stages of translation, there was an agreement to remove the question from the CAS that asked women about the use of objects in the vagina. Wording, format and order of the items were refined according to comments and suggestions made by the experts' panel and focus groups' members. The back-translated CAS showed similar wording and language of the original English version. The Arabic version of the CAS will help to measure the problem of IPV among Saudi women and possibly other Arabic-speaking women in future studies. This is important, particularly, in longitudinal studies or intervention studies among abused women and it allows a comparison of the results of studies from different cultures. However, further validations studies are needed to ensure accurate and equivalent Arabic translation of the CAS.
Publisher: Springer Science and Business Media LLC
Date: 06-1986
DOI: 10.1007/BF01106707
Abstract: Withania somnifera is one of the most reputed medicinal plants of Indian systems of medicine synthesizing erse types of secondary metabolites such as withanolides, alkaloids, withanamides etc. Present study comprises cloning and E. coli over-expression of a tropinone reductase gene (WsTR-I) from W. somnifera, and elucidation of biochemical characteristics and physiological role of tropinone reductase enzyme in tropane alkaloid biosynthesis in aerial tissues of the plant. The recombinant enzyme was demonstrated to catalyze NADPH-dependent tropinone to tropine conversion step in tropane metabolism, through TLC, GC and GC-MS-MS analyses of the reaction product. The functionally active homodimeric ~60 kDa enzyme catalyzed the reaction in reversible manner at optimum pH 6.7. Catalytic kinetics of the enzyme favoured its forward reaction (tropine formation). Comparative 3-D models of landscape of the enzyme active site contours and tropinone binding site were also developed. Tissue-wide and ontogenic stage-wise assessment of WsTR-I transcript levels revealed constitutive expression of the gene with relatively lower abundance in berries and young leaves. The tissue profiles of WsTR-I expression matched those of tropine levels. The data suggest that, in W. somnifera, aerial tissues as well possess tropane alkaloid biosynthetic competence. In vivo feeding of U-[(14)C]-sucrose to orphan shoot (twigs) and [(14)C]-chasing revealed substantial radiolabel incorporation in tropinone and tropine, confirming the de novo synthesizing ability of the aerial tissues. This inherent independent ability heralds a conceptual novelty in the backdrop of classical view that these tissues acquire the alkaloids through transportation from roots rather than synthesis. The TR-I gene expression was found to be up-regulated on exposure to signal molecules (methyl jasmonate and salicylic acid) and on mechanical injury. The enzyme's catalytic and structural properties as well as gene expression profiles are discussed with respect to their physiological overtones.
Publisher: Springer Science and Business Media LLC
Date: 06-1986
DOI: 10.1007/BF01106708
Abstract: The ambient temperature experienced during development is a crucial factor affecting survival and adult phenotype in ectotherms. Moreover, the exact response of in iduals to different temperature regimes is frequently sex-specific. This sex-specific response can result in varying levels of sexual dimorphism according to the experienced conditions. The majority of studies have investigated the effects of temperature on in iduals reared under a constant temperature regime throughout their whole preimaginal development, whereas information on stage-dependent variation in temperature effects is scarce. Here we investigate how the stage at which elevated temperature is experienced influences survival, adult body size and colouration in the harlequin ladybird Harmonia axyridis form succinea. The effects of timing of exposure to elevated temperature on the adult phenotype are assessed separately for males and females. Control in iduals were reared at a constant temperature of 20 °C. Beetles in other treatments were additionally exposed to 33 °C for 48 hours during the following developmental stages: egg, 1(st) to 2(nd) larval instar, 3(rd) larval instar, 4(th) larval instar and pupa. Exposure to an elevated temperature during the early developmental stages resulted in lower survival, but the adult phenotype of survivors was almost unaffected. Exposure to an elevated temperature during the later developmental stages (4(th) larval instar or pupa) resulted in the decreased melanisation of elytra, decreased structural body size and increased dry mass. Furthermore, the timing of high temperature exposure affected the degree of sexual dimorphism in elytral melanisation and dry mass. We demonstrate that the effects of elevated temperature can vary according to the developmental stage at exposure. Detailed information on how ambient temperature affects the developmental biology of ectotherms is crucial for modeling population growth and predicting the spread of invasive species such as Harmonia axyridis.
Publisher: Springer Science and Business Media LLC
Date: 13-07-2010
DOI: 10.1007/S11095-010-0204-9
Abstract: To develop a semi-distributed liver model for the evaluation of saturable sinusoidal uptake and binding kinetics of the Oatp1a4 substrate digoxin. In the perfused rat liver, two successive digoxin doses of 42 and 125 microg were administered, and the outflow concentration was determined by LC/MS/MS. [14C]-sucrose was used as vascular reference. The data were analyzed simultaneously by a population approach using sucrose to determine the sinusoidal mixing of digoxin. The results suggest the existence of a high-affinity, low-capacity system, and a low-affinity, high-capacity system for sinusoidal uptake with apparent Michaelis constants (K(M)) of 0.24 and 332 microg/ml, respectively. Incorporation of saturable sinusoidal binding of digoxin considerably improved the fit, and the parameter estimates were consistent with those of binding to hepatic Na,K-ATPase. Simpler models that neglect the concentration gradient in flow direction failed to describe the outflow data in the high dose range. The semi-distributed liver model with saturable uptake should be useful for a functional characterization of transporters in the in situ rat liver.
Publisher: Oxford University Press (OUP)
Date: 2003
Publisher: Informa UK Limited
Date: 20-12-2018
DOI: 10.1080/03007995.2018.1551194
Abstract: The nonsteroidal anti-inflammatory drug (NSAID) diclofenac epolamine (DHEP) formulated as a topical patch has demonstrated efficacy and safety in the localized treatment of acute pain from minor strains, sprains and contusions, and for epicondylitis and knee osteoarthritis. The glycosaminoglycan heparin enhances the activity of topical NSAIDs formulated as a medicated plaster, even in the absence of any significant release of heparin. Therefore, DHEP plus, a new formulation of the DHEP medicated plaster containing a small amount of heparin sodium as excipient, has been developed. We reviewed the pivotal and supportive studies of the clinical development program of the new patch and evaluated the role of heparin as an enhancer in the treatment of localized pain/inflammation of musculoskeletal structures, associated with post-traumatic and/or rheumatic conditions. The data was consistent with the concept that heparin increased the clinical activity of the DHEP plus medicated plaster versus the reference DHEP medicated plaster through improved bioavailability due to enhanced movement of diclofenac from the plaster. Both DHEP formulations have the same dissolution profile, indicating that heparin does not change the physical and chemical characteristics of the plaster. Permeation testing showed that heparin is not released from the DHEP plus medicated plaster. Efficacy studies showed that the DHEP plus medicated plaster was significantly more effective in reducing pain than the reference marketed DHEP medicated plaster. The benefit/risk assessment of DHEP plus 180 mg medicated plaster is favorable, with a safety profile equal to placebo and improved efficacy over the reference marketed DHEP medicated plaster.
Publisher: Elsevier BV
Date: 07-2006
Publisher: Wiley
Date: 05-2005
Publisher: Springer Science and Business Media LLC
Date: 30-06-2011
DOI: 10.1007/S11095-011-0515-5
Abstract: There is a lack of relevant, non-animal alternatives for assessing exposure and toxicity of nanoparticle-containing cosmetics, e.g. sunscreens. Our goal was to evaluate timecorrelated single photon counting (TCSPC) for simultaneous monitoring of zinc oxide nanoparticles (ZnO-NP) and the metabolic state of volunteer skin. We separated the fluorescence lifetime signatures of endogenous fluorophore signals (i.e. nicotinamide adenine dinucleotide phosphate, NAD(P)H and keratin) and the ZnO-NP signal using advanced TCSPC to simultaneously determine ZnO-NP penetration profiles and NAD(P)H changes in subjects with altered barrier function, including tape-stripped skin and in psoriasis or atopic dermatitis lesions. We detected no ZnO-NP penetration into viable human skin in any group. ZnO-NP signal was significantly increased (p < 0.01) on the surface of tape-stripped and lesional skin after 4 and 2 h of treatment, respectively. Free NAD(P)H signal significantly increased in tape-stripped viable epidermis treated for 4 h of ZnO-NP compared to vehicle control. No significant NAD(P)H changes were noted in the lesional study. TCSPC techniques enabled simultaneous, real-time quantification of ZnO-NP concentration and NAD(P)H via non-invasive imaging in the stratum corneum and viable epidermis of volunteers.
Publisher: Informa Healthcare
Date: 02-09-2011
DOI: 10.1517/17425255.2011.615309
Abstract: Invasive candidiasis has emerged over the last few decades as an increasingly important nosocomial problem for the critically ill, affecting around 2% of intensive care unit patients. Although poor outcomes associated with invasive candidiasis among critically ill patients may relate to severe underlying disease processes and delayed institution of antifungal therapy, inadequate dosing of antifungal agents may also contribute. This drug evaluation provides a critical appraisal of the published literature pertaining to the pharmacokinetics of fluconazole in critically ill, obese or severely burned patients, including those receiving acute renal replacement therapy. The pharmacodynamics of fluconazole is also covered, as well as the likely clinical implications for optimal dosing and the toxicity of fluconazole. Last, variations in fluconazole susceptibility patterns of Candida spp. are also discussed. Recently, there has been an increased but geographically variable prevalence of non-albicans Candida spp., causing invasive candidiasis and an overall trend towards reduced fluconazole susceptibility. The pathophysiological changes of critical illness, coupled with a lack of dose finding studies, support the use of local susceptibility patterns to guide fluconazole dosing until such time as pharmacokinetic-pharmacodynamic information to guide optimal fluconazole dosing strategies and pharmacodynamic targets becomes available.
Publisher: Wiley
Date: 11-2017
DOI: 10.1002/CPSC.39
Abstract: This unit describes a protocol for elucidating the in vivo disposition of administered mesenchymal stem cells (MSCs). Specifically, direct visualization of donor cell spatiotemporal distribution and assessment of donor cell quantity in recipient organs are described. Protocols for data analysis are suggested, with the goal of developing a model to characterize and predict the physiological kinetics of administered MSCs. The use of this model is described, suggesting that it can be applied to abnormal conditions and has potential interspecies and inter-route predictive capability. These universal methods can be employed, regardless of the type of stem cell or disease, to guide future experiments and design treatment protocols. © 2017 by John Wiley & Sons, Inc.
Publisher: Elsevier BV
Date: 06-2022
Publisher: Springer Science and Business Media LLC
Date: 1997
Abstract: Predicted area under curve (AUC), mean transit time (MTT) and normalized variance (CV2) data have been compared for parent compound and generated metabolite following an impulse input into the liver. Models studied were the well-stirred (tank) model, tube model, a distributed tube model, dispersion model (Danckwerts and mixed boundary conditions) and tanks-in-series model. It is well known that discrimination between models for a parent solute is greatest when the parent solute is highly extracted by the liver. With the metabolite, greatest model differences for MTT and CV2 occur when parent solute is poorly extracted. In all cases the predictions of the distributed tube, dispersion, and tanks-in-series models are between the predictions of the tank and tube models. The dispersion model with mixed boundary conditions yields identical predictions to those for the distributed tube model (assuming an inverse gaussian distribution of tube transit times). The dispersion model with Danckwerts boundary conditions and the tanks-in series models give similar predictions to the dispersion (mixed boundary conditions) and the distributed tube. The normalized variance for parent compound is dependent upon hepatocyte permeability only within a distinct range of permeability values. This range is similar for each model but the order of magnitude predicted for normalized variance is model dependent. Only for a one-compartment system is the MTT for generated metabolite equal to the sum of MTTs for the parent compound and preformed metabolite administered as parent.
Publisher: Springer Berlin Heidelberg
Date: 2017
Publisher: Elsevier BV
Date: 02-1995
Publisher: Wiley
Date: 29-05-2012
DOI: 10.1111/J.1440-1681.2012.05715.X
Abstract: 1. Infections and related sepsis are two of the most prevalent issues in the care of critically ill patients, with mortality as high as 70%. Appropriate antibiotic selection, as well as adequate dosing, is important to improve the clinical outcome for these patients. 2. β-Lactams are the most common antibiotic class used in critically ill sepsis patients because of their broad spectrum of activity and high tolerability. β-Lactams exhibit time-dependent antibacterial activity. Therefore, concentrations need to be maintained above the minimum inhibitory concentration (MIC) of pathogenic bacteria. β-Lactams are hydrophilic antibiotics with small distribution volumes similar to extracellular water and are predominantly excreted through the renal system. 3. Critically ill patients experience a myriad of physiological changes that result in changes in the pharmacokinetics (PK) of hydrophilic drugs such as β-lactams. A different approach to dosing with β-lactams may increase the likelihood of positive outcomes considering the pharmacodynamics (PD) of β-lactams, as well as the changes in PK in critically ill patients. 4. The present review describes the strategies for dose optimization of β-lactams in critically ill patients in line with the PK and PD of these drugs.
Publisher: Springer Berlin Heidelberg
Date: 2017
Publisher: Elsevier BV
Date: 02-1992
Publisher: SPIE
Date: 21-03-2016
DOI: 10.1117/12.2235828
Publisher: Springer Science and Business Media LLC
Date: 25-05-1993
DOI: 10.1007/BF01061687
Publisher: American Chemical Society (ACS)
Date: 13-01-2016
Abstract: While biodistribution of nanoparticles (NPs) has been widely studied at the organ level, relatively little is known about their disposition in organs at the cellular level, especially after long-term exposure. The kidney is regarded as the key organ for the clearance of ultrasmall NPs (<5.5 nm). However, recent studies indicate that NPs in this size range could accumulate in the kidney for extended times without urinary excretion. Using negatively charged quantum dots (QDs) (∼3.7 nm) as a model system, we examined the suborgan disposition of anionic ultrasmall NPs in the kidney at the cellular level after intravenous injection by multiphoton microscopy coupled with fluorescence lifetime imaging. Most of the NPs were initially distributed in the peritubular capillaries or glomerular arterioles after injection, whereas they passed through the fenestrated glomerular endothelium and were gradually taken up by mesangial cells up to 30 days after injection. Only trace amounts of anionic QDs could be detected in the urine, which could be attributed to the barrier of the anionic glomerular basement membrane preventing filtration of anionic QDs. In contrast, cationic QDs of similar size (∼5.67 nm) were found to be readily excreted into urine. This study thus highlights the importance of surface charge in determining renal clearance of ultrasmall NPs. It provides a framework for characterizing and predicting the subcellular disposition in organs and long-term targeting of other NPs, with a physiologically based kinetic model being subsequently developed to describe the suborgan kinetics of anionic ultrasmall NPs.
Publisher: Georg Thieme Verlag KG
Date: 11-09-2009
Abstract: Shenmai injection (SMI), a mixture of Radix Ginseng and Radix Ophiopogonis, is one of the most popular herbal medicinal products and is widely used for the treatment of coronary atherosclerotic cardiopathy and viral myocarditis. The purpose of this study was to investigate the effect of SMI, in vivo and in vitro, on the metabolic activities of hepatic cytochrome CYP450 3A1/2, 2C6, 2E1, and 1A2 in rats. After a single or multiple pretreatment with SMI, the rats were administrated intravenously a cocktail containing midazolam (1 mg/kg), diclofenac (0.5 mg/kg), theophylline (1 mg/kg), and chlorzoxazone (0.5 mg/kg) as probe substrates of rat CYP450 3A1/2, 2C6, 1A2, and 2E1, respectively. Single and multiple SMI pretreatment to rats resulted in a rise of 33.8 % (p < 0.01) and 25.6 % (p < 0.01) in AUC for midazolam, and an increase in AUC for diclofenac by 14.7 % (p < 0.05) and 31.2 % (p < 0.01), respectively. However, the pharmacokinetics of chlorzoxazone and theophylline in rats was not altered markedly. In rat liver microsomes, linear mixed-type inhibition of SMI against the enzyme activities of CYP3A1/2, CYP2C6, and CYP1A2 was shown with IC(50) values of 3.3 %, 2.0 %, and 3.1 % and K(i) values of 3.8 %, 1.5 %. and 1.9 %, respectively. These in vivo and in vitro results demonstrated that SMI had the potential to inhibit the activities of hepatic CYP3A1/2 and CYP2C6, but might not significantly affect CYP1A2 and CYP2E1-mediated metabolism in rats.
Publisher: Oxford University Press (OUP)
Date: 06-2010
Abstract: The development of methods to predict the transport of molecules across biological membranes, without the need for time-consuming collection of experimental data, is a rapidly growing science. The use of structural characteristics of molecules has been investigated to predict the maximum transport rates of molecules across skin epidermal and intestinal membranes, known as maximum flux and maximum absorbable dose, respectively, although different approaches have been used. The aim of the present study was to determine whether the relationship between polar surface area and number of rotatable bonds of molecules and their permeability through intestinal membranes could be applied to the permeation of solutes through the epidermis following topical application. We used a published dataset of human epidermal maximum flux values for 182 solutes and stepwise regression to determine relationships between structural predictors and maximum membrane transport rates. Results showed that diffusion processes occurring across intestinal and skin epidermal membranes cannot be estimated by the same solute molecular properties, as different combinations of partitioning and diffusion processes appear to be dominating in each type of membrane. The basis of these differences in terms of molecular weight dependence and the usefulness of polar surface area are discussed. Based on available literature, we concluded that transdermal penetration is poorly predicted by parameters derived from intestinal or Caco-2 model membranes. While this approach may be useful for small sets of structurally related compounds, it appears to have limited value for screening and selection of novel structures in the pharmaceutical industry.
Publisher: American Society for Microbiology
Date: 11-2017
DOI: 10.1128/AAC.00311-17
Abstract: Changes in the pharmacokinetics of piperacillin in febrile neutropenic patients have been reported to result in suboptimal exposures. This study aimed to develop a population pharmacokinetic model for piperacillin and perform dosing simulation to describe optimal dosing regimens for hematological malignancy patients with febrile neutropenia. Concentration-time data were obtained from previous prospective observational pharmacokinetic and interventional therapeutic drug monitoring studies. Nonparametric population pharmacokinetic analysis and Monte Carlo dosing simulations were performed with the Pmetrics package for R. A two-compartment model, with between-subject variability for clearance (CL), adequately described the data from 37 patients (21 males, age of 59 ± 12 years [means ± standard deviations] and weight of 77 ± 16 kg). Parameter estimates were CL of 18.0 ± 4.8 liters/h, volume of distribution of the central compartment of 14.3 ± 7.3 liters, rate constant for piperacillin distribution from the central to peripheral compartment of 1.40 ± 1.35 h −1 , and rate constant for piperacillin distribution from the peripheral to central compartment of 4.99 ± 7.81 h −1 . High creatinine clearance (CL CR ) was associated with reduced probability of target attainment (PTA). Extended and continuous infusion regimens achieved a high PTA of % for an unbound concentration of piperacillin remaining above the MIC ( fT MIC ) of 50%. Only continuous regimens achieved % PTA for 100% fT MIC when CL CR was high. The cumulative fraction of response (FTA, for fractional target attainment) was suboptimal ( %) for conventional regimens for both empirical and directed therapy considering 50% and 100% fT MIC . FTA was maximized with prolonged infusions. Overall, changes in piperacillin pharmacokinetics and the consequences on therapeutic dosing requirements appear similar to those observed in intensive care patients. Guidelines should address the altered dosing needs of febrile neutropenic patients exhibiting high CL CR or with known resumed infections from high-MIC bacteria.
Publisher: Elsevier BV
Date: 03-1993
DOI: 10.1016/0960-0760(93)90093-C
Abstract: Prednisolone is metabolized in the perfused human placental lobule to prednisone, 20 alpha-dihydroprednisone, 20 beta-dihydroprednisone and 20 beta-dihydroprednisolone. The pathway of metabolite formation was defined in perfusions of placental lobules using prednisone and 20 beta-dihydroprednisone separately as substrates and with prednisolone co-perfused with glycyrrhetinic acid, a potent inhibitor of the 11-oxidase component of the 11 beta-hydroxysteroid dehydrogenase enzyme system. The pattern of metabolites identified from 6 h s les indicated a reversible formation of prednisone from prednisolone, the production of the 20 alpha- and 20 beta-dihydro metabolites of prednisone from prednisone, the formation of 20 beta-dihydroprednisolone from 20 beta-dihydroprednisone only and no direct formation of 20 beta-dihydroprednisolone from prednisolone. Kinetic analysis at two substrate concentrations confirmed that the formation of three of the four steroid metabolites followed first order kinetics. In perfusions with an initial prednisolone concentration of 1 microgram/ml (n = 4) or 100 ng/ml (n = 3), the rate constants obtained were (mean +/- SD, maternal compartment, h-1): prednisone, 1.97 +/- 0.49 and 2.25 +/- 0.15, P > 0.1 20 alpha-dihydroprednisone, 0.0006 +/- 0.0004 and 0.0017 +/- 0.0006, P 0.1. In contrast, the rate constant for formation of 20 beta-dihydroprednisolone at an initial prednisolone concentration of 100 ng/ml (0.083 +/- 0.0095 h-1) was significantly (P < 0.01) greater than the corresponding rate constant at the higher initial prednisolone concentration (0.039 +/- 0.015 h-1). A significant increase (P < 0.05) was observed for the formation of 20 beta-dihydroprednisolone at the end of 6 h perfusions at the lower initial substrate concentration (11.2 +/- 1.9%) compared with the 1 microgram/ml concentration (6.0 +/- 2.5%).
Publisher: American Society for Microbiology
Date: 06-2011
DOI: 10.1128/AAC.00416-10
Abstract: This work sought to define how pancreatitis affected antibiotic distribution in a perfused rat pancreas model. The distribution kinetics of four antibiotics were examined in control animals and animals with pancreatitis. Meropenem and piperacillin distributed into the extracellular space, and their distribution kinetics were unaffected by pancreatitis. In contrast, in pancreatic cells from animals with pancreatitis, ciprofloxacin showed a reduced uptake and clindamycin showed a reduced distribution.
Publisher: SPIE-Intl Soc Optical Eng
Date: 27-11-2013
Publisher: SPIE-Intl Soc Optical Eng
Date: 27-11-2012
Publisher: Elsevier BV
Date: 12-1983
Publisher: Informa UK Limited
Date: 05-10-2016
DOI: 10.1080/17435390.2016.1236993
Abstract: The use of silver nanoparticles (Ag NPs) within the healthcare sector and consumer products is rapidly increasing. There are now a range of erse-shaped Ag NPs that are commercially available and many of the products containing nanosilver are topically applied to human skin. Currently, there is limited data on the extent to which the antimicrobial efficacy and cytotoxicity of Ag NPs is related to their shape and how the shape of the Ag NPs affects their distribution in both intact and burn wounded human skin after topical application. In this study, we related the relative Ag NP cytotoxicity to potential skin pathogens and HaCaT keratinocytes in vitro with the shape of the Ag NPs. We employed multiphoton fluorescence lifetime imaging to map the distribution of the native and unlabeled Ag NPs after topical application to both intact and burn wounded human skin using the localized surface plasmon resonance signal of the Ag NPs. Truncated plate shaped Ag NPs led to the highest cytotoxicity against both bacteria (IC
Publisher: Elsevier BV
Date: 07-1997
Publisher: Elsevier BV
Date: 05-1997
Publisher: SAGE Publications
Date: 10-2002
DOI: 10.1046/J.1440-1614.2002.01069.X
Abstract: Objective: To examine the use of pro re nata (PRN) (as needed) medication in hospitalized patients with psychotic disorders. Methods: Retrospective chart reviews were conducted at two large public psychiatry units situated in inner city general hospitals. Pro re nata medication prescription, administration and outcomes were examined during inpatient episodes of care for 184 consecutive admissions of patients diagnosed with a psychotic disorder. Patient demographics, diagnoses, and regularly prescribed medication were also recorded. All admissions were drawn from a threemonth period from December 1998–February 1999. Results: The most prevalent diagnoses were schizophrenia related disorders (n = 111) and mania (n = 34). Substance use disorders (n = 49) were the most common comorbid disorders. Pro re nata medication was administered during the acute phase of 82% of admissions. Drugs prescribed Pro re nata were mostly typical antipsychotics, benzodiazepines and/or anticholinergics. Coprescription of typical antipsychotics PRN with regularly scheduled atypical antipsychotics was common (64%). Pro re nata medications accounted for 31% of the total antipsychotic dose and 28% of the total anxiolytic dose administered during acute treatment. Higher daily doses of PRN medication were given to manic patients, males, younger patients and those with substance use disorders. Pro re nata prescriptions usually specified a maximum daily dose (87%) but rarely gave indications for use (6%). Administration records frequently lacked a specified reason for use (48%) or a notation of outcome (64%). Unit staff noted medication-related morbidity in 37% of patients receiving PRN medication, compared to 3% of patients receiving only regularly scheduled medication. Extrapyramidal symptoms (EPS) were most frequently associated with administration of PRN haloperidol (Relative Risk vs other PRN medications = 5.61, 95% CI = 2.36–13.73). Conclusions: Pro re nata medications comprised a significant part of the treatment which psychotic patients received. The common practice of coprescribing PRN typical antipsychotics with scheduled atypical antipsychotics is potentially problematical since administration of PRN medication is associated with significant medication related morbidity. Preferential use of benzodiazepines as PRN agents may minimize this morbidity and foster subsequent compliance with regularly prescribed antipsychotics.
Publisher: Elsevier BV
Date: 11-1995
DOI: 10.1016/0378-4347(95)00277-5
Abstract: A sensitive, specific and rapid reversed-phase high-performance liquid chromatographic (HPLC) assay was developed for the quantitation of melphalan and its hydrolysis products in s les from the isolated perfusion of human and rat limbs. S les of perfusate, plasma and tissue were analysed, following methanol precipitation, using a phenyl column and fluorescence detection. Dansyl-arginine (38 micrograms ml-1) was employed as the internal standard. Good resolution was observed allowing quantitation of melphalan, monohydroxymelphalan (MOH) and dihydroxymelphalan (DOH) in perfusate and plasma were all 100 +/- 10%. The recovery of melphalan in tissue was 93.5%. A linear response was demonstrated for melphalan in the concentration range 1.8 - 56.8 micrograms ml-1, for DOH in the concentration range 0.5 - 30.0 micrograms ml-1 and for MOH in the range 1.4-25.1 micrograms ml-1, in perfusate and plasma. The lower limits of quantitation of melphalan, MOH and DOH in perfusate and plasma were 1.4, 2.4 and 1.2 ng on column, respectively, and 7.2 ng of melphalan on column in tissue. Intra-assay coefficients of variation (C.V.) for melphalan, MOH and DOH, at low and high concentrations were all less than 5% and the inter-assay C.V.s were less than 9%. An ultra-filtration study to determine the protein binding of melphalan and the hydrolysis products showed that the unbound fractions (fu) of melphalan in buffer containing dextran and bovine serum albumin were 0.873 and 0.521, respectively. The assay was used to quantitate melphalan and its hydrolysis products in s les from isolated perfusions in the human limb and rat hindlimb.
Publisher: Springer Science and Business Media LLC
Date: 11-2003
DOI: 10.1023/B:PHAM.0000003382.20030.54
Abstract: The validity of using drug amount-depth profiles in stratum corneum to predict uptake of clobetasol propionate into stratum corneum and its transport into deeper skin layers was investigated. In vitro diffusion experiments through human epidermis were carried out using Franz-type glass diffusion cells. A saturated solution of clobetasol propionate in 20% (V/V) aqueous propylene glycol was topically applied for 48 h. Steady state flux was calculated from the cumulative amount of drug permeated vs. time profile. Epidermal partitioning was conducted by applying a saturated drug solution to both sides of the epidermis and allowing time to equilibrate. The tape stripping technique was used to define drug concentration-depth profiles in stratum corneum for both the diffusion and equilibrium experiments. The concentration-depth profile of clobetasol propionate in stratum corneum for the diffusion experiment is biphasic. A logarithmic decline of the drug concentration over the first four to five tape strips flattens to a relatively constant low concentration level in deeper layers. The drug concentration-depth profile for the equilibrium studies displays a similar shape. The shape of the concentration-depth profile of clobetasol propionate is mainly because of the variable partitioning coefficient in different stratum corneum layers.
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4TB01611D
Abstract: This review summarizes research progress focusing on nanoparticles targeting the liver for both diagnostic and therapeutic purposes at the cellular level.
Publisher: Elsevier BV
Date: 1987
DOI: 10.1016/0378-4347(87)80512-1
Abstract: A high-performance liquid chromatographic assay has been developed for the determination of a number of non-steroidal anti-inflammatory drugs in plasma. The s les were prepared by adding acetonitrile and perchloric acid to 200 microliter of plasma. Diclofenac, fenoprofen, ketoprofen, naproxen, phenylbutazone, piroxicam and sulindac were quantified in the supernatant produced using a mobile phase of phosphoric acid 0.03% (pH 2.5)-acetonitrile and a detecting wavelength of 254 nm. The reproducibility, linearity, precision and specificity of the assay were determined and found to be satisfactory. Alteration of the detection wavelength to 229 nm also permitted accurate determination of ibuprofen concentration in plasma. While reduction of the organic solvent content of the mobile phase and alteration of wavelength to 313 nm produced a system capable of quantifying salicylate and its metabolites in plasma and by further reducing the detecting wavelength to 237 nm, aspirin also was quantifiable. These methods have been applied in a cross-sectional study of medication compliance among rheumatoid arthritis patients treated with non-steroidal anti-inflammatory drugs.
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.JCONREL.2019.05.024
Abstract: Skin-targeting microscale medical devices are becoming popular for therapeutic delivery and diagnosis. We used cryo-SEM, fluorescence lifetime imaging microscopy (FLIM), autofluorescence imaging microscopy and inflammatory response to study the puncturing and recovery of human skin ex vivo and in vivo after discretised puncturing by a microneedle array (Nanopatch®). Pores induced by the microprojections were found to close by ~25% in diameter within the first 30 min, and almost completely close by ~6 h. FLIM images of ex vivo viable epidermis showed a stable fluorescence lifetime for unpatched areas of ~1000 ps up to 24 h. Only the cells in the immediate puncture zones (in direct contact with projections) showed a reduction in the observed fluorescence lifetimes to between ~518-583 ps. The ratio of free-bound NAD(P)H (α1/α2) in unaffected areas of the viable epidermis was ~2.5-3.0, whereas the ratio at puncture holes was almost double at ~4.2-4.6. An exploratory pilot in vivo study also suggested similar closure rate with histamine administration to the forearms of human volunteers after Nanopatch® treatment, although a prolonged inflammation was observed with Tissue Viability Imaging. Overall, this work shows that the pores created by the microneedle-type medical device, Nanopatch®, are transient, with the skin recovering rapidly within 1-2 days in the epidermis after application.
Publisher: S. Karger AG
Date: 04-11-2017
DOI: 10.1159/000481691
Abstract: The use of sunscreen products is widely promoted by schools, government agencies, and health-related organizations to minimize sunburn and skin damage. In this study, we developed stable solid lipid nanoparticles (SLNs) containing the chemical UV filter octyl methoxycinnamate (OMC). In parallel, we produced similar stable SLNs in which 20% of the OMC content was replaced by the botanical urucum oil. When these SLNs were applied to the skin of human volunteers, no changes in fluorescence lifetimes or redox ratios of the endogenous skin fluorophores were seen, suggesting that the formulations did not induce toxic responses in the skin. Ex vivo (skin diffusion) tests showed no significant penetration. In vitro studies showed that when 20% of the OMC was replaced by urucum oil, there was no reduction in skin protection factor (SPF), suggesting that a decrease in the amount of chemical filter may be a viable alternative for an effective sunscreen, in combination with an antioxidant-rich vegetable oil, such as urucum. There is a strong trend towards increasing safety of sun protection products through reduction in the use of chemical UV filters. This work supports this approach by producing formulations with lower concentrations of OMC, while maintaining the SPF. Further investigations of SPF in vivo are needed to assess the suitability of these formulations for human use.
Publisher: Elsevier BV
Date: 02-2021
Publisher: Springer Science and Business Media LLC
Date: 03-04-2021
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.JCHROMB.2009.08.039
Abstract: The aim of the present work was to develop and validate a simple RP-HPLC method with UV detection to quantify peptide dendrimers in skin permeation experiments. Six dendrimers of varying positive charges (4(+), 8(+) and 16(+)) containing either histidine or arginine as terminal aminoacids were prepared by solid phase peptide synthesis. Mobile phase containing 0.02% (v/v) heptafluorobutyric acid in 90% acetonitrile-water was capable of separating all dendrimers from interfering peaks of receptor fluid. For the calibration of each dendrimer, a different dendrimer from the same class was selected as the internal standard. The results of preliminary human skin permeation studies showed that the developed analytical method can be successfully used for the quantification of cationic poly(aminoacid)-based dendrimers in skin permeation experiments.
Publisher: Elsevier BV
Date: 09-1992
Publisher: Wiley
Date: 18-03-2015
DOI: 10.1111/BPH.13059
Publisher: Wiley
Date: 06-09-2017
DOI: 10.1002/JPPR.1256
Publisher: Springer Science and Business Media LLC
Date: 25-05-2017
Publisher: Future Medicine Ltd
Date: 05-2016
Abstract: Aim: We assessed the effects of flexing and massage on human skin penetration and toxicity of topically applied coated and uncoated zinc oxide nanoparticles (˜75 nm) in vivo. Materials & methods: Noninvasive multiphoton tomography with fluorescence lifetime imaging was used to evaluate the penetration of nanoparticles through the skin barrier and cellular apoptosis in the viable epidermis. Results: All nanoparticles applied to skin with flexing and massage were retained in the stratum corneum or skin furrows. No significant penetration into the viable epidermis was seen and no cellular toxicity was detected. Conclusion: Exposure of normal in vivo human skin to these nanoparticles under common in-use conditions of flexing or massage is not associated with significant adverse events.
Publisher: Wiley
Date: 07-1998
DOI: 10.1046/J.1365-2125.1998.00045.X
Abstract: The penetration of active ingredients from topically applied anti-inflammatory pharmaceutical products into tissues below the skin is the basis of their therapeutic efficacy. There is still controversy as to whether these agents are capable of direct penetration by diffusion through the tissues or whether redistribution in the systemic circulation is responsible for their tissue deposition below the application site. The extent of direct penetration of salicylate from commercial ester and salt formulations into the dermal and subcutaneous tissue of human volunteers was determined using the technique of cutaneous microdialysis. We also examined differences in the extent of hydrolysis of the methylester of salicylate applied topically in human volunteers and in vitro skin diffusion cells using full-thickness skin and epidermal membranes. The present study showed that whilst significant levels of salicylate could be detected in the dermis and subcutaneous tissue of volunteers treated with the methylsalicylate formulation, negligible levels of salicylate were seen following application of the triethanolamine salicylate formulation. The tissue levels ofsalicylate from the methylsalicylate formulation were approx. 30-fold higher than the plasma concentrations. The absorption and tissue concentration profiles for the commercial methylsalicylate formulation are indicative of direct tissue penetration and not solely redistribution by the systemic blood supply.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2012
Publisher: SPIE-Intl Soc Optical Eng
Date: 10-12-2012
Publisher: Oxford University Press (OUP)
Date: 06-12-2018
DOI: 10.1002/SCTM.17-0209
Abstract: Mesenchymal stem/stromal cells (MSCs) present a promising tool in cell-based therapy for treatment of various diseases. Currently, optimization of treatment protocols in clinical studies is complicated by the variations in cell dosing, erse methods used to deliver MSCs, and the variety of methods used for tracking MSCs in vivo. Most studies use a dose escalation approach, and attempt to correlate efficacy with total cell dose. Optimization could be accelerated through specific understanding of MSC distribution in vivo, long-term viability, as well as their biological fate. While it is not possible to quantitatively detect MSCs in most targeted organs over long time periods after systemic administration in clinical trials, it is increasingly possible to apply pharmacokinetic modeling to predict their distribution and persistence. This Review outlines current understanding of the in vivo kinetics of exogenously administered MSCs, provides a critical analysis of the methods used for quantitative MSC detection in these studies, and discusses the application of pharmacokinetic modeling to these data. Finally, we provide insights on and perspectives for future development of effective therapeutic strategies using pharmacokinetic modeling to maximize MSC therapy and minimize potential side effects.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 23-10-2008
Abstract: Liver disease changes the disposition properties of drugs, complicating drug therapy management. We present normal and "diseased" versions of an abstract, agent-oriented In Silico Livers (ISLs), and validate their mechanisms against disposition data from perfused normal and diseased rat livers. Dynamic tracing features enabled spatiotemporal tracing of differences in dispositional events for diltiazem and sucrose across five levels, including interactions with representations of lobular microarchitectural features, cells, and intracellular factors that sequester and metabolize. Differences in attributes map to measures of histopathology. We measured disease-causing differences in local, intralobular ISL effects, obtaining until now unavailable views of how and where hepatic drug disposition may differ in normal and diseased rat livers from diltiazem's perspective. Exploration of disposition in less and more advanced stages of disease is feasible. The approach and technology represent an important step toward unraveling the complex changes from normal to disease states and their influences on drug disposition.
Publisher: SPIE-Intl Soc Optical Eng
Date: 03-07-2013
Publisher: Wiley
Date: 22-04-2019
DOI: 10.1111/PHP.13100
Abstract: Zinc pyrithione is ubiquitous in commercial products particularly antidandruff sh oos. For the efficacy of zinc pyrithione therapeutic cleansers to be assessed accurately, the distribution of particles on the scalp needs to be visualized. Currently, no technique is available which provides the chemical specificity and sensitivity required. Here, we report application of fluorescence-lifetime imaging microscopy (FLIM) for high-contrast mapping of zinc pyrithione distribution on the scalp. Characterization of the zinc pyrithione emission by using both one-photon excitation at five specific wavelengths and two-photon excitation in the range of 740-820 nm revealed its FLIM fingerprint-a characteristic short average time-weighted emission lifetime of Τ
Publisher: Springer Berlin Heidelberg
Date: 2017
Publisher: Elsevier BV
Date: 05-2008
DOI: 10.1016/J.EJPB.2007.10.002
Abstract: The safety of topical application of Australian tea tree Oil (TTO) is confounded by a lack of transdermal penetration data, which adequately informs opinions and recommendations. In this study we applied TTO in its pure form and as a 20% solution in ethanol in vitro to human epidermal membranes from three different donors, mounted in horizontal Franz-type diffusion cells, using normal 'in use' dosing conditions (10 mg/cm2). In addition, we examined the effect of partially occluding the application site on the penetration of TTO components. Our data showed that only a small quantity of TTO components, 1.1-1.9% and 2-4% of the applied amount following application of a 20% TTO solution and pure TTO, respectively, penetrated into or through human epidermis. The largest TTO component penetrating the skin was terpinen-4-ol. Following partial occlusion of the application site, the penetration of terpinen-4-ol increased to approximately 7% of the applied TTO. Measurement of the rate of evaporation of tea tree oil from filter paper (7.4 mg/cm2) showed that 98% of the oil evaporated in 4 hours. Overall, it is apparent that the penetration of TTO components through human skin is limited.
Publisher: AMPCo
Date: 10-2014
DOI: 10.5694/MJA13.00200
Abstract: Deprescribing is the process of trial withdrawal of inappropriate medications. Currently, the strongest evidence for benefit of deprescribing is from cohort and observational studies of withdrawal of specific medication classes that have shown better patient outcomes, mainly through resolution of adverse drug reactions. Additional potential benefits of deprescribing include reduced financial costs and improved adherence with other medications. The harms of ceasing medication use include adverse drug withdrawal reactions, pharmacokinetic and pharmacodynamic changes and return of the medical condition. These can be minimised with proper planning (ie, tapering), monitoring after withdrawal, and reinitiation of the medication if the condition returns. More evidence is needed regarding negative, non-reversible effects of ceasing use of certain classes of medication, such as acetylcholinesterase inhibitors. Cessation of use has not been studied for many medication classes, and large-scale randomised controlled trials of systematic deprescribing are required before the true benefits and harms can be known.
Publisher: Wiley
Date: 03-2001
DOI: 10.1046/J.1365-2125.2001.00347.X
Abstract: To evaluate whether a year long clinical pharmacy program involving development of professional relationships, nurse education on medication issues, and in idualized medication reviews could change drug use, mortality and morbidity in nursing home residents. A cluster randomised controlled trial, where an intervention home was matched to three control homes, was used to examine the effect of the clinical pharmacy intervention on resident outcomes. The study involved 905 residents in 13 intervention nursing homes and 2325 residents in 39 control nursing homes in south-east Queensland and north-east New South Wales, Australia. The outcome measures were: continuous drug use data from government prescription subsidy claims, cross-sectional drug use data on prescribed and administered medications, deaths and morbidity indices (hospitalization rates, adverse events and disability indices). This intervention resulted in a reduction in drug use with no change in morbidity indices or survival. Differences in nursing home characteristics, as defined by cluster analysis with SUDAAN, negated intervention-related apparent significant improvements in survival. The use of benzodiazepines, nonsteroidal anti-inflammatory drugs, laxatives, histamine H2-receptor antagonists and antacids was significantly reduced in the intervention group, whereas the use of digoxin and diuretics remained similar to controls. Overall, drug use in the intervention group was reduced by 14.8% relative to the controls, equivalent to an annual prescription saving of A64 dollars per resident (approximately 25 pound sterling). This intervention improved nursing home resident outcomes related to changes in drug use and drug-related expenditure. The continuing ergence in both drug use and survival at the end of the study suggests that the difference would have been more significant in a larger and longer study, and even more so using additional instruments specific for measuring outcomes related to changes in drug use.
Publisher: Bentham Science Publishers Ltd.
Date: 06-2009
DOI: 10.2174/138920009788898037
Abstract: Drug transporters expressed on the hepatocyte membrane play an important role in hepatic drug disposition. In the last two decades, systematic research has resulted in a better understanding of the ersity, expression and substrate specificities of drug transporters in the liver. Here we review recent studies on the role of transporters in drug-drug interactions and disease states such as cirrhosis. We conclude the review by considering techniques and model systems used to study hepatic transporters, including the latest technological developments such as multiphoton microscopy.
Publisher: Public Library of Science (PLoS)
Date: 21-04-2010
Publisher: Elsevier BV
Date: 08-1991
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.ADDR.2012.04.009
Abstract: Topical delivery to the various regions of the skin and underlying tissues, transdermal drug delivery and dermal exposure to environmental chemicals are important areas of research. Mathematical models of epidermal and dermal transport, involving penetration of a solute through various layers of the skin, metabolism in the skin and its subsequent distribution and clearance into systemic circulation from underlying tissues, play an essential role in this research area and are reviewed in this work.
Publisher: Oxford University Press (OUP)
Date: 22-09-2009
DOI: 10.1111/J.1365-2133.2009.09511.X
Abstract: Keloids are recognized as benign tumours characterized by fibroblastic proliferation and accumulation of extracellular matrix, especially collagen deposition. The transforming growth factor (TGF)-beta(1)/Smad pathway plays an important role in keloid pathogenesis however the underlying mechanisms are not fully understood. To define further the mechanisms of TGF-beta(1)/Smad signal transduction mediated by mitogen-activated protein kinases (MAPKs), including the extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 pathways, in keloid fibroblasts. In the absence or presence of three MAPK (ERK, JNK and p38)-specific inhibitors, keloid fibroblasts were stimulated with exogenous TGF-beta(1) to activate Smad signalling. Smad protein expression was measured by immunoprecipitation/immunoblotting and immunofluorescence plasminogen activator inhibitor (PAI)-1 transcriptional activity was measured by real-time reverse transcriptase-polymerase chain reaction analysis. TGF-beta(1) induced Smad2/3 phosphorylation at both the C-terminal and the linker region, thus promoting formation of the Smad2/3/4 complex and nuclear translocation, and PAI-1 mRNA expression in keloid fibroblasts in addition, TGF-beta(1) decreased inhibitory Smad7 expression. Meanwhile, the p38 inhibitor significantly inhibited Smad2/3 phosphorylation, especially at the linker region, and furthermore blocked Smad2/3/4 complex formation, and thus decreased PAI-1 mRNA expression decreased Smad7 expression induced by TGF-beta(1) was also reversed by the p38 inhibitor. The ERK and JNK inhibitors interrupted Smad2/3/4 complex translocation into the nucleus and consequently decreased PAI-1 mRNA expression. These results suggested that the ERK, JNK and p38 pathways mediate TGF-beta(1)/Smad signal transduction and might be considered as specific targets of drug therapy for keloids.
Publisher: Elsevier BV
Date: 04-1991
DOI: 10.1016/0378-4347(91)80392-P
Abstract: A novel direct high-performance liquid chromatographic (HPLC) assay for the simultaneous determination of three salicylate glucuronide conjugates and other salicylate metabolites in human urine has been developed. Salicylate glucuronide conjugates were purified by HPLC from the urine of a volunteer after oral administration of aspirin and identified by selective hydrolysis with beta-glucuronidase and with sodium hydroxide. This method gave high reproducibility with coefficients of variation less than 10%. The total urinary recovery of salicylic acid after a single 1.2-g dose of soluble aspirin was greater than 90%. This assay has been successfully used to re-evaluate the capacity-limited pharmacokinetics of salicylic acid in humans.
Publisher: American Society for Microbiology
Date: 2009
DOI: 10.1128/AAC.00718-08
Abstract: Burn tissue sites are a potential source of bacteremia during debridement surgery. Burn injury is likely to affect the distribution of antibiotics to tissues, but direct evidence of this is lacking. The aim of this study was to directly evaluate the influence of burn trauma on the distribution of cephalothin to peripheral tissues. We used subcutaneous microdialysis techniques to monitor interstitial fluid concentrations of cephalothin in the burnt and nonburnt tissues of adult patients with severe burns following parenteral administration of 1 g cephalothin for surgical prophylaxis. Analogous simultaneous studies conducted with healthy adult volunteers provided reference tissue concentration data. Equivalent tissue exposures were seen for burn and nonburn sites, giving overall median interstitial cephalothin concentrations (from 0 to 240 min) of 2.84 mg/liter and 3.06 mg/liter, respectively. A lower overall median interstitial cephalothin concentration of 0.54 mg/liter was observed for healthy in iduals, and the patient nonburnt tissue and volunteer control tissue cephalothin concentrations exhibited significantly different data distributions ( P 0.001 Kolmogorov-Smirnov nonparametric test). The duration of tissue residence for cephalothin was longer for burn patients than for healthy volunteers. The results demonstrate the potential fallibility of using healthy population models to extrapolate tissue pharmacodynamic predictions from plasma data for burn patients.
Publisher: SPIE
Date: 09-12-2016
DOI: 10.1117/12.2242883
Publisher: Springer Science and Business Media LLC
Date: 29-02-2016
DOI: 10.1038/SREP22293
Abstract: Although mesenchymal stem cells (MSCs) present a promising tool in cell therapy for the treatment of various diseases, the in vivo distribution of administered MSCs has still been poorly understood, which h ers the precise prediction and evaluation of their therapeutic efficacy. Here, we developed the first model to characterize the physiological kinetics of administered MSCs based on direct visualization of cell spatiotemporal disposition by intravital microscopy and assessment of cell quantity using flow cytometry. This physiologically based kinetic model was validated with multiple external datasets, indicating potential inter-route and inter-species predictive capability. Our results suggest that the targeting efficiency of MSCs is determined by the lung retention and interaction between MSCs and target organs, including cell arrest, depletion and release. By adapting specific parameters, this model can be easily applied to abnormal conditions or other types of circulating cells for designing treatment protocols and guiding future experiments.
Publisher: Springer Science and Business Media LLC
Date: 13-11-2018
Publisher: Springer Science and Business Media LLC
Date: 12-2015
DOI: 10.1186/S13054-015-0818-8
Abstract: Continuous renal replacement therapy (CRRT) may alter antibiotic pharmacokinetics and increase the risk of incorrect dosing. In a nested cohort within a large randomized controlled trial, we assessed the effect of higher (40 mL/kg per hour) and lower (25 mL/kg per hour) intensity CRRT on antibiotic pharmacokinetics. We collected serial blood s les to measure ciprofloxacin, meropenem, piperacillin-tazobactam, and vancomycin levels. We calculated extracorporeal clearance (CL), systemic CL, and volume of distribution (Vd) by non-linear mixed-effects modelling. We assessed the influence of CRRT intensity and other patient factors on antibiotic pharmacokinetics. We studied 24 patients who provided 179 pairs of s les. Extracorporeal CL increased with higher-intensity CRRT but the increase was significant for vancomycin only (mean 28 versus 22 mL/minute P = 0.0003). At any given prescribed CRRT effluent rate, extracorporeal CL of in idual antibiotics varied widely, and the effluent-to-plasma concentration ratio decreased with increasing effluent flow. Overall, systemic CL varied to a greater extent than Vd, particularly for meropenem, piperacillin, and tazobactam, and large intra-in idual differences were also observed. CRRT dose did not influence overall (systemic) CL, Vd, or half-life. The proportion of systemic CL due to CRRT varied widely and was high in some cases. In patients receiving CRRT, there is great variability in antibiotic pharmacokinetics, which complicates an empiric approach to dosing and suggests the need for therapeutic drug monitoring. More research is required to investigate the apparent relative decrease in clearance at higher CRRT effluent rates. ClinicalTrials.gov NCT00221013 . Registered 14 September 2005.
Publisher: Wiley
Date: 02-10-2018
DOI: 10.1111/BCP.13747
Publisher: Springer Science and Business Media LLC
Date: 12-2015
DOI: 10.1186/S13054-015-0750-Y
Abstract: The aim of this study was to explore the impact of augmented creatinine clearance and differing minimum inhibitory concentrations (MIC) on piperacillin pharmacokinetic harmacodynamic (PK/PD) target attainment (time above MIC ( f T MIC )) in critically ill patients with sepsis receiving intermittent dosing. To be eligible for enrolment, critically ill patients with sepsis had to be receiving piperacillin-tazobactam 4.5 g intravenously (IV) by intermittent infusion every 6 hours for presumed or confirmed nosocomial infection without significant renal impairment (defined by a plasma creatinine concentration greater than 171 μmol/L or the need for renal replacement therapy). Over a single dosing interval, blood s les were drawn to determine unbound plasma piperacillin concentrations. Renal function was assessed by measuring creatinine clearance (CL CR ). A population PK model was constructed, and the probability of target attainment (PTA) for 50% and 100% f T MIC was calculated for varying MIC and CL CR values. In total, 48 patients provided data. Increasing CL CR values were associated with lower trough plasma piperacillin concentrations ( P 0.01), such that with an MIC of 16 mg/L, 100% f T MIC would be achieved in only one-third ( n = 16) of patients. Mean piperacillin clearance was approximately 1.5-fold higher than in healthy volunteers and correlated with CL CR ( r = 0.58, P 0.01). A reduced PTA for all MIC values, when targeting either 50% or 100% f T MIC , was noted with increasing CL CR measures. Standard intermittent piperacillin-tazobactam dosing is unlikely to achieve optimal piperacillin exposures in a significant proportion of critically ill patients with sepsis, owing to elevated drug clearance. These data suggest that CL CR can be employed as a useful tool to determine whether piperacillin PK/PD target attainment is likely with a range of MIC values.
Publisher: Springer Science and Business Media LLC
Date: 06-2004
DOI: 10.1023/B:PHAM.0000029295.38564.E1
Abstract: Simple rules based on readily accessible physicochemical properties enable identification of solutes that penetrate skin very slowly or rapidly. Literature in vitro maximal flux values (Jmax) across human skin were collected for 87 penetrants. Penetrants were assigned as "good" (Jmax > 10(-5.52) mole x cm(-2) x h(-1)), "bad" (Jmax < 10(-8.84) mole x cm(-2) x h(-1)) or "intermediate" based on mean +/- 1SD. The feasibility of using readily available physicochemical properties, such as molecular weight (MW), melting point (MP, degrees K), octanol-water partition coefficient (K), water solubility (S, molarity), number of atoms available for H-bonding (HB), in assigning solutes was examined. Good penetrants had MW -2.3, HB < or = 5, log K < 2.6, MP 213, log S or = 4, log K > 1.2, MP > or = 223. Discriminant analysis using MW, HB, log K correctly assigned 70% of compounds. In idual success rates were good (88%), intermediate (58%), bad (93%). Aqueous Jmax data for 148 test solutes were used for validation. Discriminant analysis assigned 76% of compounds, with in idual rates of good (76%), intermediate (67%), and bad (97%). No good penetrants were misclassified as bad or vice versa. These rules enable rapid screening of potential drug delivery candidates and environmental exposure risks.
Publisher: Elsevier BV
Date: 1994
Publisher: MDPI AG
Date: 09-08-2023
Abstract: The presence of esterase enzymes in human skin and their role in drug metabolism has been reported, but their distribution in the various skin layers and the relative contributions of those layers to metabolism is poorly defined. To gain further insight into esterase distribution, we performed in vitro skin permeation of a commercial 28.3% methyl salicylate (MeSA) cream (Metsal™) in Franz diffusion cells, using a range of human skin membranes, all from the same donor. The membranes were viable epidermis separated by a dispase II enzymatic method, heat separated epidermis, dermatomed skin, and dermis separated by a dispase II enzymatic method. Methyl salicylate and its metabolite, salicylic acid (SA), were measured by high-performance liquid chromatography. Alpha naphthyl acetate and Hematoxylin and Eosin staining provided qualitative estimations of esterase distribution in these membranes. The permeation of methyl salicylate after 24 h was similar across all membranes. Salicylic acid formation and permeation were found to be similar in dermatomed skin and dermis, suggesting dermal esterase activity. These results were supported by the staining studies, which showed strong esterase activity in the dermal–epidermal junction region of the dermis. In contrast with high staining of esterase activity in the stratum corneum and viable epidermis, minimal stained and functional esterase activity was found in heat-separated and dispase II-prepared epidermal membranes. The results are consistent with dispase II digesting hemidesmosomes, penetrating the epidermis, and affecting epidermal esterases but not those in the dermis. Accordingly, whilst the resulting dispase II-generated dermal membranes may be used for in vitro permeation tests (IVPT) involving esterase-based metabolic studies, the dispase II-generated epidermal membranes are not suitable for this purpose.
Publisher: SAGE Publications
Date: 10-11-2015
Abstract: Background: Proton pump inhibitors (PPIs) are inappropriately prescribed in up to 50% of users. Systematic medication review and cessation of inappropriate medications or deprescribing may improve patient outcomes and reduce costs. Objective: The aim of this study was to assess the feasibility of a patient-centered deprescribing process in a population of adults with complex polypharmacy. Methods: This was a prospective feasibility study. Participants were recruited from hospital outpatient clinics. The patient-centered deprescribing process consisted of 5 steps: comprehensive medication history, identification of potentially inappropriate medications, determining if the medication can be ceased, planning the withdrawal regimen (eg, tapering where necessary), and provision of monitoring, support, and documentation. Feasibility was determined by assessing time taken to complete the different steps of the deprescribing process and participant feedback. Results: In all, 57 PPI users were recruited participants were 70 ± 14 years old and took 14 ± 6 medications. The indication for PPI use was verified in 43 participants and judged as potentially inappropriate in 19 (44%) 8 were suitable for trial withdrawal, and 6 consented. All 6 successfully ceased (n = 3) or reduced (n = 3) their PPI use, and this was sustained at 6 months postintervention in 4 participants. Conclusions: The patient-centered deprescribing process can safely reduce inappropriate PPI prescribing in a small proportion of people. Although the process was acceptable to participants, difficulties in accessing complete medical histories, time limitations, and minimal evidence to support effectiveness in certain indications were barriers to implementation of the process in clinical practice.
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.JEMERMED.2016.05.068
Abstract: Intentional poisoning with warfarin is not the same as over-anticoagulation, for which guidelines exist. The coagulopathy resulting from a warfarin overdose is reversed with vitamin K We report a case of a 50-year-old man who ingested an unknown amount of his warfarin, venlafaxine, and paracetamol. He presented with an international normalized ratio (INR) of 2.5, which steadily increased over 24 h to 7, despite receiving an initial 1 mg of vitamin K
Publisher: Wiley
Date: 05-03-2020
DOI: 10.1002/IJC.32899
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.IJANTIMICAG.2015.02.017
Abstract: Acute kidney injury is a common complication in critically ill patients, and hybrid techniques including sustained low-efficiency dialysis/diafiltration (SLED-f) are being increasingly utilised in intensive care units. Most fungal infections occur in the interstitial fluid (ISF) of tissues and successful treatment of a fungal infection relies on the ability of an antifungal agent to achieve adequate concentrations at the site of infection. Tissue distribution of antimicrobials is impaired in critically ill patients owing to a variety of disease-related physiological changes, e.g. sepsis. Fluconazole is a widely used antifungal agent used to treat Candida spp. infections in critically ill patients. The implications for ISF concentrations of enhanced elimination during renal replacement therapy have not yet been reported for fluconazole. The aim of this single-patient case report was to describe the influence of SLED-f on subcutaneous (SC) ISF concentrations of fluconazole and the implications for achieving pharmacokinetic harmacodynamic targets. Serial blood and ISF s les were collected at pre- and post-filter ports within the SLED-f circuit and subcutaneously inserted microdialysis probe, respectively. Fluconazole concentrations were measured using a validated chromatography method. The SC ISF-to-plasma partition coefficient of fluconazole in this patient was 0.91, indicating rapid equilibrium. SC ISF fluconazole concentrations consistently decreased after initiating SLED-f. The majority of the fluconazole was eliminated from the SC ISF as a result of redistribution. Considering the extensive tissue re-distribution of fluconazole and observed elimination from tissue compartments, higher doses may be required to treat deep-seated fungal infections.
Publisher: Informa UK Limited
Date: 09-10-2018
DOI: 10.1080/15563650.2017.1385790
Abstract: Ingestion of bromoxynil and 2-methyl-4-chlorophenoxyacetic acid (MCPA) in combination is associated with high mortality. Toxicity is characterised by hyperthermia and metabolic acidosis. Dialysis is a proposed treatment, but little data exist regarding its effectiveness. Case 1: A 50-year-old female presented 18 h post-ingestion of 200 mL of bromoxynil(200 g/L) and MCPA(200 g/L). She was agitated, tachycardic and tachypnoeic. She was intubated and continuous venovenous haemodiafiltration (CVVHDF) was commenced. She deteriorated, becoming hypotensive, hyperthermic (39.5 °C) and hypercapnic (80 mmHg). She was cooled, paralysed, received CVVHDF for 2d and was extubated on day 4 making a full recovery. Case 2: A 60-year-old male presented 6 h post-ingestion of an unknown amount of bromoxynil (200 g/L) and MCPA (200 g/L). On arrival, he was tachycardic and tachypneic (pCO CVVHDF did not result in significant clearance of either herbicide but may have assisted with hyperthermia control. Both patients survived with vigorous cooling, paralysis and ventilatory support.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.JCONREL.2014.09.028
Abstract: The buccal mucosa (inner cheek) is an attractive site for delivery of immunotherapeutics, due to its ease of access and rich antigen presenting cell (APC) distribution. However, to date, most delivery methods to the buccal mucosa have only been topical-with the challenges of: 1) an environment where significant biomolecule degradation may occur 2) inability to reach the APCs that are located deep in the epithelium and lamina propria and 3) salivary flow and mucous secretion that may result in removal of the therapeutic agent before absorption has taken place. To overcome these challenges and achieve consistent, repeatable targeted delivery of immunotherapeutics to within the buccal mucosa (not merely on to the surface), we utilised microprojection arrays (Nanopatches-110 μm length projections, 3364 projections, 16 mm2 surface area) with a purpose built clip applicator. The mechanical application of Nanopatches bearing a dry-coated vaccine (commercial influenza vaccine, as a test case immunotherapeutic) released the vaccine to a depth of 47.8±14.8 μm (mean±SD, n=4), in the mouse buccal mucosa (measured using fluorescent delivered dyes and CryoSEM). This location is in the direct vicinity of APCs, facilitating antigenic uptake. Resultant systemic immune responses were similar to systemic immunization methods, and superior to comparative orally immunised mice. This confirms the Nanopatch administered vaccine was delivered into the buccal mucosa and not ingested. This study demonstrates a minimally-invasive delivery device with rapid (2 min of application time), accurate and consistent release of immunotherapeutics in to the buccal mucosa-that conceptually can be extended in to human use for broad and practical utility.
Publisher: MDPI AG
Date: 25-01-2018
Publisher: MDPI AG
Date: 17-05-2022
DOI: 10.3390/PHARMACEUTICS14051076
Abstract: Zinc pyrithione (ZnPT) is a widely used antifungal, usually applied as a microparticle suspension to facilitate delivery into the hair follicles, where it then dissociates into a soluble monomeric form that is bioactive against yeast and other microorganisms. In this study, we use multiphoton microscopy (MPM) and fluorescence lifetime imaging microscopy (FLIM) to characterise ZnPT formulations and map the delivery of particles into follicles within human skin. To simulate real-world conditions, it was applied using a massage or no-massage technique, while simultaneously assessing the dissolution using Zinpyr-1, a zinc labile fluorescent probe. ZnPT particles can be detected in a range of sh oo formulations using both MPM and FLIM, though FLIM is optimal for detection as it allows spectral and lifetime discrimination leading to increased selectivity and sensitivity. In aqueous suspensions, the ZnPT 7.2 µm particles could be detected up to 500 µm in the follicle. The ZnPT particles in formulations were finer (1.0–3.3 µm), resulting in rapid dissolution on the skin surface and within follicles, evidenced by a reduced particle signal at 24 h but enhanced Zinpyr-1 intensity in the follicular and surface epithelium. This study shows how MPM-FLIM multimodal imaging can be used as a useful tool to assess ZnPT delivery to skin and its subsequent dissolution.
Publisher: SPIE-Intl Soc Optical Eng
Date: 2010
DOI: 10.1117/1.3466580
Abstract: Ex vivo human skin has been used extensively for cosmeceutical and drug delivery studies, transplantable skin allografts, or skin flaps. However, it has a half-life of a few days due to ischemic necrosis. Traditional methods of assessing viability can be time-consuming and provide limited metabolic information. Using multiphoton tomography and fluorescence lifetime imaging (MPT-FLIM) we assess ischemic necrosis of ex vivo skin by NAD(P)H autofluorescence intensity and fluorescence lifetime. Ex vivo skin is stored in the presence and absence of nutrient media (Dulbecco Modified Eagle Medium) at -20, 4, and 37 degrees C and room temperature over a 7-day time course to establish different rates of metabolic deterioration. At higher temperatures we observe a decrease in NAD(P)H autofluorescence, higher image noise, and a significant increase in the average fluorescence lifetime (tau(m)) from approximately 1000 to 2000 ps. Additionally, significant distortions in NAD(P)H fluorescence lifetime histograms correspond to the reduction in autofluorescence. Skin kept at 4 degrees C, with or without media, showed the least change. Our findings suggest that MPT-FLIM enables useful noninvasive optical biopsies to monitor the metabolic state and deterioration of human skin for research and clinical purposes.
Publisher: SPIE
Date: 30-04-2010
DOI: 10.1117/12.854561
Publisher: Elsevier BV
Date: 12-1999
DOI: 10.1016/S0378-5173(99)00314-2
Abstract: For diabetic patients, blood glucose monitoring is an important part in the management of their disease, however the acquisition of blood requires the use of invasive and often painful methods, and the development of a technique that removes these problems would represent a major advance. The uppermost membrane of the skin, the stratum corneum, has been shown to be the main barrier to percutaneous absorption, but there have been claims that polar water-soluble compounds diffuse across it via aqueous pathways. In this study, skin diffusion cells were used to investigate the back diffusion of tritiated water and the convective transport of 3H-glucose across full thickness human skin after the application of a number of different materials to the stratum corneum. Significant amounts of 3H-glucose back diffused only after complete removal of the stratum corneum by tape stripping, and it is likely that any future attempts to monitor blood glucose levels using non-physical techniques will require a certain degree of damage to the stratum corneum. The extraction through the skin of tritiated water and 3H-glucose after the application of solutions with different osmotic pressures were consistent with the theory that solutions with high osmotic pressures dehydrate the stratum corneum which suggests that passive transport of these radiolabelled molecules through porous pathways was insignificant.
Publisher: Informa UK Limited
Date: 03-12-2021
DOI: 10.1080/17425255.2020.1832081
Abstract: In the past, mathematical modeling of the transport of transdermal drugs has been primarily focused on the stratum corneum. However, the development of pharmaceutical technologies, such as chemical enhancers, iontophoresis, and microneedles, has led to two outcomes an increase in permeability in the stratum corneum or the ability to negate the layer entirely. As a result, these outcomes have made the transport of a solute in the viable skin far more critical when studying transdermal drug delivery. The review will explicitly show the various attempts to model drug transport within the viable skin. Furthermore, a brief review will be conducted on the different models that explain stratum corneum transport, microneedle dynamics and estimation of the diffusion coefficient. Future development of mathematical models requires the focus to be changed from traditional diffusion-based tissue models to more sophisticated three-dimensional models that incorporate the physiology of the skin.
Publisher: MDPI AG
Date: 21-09-2017
Publisher: Informa UK Limited
Date: 21-07-2016
DOI: 10.1080/15563650.2016.1209768
Abstract: Acute beta-blocker overdose can cause severe cardiac dysfunction. Chronic toxicity is rare but potentially severe. We report therapeutic dosing of metoprolol resulting in unusual pharmacokinetics and toxicity, given high-dose insulin therapy for treatment. A 90-year-old female presented with hypotension, tachycardia and severe cardiac dysfunction after commencing a rapidly increasing metoprolol dose of 250 mg split daily. She was admitted to intensive care and given high-dose insulin therapy (10 U/kg/h), noradrenaline, adrenaline and dobutamine for severe cardiac dysfunction (cardiac index, 0.76 L/min/m The time course of cardiac dysfunction was longer than acute overdose but consistent with prolonged zero order elimination of metoprolol, suggesting the patient was a poor CYP2D6 metaboliser. High-dose insulin euglycaemia appeared to be effective in combination with vasoconstrictors/inotropes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-1997
DOI: 10.1097/00008390-199702000-00004
Abstract: We have established a surviving model of isolated limb perfusion using xenografts of the human melanoma cell line MM 96L injected subcutaneously into the hindlimb of a nude rat. The femoral artery and vein were cannulated via the left renal artery and vein and the hind limb was isolated using tourniquets. The limb was perfused with Krebs Heinseleit buffer at 37 degrees C containing 4.7% bovine serum albumin at a constant flow rate of 4 ml per min for 30-60 min with 100% survival of the animals. Tumour vascularization and blood flow were demonstrated using vascular casts and [51Cr]-microspheres. Following the addition of melphalan (15 or 100 micrograms/ml), drug concentrations in the perfusate, tissues and systemic circulation were determined using high pressure liquid chromatography (HPLC). Systemic leakage, assessed using [125I]albumin and melphalan and detected by a gamma-counter and HPLC respectively, was < 0.5%. The melphalan concentration and tissue flow rate in the tumour deposits were 40 and 30% respectively, when compared with the surrounding subcutaneous tissue. At a dose of 15 micrograms/ml, melphalan caused a reduction in tumour growth after 60 min perfusion, and a significant reduction in tumour size was seen when the melphalan dose was 100 micrograms/ml. The surviving nude rat model of isolated limb perfusion for recurrent melanoma will allow examination of optimal perfusion conditions, along with the pharmacokinetics, pharmacodynamics and efficacy of melphalan and other drugs.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.TOXLET.2014.01.018
Abstract: For improved early detection and assessment of severe acute kidney damage following accidental or intentional ingestion of the herbicide MCPA, we compared a panel of 14 novel kidney injury biomarkers with plasma creatinine. Male Wistar rats received four different oral doses of MCPA and plasma and urine biomarker levels were measured at 8, 24 and 48 h after MCPA exposure. Diagnostic performances using absolute levels, urine levels normalized to urine creatinine or urinary excretion rate were determined by ROC analysis. Plasma creatinine remained the best early biomarker for predicting histological changes at 48 h. The performance of plasma cystatin C in mirroring kidney function was similar to that of plasma creatinine. While urine concentrations were generally less predictive, normalization by urine creatinine greatly improved the performance of several biomarkers. This may be due to an apparent lification of the biomarker signal on normalizing to creatinine, in the presence of a declining glomerular filtration rate prior to reaching steady state. Normalized 8 h osteopontin and albumin concentrations outperformed other normalized biomarkers in predicting histological changes at later times. Normalized urinary kidney injury molecule-1 at 48 h also correlated well with the degree of kidney damage.
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.VASCN.2013.03.002
Abstract: A number of hepatic ischemia/hypoxia-reperfusion models have been described. This study characterised the functional and structural changes induced by the most commonly used in vivo and in situ models for hypoxia/ischemia-reperfusion in the rat liver. A range of no-flow, slow-flow and lobar ischemia and reperfusion models were established in the rat liver. Changes following reperfusion were monitored using physiological, biochemical, histological and pharmacological assessments, including bile production, oxygen consumption, lignocaine extraction, enzyme release, and disposition of exogenous markers. Short periods of hepatic ischemia/hypoxia-reperfusion led to minimal changes in liver function whereas long periods of ischemia-reperfusion led to substantial liver injury. The most severe injury was found with the slow flow, reflow model. The formation of cell vacuoles, blebs and focal hepatitis were the most important liver morphological changes observed as a consequence of ischemia/hypoxia. The major liver histological findings after reperfusion were dispersed apoptosis and local necrosis. Hepatic ischemia/hypoxia-reperfusion was also associated with significant changes in the hepatic extracellular and intracellular spaces. The morphology and function of the liver associated with a range of hepatic ischemia/hypoxia-reperfusion models varies with the duration of the insult and between models. The choice of model is therefore an important consideration in seeking to resolve any particular hypothesis associated with hepatic ischemia/hypoxia-reperfusion.
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.TOXLET.2013.08.003
Abstract: Paraquat is a widely used herbicide which has been involved in many accidental and intentional deaths. Nephrotoxicity is common in severe acute paraquat poisoning. We examined seven renal injury biomarkers, including cystatin-C, kidney injury molecule-1, β2-microglobulin, clusterin, albumin, neutrophil gelatinase-associated lipocalin and osteopontin, to develop a non-invasive method to detect early renal damage and dysfunction and to compare with the conventional endogenous marker creatinine. Male Wistar rats were dosed orally with four different doses of paraquat, and the biomarker patterns in urine and plasma were investigated at 8, 24 and 48h after paraquat exposure. By Receiver Operating Characteristic analysis, urinary kidney injury molecule-1 was the best marker at predicting histological changes, with areas under the Receiver Operating Characteristic curve of 0.81 and 0.98 at 8 and 24h (best cut-off value>0.000326μg/ml), respectively. Urinary kidney injury molecule-1, urinary albumin and urinary Cystatin-C elevations correlated with the degree of renal damage and injury development. Further study is required to compare biomarkers changes in rats with those seen in human poisoning.
Publisher: Informa UK Limited
Date: 26-06-2015
DOI: 10.3109/15563650.2015.1059945
Abstract: Toxicity from recreational substances marketed for other purposes is a well-documented clinical entity. We present two cases of phenibut toxicity procured via the internet. A 20-year-old female presented to the emergency department (ED) having used phenibut the prior day. The main finding was a decreased level of consciousness, however when roused she became delirious. Supportive care only was required with no specific intervention. The patient made a full recovery over a 24-hour period and admitted to use of phenibut purchased online. Plasma phenibut concentration was 29.7 μg/ml. A 38-year-old male presented to ED with an agitated delirium. The prior evening he had used tetrahydrocannabinol or THC, alcohol and phenibut, the latter purchased via the internet. His behavioural state had a suboptimal response to parenteral sedation. He was subsequently intubated for airway protection in the context of ongoing sedation to optimally manage his behavioural state. Post extubation the next morning he admitted using phenibut. Plasma phenibut concentration was 36.5 μg/ml. Altered mental status was the predominant manifestation of phenibut toxicity in these cases. Clinicians to be aware of how phenibut toxicity may present as the internet has widened access to such substances.
Publisher: American Physiological Society
Date: 2005
Abstract: Nonalcoholic fatty liver disease is the most common of all liver diseases. The hepatic disposition [ 3 H]palmitate and its low-molecular-weight metabolites in perfused normal and steatotic rat liver were studied using the multiple indicator dilution technique and a physiologically based slow diffusion/bound pharmacokinetic model. The steatotic rat model was established by administration of 17α-ethynylestradiol to female Wistar rats. Serum biochemistry markers and histology of treated and normal animals were assessed and indicated the presence of steatosis in the treatment group. The steatotic group showed a significantly higher alanine aminotransferase-to-aspartate aminotransferase ratio, lower levels of liver fatty acid binding protein and cytochrome P-450, as well as microvesicular steatosis with an enlargement of sinusoidal space. Hepatic extraction for unchanged [ 3 H]palmitate and production of low-molecular-weight metabolites were found to be significantly decreased in steatotic animals. Pharmacokinetic analysis suggested that the reduced extraction and sequestration for palmitate and its metabolites was mainly attributed to a reduction in liver fatty acid binding protein in steatosis.
Publisher: MDPI AG
Date: 12-2019
DOI: 10.3390/PHARMACEUTICS11120639
Abstract: Curcumin is a natural product with chemopreventive and other properties that are potentially useful in treating skin diseases, including psoriasis and melanoma. However, because of the excellent barrier function of the stratum corneum and the relatively high lipophilicity of curcumin (log P 3.6), skin delivery of curcumin is challenging. We used the principles of a Quality by Design (QbD) approach to develop nanoemulsion formulations containing biocompatible components, including Labrasol and Lecithin as surfactants and Transcutol and ethanol as cosurfactants, to enhance the skin delivery of curcumin. The nanoemulsions were characterised by cryo-SEM, Zeta potential, droplet size, pH, electrical conductivity (EC) and viscosity (η). Physicochemical long-term stability (6 months) was also investigated. The mean droplet sizes as determined by dynamic light scattering (DLS) were in the lower submicron range (20–50 nm) and the average Zeta potential values were low (range: −0.12 to −2.98 mV). Newtonian flow was suggested for the nanoemulsions investigated, with dynamic viscosity of the nanoemulsion formulations ranging from 5.8 to 31 cP. The droplet size of curcumin loaded formulations remained largely constant over a 6-month storage period. The inclusion of terpenes to further enhance skin permeation was also examined. All nanoemulsions significantly enhanced the permeation of curcumin through heat-separated human epidermal membranes, with the greatest effect being a 28-fold increase in maximum flux (Jmax) achieved with a limonene-based nanoemulsion, compared to a 60% ethanol in water control vehicle. The increases in curcumin flux were associated with increased skin diffusivity. In summary, we demonstrated the effectiveness of nanoemulsions for the skin delivery of the lipophilic active compound curcumin, and elucidated the mechanism of permeation enhancement. These formulations show promise as delivery vehicles for curcumin to target psoriasis and skin cancer, and more broadly for other skin delivery applications.
Publisher: Wiley
Date: 08-1997
DOI: 10.1111/J.1471-0528.1997.TB14356.X
Abstract: We have examined whether insulin dependent diabetes mellitus (IDDM) affects maternal serum levels of inhibin-A, a recently described prenatal marker of Down's syndrome, by comparing levels in 169 women with IDDM with levels in 432 nondiabetic pregnant women between 15 and 20 weeks of gestation. There was a small but significant increase in the inhibin-A level in the diabetic women only when levels were corrected for maternal weight: median MoM 1.17 (P < 0.01 vs controls, Student's t test). The underlying mechanism for this elevation in pregnancies complicated by IDDM currently remains obscure.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2009
Publisher: Oxford University Press (OUP)
Date: 03-2018
DOI: 10.1093/JAC/DKY057
Abstract: Piperacillin is a β-lactam penicillin antibiotic commonly used for the empirical therapy of sepsis and other hospital-acquired infections. However, knowledge regarding the effect of sustained low-efficiency diafiltration (SLED-f), a technique increasingly being used in ICUs, on piperacillin pharmacokinetics (PK) and dosing in critically ill patients is lacking. To describe the PK of piperacillin during SLED-f and compare the results with those reported for other forms of renal replacement therapies. Serial blood s les were collected at pre- and post-filter ports within the SLED-f circuit during SLED-f in one session and from an arterial catheter during s ling without SLED-f. Piperacillin concentrations were measured using a validated chromatography method. Non-compartmental PK analysis of the data was performed. The median clearance and area under the concentration-time curve during SLED-f were 6 L/h and 532 mg·h/L, respectively. Fifty-eight percent of piperacillin was cleared by a single SLED-f session (6 h) compared with previous reports of 30%-45% clearance by a 3.5 h intermittent haemodialysis session. Clearance, half-life and area under the concentration-time curve during SLED-f obtained from this study were comparable with those reported in the post-dilution mode of continuous veno-venous haemodiafiltration studies. As it can be challenging to accurately predict when SLED-f will be initiated in the critically ill, a maintenance dose of at least 4 g every 12 h with at least a 2 g replacement dose post-SLED-f would be a practical approach to piperacillin dosing in ICU patients with anuria receiving SLED-f with a duration similar to the current study.
Publisher: Elsevier BV
Date: 05-2003
DOI: 10.1046/J.1523-1747.2003.12131.X
Abstract: In order to establish the relationship between solute lipophilicity and skin penetration (including flux and concentration behavior), we examined the in vitro penetration and membrane concentration of a series of homologous alcohols (C2-C10) applied topically in aqueous solutions to human epidermal, full-thickness, and dermal membranes. The partitioning/distribution of each alcohol between the donor solution, stratum corneum, viable epidermis, dermis, and receptor phase compartments was determined during the penetration process and separately to isolated s les of each tissue type. Maximum flux and permeability coefficients are compared for each membrane and estimates of alcohol diffusivity are made based on flux/concentration data and also the related tissue resistance (the reciprocal of permeability coefficient) for each membrane type. The permeability coefficient increased with increasing lipophilicity to alcohol C8 (octanol) with no further increase for C10 (decanol). Log vehicle:stratum corneum partition coefficients were related to logP, and the concentration of alcohols in each of the tissue layers appeared to increase with lipophilicity. No difference was measured in the diffusivity of smaller more polar alcohols in the three membranes however, the larger more lipophilic solutes showed slower diffusivity values. The study showed that the dermis may be a much more lipophilic environment than originally believed and that distribution of smaller nonionized solutes into local tissues below a site of topical application may be estimated based on knowledge of their lipophilicity alone.
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.JEP.2008.09.023
Abstract: To evaluate the anti-fibrotic effects of BJ-JN (a traditional Chinese formulation) in CCl(4)-induced liver fibrosis in rats. BJ-JN (0.5, 1.0, 2.0 g/kg) was administrated via gavage once a day starting from the fifth weeks after the CCl(4) treatment for subsequent 9 weeks. Evaluated with liver and spleen index, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), nitric oxide (NO), hepatic malondialdehyde (MDA) content and superoxide dismutase (SOD) activity, as well as with histopathologic changes of liver. The proliferation and collagen synthesis of primary hepatic stellate cells (HSCs) from normal, model and BJ-JN (2.0 g/kg) treatment rats were examined with (3)H-TdR and (3)H-Pro uptake assay, respectively. BJ-JN (0.5, 1.0, 2.0 g/kg) effectively reduced the elevated levels of liver and spleen index, serum ALT, AST, NO, HA, and hepatic MDA contents, enhance the reduced hepatic SOD activity in CCl(4)-treated rats. The histopathological analysis suggested that BJ-JN obviously alleviated the degree of liver fibrosis induced by CCl(4). The proliferation and collagen synthesis of HSC isolated from BJ-JN (2.0 g/kg) treatment rats were remarkably inhibited. Those results suggest BJ-JN has a protective and therapeutic effect on liver fibrosis induced by CCl(4), which might be associated with its anti-oxidative activity, inhibitory activity on HSC proliferation and collagen synthesis.
Publisher: S. Karger AG
Date: 22-12-2003
DOI: 10.1159/000074057
Abstract: The reservoir function of the skin is an important determinant of the duration of action of a topical solute. The reservoir can exist in the stratum corneum, in the viable avascular tissue (viable epidermis and supracapillary dermis) and in the dermis. A steroid reservoir in the stratum corneum has been demonstrated by the reactivation of a vasoconstrictor effect by occlusion or application of a placebo cream to the skin some time after the original topical application of steroid. Other solutes have also been reported to show a reservoir effect in the skin after topical application. A simple compartmental model is used to understand why reactivation of vasoconstriction some time after a topical steroid application shows dependency on time, topical solute concentration and the product used to cause reactivation. The model is also used to show which solutes are likely to show a reservoir effect and could be potentially affected by desquamation, especially when the turnover of the skin is abnormally rapid. A similar form of the model can be used to understand the promotion of reservoir function in the viable tissue and in the dermis in terms of effective removal by blood perfusing the tissues.
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.ADDR.2012.04.003
Abstract: Many drugs are presently delivered through the skin from products developed for topical and transdermal applications. Underpinning these technologies are the interactions between the drug, product and skin that define drug penetration, distribution, and elimination in and through the skin. Most work has been focused on modeling transport of drugs through the stratum corneum, the outermost skin layer widely recognized as presenting the rate-determining step for the penetration of most compounds. However, a growing body of literature is dedicated to considering the influence of the rest of the skin on drug penetration and distribution. In this article we review how our understanding of skin physiology and the experimentally observed mechanisms of transdermal drug transport inform the current models of drug penetration and distribution in the skin. Our focus is on models that have been developed to describe particular phenomena observed at particular sites of the skin, reflecting the most recent directions of investigation.
Publisher: Springer Netherlands
Date: 2014
Publisher: Springer Science and Business Media LLC
Date: 20-05-2009
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.EJPS.2012.07.008
Abstract: The mechanism by which quinidine affects hepatic digoxin pharmacokinetics remains controversial. Here, we study the role of displacement of digoxin from hepatic sinusoidal binding sites by quinidine. We used the impulse-response technique in the single-pass perfused rat liver to describe the digoxin hepatic disposition by a physiologically-based pharmacokinetic liver model. The impulse-response study involved analysis of outflow curves following two consecutive doses of digoxin (42 and 125 μg) without and with quinidine (10 μM) in perfusate. In addition, the effect of quinidine on digoxin binding in liver subcellular fractions was quantified. Quinidine increased the peak outflow concentration for digoxin at the low digoxin dose but not at the high dose. This increase could be adequately described when digoxin displacement from sinusoidal and intrahepatic binding sites was included in the model. Inhibition of digoxin binding by quinidine was also observed in vitro. The decrease of biliary excretion of digoxin by quinidine was accompanied by a linear increase in sinusoidal efflux of digoxin's primary metabolite, digoxigenin bisdigitoxoside (Dg2). In contrast to biliary excretion, inhibition of sinusoidal uptake may become dominant only for high concentrations of quinidine.
Publisher: Springer Science and Business Media LLC
Date: 2003
Abstract: As reductions in dermal clearance increase the residence time of solutes in the skin and underlying tissues we compared the topical penetration of potentially useful vasoconstrictors (VCs) through human epidermis as both free bases and ion-pairs with salicylic acid (SA). We determined the in vitro epidermal flux of ephedrine, naphazoline, oxymetazoline, phenylephrine, and xylometazoline applied as saturated solutions in propylene glycol:water (1:1) and of ephedrine, naphazoline and tetrahydrozoline as 10% solutions of 1:1 molar ratio ion-pairs with SA in liquid paraffin. As free bases, ephedrine had the highest maximal flux, Jmax = 77.4 +/- 11.7 microg/cm2/h, being 4-fold higher than tetrahydrozoline and xylometazoline, 6-fold higher than phenylephrine, 10-fold higher than naphazoline and 100-fold higher than oxymetazoline. Stepwise regression of solute physicochemical properties identified melting point as the most significant predictor of flux. As ion-pairs with SA, ephedrine and naphazoline had similar fluxes (11.5 +/- 2.3 and 12.0 +/- 1.6 microg/cm2/h respectively), whereas tetrahydrozoline was approximately 3-fold slower. Corresponding fluxes of SA from the ion-pairs were 18.6 +/- 0.6, 7.8+/- 0.8 and 1.1 +/- 0.1 respectively. Transdermal transport of VC's is discussed. Epidermal retention of VCs and SA did not correspond to their molar ratio on application and confirmed that following partitioning into the stratum corneum, ion-pairs separate and further penetration is governed by in idual solute characteristics.
Publisher: MDPI AG
Date: 16-11-2021
Abstract: Zinc oxide nanoparticle (ZnO NP)-based sunscreens are generally considered safe because the ZnO NPs do not penetrate through the outermost layer of the skin, the stratum corneum (SC). However, cytotoxicity of zinc ions in the viable epidermis (VE) after dissolution from ZnO NP and penetration into the VE is ill-defined. We therefore quantified the relative concentrations of endogenous and exogenous Zn using a rare stable zinc-67 isotope (67Zn) ZnO NP sunscreen applied to excised human skin and the cytotoxicity of human keratinocytes (HaCaT) using multiphoton microscopy, zinc-selective fluorescent sensing, and a laser-ablation inductively coupled plasma–mass spectrometry (LA-ICP-MS) methodology. Multiphoton microscopy with second harmonic generation imaging showed that 67ZnO NPs were retained on the surface or within the superficial layers of the SC. Zn fluorescence sensing revealed higher levels of labile and intracellular zinc in both the SC and VE relative to untreated skin, confirming that dissolved zinc species permeated across the SC into the VE as ionic Zn and significantly not as ZnO NPs. Importantly, the LA-ICP-MS estimated exogenous 67Zn concentrations in the VE of 1.0 ± 0.3 μg/mL are much lower than that estimated for endogenous VE zinc of 4.3 ± 0.7 μg/mL. Furthermore, their combined total zinc concentrations in the VE are much lower than the exogenous zinc concentration of 21 to 31 μg/mL causing VE cytotoxicity, as defined by the half-maximal inhibitory concentration of exogenous 67Zn found in human keratinocytes (HaCaT). This speaks strongly for the safety of ZnO NP sunscreens applied to intact human skin and the associated recent US FDA guidance.
Publisher: SPIE
Date: 24-11-2016
DOI: 10.1117/12.2242964
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2002
Publisher: Elsevier BV
Date: 09-1998
DOI: 10.1016/S0168-8278(98)80068-8
Abstract: Liver clearance models are based on information (or assumptions) on solute distribution kinetics within the microvasculatory system. The aim was to study albumin distribution kinetics in regenerated livers and in livers of normal adult rats. A novel mathematical model was used to evaluate the distribution space and the transit time dispersion of albumin in livers following regeneration after a two-thirds hepatectomy compared to livers of normal adult rats. Outflow curves of albumin measured after bolus injection in single-pass perfused rat livers were analyzed by correcting for the influence of catheters and fitting a long-tailed function to the data. The curves were well described by the proposed model. The distribution volume and the transit time dispersion of albumin observed in the partial hepatectomy group were not significantly different from livers of normal adult rats. These findings suggest that the distribution space and the transit time dispersion of albumin (CV2) is relatively constant irrespective of the presence of rapid and extensive repair. This invariance of CV2 implies, as a first approximation, a similar degree of intrasinusoidal mixing. The finding that a sum of two (instead of one) inverse Gaussian densities is an appropriate empirical function to describe the outflow curve of vascular indicators has consequences for an improved prediction of hepatic solute extraction.
Publisher: SPIE
Date: 09-12-2016
DOI: 10.1117/12.2242962
Publisher: Elsevier
Date: 2017
Publisher: Elsevier BV
Date: 11-1981
DOI: 10.1016/S0378-4347(00)84218-8
Abstract: A reversed-phase high-performance liquid chromatographic method for the determination of tetrabenazine and a hydroxy metabolite in plasma is described. Tetrabenazine and the hydroxy metabolite are quantified as their dehydro derivatives using fluorescence detection. This method has been applied to the analysis of plasma s les from patients with Huntington's chorea and has been found to be sensitive, reliable and specific for tetrabenazine and the hydroxy metabolite. The plasma concentrations of tetrabenazine found in patients were lower than could be detected using previously published methods.
Publisher: Apollo - University of Cambridge Repository
Date: 2018
DOI: 10.17863/CAM.41204
Publisher: Elsevier BV
Date: 04-2004
Publisher: SPIE
Date: 24-11-2016
DOI: 10.1117/12.2242978
Publisher: Elsevier BV
Date: 05-1986
DOI: 10.1016/S0140-6736(86)91865-9
Abstract: To identify whether parental history of myopia and/or parent-reported children's visual activity levels can predict juvenile-onset myopia. Survey-based data from Orinda Longitudinal Study of Myopia subjects from 1989 to 2001 were used to predict future myopia. Univariate and multiple logistic regression analyses were performed, and receiver operator characteristic (ROC) curves were generated. Differences among the areas under the ROC curves were compared using the method of multiple comparison with the best. Of the 514 children eligible for this analysis, 111 (21.6%) became myopic. Differences in the third grade between eventual myopes and nonmyopes were seen for the number of myopic parents (P < 0.001) and for the number of sports and outdoor activity hours per week (11.65 +/- 6.97 hours for nonmyopes vs. 7.98 +/- 6.54 hours for future myopes, P < 0.001). Analysis of the areas under the ROC curves showed three variables with a predictive value better than chance: the number of myopic parents, the number of sports and outdoor activity hours per week, and the number of reading hours per week. After controlling for sports and outdoor hours per week and parental myopia history, reading hours per week was no longer a statistically significant factor. The area under the curve for the parental myopia history and sports and outdoor activities model was 0.73. A significant interaction in the logistic model showed a differential effect of sport and outdoor activity hours per week based on a child's number of myopic parents. Parental history of myopia was an important predictor in univariate and multivariate models, with a differential effect of sports and outdoor activity hours per week based on the number of myopic parents. Lower amounts of sports and outdoor activity increased the odds of becoming myopic in those children with two myopic parents more than in those children with either zero or one myopic parent. The chance of becoming myopic for children with no myopic parents appears lowest in the children with the highest amount of sports and outdoor activity, compared with those with two myopic parents.
Publisher: Elsevier BV
Date: 10-1993
Publisher: Springer Science and Business Media LLC
Date: 12-2009
DOI: 10.2165/11318890-000000000-00000
Abstract: Inappropriate prescribing of medicines may lead to a significant risk of an adverse drug-related event. In particular, prescribing may be regarded as inappropriate when alternative therapy that is either more effective or associated with a lower risk exists to treat the same condition. This review aims to identify interventions and strategies that can significantly reduce inappropriate prescribing in the elderly. The review is based on a search of electronic databases using synonyms of keywords such as 'elderly', 'interventions', 'optimized prescribing' and 'inappropriate prescribing' to identify reported interventions intended to improve inappropriate prescribing in the elderly. A total of 711 articles published in English were retrieved and considered. Of these, 24 original studies, involving 56 to 124,802 participants, met the inclusion criteria and were included in the systematic review. In 16 studies, the statistical power used to assess the impact of the intervention was >90% at a significance level of alpha=0.05. Various interventions were included in this study, such as educational interventions, medication reviews, geriatricians' services, multidisciplinary teams, computerized support systems, regulatory policies and multi-faceted approaches. Because of variability in assessment methodologies, mixed responses were found for education interventions aimed at improving inappropriate prescribing. For ex le, some studies did not assess what data were required to define whether a given level of intervention would be adequate, and others did not consider how many participants would be needed to demonstrate that a significant difference existed. Each of the three computerized support system interventions reported produced a significant enhancement in both prescribing and dispensing practices. Pharmacist interventions in community and hospital settings were evaluated in seven studies. However, variable criteria were used, with two studies using the Medication Appropriateness Index, another two studies using self-designed criteria for inappropriate prescribing, and the remaining three studies using Beers' criteria. A difficulty in assessing studies involving nursing home residents is that both consultant pharmacists and onsite pharmacist services may be involved, and, in one of the studies, only the role of the consultant pharmacist was considered. One of the most effective interventions appeared to be multidisciplinary case conferences involving a geriatrician, which resulted in a number of ex les of reduced inappropriate prescribing in both community and hospital settings. As the effect of regulatory policies as an intervention is dependent on the target population involved, the effectiveness of this type of intervention was variable. Different strategies may be useful in reducing inappropriate prescribing in the elderly. It is not clear whether combined strategies undertaken simultaneously have a synergistic effect.
Publisher: Bentham Science Publishers Ltd.
Date: 29-05-2019
DOI: 10.2174/1567201816666190201143457
Abstract: This overview on skin delivery considers the evolution of the principles of percutaneous absorption and skin products from ancient times to today. Over the ages, it has been recognised that products may be applied to the skin for either local or systemic effects. As our understanding of the anatomy and physiology of the skin has improved, this has facilitated the development of technologies to effectively and quantitatively deliver solutes across this barrier to specific target sites in the skin and beyond. We focus on these technologies and their role in skin delivery today and in the future.
Publisher: Wiley
Date: 05-04-2012
Publisher: Elsevier BV
Date: 04-1996
Publisher: Elsevier BV
Date: 02-2001
DOI: 10.1016/S0895-4356(00)00282-1
Abstract: Medication data retrieved from Australian Repatriation Pharmaceutical Benefits Scheme (RPBS) claims for 44 veterans residing in nursing homes and Pharmaceutical Benefits Scheme (PBS) claims for 898 nursing home residents were compared with medication data from nursing home records to determine the optimal time interval for retrieving claims data and its validity. Optimal matching was achieved using 12 weeks of RPBS claims data, with 60% of medications in the RPBS claims located in nursing home administration records, and 78% of medications administered to nursing home residents identified in RPBS claims. In comparison, 48% of medications administered to nursing home residents could be found in 12 weeks of PBS data, and 56% of medications present in PBS claims could be matched with nursing home administration records. RPBS claims data was superior to PBS, due to the larger number of scheduled items available to veterans and the veteran's file number, which acts as a unique identifier. These findings should be taken into account when using prescription claims data for medication histories, prescriber feedback, drug utilisation, intervention or epidemiological studies.
Publisher: Elsevier BV
Date: 04-1998
DOI: 10.1016/S0021-9975(05)80128-8
Abstract: The morphological and functional characteristics of stingray liver were studied, including the effect of ischaemia/reperfusion. With an isolated perfused model, it was shown that the stingray liver was more resistant than the rat liver to ischaemia/reperfusion injury this was consistent with the differing partial oxygen tensions usually present in the two species. This study confirmed that whereas stingray hepatocytes form tubules with central bile canaliculi as in other fish, the stingray liver has portal triads and a lobular architecture as in mammals. Apoptosis of hepatocytes, demonstrated in the normal liver, was only marginally enhanced by ischaemia/reperfusion. Resulting apoptotic bodies were phagocytized by macrophage-like cells in hepatocyte tubules. In contrast to rat liver, the stingray liver showed no necrosis after ischaemia-reperfusion.
Publisher: American Society for Microbiology
Date: 12-2009
DOI: 10.1128/AAC.01600-08
Abstract: Cephalothin (cefalotin) pharmacokinetics were evaluated for nine severely burned patients (42% ± 9% mean burn areas) and five healthy volunteers by using non-plasma-protein-bound concentration-time profiles. Burn patients gave increased mean residence times (36%) and reduced total clearances (25%). Mean residence times and distribution volumes increased between 1 and 4 days posttrauma, suggesting that burn patient pharmacokinetics change during the initial fluid resuscitation phase of treatment.
Publisher: Elsevier BV
Date: 03-2020
Publisher: Springer Science and Business Media LLC
Date: 1986
DOI: 10.1007/BF00608225
Abstract: Recent research has shown the importance of networks in the spread of obesity. Yet, the translation of research on social networks and obesity into health promotion practice has been slow. To review the types of obesity interventions targeting social relational factors. Six databases were searched in January 2013. A Boolean search was employed with the following sets of terms: (1) social dimensions: social capital, cohesion, collective efficacy, support, social networks, or trust (2) intervention type: intervention, experiment, program, trial, or policy and (3) obesity in the title or abstract. Titles and abstracts were reviewed. Articles were included if they described an obesity intervention with the social relational component central. Articles were assessed on the social relational factor(s) addressed, social ecological level(s) targeted, the intervention's theoretical approach, and the conceptual placement of the social relational component in the intervention. Database searches and final article screening yielded 30 articles. Findings suggested that (1) social support was most often targeted (2) few interventions were beyond the in idual level (3) most interventions were framed on behaviour change theories and (4) the social relational component tended to be conceptually ancillary to the intervention. Theoretically and practically, social networks remain marginal to current interventions addressing obesity.
Publisher: Bentham Science Publishers Ltd.
Date: 2008
DOI: 10.2174/138920008783331103
Abstract: The in vivo hepatic clearance of tanshinone IIA in the rat was predicted using microsome, cytosol and S9 fractions combined with two different cofactor systems, NADPH-regenerating and UDPGA system. Two different models, the well stirred model and the parallel-tube model, were used in predicting the in vivo clearance in the rat. The in vivo clearance of tanshinone IIA was acquired from a pharmacokinetic study in rat. The results show that the prediction accuracy acquired from the microsome combined with the NADPH is poor. The in vivo clearance in the rat is almost 32 fold higher than the clearance predicted in microsome. The predicted clearance of the S9 model combined with both NADPH and UDPGA system is about 4 fold lower than the in vivo clearance. The predicted clearance of the cytosol combined with the two cofactor system is about 7 fold lower than the in vivo clearance. Although the prediction accuracy acquired from the S9 and cytosol system is not perfect, the prediction accuracy is improved in these two incubation systems. Using S9 combined with both the phase I and phase II metabolism can improve the prediction accuracy.
Publisher: Elsevier BV
Date: 06-1987
DOI: 10.1016/S0022-5193(87)80152-2
Abstract: Two models of hepatic elimination, the distributed sinusoidal perfusion model, and the convection-dispersion model, are extended and then compared for first order kinetics in the steady-state. The sinusoidal perfusion model is extended by the inclusion of intrahepatic sites of mixing between sinusoids. The degree of such mixing is estimated for taurocholate elimination by isolated perfused rat livers by a comparison of anatomical and kinetic estimates of uptake heterogeneity, using previously published data. The dispersion model is generalized by the inclusion of distributions of enzyme activity along the flow. Direct comparison of the two models in the limit in which the degree of dispersion is small, allows the flow-dependence of the dispersion coefficient to be determined, thereby greatly extending the explanatory power of the convection-dispersion model. Finally, the effect of intrahepatic mixing sites on uptake by Michaelis-Menten kinetics is quantified in terms of the distributed sinusoidal perfusion model, with results which may be applicable to capillary beds in general.
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1016/J.CCA.2009.12.009
Abstract: Whilst it is formally stated that cardiac troponin is only released when cardiac myocytes undergo necrosis, there are a number of clinical situations where troponin is present in the circulation, without any apparent cardiac injury. In these cases, troponin half-life in the circulation is usually substantially shorter than that seen when troponin is released following myocardial infarction with frank necrosis. A mechanism has been described in liver, where large cytoplasmic molecules can pass from the intra- to extra-cellular space without cellular necrosis occurring. This occurs by the formation of membranous blebs which bud off from the plasma membrane of the cell. Blebs develop during cellular ischemia. If the ischemia is limited and re-oxygenation occurs, the blebs may be released into the circulation without rupture of the plasma membrane, resulting in a one-off release of cytoplasmic contents including macromolecules. Evidence from cardiac studies is presented supporting the presence of membranous blebs in cardiac myocytes, enabling troponin to be released from cardiac cells due to ischemia alone, without necrosis.
Publisher: Springer Science and Business Media LLC
Date: 2000
Abstract: To develop a viable, single pass rat head perfusion model useful for pharmacokinetic studies. A viable rat head preparation, perfused with MOPS-buffered Ringer's solution, was developed. Radiolabelled markers (red blood cells, water and sucrose) were injected in a bolus into the internal carotid artery and collected from the posterior facial vein over 28 minutes. The double inverse Gaussian function was used to estimate the statistical moments of the markers. The viability of the perfusion was up to one hour, with optimal perfusate being 2% bovine serum albumin at 37 degrees C, pH 7.4. The distribution volumes for red blood cells, sucrose and water (from all studies, n = 18) were 1.0 +/- 0.3 ml, 6.4 +/- 4.2 ml and 18.3 +/- 11.9 ml, respectively. A high normalised variance for red blood cells (3.1 +/- 2.0) suggests a marked vascular heterogeneity. A higher normalised variance for water (6.4 +/- 3.3) is consistent with additional diffusive ermeability limitations. Analysis of the physiological parameters derived from the moments suggested that the kinetics of the markers were consistent with distribution throughout the head (weight 25 g) rather than just the brain (weight 2 g). This model should assist in studying solute pharmacokinetics in the head.
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.VIROL.2010.07.046
Abstract: Information about serostability of cutaneous HPV types over time is very limited. We investigated seroprevalence and serostability of 37 different HPV types over 4½ years in an Australian population-based study. Sera and data were analyzed for 390 people who had never been diagnosed with SCC and had blood collected in 1992, 1993 and 1996. Eighty-six percent of participants were seropositive to at least one of the 37 HPV types at baseline. HPV-4 was the type with the highest seroprevalence (41%), followed by HPV-38 and HPV-8 (both 33%). Over 90% of people retained their baseline serostatus during the 4½ year follow-up. Highest serostability was observed for HPV-88 (99.7% stayed seropositive or seronegative), while HPV-65 was least stable with 17% altering their serostatus during follow-up. Seroprevalence to cutaneous HPV types are relatively stable over time, and a single measure can be used as a reasonable marker of long-term antibody status.
Publisher: Elsevier BV
Date: 12-2009
Publisher: Springer International Publishing
Date: 2015
Publisher: Elsevier BV
Date: 12-2000
DOI: 10.1002/1520-6017(200012)89:12<1579::AID-JPS8>3.0.CO;2-Y
Abstract: The convection-dispersion model and its extended form have been used to describe solute disposition in organs and to predict hepatic availabilities. A range of empirical transit-time density functions has also been used for a similar purpose. The use of the dispersion model with mixed boundary conditions and transit-time density functions has been queried recently by Hisaka and Sugiyama in this journal. We suggest that, consistent with soil science and chemical engineering literature, the mixed boundary conditions are appropriate providing concentrations are defined in terms of flux to ensure continuity at the boundaries and mass balance. It is suggested that the use of the inverse Gaussian or other functions as empirical transit-time densities is independent of any boundary condition consideration. The mixed boundary condition solutions of the convection-dispersion model are the easiest to use when linear kinetics applies. In contrast, the closed conditions are easier to apply in a numerical analysis of nonlinear disposition of solutes in organs. We therefore argue that the use of hepatic elimination models should be based on pragmatic considerations, giving emphasis to using the simplest or easiest solution that will give a sufficiently accurate prediction of hepatic pharmacokinetics for a particular application.
Publisher: Springer Science and Business Media LLC
Date: 11-04-2022
DOI: 10.1007/S11095-022-03245-7
Abstract: The quality testing and approval procedure for most pharmaceutical products is a streamlined process with standardized procedures for the determination of critical quality attributes. However, the evaluation of semisolid dosage forms for topical drug delivery remains a challenging task. The work presented here highlights confocal Raman microscopy (CRM) as a valuable tool for the characterization of such products. CRM, a laser-based method, combining chemically-selective analysis and high resolution imaging, is used for the evaluation of different commercially available topical acyclovir creams. We show that CRM enables the spatially resolved analysis of microstructural features of semisolid products and provides insights into drug distribution and polymorphic state as well as the composition and arrangement of excipients. Further, we explore how CRM can be used to monitor phase separation and to study skin penetration and the interaction with fresh and cryopreserved excised human skin tissue. This study presents a comprehensive overview and illustration of how CRM can facilitate several types of key analyses of semisolid topical formulations and of their interaction with their biological target site, illustrating that CRM is a useful tool for research, development as well as for quality testing in the pharmaceutical industry.
Publisher: Oxford University Press (OUP)
Date: 07-05-2015
DOI: 10.1093/JAC/DKV123
Abstract: The objectives of this study were to describe piperacillin exposure in febrile neutropenia patients and determine whether therapeutic drug monitoring (TDM) can be used to increase the achievement of pharmacokinetic (PK) harmacodynamic (PD) targets. In a prospective randomized controlled study (Australian New Zealand Registry, ACTRN12615000086561), patients were subjected to TDM for 3 consecutive days. Dose was adjusted in the intervention group to achieve a free drug concentration above the MIC for 100% of the dose interval (100% fT& MIC), which was also the primary outcome measure. The secondary PK/PD target was 50% fT& MIC. Duration of fever and days to recovery from neutropenia were recorded. Thirty-two patients were enrolled. Initially, patients received 4.5 g of piperacillin/tazobactam every 8 h or every 6 h along with gentamicin co-therapy in 30/32 (94%) patients. At the first TDM, 7/32 (22%) patients achieved 100% fT& MIC and 12/32 (38%) patients achieved 50% fT& MIC. Following dose adjustment, 11/16 (69%) of intervention patients versus 3/16 (19%) of control patients (P = 0.012) attained 100% fT& MIC, and 15/16 (94%) of intervention patients versus 5/16 (31%) of control patients (P = 0.001) achieved 50% fT& MIC. After the third TDM, the proportion of patients attaining 100% fT& MIC improved from a baseline 3/16 (19%) to 11/15 (73%) in the intervention group, while it declined from 4/16 (25%) to 1/15 (7%) in the control group. No difference was noted in the duration of fever and days to recovery from neutropenia. Conventional doses of piperacillin/tazobactam may not offer adequate piperacillin exposure in febrile neutropenic patients. TDM provides useful feedback of dosing adequacy to guide dose optimization.
Publisher: Informa UK Limited
Date: 04-2012
DOI: 10.3109/17435390.2011.569092
Abstract: Systematic studies probing the effects of nanoparticle surface modification and formulation pH are important in nanotoxicology and nanomedicine. In this study, we use laser-scanning fluorescence confocal microscopy to evaluate nanoparticle penetration in viable excised human skin that was intact or tape-stripped. Quantum dot (QD) fluorescent nanoparticles with three surface modifications: Polyethylene glycol (PEG), PEG-amine (PEG-NH₂) and PEG-carboxyl (PEG-COOH) were evaluated for human skin penetration from aqueous solutions at pH 7.0 and at pHs of solutions provided by the QD manufacturer: 8.3 (PEG, PEG-NH₂) and 9.0 (PEG-COOH). There was some penetration into intact viable epidermis of skin for the PEG-QD at pH 8.3, but not at pH 7.0 nor for any other QD at the pHs used. Upon tape stripping 30 strips of stratum corneum, all QDs penetrated through the viable epidermis and into the upper dermis within 24 h.
Publisher: American Geophysical Union (AGU)
Date: 06-1996
DOI: 10.1021/JS9500621
Publisher: Elsevier BV
Date: 08-2008
DOI: 10.1016/J.EJPS.2008.05.007
Abstract: Although the organic anion transporter Oatp2 plays a critical role in determining the hepatic clearance of some drugs, little quantitative information exists about its functional characteristics in relation to inhibition of sinusoidal drug uptake. We investigated the uptake kinetics of the Oatp2 substrate digoxin in the isolated perfused rat liver. In the single-pass perfused liver three consecutive digoxin doses of 15, 30 and 45 micorg were administered in the presence or absence of rif icin (100 micorM), an inhibitor of Oatp2. Digoxin was determined in the outflow s les by HPLC and all data were analyzed by simultaneous nonlinear regression assuming a Michaelis-Menten uptake mechanism. Hepatocellular uptake of digoxin was concentration-dependent with a Michaelis constant (K(M)) of 577.8 ng/ml. Rif icin significantly reduced uptake (K(M) increased 2.5-fold) without affecting other parameters.
Publisher: Elsevier BV
Date: 29-12-1995
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.IJPHARM.2022.122114
Abstract: This study examined a number of factors that can impact the outcomes of in vitro human epidermal permeation coefficients for aliphatic alcohols and steroids, including receptor phase composition and study conditions. We determined experimentally the solubilities and IVPT permeation of a homologous series of
Publisher: Informa UK Limited
Date: 02-06-2016
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1016/J.IJANTIMICAG.2009.10.008
Abstract: The objectives of this study were (i) to compare the plasma concentration-time profiles for first-dose and steady-state piperacillin administered by intermittent or continuous dosing to critically ill patients with sepsis and (ii) to use population pharmacokinetics to perform Monte Carlo dosing simulations in order to assess the probability of target attainment (PTA) by minimum inhibitory concentration (MIC) for different piperacillin dosing regimens against bacterial pathogens commonly encountered in critical care units. Plasma s les were collected on Days 1 and 2 of therapy in 16 critically ill patients, with 8 patients receiving intermittent bolus dosing and 8 patients receiving continuous infusion of piperacillin (administered with tazobactam). A population pharmacokinetic model was developed using NONMEM, which found that a two-compartment population pharmacokinetic model best described the data. Total body weight was found to be correlated with drug clearance and was included in the final model. In addition, 2000 critically ill patients were simulated for pharmacodynamic evaluation of PTA by MIC [free (unbound) concentration maintained above the MIC for 50% of the dosing interval (50% f(T>MIC))] and it was found that continuous infusion maintained superior free piperacillin concentrations compared with bolus administration across the dosing interval. Dosing simulations showed that administration of 16g/day by continuous infusion vs. bolus dosing (4g every 6h) provided superior achievement of the pharmacodynamic endpoint (PTA by MIC) at 93% and 53%, respectively. These data suggest that administration of piperacillin by continuous infusion, with a loading dose, both for first dose and for subsequent dosing achieves superior pharmacodynamic targets compared with conventional bolus dosing.
Publisher: Springer Science and Business Media LLC
Date: 04-2005
DOI: 10.1007/S10620-005-2567-Z
Abstract: The effects of a Chinese snake venom preparation from Agkistrodon halys pallas, used for treatment of hepatic fibrosis/cirrhosis in China, was investigated in an in vivo rat model and using in situ hepatic perfusion. Four groups were used in the experiments: (i) healthy, (ii) healthy/venom-treated, (iii) carbon tetrachloride (CCl4)-treated, and (iv) CCl4/venom-treated. Treatment effects were assessed by determining hepatic histopathology, biochemistry and fibrosis index parameters, bile production, biliary taurocholate recovery, hepatic mRNA expression of four bile salt transporters (Ntcp, Bsep, Oatp-1, and Oatp-3), comparison of hepatic microcirculation, fibrinolytic activity, and antithrombotic effects. Liver histopathology, biochemistry, and fibrosis index showed a dramatic improvement in venom-treated animals. There were significant differences in bile production between healthy/venom-treated and all other experimental groups and between CCl4/venom-treated and CCl4-treated animals, but no significant differences were found between CCl4/venom-treated and healthy animals. Biliary taurocholate recovery was significantly increased in healthy/venom-treated and CCl4/venom-treated animals. The expression of mRNA levels of the four bile salt transporters showed an increase after venom treatment. The hepatic microcirculation studies showed normalized sinusoidal beds in CCl4/venom-treated animals compared to healthy animals, whereas CCl4-treated animals showed abnormal profiles to the healthy and the CCl4/AHPV-treated animals. The fibrinogen and plasma thromboxane B2 levels of healthy rats decreased with increasing dose after venom treatment. It was concluded that snake venom treatment may be therapeutic in treatment of hepatic fibrosis/cirrhosis by possibly a combination of increased bile flow and improved hepatic microcirculation, changes in bile salt transporter expression, and fibrinolytic and antithrombotic effects of the snake venom preparation.
Publisher: Wiley
Date: 23-07-2010
DOI: 10.1111/J.1440-1681.2010.05434.X
Abstract: 1. The present study sought to explain the mechanism leading to reduced availability of propranolol when given after a priming dose in the single-pass perfused rat liver. 2. Extracellular sucrose space (as a measure of sinusoidal relaxation) in perfused rat liver before and after propranolol or propranolol and N(G)-nitro-L-arginine methyl ester (L-NAME nitric oxide (NO) synthase inhibitor) treatment were examined. The results showed that propranolol induces sinusoidal relaxation in the perfused liver and this effect could be abolished by NO synthase inhibitor L-NAME. 3. Two bolus injections of propranolol were given to the isolated perfused rat liver and outflow concentration-time profiles of intact propranolol were determined. A two-phase physiologically based organ pharmacokinetic model was applied to estimate hepatocellular influx, efflux, binding, ion-trapping and metabolic elimination pharmacokinetic parameters for propranolol. The recovery of propranolol in the second injection was approximately 54% of that in the first injection. The permeability-surface area product, the binding and the intrinsic clearance all increased significantly after prior exposure of the rat liver to the first bolus of propranolol (P < 0.05). 4. Based on the findings of the present study, we propose that the most likely explanation for the reduced availability of a second propranolol dose (after administration of a priming dose) in the perfused liver is a consequence of the NO-mediated sinusoidal relaxation effect of propranolol, arising from the priming dose. This observation supports the view that the pharmacokinetics of some drugs might be altered by the pharmacodynamic effects of the same drug given earlier in the perfused liver.
Publisher: Elsevier BV
Date: 12-1985
Publisher: Elsevier BV
Date: 06-2008
Publisher: Informa UK Limited
Date: 07-04-2015
DOI: 10.3109/15563650.2015.1030025
Abstract: We report a fatal case of a 37 year old gentleman who ingested a MCPA/bromoxynil co-formulation herbicide. Although clinically well on initial examination, our patient declined dramatically over his 18 h admission with increasing CO2 production, hyperthermia and metabolic derangement to eventually die from cardiac asystole 20 h post ingestion. Two hours after ingestion the MCPA concentration was 83.9 μg/mL and bromoxynil concentration was 137 μg/mL. The patients' mechanism of death appeared to be uncoupling of oxidative phosphorylation, excess CO2 production and hyperthermia. There is limited knowledge on the acute toxicity of these herbicides, in particular bromoxynil, and this case highlights the relentless progression of severe toxicity in humans.
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.IJPHARM.2011.02.023
Abstract: Mathematical models of skin permeability play an important role in various fields including prediction of transdermal drug delivery and assessment of dermal exposure to industrial chemicals. Extensive research has been performed over the last several decades to yield predictions of skin permeability to various molecules. These efforts include the development of empirical approaches such as quantitative structure-permeability relationships and porous pathway theories as well as the establishment of rigorous structure-based models. In addition to establishing the necessary mathematical framework to describe these models, efforts have also been dedicated to determining the key parameters that are required to use these models. This article provides an overview of various modeling approaches with respect to their advantages, limitations and future prospects.
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.ADDR.2014.10.004
Abstract: Skin offers easy access, convenience and non-invasiveness for drug delivery and diagnosis. In principle, these advantages of skin appear to be attractive for critically ill patients given potential difficulties that may be associated with oral and parenteral access in these patients. However, the profound changes in skin physiology that can be seen in these patients provide a challenge to reliably deliver drugs or provide diagnostic information. Drug delivery through skin may be used to manage burn injury, wounds, infection, trauma and the multisystem complications that rise from these conditions. Local anaesthetics and analgesics can be delivered through skin and may have wide application in critically ill patients. To ensure accurate information, diagnostic tools require validation in the critically ill patient population as information from other patient populations may not be applicable.
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.IJANTIMICAG.2011.07.013
Abstract: The prevalence of invasive fungal infections (IFIs) caused by Candida spp. is increasing in critically ill patients. Recent development of new antifungal agents has significantly contributed to the successful treatment of IFIs. However, the pharmacokinetics of antifungal agents can be altered in a number of disease states, including critical illness. Therefore, doses established in healthy volunteers and other patient groups may not be appropriate for the critically ill. Moreover, inadequate dosing may contribute to treatment failure and the emergence of resistance. This systematic review provides a critical analysis of the pharmacokinetics of antifungal agents in the critically ill and their relevance to dosing requirements in clinical practice. Based on the limited data available, dosing of some antifungal agents may have to be adjusted in critically ill patients with conserved renal function as well as in those requiring renal replacement therapy. Further research to confirm the appropriateness of current dosing strategies to attain the appropriate pharmacodynamic targets is recommended.
Publisher: American Geophysical Union (AGU)
Date: 11-1999
DOI: 10.1021/JS990053I
Abstract: A diffusion model for the percutaneous absorption of a solute through the skin is developed for the specific case of a constant donor concentration with a finite removal rate from the receptor due to either perfusion rate or s ling. The model has been developed to include a viable epidermal resistance and a donor-stratum corneum interfacial resistance. Numerical inversion of the Laplace domain solutions were used for simulations of solute flux and cumulative amount absorbed and to model specific ex les of percutaneous absorption. Limits of the Laplace domain solutions were used to define the steady-state flux, lag time, and receptor concentration. Steady-state approximations obtained from the solutions were used to relate the steady-state flux and the effective permeability coefficient to the viable epidermis resistance, a donor-stratum corneum interfacial resistance, receptor removal rate, and partitioning between the receptor and donor phases. The lag time was shown to be dependent on these parameters and on the volume of the receptor phase. It is concluded that curvilinear cumulative amount and flux-time profiles are dependent on the processes affecting percutaneous absorption, the shapes of the profiles reflecting the processes most determining transport.
Publisher: Informa UK Limited
Date: 1993
DOI: 10.3109/15563659309000391
Abstract: Knowledge of the kinetics of an intoxicant is required for designing potential therapies in poisoned patients. In the case of paraquat, elucidating the kinetics has been made difficult by the paraquat-induced renal failure and the consequent dose- and time-dependent elimination of the herbicide. In the current study, we have modelled the plasma and urinary concentrations of paraquat in dogs given a toxic dose, the elimination of which was nonlinear. This enabled us, in turn, to simulate the apparent concentrations of paraquat in the deep tissue compartment, part of which is constituted by the major target organ for paraquat toxicity, the lung. Finally, we defined conditions, if any, under which charcoal hemoperfusion could reduce exposure of the deep compartment to paraquat by > or = 25%. We found that the plasma concentrations of paraquat could be described by a two compartment model with non-linear elimination from the central compartment. Use of a three compartment model did not improve the fit over that for a two compartment. The volume of distribution of paraquat at steady state approximated that of total body water. Simulated hemoperfusion performed for eight or eighty hours did not reduce exposure of the deep compartment to paraquat by > or = 25%, unless begun at times < or = two hours of the infusion commencing. This is consistent with our experimental data in the dog. The lack of efficacy of hemoperfusion is due to the rapid renal elimination of most of the absorbed dose of paraquat over the first 12 hours after its administration, and the later limitation of the rate of removal of paraquat from the body by the slow efflux rate from the deep to central compartment.
Publisher: American Chemical Society (ACS)
Date: 07-01-2019
Publisher: Wiley
Date: 19-09-2014
DOI: 10.1111/BCP.12386
Publisher: SPIE-Intl Soc Optical Eng
Date: 14-01-2020
Publisher: Elsevier BV
Date: 2000
DOI: 10.1002/(SICI)1520-6017(200001)89:1<144::AID-JPS14>3.0.CO;2-U
Publisher: Wiley
Date: 19-09-2014
DOI: 10.1111/BCP.12389
Publisher: Wiley
Date: 2011
DOI: 10.1002/BIP.21520
Abstract: Poor skin permeability limits the application of peptides to the skin. Enhanced skin permeation could facilitate the development of new therapies for dermatologic and cosmeceutical applications. The aim of this study was to investigate the application of iontophoresis to the delivery of small peptide model compounds (5-aminolevulinic acid and L-alanine-L-tryptophan) across human skin. Under the conditions tested, iontophoresis increased the in vitro permeability coefficient of ALA.HCl across human epidermis from 7 X 10(-5) cm/h with passive diffusion to 110 x 10(-5) cm/h with iontophoresis. D-Glucose permeation elucidated the iontophoretic electrotransport of ALA.HCl to have contributions of both electrorepulsion and electroosmosis. The L-alanine-L-tryptophan permeability coefficient was increased from 1.5 x 10(-5) cm/h to 35 x 10(-5) cm/h with iontophoretic application. Iontophoretic delivery of the dipeptide increased markedly at lower pH because of an increase in electrorepulsive transport. The study demonstrates that iontophoresis can enhance epidermal permeation of a small peptide and peptide-like drug by up to 15- and 22-fold under the conditions tested.
Publisher: Wiley
Date: 26-08-2013
DOI: 10.1111/JGS.12418
Abstract: To capture people's attitudes, beliefs, and experiences regarding the number of medications they are taking and their feelings about stopping medications. Administration of a validated questionnaire. Multidisciplinary ambulatory consulting service at the Royal Adelaide Hospital. Participants were in iduals aged 18 and older (median 71.5) taking at least one regular prescription medication 100 participants completed all items of the questionnaire, 65 of whom were aged 65 and older. Participants were administered the 15-item Patients' Attitudes Towards Deprescribing (PATD) questionnaire. Participants were taking an average of 10 different prescription and nonprescription (including complementary), regular and as-needed medications. More than 60% felt that they were taking a "large number" of medications, and 92% stated that they would be willing to stop one or more of their current medications if possible. Number of regular medications, age, and number of medical conditions were not found to be correlated with willingness to stop a medication. The findings were similar in older and younger participants. This study has shown that a cohort of mostly older adults were largely accepting of a trial of cessation of medication(s) that their prescriber deemed to be no longer required. Because few factors were associated with willingness to cease medications, all patients should be in idually evaluated for deprescribing.
Publisher: Wiley
Date: 10-06-2011
Publisher: Elsevier BV
Date: 26-07-1996
Publisher: S. Karger AG
Date: 2007
DOI: 10.1159/000098701
Abstract: The extent to which topically applied solid nanoparticles can penetrate the stratum corneum and access the underlying viable epidermis and the rest of the body is a great potential safety concern. Therefore, human epidermal penetration of a novel, transparent, nanoparticulate zinc oxide sunscreen formulation was determined using Franz-type diffusion cells, 24-hour exposure and an electron microscopy to verify the location of nanoparticles in exposed membranes. Less than 0.03% of the applied zinc content penetrated the epidermis (not significantly more than the zinc detected in receptor phase following application of a placebo formulation). No particles could be detected in the lower stratum corneum or viable epidermis by electron microscopy, suggesting that minimal nanoparticle penetration occurs through the human epidermis.
Publisher: SPIE-Intl Soc Optical Eng
Date: 19-12-2012
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 10-06-2004
Publisher: Elsevier BV
Date: 08-2020
Publisher: American Society for Microbiology
Date: 11-2011
DOI: 10.1128/AAC.05033-11
Abstract: Surgical site infections are common, so effective antibiotic concentrations at the sites of infection, i.e., in the interstitial fluid (ISF), are required. The aim of this study was to evaluate contemporary perioperative prophylactic dosing of cefazolin by determining plasma and subcutaneous ISF concentrations in patients undergoing elective/semielective abdominal aortic aneurysm (AAA) open repair surgery. This was a prospective pharmacokinetic study in a tertiary referral hospital. Cefazolin (2 g) was administered as a 3-min slow bolus 30 min prior to incision in 12 enrolled patients undergoing elective/semielective AAA open repair surgery. Serial blood, urine, and ISF (via microdialysis) s les were collected and analyzed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Cardiac output was determined using pulse waveform contours with Vigileo. The recruited patients had a median (interquartile range) age of 70 (66 to 76) years and weight of 88 (81 to 95) kg. The median (interquartile range) terminal volume of distribution was 0.14 (0.11 to 0.15) liter/kg, total clearance was 0.05 (0.03 to 0.06) liter/h, and minimum observed unbound concentration was 5.7 (5.4 to 8.1) mg/liter. The penetration of unbound drug from plasma to ISF was 85% (78% to 106%). We found correlations present, albeit weak, between cefazolin clearance and cardiac output ( r 2 = 0.11) and urinary creatinine clearance ( r 2 = 0.12). In conclusion, we found that a single 2-g dose of cefazolin administered 30 min before incision provides plasma and ISF concentrations in excess of the likely MICs for susceptible pathogens in patients undergoing AAA open repair surgery.
Publisher: Springer Science and Business Media LLC
Date: 02-2005
DOI: 10.1007/S11010-005-5267-2
Abstract: Understanding the driving forces for the hepatic uptake of endogenous and exogenous substrates in isolated cells and organs is fundamental to describing the underlying hepatic physiology harmacology. In this study we investigated whether uptake of plasma protein-bound [3H]-palmitate across the hepatocyte wall is governed by the transmembrane electrical potential difference (PD). Uptake was studied in isolated hepatocytes and isolated perfused rat livers (IPL). Protein-binding and vasoactive properties of the different perfusates were determined using in vitro heptane/buffer partitioning studies and the multiple indicator dilution (MID) technique in the IPL, respectively. Altering hepatocyte PD by perfusate ion substitution resulted in either a substantial depolarization (-14 +/- 1 mV, n = 12, mean +/- S.E., substituting choline for Na+) or hyperpolarization (-46 +/- 3 mV, n = 12, mean +/- S.E., substituting nitrate for Cl-). Perfusate ion substitution also affected the equilibrium binding constant for the palmitate-albumin complex. IPL studies suggested that, other than with gluconate buffer, hepatic [3H]-palmitate extraction was not affected by the buffer used, implying PD was not a determinant of extraction. [3H]-Palmitate extraction was much lower (p < 0.05) when gluconate was substituted for Cl- ion. This work contrasts with that for the extraction of [3H]-alanine where hepatic extraction fraction was significantly reduced during depolarization. Changing the albumin concentration did not affect hepatocyte PD, and [3H]-palmitate clearance into isolated hepatocytes was not affected by the buffers used. MID studies with vascular and extravascular references revealed that, with the gluconate substituted buffer, the extravascular volume possibly increased the diffusional path length thus explaining reduced [3H]-palmitate extraction fraction in the IPL.
Publisher: Royal College of Psychiatrists
Date: 02-05-2018
DOI: 10.1192/BJP.2018.13
Abstract: There are no available medications for the management of alcohol dependence for patients with alcoholic liver disease (ALD). To conduct a multisite, double blind, placebo-controlled, randomised clinical trial of baclofen in the treatment of alcohol dependence, with or without liver disease (trial registration: ClinicalTrials.gov, NCT01711125). Patients ( n = 104) were randomised to placebo, baclofen 30 mg/day or 75 mg/day for 12 weeks. Primary outcomes included survival time to lapse (any drinking), relapse (≥5 drinks per day in men and ≥4 in women), and the composite outcome of drinks per drinking day, number of heavy drinking days, and percentage days abstinent. There was a significant effect of baclofen (composite groups) on time to lapse (χ 2 = 6.44, P .05, Cohen's d = 0.56) and relapse (χ 2 = 4.62, P .05, d = 0.52). A significant treatment effect of baclofen was observed for percentage days abstinent (placebo 43%, baclofen 30 mg 69%, baclofen 75 mg 65% P .05). There was one serious adverse event (overdose) directly related to medication (75 mg). Baclofen may be an effective treatment option for patients with ALD. However, given the profile of adverse events, the role for this medication might be best limited to specialist services. None.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 07-11-2014
Abstract: Ischemia-reperfusion injury, a common complication during liver surgery where steatotic livers are more prone to the injury, may become more prevalent in the growing obese population. This study characterizes liver morphology toward understanding changes in subcellular function in steatotic livers exposed to ischemia-reperfusion injury through quantitative description of fluorescein distribution obtained by minimally invasive in vivo multiphoton microscopy using a physiologic pharmacokinetic model. Rats were fed a high-fat diet for 7 days to induce liver steatosis. Partial ischemia was induced after reperfusion for 4 hours, when fluorescein (10 mg/kg) was injected intravenously. Liver images, bile, and blood were collected up to 180 minutes after injection. Ischemia-reperfusion injury was associated with an increase in alanine transaminase levels and apoptosis. In addition, steatosis featured lipid droplets and an increase in fluorescein-associated fluorescence observed in hepatocytes via multiphoton imaging. Analysis of the hepatic concentration-time profiles has suggested that the steatosis-induced increase in fluorescein-associated fluorescence mainly arises by inducing hepatic fluorescein metabolism. The combination of ischemia-reperfusion with steatosis exacerbates these effects further. This was confirmed by fluorescence lifetime imaging microscopy showing a decreased average fluorescence lifetime of the liver, which is indicative of an increased production of the metabolite. Our results show the potential of noninvasive dye imaging for improving our understanding of liver disease induced by subcellular changes in vivo, providing further quantitative measures of metabolic and biliary liver function, and hence extending the qualitative liver function tests now available.
Publisher: ALTEX Edition
Date: 2015
Abstract: Models of the outer epithelia of the human body - namely the skin, the intestine and the lung - have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-1994
DOI: 10.1097/00008390-199412000-00004
Abstract: Isolated limb perfusion with melphalan is a long-standing treatment for melanoma but the clinical conditions have not been subjected to a systematic evaluation. In order to establish optimal conditions for perfusion, three human melanoma cell lines were cultured with melphalan in vitro under conditions comparable to in vivo therapy. The most important findings were that: (a) 41.5 degrees C was synergistic for melphalan killing of three human melanoma cell lines (b) prolonging the treatment time beyond 1 h had little additional toxicity and (c) varying the initial pH of the culture medium had no effect. After 1 h of treatment, cells accumulated more melphalan at 41.5 degrees C than at 37 degrees C, relative to the extracellular concentration. A cell line (MM418) derived from a primary tumour was the most resistant of the three lines pigmented or non-pigmented sublines were equally resistant. The A2058 line showed the lowest level of synergism with hyperthermia, and displayed a marked plateau at 10% of controls in the dose-response for survival, yet no melphalan-resistant subpopulation could be isolated. The implications of this work are that (a) enhanced cellular uptake of melphalan may account for hyperthermic synergism of melphalan (b) varying conditions other than treatment time will be necessary to deal with the variation in resistance between tumours and (c) repeated cycles of treatment may be needed for phenotypes such as A2058 where melphalan resistance appears to be based on an epigenetic mechanism.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 20-04-2010
Abstract: Hepatic drug disposition is different in normal and diseased livers. Different disease types alter disposition differently. What are the responsible micromechanistic changes and how do they influence drug movement within the liver? We provide plausible, concrete answers for two compounds, diltiazem and sucrose, in normal livers and two different types of cirrhotic rat livers: chronic pretreatment of rats with carbon tetrachloride (CCl(4)) and alcohol caused different types of cirrhosis. We started with simulated disposition data from normal, multilevel, physiologically based, object-oriented, discrete event in silico livers (normal ISLs) that validated against diltiazem and sucrose disposition data from normal livers. We searched the parameter space of the mechanism and found three parameter vectors that enabled matching the three wet-lab data sets. They specified micromechanistic transformations that enabled converting the normal ISL into two different types of diseased ISLs. Disease caused lobular changes at three of six levels. The latter provided in silico disposition data that achieved a prespecified degree of validation against wet-lab data. The in silico transformations from normal to diseased ISLs stand as concrete theories for disease progression from the disposition perspective. We also developed and implemented methods to trace objects representing diltiazem and sucrose during disposition experiments. This allowed valuable insight into plausible disposition details in normal and diseased livers. We posit that changes in ISL micromechanistic details may have disease-causing counterparts.
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.JCONREL.2016.12.022
Abstract: The goal of topical and cutaneous delivery is to deliver therapeutic and other substances to a desired target site in the skin at appropriate doses to achieve a safe and efficacious outcome. Normally, however, when the stratum corneum is intact and the skin barrier is uncompromised, this is limited to molecules that are relatively lipophilic, small and uncharged, thereby excluding many potentially useful therapeutic peptides, proteins, vaccines, gene fragments or drug-carrying particles. In this review we will describe how nanosystems are being increasingly exploited for topical and cutaneous delivery, particularly for these previously difficult substances. This is also being driven by the development of novel technologies, which include minimally invasive delivery systems and more precise fabrication techniques. While there is a vast array of nanosystems under development and many undergoing advanced clinical trials, relatively few have achieved full translation to clinical practice. This slow uptake may be due, in part, to the need for a rigorous demonstration of safety in these new nanotechnologies. Some of the safety aspects associated with nanosystems will be considered in this review.
Publisher: Elsevier BV
Date: 03-1994
Abstract: The anodal iontophoretic transdermal delivery of a model cation, phenylethylamine (PEA), across excised human skin was investigated to define the role of conductivity in iontophoresis. The ratio of the specific conductance of PEA in deionized-distilled water to that of the solution applied in the donor compartment (buffer+PEA) was employed to assess the relationship between the flux of PEA and the conductivity. The flux of PEA was linearly related to the ratio of specific conductance at 5 and 20 mM PEA for a variety of experimental conditions. A curvilinear relationship was observed at 1 mM PEA concentration, particularly when the conductivity of the donor solution was low. It is therefore hypothesized that a threshold conductivity in solution exists above which a linear relationship between iontophoretic flux and specific conductance is observed. The present study confirms that conductivity of an ion in a solution provides a simple means of estimating the competitive transport between solute and other ions during transdermal iontophoresis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2005
DOI: 10.1002/HEP.20857
Abstract: Liver fatty acid binding protein (L-FABP) contains amino acids that are known to possess antioxidant function. In this study, we tested the hypothesis that L-FABP may serve as an effective endogenous cytoprotectant against oxidative stress. Chang liver cells were selected as the experimental model because of their undetectable L-FABP mRNA level. Full-length L-FABP cDNA was subcloned into the mammalian expression vector pcDNA3.1 (pcDNA-FABP). Chang cells were stably transfected with pc-DNA-FABP or vector (pcDNA3.1) alone. Oxidative stress was induced by incubating cells with 400 micromol/L H2O2 or by subjecting cells to hypoxia/reoxygenation. Total cellular reactive oxygen species (ROS) was determined using the fluorescent probe DCF. Cellular damage induced by hypoxia/reoxygenation was assayed by lactate dehydrogenase (LDH) release. Expression of L-FABP was documented by regular reverse transcription polymerase chain reaction (RT-PCR), real-time RT-PCR, and Western blot. The pcDNA-FABP-transfected cells expressed full-length L-FABP mRNA, which was absent from vector-transfected control cells. Western blot showed expression of 14-kd L-FABP protein in pcDNA-FABP-transfected cells, but not in vector-transfected cells. Transfected cells showed decreased DCF fluorescence intensity under oxidative stress (H2O2 and hypoxia/reoxygenation) conditions versus control in inverse proportion to the level of L-FABP expression. Lower LDH release was observed in the higher L-FABP-expressed cells in hypoxia/reoxygenation experiments. In conclusion, we successfully transfected and cloned a Chang liver cell line that expressed the L-FABP gene. The L-FABP-expressing cell line had a reduced intracellular ROS level versus control. This finding implies that L-FABP has a significant role in oxidative stress.
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.EJPB.2013.01.020
Abstract: The use of nanoparticulate zinc oxide (ZnO-NP) in sunscreens and other cosmetic products has raised public health concerns. The two key issues are the extent of exposure to ZnO-NP and the likely hazard after the application of ZnO-NP in sunscreen and cosmetic products to humans in vivo. Our aims were to assess exposure by the extent of ZnO-NP penetration into the viable epidermis and hazard by changes in the viable epidermal redox state for a number of topical products. Of particular interest is the role of the particle coating, formulation used, and the presence of any enhancers. Multiphoton tomography with fluorescence lifetime imaging microscopy (MPT-FLIM) was used to simultaneously observe ZnO-NP penetration and potential metabolic changes within the viable epidermis of human volunteers after topical application of various ZnO-NP products. Coated and uncoated ZnO-NP remained in the superficial layers of the SC and in the skin furrows. We observed limited penetration of coated ZnO-NP dispersed in a water-in-oil emulsion formulation, which was predominantly localized adjacent to the skin furrow. However, the presence of ZnO-NP in the viable epidermis did not alter the metabolic state or morphology of the cells. In summary, our data suggest that some limited penetration of coated and uncoated ZnO-NP may occur into viable stratum granulosum epidermis adjacent to furrows, but that the extent is not sufficient to affect the redox state of those viable cells.
Publisher: Wiley
Date: 11-10-2011
Publisher: MDPI AG
Date: 27-08-2021
DOI: 10.3390/PHARMACEUTICS13091351
Abstract: Rheological characteristics and shear response have potential implication in defining the pharmaceutical equivalence, therapeutic equivalence, and perceptive equivalence of commercial topical products. Three creams (C1 and C3 as oil-in-water and C2 as water-in-oil emulsions), and two gels (G1 and G2 carbomer-based) were characterized using the dynamic range of controlled shear in steady-state flow and oscillatory modes. All products, other than C3, met the Critical Quality Attribute criteria for high zero-shear viscosity (η0) of 2.6 × 104 to 1.5 × 105 Pa∙s and yield stress (τ0) of 55 to 277 Pa. C3 exhibited a smaller linear viscoelastic region and lower η0 (2547 Pa∙s) and τ0 (2 Pa), consistent with lotion-like behavior. All dose forms showed viscoelastic solid behavior having a storage modulus (G′) higher than the loss modulus (G″) in the linear viscoelastic region. However, the transition of G′ G″ to G″ G′ during the continual strain increment was more rapid for the creams, elucidating a relatively brittle deformation, whereas these transitions in gels were more prolonged, consistent with a gradual disentanglement of the polymer network. In conclusion, these analyses not only ensure quality and stability, but also enable the microstructure to be characterized as being flexible (gels) or inelastic (creams).
Publisher: Springer Science and Business Media LLC
Date: 15-09-2016
DOI: 10.1208/S12248-016-9984-0
Abstract: We sought to understand when and how hydration enhances the percutaneous absorption of salicylate esters. Human epidermal membrane fluxes and stratum corneum solubilities of neat and diluted solutions of three esters were determined under hydrated and dehydrated conditions. Hydration doubled the human epidermal flux seen for methyl and ethyl salicylate under dehydrated conditions and increased the flux of neat glycol salicylate 10-fold. Mechanistic analyses showed that this hydration-induced enhancement arises mainly from an increase in the stratum corneum diffusivity of the three esters. Further, we showed that unlike methyl and ethyl salicylate, glycol salicylate is hygroscopic and the ∼10-fold hydration-induced flux enhancement seen with neat glycol salicylate may be due to its ability to hydrate the stratum corneum to a greater extent. The hydration-induced enhancements in in vitro epidermal flux seen here for glycol and ethyl salicylate were similar to those reported for their percutaneous absorption rates in a comparable in vivo study, whilst somewhat higher enhancement was seen for methyl salicylate in vivo. This may be explained by a physiologically induced self enhancement of neat methyl salicylate absorption in vivo which is not applicable in vitro.
Publisher: Oxford University Press (OUP)
Date: 09-03-2020
DOI: 10.1093/CID/CIAA224
Abstract: The optimal dosing of antibiotics in critically ill patients receiving renal replacement therapy (RRT) remains unclear. In this study, we describe the variability in RRT techniques and antibiotic dosing in critically ill patients receiving RRT and relate observed trough antibiotic concentrations to optimal targets. We performed a prospective, observational, multinational, pharmacokinetic study in 29 intensive care units from 14 countries. We collected demographic, clinical, and RRT data. We measured trough antibiotic concentrations of meropenem, piperacillin-tazobactam, and vancomycin and related them to high- and low-target trough concentrations. We studied 381 patients and obtained 508 trough antibiotic concentrations. There was wide variability (4–8-fold) in antibiotic dosing regimens, RRT prescription, and estimated endogenous renal function. The overall median estimated total renal clearance (eTRCL) was 50 mL/minute (interquartile range [IQR], 35–65) and higher eTRCL was associated with lower trough concentrations for all antibiotics (P & .05). The median (IQR) trough concentration for meropenem was 12.1 mg/L (7.9–18.8), piperacillin was 78.6 mg/L (49.5–127.3), tazobactam was 9.5 mg/L (6.3–14.2), and vancomycin was 14.3 mg/L (11.6–21.8). Trough concentrations failed to meet optimal higher limits in 26%, 36%, and 72% and optimal lower limits in 4%, 4%, and 55% of patients for meropenem, piperacillin, and vancomycin, respectively. In critically ill patients treated with RRT, antibiotic dosing regimens, RRT prescription, and eTRCL varied markedly and resulted in highly variable antibiotic concentrations that failed to meet therapeutic targets in many patients.
Publisher: Springer Science and Business Media LLC
Date: 05-06-2009
DOI: 10.1007/S11095-009-9912-4
Abstract: The maximum flux of solutes penetrating the epidermis has been known to depend predominantly on solute molecular weight. Here we sought to establish the mechanistic dependence of maximum flux on other solute physicochemical parameters. Maximum fluxes, stratum corneum solubilities and estimated diffusivities through human epidermis were therefore determined for 10 phenols with similar molecular weights and hydrogen bonding but varying in lipophilicity. Maximum flux and stratum corneum solubilities of the phenolic compounds both showed a bilinear dependence on octanol-water partition coefficient (P), with solutes having a maximum solubility in the stratum corneum when 2.7<log P<3.1. In contrast, lag times and diffusivities were relatively independent of P. Stratum corneum-water partition coefficients and epidermal permeability coefficients were consistent with previously reported data. A key finding is that the convex dependence of maximum flux on lipophilicity arises primarily from variations in stratum corneum solubility, and not from diffusional or partitioning barrier effects at the stratum corneum-viable epidermis interface for the more lipophilic phenols. Our data support a solute structure-skin transport model for aqueous solutions in which permeation rates depend on both partitioning and diffusivity: partitioning is related to P, and diffusivity to solute size and hydrogen bonding.
Publisher: American Society for Microbiology
Date: 06-2014
DOI: 10.1128/AAC.02340-14
Abstract: This study assessed the pharmacokinetics and dosing adequacy of piperacillin in febrile neutropenic patients after the first dose. Pharmacokinetic analysis was performed using noncompartmental methods. We observed an elevated volume of distribution (29.7 ± 8.0 liters [mean ± standard deviation]) and clearance (20.2 ± 7.5 liters/h) compared to data from other patient populations. Antibiotic exposure did not consistently result in therapeutic targets. We conclude that alternative dosing strategies guided by therapeutic drug monitoring may be required to optimize exposure.
Publisher: Elsevier BV
Date: 04-2003
DOI: 10.1046/J.1523-1747.2003.12083.X
Abstract: Based on the hypothesis that limited receptor solubility of lipophilic compounds may result in lower observed permeability parameters, the aim of this study was to determine the in vitro human epidermal permeability coefficients and membrane retention of a series of aliphatic alcohols (C1-C10, log p-0.72 to 4.06) using two different receptor solutions (water and 4% bovine serum albumin in phosphate-buffered saline). Aqueous solutions of radiolabeled alcohols were dosed into the stratum corneum side of membranes mounted in side-by-side glass diffusion cells. Appearance of alcohol in the receptor compartment filled with either of the two solutions was monitored over a 7 h period when both stratum corneum (assessed by tape stripping) and the remaining epidermis levels of radioactivity were determined. In a separate study the degree of binding of alcohols to 4% bovine serum albumin was determined. The data showed increased receptor phase solubility in the bovine serum albumin solution and higher permeability coefficients for the more lipophilic alcohols in the series. No changes were seen in the partitioning of the alcohols from the vehicle into either the stratum corneum or tape-stripped epidermis with the two receptor phases however, a decrease in the amount of the more lipophilic alcohols partitioning into the water receptor phase from the tape-stripped epidermis was observed. We conclude that bovine serum albumin receptor phase allows better estimation of real permeability parameters for lipophilic compounds due to its increased solubility capacity and we question whether permeability parameters for lipophilic solutes from older data sets based on aqueous receptor phases are completely reliable.
Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1002/JPS.21631
Publisher: Elsevier BV
Date: 02-2007
Abstract: The presence of surfactant proteins (SPs), critical to local barrier and defense functions and usually associated with the lung, was revealed in adult and fetal human skin complementary deoxyribonucleic acid, in skin s les from three adult female donors and also in cultured fibroblasts, keratinocytes, and melanocytes. Using reverse transcription-PCR, SP-A, SP-B, SP-C, and SP-D messenger ribonucleic acid expression was detected to varying extents in the different skin sources. The stronger expression of SP-C in fetal skin, compared to adult skin, suggested that the role of this protein alters with age. Immunohistochemical studies showed variable distribution of SPs in human epidermis and dermis, confirming that these proteins are indeed translated and expressed in skin tissue. In vitro studies showed that the surface tension of SP-deficient artificial sebum is (a) lowered by skin-extracted SP-B and (b) further reduced to a level comparable to normal sebum by the additional presence of skin-extracted SP-A and SP-D, consistent with their surface tension-lowering capabilities in lung. The possible roles of SPs in skin, based on their known functions in the lung are discussed. However, their potential as therapeutic targets or diagnostic markers of skin disease remains to be elucidated.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.ADDR.2018.09.003
Abstract: Both drug delivery performance and various age-related physical, mental and physiological changes can affect drug effectiveness and safety in elderly patients. The many drug delivery systems developed over the years include recent novel transdermal, nasal, pulmonary and orally disintegrating tablets that provide consistent, precise, timely and more targeted drug delivery. Certain drug delivery systems may be associated with suboptimal outcomes in the elderly because of the nature of drug present, a lack of appreciation of the impact of age-related changes in drug absorption, distribution and clearance, the limited availability of pharmacokinetic, safety and clinical data. Polypharmacy, patient morbidity and poor adherence can also contribute to sub-optimal drug delivery systems outcomes in the elderly. The development of drug delivery systems for the elderly is a poorly realised opportunity, with each system having specific advantages and limitations. A key challenge is to provide the innovation that best meets the specific physiological, psychological and multiple drug requirements of in idual elderly patients.
Publisher: Future Medicine Ltd
Date: 06-2021
Abstract: Although statins are effective in treating high cholesterol, adverse effects do occur with their use. Efficacy and tolerability vary among statins in different ethnic groups. Indigenous Australians have a high risk for cardiovascular and kidney diseases. Prescribing statins to Indigenous Australians with multi-morbidity requires different strategies to increase efficacy and reduce their toxicity. Previous studies have reported that Indigenous Australians are more susceptible to severe statin-induced myopathies. However, there is a lack of evidence in the underlying genetic factors in this population. This review aims to identify: inter-ethnic differences in the efficacy and safety of statins major contributing factors accounting for any identified differences and provide an overview of statin-induced adverse effects in Indigenous Australians.
Publisher: Elsevier BV
Date: 04-1999
DOI: 10.1016/S0168-3659(98)00172-2
Abstract: This study sought to examine the extent the ionic mobility-pore model, used to describe epidermal iontophoretic structure-permeability relationships, could describe a range of published iontophoretic data. The model incorporates, as determinants of iontophoretic transport, solute size, solute mobility, total current applied, presence of extraneous ions, determined by conductivities of both donor and receptor solutions, permselectivity of the epidermis, as well as a solute pore interaction term which together provided an excellent regression for iontophoretic permeability. The 'pore' radii for solute transport estimated from literature iontophoretic permeabilities using the model ranged from 6.8 to 17 A depending on the degree of hydration and conformation of solute assumed. The pore size range is consistent with transport through the polar intercellular and transappendageal pathway for transport. The pore restriction form of the model better describes the data obtained to date than other models described previously (Yoshida, N.H., Roberts, M.S., Solute molecular size and transdermal iontophoresis across excised human skin. J. Control. Release 25 (1993) 177-195).
Publisher: Elsevier BV
Date: 04-2020
Publisher: Springer Science and Business Media LLC
Date: 15-02-2022
Publisher: Wiley
Date: 12-2008
Abstract: Multiphoton tomography was used to examine xenobiotic transport in vivo. We used the photochemical properties of zinc oxide and fluorescein and multiphoton tomography to study their transport in the skin and in the rat liver in vivo. Zinc oxide nanoparticles were visualised in human skin using the photoluminescence properties of zinc oxide and either a selective emission wavelength band pass filter or a filter with fluorescence lifetime imaging (FLIM). Zinc oxide nanoparticles (30 nm) did not penetrate into human skin in vitro and in vivo and this was validated by scanning electron microscopy with X-ray photoelectron spectroscopy. Fluorescein was measured in the liver using FLIM. Fluorescein is rapidly extracted from the blood into the liver cells and then transported into the bile. It is suggested that multiphoton tomography may be of particular use in defining in vivo 4D (in both space and time) pharmacokinetics.
Publisher: American Thoracic Society
Date: 04-2013
Publisher: S. Karger AG
Date: 2006
DOI: 10.1159/000095254
Abstract: The skin localization of steroids following topical application is largely unknown. We determined the distribution of five steroids in human skin using excised epidermal, dermal, and full-thickness membranes in vitro. There was no significant difference in steroid maximum flux through epidermal and full-thickness membranes, other than significantly lower fluxes for the most polar steroid, aldosterone. Hydrocortisone had the highest dermal diffusivity and dermal penetration, and the accumulation of hydrocortisone and corticosterone was higher than that of the other steroids. Slower penetration and higher accumulation in the viable epidermis of progesterone in full-thickness skin were consistent with dermal penetration limitation effects associated with high lipophilicity.
Publisher: S. Karger AG
Date: 2019
DOI: 10.1159/000497225
Abstract: b i Background/Aims: /i /b The mechanisms by which permeation enhancers increase human skin permeation of caffeine and naproxen were assessed in vitro. b i Methods: /i /b Active compound solubility in the vehicles and in the stratum corneum (SC), active compound flux across epidermal membranes and uptake of active and vehicle components into the SC were measured. The effect of vehicle pH on the permeation of caffeine and naproxen was also determined. b i Results: /i /b Oleic acid and eucalyptol significantly enhanced the skin penetration of caffeine and naproxen, compared to aqueous controls. Naproxen permeation was increased from vehicles with pH presenting more ionized naproxen. Caffeine maximum flux enhancement was associated with an increase in caffeine SC solubility and skin diffusivity, whereas for naproxen a penetration enhancer/vehicle-induced increase in solubility in the SC correlated with an increase in maximum flux. SC solubility was related to experimentally determined active uptake, which was in turn predicted by vehicle uptake and active compound solubility in the vehicle. b i Conclusion: /i /b A permeation enhancer-induced alteration in diffusivity, rather than effects on SC solubility, was the main driving force behind increases in permeation flux of the hydrophilic molecule caffeine. For the more the lipophilic molecule naproxen, increased SC solubility drove the increases in permeation flux.
Publisher: Oxford University Press (OUP)
Date: 1998
Publisher: Springer Science and Business Media LLC
Date: 1999
Abstract: Many compounds are applied to the skin with the aim of targeting deeper underlying tissues. This work sought to define the pharmacokinetics of solutes in tissues below a topical application site in terms of perfusate binding, tissue binding and perfusate flow rate. The disposition kinetics of diclofenac in a single pass perfused limb preparation after dermal application disposition was studied using dextran and bovine serum albumin (BSA) containing perfusates. A pharmacokinetic model was then developed to relate the tissue retention half lives for diclofenac, diazepam, water, lignocaine and salicylate to their fraction unbound in the tissues, their fraction unbound in the perfusate and the perfusate flow rate. Diclofenac had estimated tissue retention half lives of 18.1 hr and 3.5 hr for the dextran and BSA containing perfusates, respectively. The fraction of diclofenac and other solutes unbound in the tissues correlated with their corresponding fraction unbound in the perfusate. The tissue retention half lives for diclofenac and other solutes could be described in terms of the fraction of solute unbound in the tissues and perfusate, together with the flow rate. The tissue pharmacokinetics of solutes below a topical application are a function of their binding in the tissues, binding in perfusate and local blood flow.
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.JCHROMB.2011.09.008
Abstract: Simple, sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods have been developed and validated for quantification of paraquat (PQ) in plasma and urine. Plasma and urine s le preparation were carried out by one-step protein precipitation using cold acetonitrile (-20 to -10 °C). After centrifugation, an aliquot of 10 μL of supernatant was injected into a Kinetex™ hydrophilic interaction chromatography (HILIC) column with a KrudKatcher™ Ultra in-line filter. The chromatographic separation was achieved using the mobile phase mixture of 250 mM ammonium formate (with 0.8% aqueous formic acid) in water and acetonitrile at a flow rate of 0.3 mL/min. Detection was performed using an API2000 triple quadrupole tandem mass spectrometer in multiple reaction monitoring (MRM) mode via an electrospray ionization (ESI) source. The calibration curve was linear over the concentration range of 10-5000 ng/mL, with an LLOQ of 10 ng/mL. The inter- and intra-day precision (% R.S.D.) were <8.5% and 6.4% for plasma and urine, respectively with the accuracies (%) within the range of 95.1-102.8%. PQ in plasma and urine s les was stable when stored at -70 °C for three freeze-thaw cycles. The methods were successfully applied to determine PQ concentration in rat and human s les.
Publisher: Elsevier BV
Date: 09-2009
Abstract: Diet is an important factor in colorectal carcinogenesis thus, dietary supplements may have a role in colorectal cancer prevention. The objective was to establish the relative luminal, epithelial, and epigenetic consequences of prebiotic, probiotic, and synbiotic dietary supplementation in humans. This was a randomized, double-blind, placebo-controlled, 4-wk crossover trial of resistant starch and Bifidobacterium lactis, either alone or as a combined synbiotic preparation, in 20 human volunteers. Rectal biopsy, feces, and serum s les were collected. The rectal mucosal endpoints were DNA methylation at 16 CpG island loci and LINE-1, epithelial proliferation (Ki67 immunohistochemistry), and crypt cellularity. The fecal endpoints were short-chain fatty acid concentrations, pH, ammonia, and microbiological profiles (by denaturing gradient gel electrophoresis and sequencing). Serum endpoints were a panel of cytokines and high-sensitivity C-reactive protein. Seventeen subjects completed the entire study. The synbiotic intervention fostered a significantly different fecal stream bacterial community than did either the prebiotic (P = 0.032) or the probiotic (P = 0.001) intervention alone, in part because of a greater proportion of patients harboring fecal Lachnospiraceae spp. These changes developed in the absence of any significant differences in fecal chemistry. There were no differences in epithelial kinetics. This synbiotic supplementation with B. lactis and resistant starch, in the doses used, induced unique changes in fecal microflora but did not significantly alter any other fecal, serum, or epithelial variables. This trial was registered in the Australian New Zealand Clinical Trials Registry at www.anzctr.org.au as ACTRN012606000115538.
Publisher: Wiley
Date: 11-2012
DOI: 10.1111/J.1549-8719.2012.00208.X
Abstract: Up to now, vascular indicator-dilution curves have been analyzed by numerical integration or by fitting empirical functions to the data. Here, we apply a recently developed mechanistic model with the goal to quantitatively describe flow distribution in the sinusoidal network of normal rat livers and those with high-fat emulsion-induced NASH. Single-pass outflow concentration data of sucrose were obtained from in situ perfused rat livers after impulse injection. The model fitted to the data consists of a continuous mixture of inverse Gaussian densities assuming a normal distribution of regional flow. It accounts for the fractal flow heterogeneity in the organ and has three adjustable parameters with a clear physiological interpretation. The model fitted the data well and revealed that the intrahepatic flow dispersion of 49.6 % in the control group increased significantly to 87.2 % in the NASH group (p < 0.01). In contrast to previously used empirical functions, the present model exhibits a power-law tail (~t(-2.4)), which is a signature of fractal microvascular networks. The approach offers the possibility to determine hepatic blood flow heterogeneity in perfused livers and to evaluate the functional implications.
Publisher: Wiley
Date: 23-02-2007
DOI: 10.1111/J.1440-1681.2007.04550.X
Abstract: 1. Ischaemia-reperfusion injury is known to be associated with a range of functional and structural alterations in the liver. However, the effect of this injury on drug disposition is not well understood. The present study was designed to examine the effects of hypoxia/reperfusion on the disposition of glutamate and propranolol in the rat isolated perfused liver. Both glutamate and propranolol are mainly metabolised in the pericentral region of the liver. 2. Hypoxia/reperfusion was established using the slow flow-reflow method of perfusion in both anterograde and retrograde perfusion. Glutamate metabolism was measured by the recovery of [(14)C]-glutamic acid and [(14)C]-labelled metabolites in a single pass in both anterograde and retrograde perfusion in the presence of a steady state concentration of unlabelled glutamic acid. Propranolol disposition, mean transit time and normalized variance were assessed from the outflow concentration-time profile of unchanged [(3)H]-propranolol determined after a bolus injection of [(3)H]-propranolol using HPLC and liquid scintillation counting. 3. Hypoxia/reperfusion of livers did not affect oxygen consumption, but caused significant changes in enzyme release, lignocaine hepatic availability and bile flow. 4. Hypoxia/reperfusion did not affect the hepatic metabolism of glutamate to carbon dioxide or the hepatic extraction of propranolol. Small but significant changes were evident in the distribution parameters of mean transit time and vascular disposition for the hypoxic-ischaemic liver. 5. It is concluded that reperfusion injury induced by slow flow-reflow perfusion did not influence the extraction of glutamate or propranolol, but may have affected pericentral morphology and solute distribution.
Publisher: Elsevier BV
Date: 10-2010
DOI: 10.1016/J.IJANTIMICAG.2010.06.008
Abstract: The extreme pharmacokinetic behaviour of drugs sometimes observed in critically ill patients poses a significant threat to the achievement of optimal antibiotic treatment outcomes. Scant information on beta-lactam antibiotic therapeutic drug monitoring (TDM) is available. The objective of this prospective study was to evaluate the practicality and utility of a beta-lactam TDM programme in critically ill patients. TDM was performed twice weekly on all eligible patients at a 30-bed tertiary referral critical care unit. Blood concentrations were determined by fast-throughput high-performance liquid chromatography (HPLC) assays and were available within 12h of s ling. Dose adjustment was instituted if the trough or steady-state blood concentration was below 4-5x the minimum inhibitory concentration (MIC) or above 10x MIC. A total of 236 patients were subject to TDM over an 11-month period. The mean+/-standard deviation age was 53.5+/-18.3 years. Dose adjustment was required in 175 (74.2%) of the patients, with 119 of these patients (50.4%) requiring dose increases after the first TDM. For outcome of therapy, 206 (87.3%) courses resulted in a positive treatment outcome and there were 30 (12.7%) treatment failures observed including 14 deaths and 15 courses requiring escalation to broader-spectrum agents 1 course was ceased due to an adverse drug reaction. Using binomial logistic regression, only an elevated Acute Physiology and Chronic Health Evaluation (APACHE) II score (P<0.01) and elevated plasma creatinine concentration (P=0.05) were found to be predictive of mortality. In conclusion, further research is required to determine definitively whether achievement of optimal beta-lactam pharmacodynamic targets improves clinical outcomes.
Publisher: Elsevier BV
Date: 1999
Publisher: Wiley
Date: 12-2004
Publisher: Informa UK Limited
Date: 07-05-2021
DOI: 10.1080/15563650.2021.1917596
Abstract: The clinical characteristics following self-poisoning with organophosphorus (OP) insecticides differs according to the insecticide ingested. Phenthoate is a dimethoxy WHO Hazard Class II OP pesticide with limited literature on its clinical characteristics and outcome. We aimed to better understand its clinical characteristics by studying patients with phenthoate self-poisoning in Sri Lanka. We conducted a prospective cohort study of patients presenting with phenthoate self-poisoning to eight hospitals in Sri Lanka between 2002 and 2018. Clinical outcomes were recorded for each patient. Blood s les for measuring plasma phenthoate concentration, cholinesterase activity, and response to oximes were available for a very small number of patients recruited to a clinical trial. Two hundred and ninety-two patients who ingested agricultural phenthoate formulations were included in the study. Median time to admission was 3.9 (IQR 2.4 - 6.8) h. Forty-two (14.4%) patients were intubated, mostly (30/37, 81%) within 24 h of ingestion (median time to intubation 7.2 [IQR 2.6-20.9] h). Median duration of intubation was 74.8 (IQR 26.8-232.5) h the longest duration in a survivor was 592 h. Nineteen died (case fatality 6.5%, 95% CI 4.0-10.0) median time to death was 37 (IQR 16 - 101.7) h. Median plasma phenthoate concentration in patients with s les ( Phenthoate self-poisoning has a 6.5% case fatality rate. Most patients who experience respiratory failure undergo early intubation most deaths occurred among those patients who were intubated less than 24 h after ingestion. There was a non-sustained increase in cholinesterase activity with pralidoxime, but further studies are required to analyse the extent to which oximes are clinically effective in phenthoate self-poisoning.
Publisher: Wiley
Date: 12-2010
Abstract: This article describes how a model-based analysis was used to aid development of a novel formulation technology. Paracetamol (acetaminophen) was used as the motivating ex le with 4 different formulations (2 developmental and 2 commercial) compared using stochastic (Monte Carlo) pharmacokinetic (PK)-pharmacodynamic (PD) simulations to explore potential differences in pharmacodynamic outcomes. PK models were developed from data collected during an intensively s led, 4-arm crossover trial in 25 fasted healthy subjects, administered 1 g of paracetamol in 4 different formulations. The PK models were linked to a previously published PD model that quantified pain relief over time following tonsillectomy. The number needed to treat (NNT) was the primary numeric used to compare effectiveness. The developmental formulations were likely to produce faster and greater analgesia with an NNT (compared with placebo) to reduce pain by 50% over a 45-minute interval post dose of 2.75 and 2.88 compared with 4.31 and 3.2 for the commercial products. Over the course of 1 hour, all formulations were comparable. The stochastic simulations provided support that the novel formulation technology was likely to provide a clinically meaningful advantage and should be developed further.
Publisher: Springer Science and Business Media LLC
Date: 09-1975
DOI: 10.1038/257225A0
Abstract: 1. Total, active and latent collagenase activities were determined by direct assay of tissue homogenates. 2. The rate of collagen breakdown during post-partum involution of the rat uterus is correlated with the total activity of collagenase. Both are low at parturition, reach a maximum within 24h and fall slowly to low values of 5 days post partum. This temporal correlation strongly supports the hypothesis that collagenase participates in collagen breakdown in vivo. 3. Further support for this hypothesis is provided by the finding that oestradiol-17 beta (100 micrograms/day, intraperitoneally injected), which inhibits the breakdown of collagen by 36% during the first 4 days of involution, produces a closely corresponding decrease in total collagenase activity. 3. The effect of oestradiol in lowering collagenase activity is not due to alterations in collagen substrate, collagenase kinetic behaviour or latent-to-active enzyme conversion. 4. Of the total assayable collagenase, about 35% is fully active and 65% is in a latent form. 5. About 70% of this latent form can be activated by a serine proteinase found, together with collagenase, in the insoluble fraction of uterine homogenates.
Publisher: Wiley
Date: 02-2004
DOI: 10.1111/J.1365-2885.2004.00547.X
Abstract: A model to investigate hepatic drug uptake and metabolism in the dog was developed for this study. Catheters were placed in the portal and hepatic veins during exploratory laparotomy to collect pre- and posthepatic blood s les at defined intervals. Drug concentrations in the portal vein were taken to reflect intestinal uptake and metabolism of an p.o. administered drug (propranolol), while differences in drug and metabolite concentrations between portal and hepatic veins reflected hepatic uptake and metabolism. A significant difference in propranolol concentration between hepatic and portal veins confirmed a high hepatic extraction of this therapeutic agent in the dog. This technically uncomplicated model may be used experimentally or clinically to determine hepatic function and metabolism of drugs that may be administered during anaesthesia and surgery.
Publisher: Hindawi Limited
Date: 10-2006
DOI: 10.1111/J.1365-2710.2006.00768.X
Abstract: Patients can have medication-related risk factors associated with poor health outcomes that become evident through visiting them in their homes. These medication-related risk factors may not be apparent in pharmacy and general practitioner (GP) records. The aim was to determine the prevalence and inter-relationships of medication-related risk factors for poor patient health outcomes identifiable through 'in-home' observations. The design was a cross-sectional study of 204 general practice patients living in their own homes and at risk of medication-related poor health outcomes. Medication-related risk factors were identified in the patients' homes by community pharmacists and GPs. The prevalence of risk factors varied from 8.3% (multiple medication storage locations) to 55.9% (confused by generic and trade names). There were many relationships observed between the medication-related risk factors, with expired medication having the most relationships with other risk factors followed by therapeutic duplication and poor adherence (9, 6 and 6 relationships respectively). Visiting patients' homes may identify medication-related risk factors not otherwise apparent through patient visits to the health practitioner when medications may be brought for review (i.e. 'brown bag' reviews).
Publisher: Elsevier BV
Date: 2002
Publisher: Japanese Society for the Study of Xenobiotics
Date: 2010
DOI: 10.2133/DMPK.DMPK-10-RG-031
Abstract: This study aims to investigate hepatic pharmacokinetics of the four most common drugs (metoprolol, omeprazole, spironolactone, and furosemide) given to patients undergoing liver transplantation before surgery. The investigation was carried out in CCl(4)-induced fibrotic perfused rat livers and the results were compared to those in normal rat liver. Drug outflow fraction-time profiles were obtained after bolus injection into a single-pass-perfused normal or fibrotic rat liver. The pharmacokinetic parameters were estimated using previously developed barrier-limited and space-distributed models. The results showed a marked increase in the liver fibrosis index for CCl(4)-treated rats compared to controls (p<0.05). The extraction ratios (E) for all drugs were significantly lower (p<0.05) in fibrotic than in normal livers and the decrease in E was consistent with the decrease in intrinsic clearance and permeability-surface area product. In addition, other than for furosemide, the mean transit times for all drugs were significantly longer (p<0.01) in the fibrotic livers than in normal livers. Pharmacokinetic model and stepwise regression analyses suggest that these differences arise from a reduction in both the transport of drugs across the basolateral membrane and their metabolic clearance and were in a manner similar to those previously found for another group of drugs.
Publisher: IEEE
Date: 02-2008
Publisher: Georg Thieme Verlag KG
Date: 13-11-2008
Abstract: A sensitive and rapid liquid chromatography-mass spectrometric method for the determination of ophiopogonin D in rat plasma was developed and validated. Chromatographic separation was performed on a C (18) column using a step gradient program with the mobile phase of 0.5 mmol/L ammonium chloride solution and acetonitrile. Ophiopogonin D was quantified using an electrospray negative ionization mass spectrometry in the selected ion monitoring (SIM) mode using digoxin as an internal standard. Good linearity was obtained in the concentration range of 2.5 - 480.0 ng/mL ( R2 = 0.9984). The lower limit of quantification (LLOQ) and lower limit of detection (LLOD) were 2.5 ng/mL and 1.0 ng/mL, respectively. Both the intra- and inter-day precision was less than 8.9 % and the accuracy was within 97.5 - 107.3 %. The pharmacokinetic study of ophiopogonin D in rats was then defined using the method after intravenous dosing (77.0 microg/kg). The plasma concentration-time profile for ophiopogonin D was best fitted to an open two-compartment model with a clearance of 0.024 +/- 0.010 L/min/kg and a terminal half life of 17.29 +/- 1.70 min. A comparison of the pharmacokinetics of ophiopogonin D as a pure compound and as a component of 'SHENMAI' injection revealed a significantly smaller clearance of ophiopogonin D (0.007 +/- 0.002 L/min/kg) for the latter formulation, consistent with an inhibition by one or more other components in the formulation.
Publisher: Springer Science and Business Media LLC
Date: 22-09-2007
DOI: 10.1007/S11095-007-9416-Z
Abstract: Our understanding of the differential effects of topically applied vehicles on solute partitioning and diffusion within the skin is presently limited. In this work, in vitro epidermal partitioning, penetration and multiphoton laser scanning microscopy (MPLSM) imaging studies were used to assess the distribution of 2-naphthol across human epidermis. Four commonly used liquid vehicles (100% water, 20% propylene glycol (PG)/water, 50% ethanol (EtOH)/water and 100% isopropyl myristate (IPM)) were used. The maximum flux and membrane retention of 2-naphthol from 50% EtOH/water was almost an order of magnitude or larger than from the other vehicles evaluated whereas IPM resulted in the highest membrane retention and lowest membrane penetration for 2-naphthol than other vehicles. MPLSM studies showed that 2-naphthol solute partitioned favourably into the intercellular lipids and that there was a vehicle-dependent uptake of 2-naphthol into corneocytes. The integrated evaluation using in vitro penetration, epidermal retention and MPLSM imaging has shown that vehicle effects on skin penetration occurs by an alteration in the distribution of solutes between the corneocytes and intercellular lipids in addition to the well known mechanisms of altered partitioning into the stratum corneum and enhanced epidermal diffusion.
Publisher: Informa UK Limited
Date: 2007
DOI: 10.1080/10408440601177780
Abstract: Many modern cosmetic or sunscreen products contain nano-sized components. Nanoemulsions are transparent and have unique tactile and texture properties nanocapsule, nanosome, noisome, or liposome formulations contain small vesicles (range: 50 to 5000 nm) consisting of traditional cosmetic materials that protect light-or oxygen-sensitive cosmetic ingredients. Transdermal delivery and cosmetic research suggests that vesicle materials may penetrate the stratum corneum (SC) of the human skin, but not into living skin. Depending on the physical/chemical properties of the ingredient and the formulation, nano-sized formulations may enhance or reduce skin penetration, albeit at a limited rate. Modern sunscreens contain insoluble titanium dioxide (TiO(2)) or zinc oxide (ZnO) nanoparticles (NP), which are colorless and reflect/scatter ultraviolet (UV) more efficiently than larger particles. Most available theoretical and experimental evidence suggests that insoluble NP do not penetrate into or through normal as well as compromised human skin. Oral and topical toxicity data suggest that TiO(2) and ZnO NP have low systemic toxicity and are well tolerated on the skin. In vitro cytotoxicity, genotoxicity, and photogenotoxicity studies on TiO(2) or other insoluble NP reporting uptake by cells, oxidative cell damage, or genotoxicity should be interpreted with caution, since such toxicities may be secondary to phagocytosis of mammalian cells exposed to high concentrations of insoluble particles. Caution needs to be exercised concerning topical exposure to other NP that either have characteristics enabling some skin penetration and/or have inherently toxic constituents. Studies on wear debris particles from surgical implants and other toxicity studies on insoluble particles support the traditional toxicology view that the hazard of small particles is mainly defined by the intrinsic toxicity of particles, as distinct from their particle size. There is little evidence supporting the principle that smaller particles have greater effects on the skin or other tissues or produce novel toxicities relative to micro-sized materials. Overall, the current weight of evidence suggests that nano-materials such as nano-sized vesicles or TiO(2) and ZnO nanoparticles currently used in cosmetic preparations or sunscreens pose no risk to human skin or human health, although other NP may have properties that warrant safety evaluation on a case-by-case basis before human use.
Publisher: Elsevier BV
Date: 09-1997
DOI: 10.1016/S1056-8719(97)00032-4
Abstract: We describe a method for multiple indicator dilution studies in the isolated perfused human placental lobule developed to investigate the relationships between changes in pressure and flow and solute clearance. A peripheral lobule of a human placenta is perfused with a tissue culture-based medium and the perfusate oxygen tension, arterial and venous pressures, pH and perfusion temperature continuously monitored by a computerized system. Flow rates are readily changed. Bolus injections of vascular, extracellular and water space markers, and study compounds can be made into either maternal or fetal circulations, and precisely timed outflow fractions can be collected with computer-controlled fraction collectors, allowing simultaneous determination of concentration-time profiles of each marker.
Publisher: Ivyspring International Publisher
Date: 2019
DOI: 10.7150/JCA.28377
Publisher: Springer Berlin Heidelberg
Date: 2015
Publisher: John Libbey Eurotext
Date: 06-2016
Abstract: Magnesium is an important micronutrient essential for various biological processes and its deficiency has been linked to several inflammatory disorders in humans. Topical magnesium delivery is one of the oldest forms of therapy for skin diseases, for ex le Dead Sea therapy and Epsom salt baths. Some anecdotal evidence and a few published reports have attributed amelioration of inflammatory skin conditions to the topical application of magnesium. On the other hand, transport of magnesium ions across the protective barrier of skin, the stratum corneum, is contentious. Our primary aim in this study was to estimate the extent of magnesium ion permeation through human skin and the role of hair follicles in facilitating the permeation. Upon topical application of magnesium solution, we found that magnesium penetrates through human stratum corneum and it depends on concentration and time of exposure. We also found that hair follicles make a significant contribution to magnesium penetration.
Publisher: Springer Science and Business Media LLC
Date: 08-1983
DOI: 10.1007/BF00543800
Abstract: The global prevalence of dementia is growing rapidly, driving an increased use of residential long-term care (LTC) services. Performance indicators for residential LTC should support targeting of limited resources to promote person-centered care, health, and well-being for both patients and caregivers (formal and informal), yet many performance indicators remain focused on structure, process, or outcome measures that are only assumed to support personally relevant outcomes for those with dementia, without direct evidence of meaningfulness for these in iduals. In this article, two complementary approaches to assessing quality in residential LTC serve as a lens for examining a series of tensions related to assessment in this setting. These include measurement-focused approaches using generic psychometrically valid instruments, often used to monitor quality of services, and meaning-focused approaches using in idual subjective assessment of personally relevant outcomes, often used to monitor care planning. Ex les from the European and U.S. literature suggest an opportunity to strengthen an emphasis on personally meaning-focused outcomes in quality assessment.
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1002/JPS.21856
Publisher: Canadian Science Publishing
Date: 2001
Publisher: Elsevier
Date: 2016
Publisher: S. Karger AG
Date: 2013
DOI: 10.1159/000348469
Abstract: b i Purpose of the Study: /i /b The overall aim of the present work was to elucidate the effects of iontophoresis on assisting permeation/deposition of peptide dendrimers across/within human skin. b i Procedures: /i /b A series of peptide dendrimers containing arginine and histidine as terminal acids were synthesized and characterized. These dendrimers were subjected to passive and iontophoretic permeation studies across human epidermis. b i Results: /i /b The synthesized peptide dendrimers were found to be stable in epidermal, dermal and skin extracts up to 6 h. Passive diffusion studies revealed that none of the synthesized peptide dendrimers permeated human epidermis up to 6 h, although minute concentrations of low molecular weight dendrimers were detected in receptor medium at the end of 24 h. Application of iontophoresis significantly increased the permeation of all the tested peptide dendrimers across human skin in a molecular weight-dependent manner compared to simple passive diffusion. Electromigration was found to be the dominant mechanism behind the iontophoretic permeation of peptide dendrimers across human skin. b i Conclusions: /i /b The present study demonstrates that iontophoresis is an effective technique in enhancing the transdermal permeation of peptide dendrimers. b i Message of the Paper: /i /b This study foresees the possibility of applying peptide dendrimers in iontophoretic delivery of drugs and macromolecules across/within the skin.
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9SC02650A
Abstract: We present a new cell membrane modification methodology where the inherent heart tissue homing properties of the infectious bacteria Streptococcus gordonii are transferred to human stem cells.
Publisher: American Chemical Society (ACS)
Date: 21-01-2016
DOI: 10.1021/ACS.NANOLETT.5B03854
Abstract: A physiologically based pharmacokinetic model was developed for accurately characterizing and predicting the in vivo fate of long-circulating inorganic nanoparticles (NPs). This model is built based on direct visualization of NP disposition details at the organ and cellular level. It was validated with multiple data sets, indicating robust inter-route and interspecies predictive capability. We suggest that the biodistribution of long-circulating inorganic NPs is determined by the uptake and release of NPs by phagocytic cells in target organs.
Publisher: Informa UK Limited
Date: 22-05-2023
Publisher: American Geophysical Union (AGU)
Date: 08-1998
DOI: 10.1021/JS970485Y
Publisher: Elsevier BV
Date: 09-1997
Abstract: The distributed-tubes model of hepatic elimination is extended to include intermixing between sinusoids, resulting in the formulation of a new, interconnected-tubes model. The new model is analysed for the simple case of two interconnected tubes, where an exact solution is obtained. For the case of many strongly-interconnected tubes, it is shown that a zeroth-order approximation leads to the convection-dispersion model. As a consequence the dispersion number is expressed, for the first time, in terms of its main physiological determinants: heterogeneity of flow and density of interconnections between sinusoids. The analysis of multiple indicator dilution data from a perfused liver preparation using the simplest version of the model yields the estimate 10.3 for the average number of interconnections. The problem of boundary conditions of the dispersion model is considered from the viewpoint that the dispersion-convection equation is a zeroth-order approximation to the equations for the interconnected-tubes model.
Publisher: American Society for Microbiology
Date: 09-2015
DOI: 10.1128/AAC.00389-15
Abstract: While guidelines recommend empirical cefepime therapy in febrile neutropenia, the mortality benefit of cefepime has been controversial. In light of this, recent reports on pharmacokinetic changes for several antibiotics in febrile neutropenia and the consequent suboptimal exposure call for a pharmacokinetic harmacodynamic evaluation of current dosing. This study aimed to assess pharmacokinetic harmacodynamic target attainment from a 2-g intravenous (i.v.) every 8 h (q8h) cefepime regimen in febrile neutropenic patients with hematological malignancies. Cefepime plasma concentrations were measured in the 3rd, 6th, and 9th dosing intervals at 60% of the interval and/or trough point. The selected pharmacokinetic harmacodynamic targets were the proportion of the dosing interval (60% and 100%) for which the free drug concentration remains above the MIC ( f T MIC ). Target attainment was assessed in reference to the MIC of isolated organisms if available or empirical breakpoints if not. The percentage of f T MIC was also estimated by log-linear regression analysis. All patients achieved % f T MIC in the 3rd and 6th dosing intervals. A 100% f T MIC was not attained in 6/12, 4/10, and 4/9 patients in the 3rd, 6th, and 9th dose intervals, respectively, or in 14/31 (45%) of the dosing intervals investigated. On the other hand, 29/31 (94%) of trough concentrations were at or above 4 mg/liter. In conclusion, for patients with normal renal function, a high-dose 2-g i.v. q8h cefepime regimen appears to provide appropriate exposure if the MIC of the organism is ≤4 mg/liter but may fail to cover less susceptible organisms.
Publisher: Elsevier BV
Date: 03-2007
DOI: 10.1016/J.EJPHAR.2007.01.015
Abstract: Liver fatty acid binding protein has recently been shown to possess antioxidant properties but its role in liver disease, such as cholestasis, is not known. Since oxidative stress has been recognized as an important contributing factor in liver disease, we investigated the expression and antioxidative function of this protein using the bile-duct ligated model of cholestasis. Rats were ided into 3 groups: sham, bile-duct ligated and bile-duct ligated plus clofibrate. Animals were sacrificed at various time points after bile-duct ligation. RT-PCR and Western blot were used to analyze liver fatty acid binding protein expression. Cellular lipid peroxidation products were assessed by measuring thiobarbituric acid-reactive substances. Liver function was evaluated by measuring serum total bilirubin, alanine aminotransferase and ammonia. Liver fatty acid binding protein mRNA and protein levels were reduced to 51% and 20% of sham, respectively at 2 weeks following bile-duct ligation (p<0.05). The decreased liver fatty acid binding protein was associated with a statistical increase in hepatic lipid peroxidation products (224%) and decrease in hepatic function. Clofibrate treatment restored protein level and improved hepatic function. Clofibrate treatment also reduced hepatic lipid peroxidation products by 68% as compared with the bile-duct ligated group (p<0.05). Liver fatty acid binding protein likely has important antioxidant function during hepatocellular oxidative stress.
Publisher: Elsevier BV
Date: 03-2008
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.CMI.2015.05.002
Abstract: Treatment of infectious diseases is becoming increasingly challenging with the emergence of less-susceptible organisms that are poorly responsive to existing antibiotic therapies, and the unpredictable pharmacokinetic alterations arising from complex pathophysiologic changes in some patient populations. In view of this fact, there has been a progressive work on novel dose optimization strategies to renew the utility of forgotten old antibiotics and to improve the efficacy of those currently in use. This review summarizes the different approaches of optimization of antibiotic dosing regimens and the special patient populations which may benefit most from these approaches. The existing methods are based on monitoring of antibiotic concentrations and/or use of clinical covariates. Measured concentrations can be correlated with predefined pharmacokinetic harmacodynamic targets to guide clinicians in predicting the necessary dose adjustment. Dosing nomograms are also available to relate observed concentrations or clinical covariates (e.g. creatinine clearance) with optimal dosing. More precise dose prediction based on observed covariates is possible through the application of population pharmacokinetic models. However, the most accurate estimation of in idualized dosing requirements is achieved through Bayesian forecasting which utilizes both measured concentration and clinical covariates. Various software programs are emerging to ease clinical application. Whilst more studies are warranted to clarify the clinical outcomes associated with the different dose optimization approaches, severely ill patients in the course of marked infections and/or inflammation including those with sepsis, septic shock, severe trauma, burns injury, major surgery, febrile neutropenia, cystic fibrosis, organ dysfunction and obesity are those groups which may benefit most from in idualized dosing.
Publisher: Springer Science and Business Media LLC
Date: 1980
DOI: 10.1007/BF00561587
Publisher: Springer Science and Business Media LLC
Date: 1988
DOI: 10.1007/BF00542500
Abstract: This study evaluated the ability of delinquent peer affiliation to mediate the effects of multidimensional treatment foster care (MTFC Chamberlain, 2003) on girls' delinquent behavior. This study used a s le of girls from 2 cohorts (N = 166 M = 15.31 years old at baseline, range 13-17 years 74% European American, 2% African American, 7% Hispanic, 4% Native American, 1% Asian, and 13% mixed ethnicity) and measures of delinquent behavior, including general delinquency, number of criminal referrals, and number of days in locked settings. As the mediator, we used self-reports of affiliation with delinquent peers. Our analytic plan specified an intent-to-treat analysis within the framework of a randomized controlled trial comparing MTFC with traditional community-based group care. Random assignment to the MTFC program reduced girls' number of criminal referrals and number of days in locked settings at 24 months. The MTFC condition also reduced girls' exposure to delinquent peers at 12 months, which in turn reduced levels of all forms of delinquent behavior at 24 months indirect effects were statistically significant. Reduction in exposure to delinquent peers mediated MTFC effects on the number of criminal referrals and number of days in locked settings delinquent peers also served as an intervening variable between MTFC and self-report delinquency, suggesting that, by reducing contact with delinquent peers, MTFC helped to encourage lower levels of self-report delinquency. Existing prevention and intervention programs targeting similar populations may benefit from increased attention to reductions in delinquent peer affiliation in female s les.
Publisher: Springer Science and Business Media LLC
Date: 07-2001
Publisher: The Optical Society
Date: 10-02-2015
DOI: 10.1364/BOE.6.000780
Publisher: Microbiology Society
Date: 10-03-2010
Abstract: Serology has been used to indicate past infection by the human polyomaviruses BK virus (BKV) and JC virus (JCV), because the site of primary infection is not established fully. Little is known about BKV and JCV antibody stability over time. We investigated BKV and JCV seroprevalence and antibody stability over time in an Australian population-based study. Serum was collected from 458 adults participating in a longitudinal skin cancer study in Queensland in 1992, 1993 and 1996, and 117 people had a fourth s le collected in 2003. Serum s les were analysed for BKV and JCV VP1 antibodies by multiplex detection using the Luminex platform. The seroprevalence for BKV and JCV over 4.5 years was 97 and 63 %, respectively. The BKV seroprevalence was 99 % in 25-60-year-olds, and 94 % in people older than 60 years. JCV seroprevalence was around 60 % in people younger than 50 years, 68 % in people 50-70 years of age and 64 % in people older than 70 years. BKV seroprevalence was very stable over 11 years, with 96 % of people staying seropositive and 2 % remaining seronegative. JCV antibody status over time was less stable 57 % of participants remained seropositive and 31 % seronegative. The same proportion of people (4 % each) seroconverted, seroreverted or had fluctuating JCV antibody levels. These results confirm the previously believed stability of polyomavirus antibodies, with BKV antibodies being highly stable and JCV antibodies moderately so. Thus, a single measure can be used as a reasonable indicator of long-term antibody status in epidemiological studies aiming to understand associations between polyomaviruses and disease.
Publisher: Oxford University Press (OUP)
Date: 15-05-2007
DOI: 10.1093/JAC/DKM128
Abstract: To determine how long single-dose prophylactic antibiotic regimens for burns surgery maintained plasma concentrations above the MICs for target organisms during surgery. We monitored antibiotic plasma concentrations in 12 patients (mean +/- SD 43 +/- 12% total burn surface area) throughout debridement surgery after administration of the standard prophylactic antibiotic dosing regimens of either 1 g of intravenous cefalotin or 4.5 g of intravenous piperacillin/tazobactam. The eschar debridement and grafting procedures ranged in duration from 2.25 to over 8.5 h. The duration of total plasma cefalotin concentration above an MIC of 0.2 mg/L for Staphylococcus aureus was 6.49 +/- 2.85 h, whereas the mean duration of total plasma piperacillin concentration above an MIC of 64 mg/L for Pseudomonas aeruginosa was only 1.15 +/- 0.59 h. None of the patients dosed with piperacillin/tazobactam was adequately protected for the duration of their surgery and adequate prophylaxis was only evident in four of the nine patients administered cefalotin. These results suggest a need to review antibiotic prophylaxis dosage regimens for burns surgery and the adoption of regimens that will minimize the risk of infection in this high-risk patient group. It is suggested that the antibiotic prophylaxis guideline for burn debridement surgery be modified to include re-dosing or a continuous infusion of beta-lactam antibiotics.
Publisher: SAGE Publications
Date: 13-06-2014
Abstract: Dead Sea and magnesium salt therapy are two of the oldest forms of treatment for skin disease and several other disorders, supported by a body of largely anecdotal evidence. In this paper we review possible pathways for penetration of magnesium ions through the epidermis to reach the circulation, in turn replenishing cellular magnesium levels. We also discuss mechanisms for intercellular movement of magnesium ions and possible mechanisms for the interaction between magnesium ions and inflammatory mediators. Upon addition of magnesium ions in vitro, the expression of inflammatory mediators such as tumour necrosis factor α (TNFα) and nuclear factor κβ (NFκβ) is down regulated. Dysregulation of these and other inflammatory mediators has been linked to several inflammatory disorders, including asthma, arthritis, atherosclerosis and neuroinflammation.
Publisher: Springer Science and Business Media LLC
Date: 12-2012
Publisher: Wiley
Date: 15-12-2014
Abstract: Although many studies reporting the organ-level biodistribution of nanoparticles (NPs) in animals, very few have addressed the fate of NPs in organs at the cellular level. The liver appears to be the main organ for accumulation of NPs after intravenous injection. In this study, for the first time, the in vivo spatiotemporal disposition of recently developed mercaptosuccinic acid (MSA)-capped cadmium telluride/cadmium sulfide (CdTe/CdS) quantum dots (QDs) is explored in rat liver using multiphoton microscopy (MPM) coupled with fluorescence lifetime imaging (FLIM), with subcellular resolution (∼1 μm). With high fluorescence efficiency and largely improved stability in the biological environment, these QDs show a distinct distribution pattern in the liver compared to organic dyes, rhodamine 123 and fluorescein. After intravenous injection, fluorescent molecules are taken up by hepatocytes and excreted into the bile, while negatively charged QDs are retained in the sinusoids and selectively taken up by sinusoidal cells (Kupffer cells and liver sinusoidal endothelial cells), but not by hepatocytes within 3 h. The results could help design NPs targeting the specific types of liver cells and choose the fluorescent markers for appropriate cellular imaging.
Publisher: Wiley
Date: 09-09-2019
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.BURNS.2021.07.017
Abstract: Topical drug therapy is one of the most effective approaches in third-degree burn wound treatments. To optimize and enhance drug permeation through burn eschar, we need to characterize this barrier, most importantly, its affinity to drugs the subject of this investigation. Hansen Solubility Parameters (HSP), as polarity and affinity scale, were measured here for human third-degree burn eschar through uptake studies using 19 solvents at 25 °C and 32 °C and two hydration levels by gravimetric method combined with thermal analysis and Karl Fischer titration. HSP parameters of dispersion (δ
Publisher: Public Library of Science (PLoS)
Date: 27-09-2018
Publisher: MDPI AG
Date: 29-01-2020
DOI: 10.3390/PHARMACEUTICS12020108
Abstract: Resveratrol (RSV) is a potent lipophilic antioxidant with a low aqueous solubility. Novel nanoformulations have been successfully developed and evaluated to increase the potential of resveratrol as a skin targeting antioxidant. Nanoformulations were prepared using a spontaneous emulsification method, and characterized and evaluated for their capabilities to penetrate ermeate the skin. In nanoformulations, the thermodynamic activity of the RSV penetration into ermeation through the skin was correlated with the thermodynamic activity of the RSV in the formulations. When terpenes were incorporated into the nanoformulations, the permeation of RSV through the skin increased and correlated with an increasing lipophilicity of the terpene. The nanoemulsion containing eugenol showed the highest RSV penetration into the stratum corneum (SC) and the epidermis-dermis-follicle region, whereas the limonene containing nanoemulsion had the highest RSV permeation through the skin (the enhancement ratios, compared to a saturated solution of RSV, were (i) 9.55 and (ii) 12.61, respectively, based on the average RSV amount (i) in each skin region and (ii) permeation through skin).
Publisher: Bentham Science Publishers Ltd.
Date: 29-05-2018
DOI: 10.2174/1568026618666180412153214
Abstract: It is critical to develop an effective understanding of the interaction between the drug, delivery system and skin in order to predict and assess skin penetration and permeation. Experimental models for the assessment of topical and transdermal delivery systems must permit evaluation of these complex interactions. Whilst in the past, animal models were commonly used, recent regulatory guidelines, based on 3R principles (refinement, reduction, replacement), encourage the rational use of animals. Alternative methods have been proposed for use in the development of topical and transdermal delivery systems which are often used in combination. We will review the current state of the art in alternative methods for topical and transdermal delivery systems development, including technologies that can assist in the characterization of skin penetration ermeation studies.
Publisher: S. Karger AG
Date: 2018
DOI: 10.1159/000489857
Abstract: b i Background/Aims: /i /b This study aimed to investigate transfollicular delivery enhancement of caffeine from nanoemulsion formulations incorporating oleic acid (OA) and eucalyptol (EU) as chemical penetration enhancers. b i Methods: /i /b Caffeine permeation was evaluated from nanoemulsions containing OA or EU and an aqueous control solution through excised human full-thickness skin with hair follicles opened, blocked, or left untreated. Differential tape stripping was performed, followed by cyanoacrylate skin surface biopsies to determine the amount of caffeine in the hair follicles, and skin extraction to determine the retention of caffeine in the skin. b i Results: /i /b Nanoemulsions significantly increased caffeine permeation through open and untreated skin over control (untreated: 36- and 42-fold for OA and EU, respectively open: 40- and 49-fold). The follicular route contributed 53.7% of caffeine permeation for the OA nanoemulsion and 51% for EU when follicles were opened. Nanoemulsions promoted 4- and 3.4-fold increases in caffeine retention in open follicles, for OA and EU, respectively. Retention of caffeine in the stratum corneum and skin was almost equal in all cases. b i Conclusions: /i /b This study demonstrated effective delivery of caffeine as a hydrophilic model drug into and through hair follicles and showed that follicles and surrounding regions may be targeted by optimised formulations for specific treatments.
Publisher: Elsevier BV
Date: 09-1981
Publisher: Springer Science and Business Media LLC
Date: 14-07-2016
Publisher: Springer Science and Business Media LLC
Date: 2003
Abstract: The flux of a topically applied drug depends on the activity in the skin and the interaction between the vehicle and skin. Permeation of vehicle into the skin can alter the activity of drug and the properties of the skin barrier. The aim of this in vitro study was to separate and quantify these effects. The flux of four radiolabeled permeants (water, phenol, diflunisal, and diazepam) with log Koct/water values from 1.4 to 4.3 was measured over 4 h through heat-separated human epidermis pretreated for 30 min with vehicles having Hildebrand solubility parameters from 7.9 to 23.4 (cal/cm3)1/2. Enhancement was greatest after pretreatment with the more lipophilic vehicles. A synergistic enhancement was observed using binary mixtures. The flux of diazepam was not enhanced to the same extent as the other permeants, possibly because its partitioning into the epidermis is close to optimal (log Koct 2.96). An analysis of the permeant remaining in the epidermis revealed that the enhancement can be the result of either increased partitioning of permeant into the epidermis or an increasing diffusivity of permeants through the epidermis.
Publisher: Cold Spring Harbor Laboratory
Date: 14-01-2020
DOI: 10.1101/2020.01.13.905414
Abstract: Mathematical models are often applied to describe cell migration regulated by diffusible signalling molecules. A typical feature of these models is that the spatial and temporal distribution of the signalling molecule density is reported by solving a reaction–diffusion equation. However, the spatial and temporal distributions of such signalling molecules are not often reported or observed experimentally. This leads to a mismatch between the amount of experimental data available and the complexity of the mathematical model used to simulate the experiment. To address this mismatch, we develop a discrete model of cell migration that can be used to describe a new suite of co–culture cell migration assays involving two interacting subpopulations of cells. In this model, the migration of cells from one subpopulation is regulated by the presence of signalling molecules that are secreted by the other subpopulation of cells. The spatial and temporal distribution of the signalling molecules is governed by a discrete conservation statement that is related to a reaction–diffusion equation. We simplify the model by invoking a steady state assumption for the diffusible molecules, leading to a reduced discrete model allowing us to describe how one subpopulation of cells stimulates the migration of the other subpopulation of cells without explicitly dealing with the diffusible molecules. We provide additional mathematical insight into these two stochastic models by deriving continuum limit partial differential equation descriptions of both models. To understand the conditions under which the reduced model is a good approximation of the full model, we apply both models to mimic a set of novel co–culture assays and we systematically explore how well the reduced model approximates the full model as a function of the model parameters.
Publisher: Springer Science and Business Media LLC
Date: 09-03-2022
DOI: 10.1007/S11095-022-03215-Z
Abstract: The skin concentration of a substance after a topical application or exposure determines both local treatment outcomes and the dermal toxicity assessment of various products. However, quantifying the time course of those concentrations at skin effect sites, such as the viable epidermal, superficial dermis and appendages in humans is especially problematic in vivo, making physiologically based mathematical modelling an essential tool to meet this need. This work further develops our published physiologically based pharmacokinetic and COMSOL based dermal transport modelling by considering the impact of the superficial subpapillary dermal plexus, which we represent as two well stirred compartments. The work also studied the impact on dermal concentrations of subpapillary plexus size, depth, blood velocity and density of subpapillary plexus vessels. Sensitivity analyses are used to define the most important transport determinants of skin concentrations after topical application of a substance, with previously published results used to validate the resulting analyses. This resulting model describes the available experimental data better than previous models, especially at deeper dermal depths.
Publisher: Wiley
Date: 03-1999
DOI: 10.1002/(SICI)1098-2299(199903/04)46:3/4<309::AID-DDR17>3.0.CO;2-H
Publisher: American Physiological Society
Date: 02-2006
Abstract: Systemic inflammation is known to affect drug disposition in the liver. This study sought to relate and quantitate changes in hepatic pharmacokinetics of propranolol with changes in hepatic architecture and physiology in adjuvant-treated rats. Transmission electron microscopy was used to assess morphological changes in mitochondria and lysosomes of adjuvant-treated rat livers. The disposition of propranolol was assessed in the perfused rat liver using the multiple indicator dilution technique. Hepatic extraction and mean transit time were determined from outflow-concentration profiles using a nonparametric method. Kinetic parameters were derived from a two-phase physiologically based organ pharmacokinetic model. Possible relationships were then explored between the changes in hepatic drug disposition and cytochrome P-450 activity and iron concentration. Adjuvant treatment induced the appearance of mitochondrial inclusions/tubularization and irregularly shaped lysosomes in rat livers. Livers from adjuvant-treated rats had (relative to normal) significantly higher α 1 -acid glycoprotein (orosomucoid) and iron tissue concentrations but lower cytochrome P-450 content. The hepatic extraction, metabolism, and ion trapping of propranolol were significantly impaired in adjuvant-treated rats and could be correlated with altered iron store and cytochrome P-450 activity. It is concluded that adjuvant-induced systemic inflammation alters hepatocellular morphology and biochemistry and consequently influences hepatic disposition of propranolol.
Publisher: Springer Science and Business Media LLC
Date: 03-08-2013
DOI: 10.1007/S40266-013-0106-8
Abstract: Inappropriate medication use is common in the elderly and the risks associated with their use are well known. The term deprescribing has been utilised to describe the complex process that is required for the safe and effective cessation of inappropriate medications. Given the primacy of the consumer in health care, their views must be central in the development of any deprescribing process. The aim of this study was to identify barriers and enablers that may influence a patient's decision to cease a medication. A systematic search of MEDLINE, International Pharmaceutical Abstracts, EMBASE, CINAHL, Informit and Scopus was conducted and augmented with a manual search. Numerous search terms relating to withdrawal of medications and consumers' beliefs were utilised. Articles were included if the barriers or enablers were directly patient/carer reported and related to long-term medication(s) that they were currently taking or had recently ceased. Determination of relevance and data extraction was performed independently by two reviewers. Content analysis with coding was utilised for synthesis of results. Twenty-one articles met the criteria and were included in the review. Three themes, disagreement/agreement with 'appropriateness' of cessation, absence resence of a 'process' for cessation, and negative ositive 'influences' to cease medication, were identified as both potential barriers and enablers, with 'fear' of cessation and 'dislike' of medications as a fourth barrier and enabler, respectively. The most common barrier/enabler identified was 'appropriateness' of cessation, with 15 studies identifying this as a barrier and 18 as an enabler. The decision to stop a medication by an in idual is influenced by multiple competing barriers and enablers. Knowledge of these will aid in the development of a deprescribing process, particularly in approaching the topic of cessation with the patient and what process should be utilised. However, further research is required to determine if the proposed patient-centred deprescribing process will result in improved patient outcomes.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 17-10-2003
Publisher: MDPI AG
Date: 24-09-2019
DOI: 10.3390/PHARMACEUTICS11100490
Abstract: Acne vulgaris is a common inflammatory pilosebaceous condition that affects 80–90% of adolescents. Since the introduction of tretinoin over 40 years ago, topical retinoid products have been a mainstay of acne treatment. The retinoids are very effective in addressing multiple aspects of the acne pathology as they are comedolytic and anti-inflammatory, and do not contribute to antibiotic resistance or microbiome disturbance that can be associated with long-term antibiotic therapies that are a common alternative treatment. However, topical retinoids are associated with skin dryness, erythema and pain, and may exacerbate dermatitis or eczema. Thus, there is a clear need to target delivery of the retinoids to the pilosebaceous units to increase efficacy and minimise side effects in surrounding skin tissue. This paper reviews the current marketed topical retinoid products and the research that has been applied to the development of targeted topical delivery systems of retinoids for acne.
Publisher: Elsevier BV
Date: 04-2029
DOI: 10.1016/J.ADDR.2021.113929
Abstract: Topical products, widely used to manage skin conditions, have evolved from simple potions to sophisticated delivery systems. Their development has been facilitated by advances in percutaneous absorption and product design based on an increasingly mechanistic understanding of drug-product-skin interactions, associated experiments, and a quality-by-design framework. Topical drug delivery involves drug transport from a product on the skin to a local target site and then clearance by diffusion, metabolism, and the dermal circulation to the rest of the body and deeper tissues. Insights have been provided by Quantitative Structure Permeability Relationships (QSPR), molecular dynamics simulations, and dermal Physiologically Based PharmacoKinetics (PBPK). Currently, generic product equivalents of reference-listed products dominate the topical delivery market. There is an increasing regulatory interest in understanding topical product delivery behavior under 'in use' conditions and predicting in vivo response for population variations in skin barrier function and response using in silico and in vitro findings.
Publisher: Springer Japan
Date: 2017
Publisher: The Endocrine Society
Date: 09-1997
DOI: 10.1210/JC.82.9.3099
Publisher: Frontiers Media SA
Date: 06-11-2018
DOI: 10.18433/JPPS30246
Abstract: PURPOSE: Liver fatty acid binding protein (FABP1) is a cytoplasmic polypeptide that transports substrates throughout the cytosol and functions as an antioxidant. A common polymorphic variant, FABP1 T94A has a minor allele frequency of 26-38%, 8.3±1.9% homozygous in the human population. The purpose of this study was to mutate and isolate recombinant rat FABP1 to the T94A variant to evaluate the mutant’s antioxidant activity using in vitro studies. METHODS: Site-directed mutagenesis was used to generate a mutation in rat cDNA within a pGEX-6p-2 vector. This plasmid was transformed into competent cells and cultured for expression of FABP1 T94A mutant. The mutated protein was purified using GSTrap Fastflow columns within an ÄKTA FPLC system. A 2,7-dichlorofluorescein (DCF) assay was used to screen the T94A variant antioxidant activity. Additionally, Thiobarbituric Acid Reactive Substances (TBARS) assay was used in determining T94A mutant antioxidant activity in hydrophilic and lipophilic environments through the use of the azo compounds AAPH and MeO-AMVN, respectively and in the presence and absence of the long-chain fatty acid palmitate and α-bromo palmitate. RESULTS: Although the FABP1 T94A (20 μM) mutant significantly reduced DCF fluorescence compared to control (no protein P 0.001), there were no significant difference when compared to the wild-type (WT) FABP1. T94A was able to diminish the formation of malondialdehyde (MDA) in both lipophilic and hydrophilic systems. There were significant differences between T94A mutant and WT FABP1 at concentrations 1 and 10 μM (P 0.05) in the hydrophilic milieu, however, this was not seen at 20 μM and also not seen in the lipophilic milieu at all concentrations. When T94A was pre-incubated with the long-chain fatty acids palmitate or α -bromo palmitate, MDA formation was decreased in both lipid peroxidation systems. There were no statistical differences between the WT FABP1 and T94A bound with fatty acids in both lipid peroxidation systems, however, there was a slight statistical difference when the T94A and WT FABP1 bound α-Br-PA in the AAPH lipid peroxidation system only. CONCLUSIONS: The T94A has antioxidant activity in both hydrophilic and lipophilic environments. The T94A variant of FABP1 does not have a loss of function in regard to acting as an antioxidant but the extent of function may be influenced by ligand binding. We conclude that populations having the minor T94A allele frequency would have similar ROS scavenging potential as those with nascent FABP1.
Publisher: Springer Science and Business Media LLC
Date: 1986
DOI: 10.1007/BF00615962
Abstract: Chronic wasting disease (CWD) of deer and elk is a highly communicable neurodegenerative disorder caused by prions. Investigations of CWD are h ered by slow bioassays in transgenic (Tg) mice. Towards the development of Tg mice that will be more susceptible to CWD prions, we created a series of chimeric elk/mouse transgenes that encode the N terminus of elk PrP (ElkPrP) up to residue Y168 and the C terminus of mouse PrP (MoPrP) beyond residue 169 (mouse numbering), designated Elk3M(SNIVVK). Between codons 169 and 219, six residues distinguish ElkPrP from MoPrP: N169S, T173N, V183I, I202V, I214V and R219K. Using chimeric elk/mouse PrP constructs, we generated 12 Tg mouse lines and determined incubation times after intracerebral inoculation with the mouse-passaged RML scrapie or Elk1P CWD prions. Unexpectedly, one Tg mouse line expressing Elk3M(SNIVVK) exhibited incubation times of <70 days when inoculated with RML prions a second line had incubation times of 250 days for RML prions. Tg(Elk3M,SNIVVK) mice were less susceptible to CWD prions than Tg(ElkPrP) mice. Changing three C-terminal mouse residues (202, 214 and 219) to those of elk doubled the incubation time for mouse RML prions and rendered the mice resistant to Elk1P CWD prions. Mutating an additional two residues from mouse to elk at codons 169 and 173 increased the incubation times for mouse prions to >300 days, but made the mice susceptible to CWD prions. Our findings highlight the role of C-terminal residues in PrP that control the susceptibility and replication of prions.
Publisher: Springer Japan
Date: 2017
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.IJPHARM.2015.01.046
Abstract: To introduce better antibiotics for the treatment of some infectious diseases in sheep and to expand the range of antibiotics available for veterinary medicine, pharmacokinetics of two antibiotics marbofloxacin (MBX) and trovafloxacin (TVX) were investigated in sheep after intramuscular injection. Variable and irregular plasma concentration-time profiles were observed for TVX but not for MBX. To understand the mechanism of this phenomenon, intravenous studies were performed for both drugs and data were analyzed using a population approach. Deconvolution was then performed using various approaches to obtain absorption profiles of both drugs in sheep after intramuscular injection. The Loo-Riegelman and staircase deconvolution function methods were found to provide more reliable estimates of absorption rate than the Spath-spline and B-spline constraining break points deconvolution methods. The absorption profiles resulting from deconvolution indicated a zero-order absorption process for TVX and a first-order process for MBX. Precipitation of TVX at the injection site was suspected to cause the pseudo zero-order absorption. This hypothesis was supported by the observation of crystalline deposits of TVX in sheep meat after direct injection, using reflectance confocal microscopy.
Publisher: Elsevier BV
Date: 08-1978
DOI: 10.1016/S0140-6736(78)92945-8
Abstract: During initial studies with nitroglycerin infusion in patients with acute myocardial infarction, higher doses than previously reported were required to achieve the desired haemodynamic effect. A flow-rate-dependent loss of drug from the plastic infusion set was demonstrated during simulated infusion. This loss was considerably reduced when nitroglycerin was infused from glass syringes through high-density polyethylene tubing.
Publisher: Public Library of Science (PLoS)
Date: 08-04-2009
Publisher: Wiley
Date: 16-09-2010
Publisher: Springer Science and Business Media LLC
Date: 16-06-2016
DOI: 10.1007/S11095-016-1955-8
Abstract: This study explored the impact of non-sink receptor conditions on the in vitro skin permeation test (IVPT) and sought to estimate equivalent sink condition IVPT data. Simulated diffusion model and experimental IVPT data were generated for ethyl salicylate across human epidermal membranes in Franz diffusion cells using six different receptor phases, with a 10 fold variation in ethyl salicylate solubility. Both simulated and experimental IVPT - time profiles were markedly affected by receptor phase solubility and receptor s ling rates. Similar sink condition equivalent estimated maximum fluxes were obtained by nonlinear regression and adjustment of linear regression estimates of steady state flux for relative saturation of the receptor phase over time for the four receptor phases in which the ethyl salicylate was relatively soluble. The markedly lower steady - state fluxes found for the other two phases in which ethyl salicylate was less soluble was attributed to an aqueous solution boundary layer effect. Non-sink receptor phase IVPT data can be used to derive equivalent sink receptor phase IVPT data provided the receptor phase solubility and hydrodynamics are sufficient to minimise the impact of aqueous diffusion layers on IVPT data.
Publisher: S. Karger AG
Date: 2019
DOI: 10.1159/000499435
Abstract: b i Background: /i /b Pig skin is a widely acknowledged surrogate for human skin for in vitro/ex vivo skin penetration studies with application for small molecules and nanosystems. We have investigated the influence of biological factors such as age and anatomical site on the penetration and distribution of nanoparticles (2.1 nm hydrophilic CdTe/CdS quantum dots: QDs) in adult pig skin (APS), weanling pig skin (WPS) and newborn pig skin (NBPS) at two different anatomical sites (ear and abdomen). b i Methods: /i /b QDs in saline were applied to 1 × 1 cm sup /sup skin (62.5 pmol/cm sup /sup ) with 2-min finger rubbing using a standardized protocol. After 6- or 24-h incubation on Franz diffusion cells, tape stripping (×10) followed by manual follicular casting was conducted. Cadmium in QDs was quantified using inductively coupled plasma mass spectrometry for all s les. The presence of QDs in similarly treated skin s les was also captured using multiphoton tomography. b i Results: /i /b QDs were mainly localized in hair follicles after 6 and 24 h of exposure with no cadmium detected in the Franz cell receptor compartment regardless of pig age or anatomical site. The amount of QDs deposited in the follicles was similar at 6 h but higher on APS and WPS ears compared to NBPS ears at 24 h. This is associated with the high follicle density and small follicle diameter of the NBPS compared to the smaller density of much larger follicles on the APS. NBPS showed consistent QD distribution for ear and abdomen up to 24 h. b i Conclusions: /i /b There is minimal penetration of QDs through pig skin. Density and diameter of follicles in association with age of pigs and application site influenced the amount of QDs deposited in follicles. The structure of the stratum corneum, follicle density and diameter of NBPS are similar to human skin suggesting that NBPS is an appropriate model for human skin in the evaluation of topical applications of a range of chemicals including nanosystems.
Publisher: Springer Science and Business Media LLC
Date: 1996
Abstract: To design a controlled release 5-fluorouracil (5-FU) implant to provide prolonged antifibroblast concentrations of 5-FU in the subconjunctival tissues but low concentrations of 5-FU in other ocular tissues. Implants (5 mg 2.5 mm diameter x 1.2 mm thickness) of 5-FU or 9:1, 8:2, 7:3 5-FU to polymer mass ratios were made by compression. Poly(D,L-lactide-co-glycolide) polymers with 50:50 and 75:25 lactide to glycolide ratios were used. In vitro release characteristics of four types of implants were studied: 5-FU alone (CT), 5-FU/ polymer matrices (MT), coated 5-FU olymer matrices with a central hole drilled through the matrix and coating (CM1), and with a central hole in the coating (CM2). MT and CM1 (9:1 drug olymer) were selected for subconjunctival implantation in rabbits. 14C-5-FU levels in various ocular tissues and retrieved pellets were monitored. First-order release was observed from CT, MT and CM1 implants. Zero-order release profiles were observed from CM2 implants. Drug release was retarded by formulating 5-FU in a matrix comprising poly(D,L-lactide-co-glycolide) which in turn could be modified by the lactide/glycolide ratio of the polymer, the drug to polymer ratio, coating, and hole dimensions. First-order release kinetics were observed for MT and CM1 implants in the in vivo study in rabbits. A correlation between in vitro and in vivo release was established which allowed in vivo release to be predicted from in vitro release data. For CM1, therapeutic tissue concentrations of 35.2 micrograms/g (conjunctiva) and 17.7 micrograms/g (sclera) were found at the implantation site up to 200 hours post-implantation. Tracer levels were undetectable in other ocular tissues. The CM1 implant maintained steady antifibroblast levels in target tissues and minimized levels in nontarget tissues.
Publisher: SPIE-Intl Soc Optical Eng
Date: 14-02-2013
Publisher: Springer Science and Business Media LLC
Date: 28-11-2007
DOI: 10.1007/S11095-007-9494-Y
Abstract: Validate a physiologically based, mechanistic, in silico liver (ISL) for studying the hepatic disposition and metabolism of antipyrine, atenolol, labetalol, diltiazem, and sucrose administered alone or in combination. Autonomous software objects representing hepatic components such as metabolic enzymes, cells, and microarchitectural details were plugged together to form a functioning liver analogue. Microarchitecture features were represented separately from drug metabolizing functions. Each ISL component interacts uniquely with mobile objects. Outflow profiles were recorded and compared to wet-lab data. A single ISL structure was selected, parameterized, and held constant for all compounds. Parameters sensitive to drug-specific physicochemical properties were tuned so that ISL outflow profiles matched in situ outflow profiles. ISL simulations were validated separately and together against in situ data and prior physiologically based pharmacokinetic (PBPK) predictions. The consequences of ISL parameter changes on outflow profiles were explored. Selected changes altered outflow profiles in ways consistent with knowledge of hepatic anatomy and physiology and drug physicochemical properties. A synthetic, agent-oriented in silico liver has been developed and successfully validated, enabling us to posit that static and dynamic ISL mechanistic details, although abstract, map realistically to hepatic mechanistic details in PBPK simulations.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.TAAP.2018.02.012
Abstract: Zinc pyrithione is an active component incorporated in an extensive range of topically applied commercial products that are used worldwide. Despite its prevalence, no published study has investigated the penetration of zinc from the zinc pyrithione complex into human skin. Zinc is crucial for healthy skin function however an elevated concentration of labile zinc is toxic outside a narrow concentration range. Synchrotron X-ray fluorescence microscopy in conjunction with X-ray absorption near edge structure spectroscopy was used to map the deposition of zinc, quantitate the amount of zinc within the skin and to identify a change in the chemical form of zinc after application. This study has demonstrated a ~3.8 fold increase in zinc concentration within the viable epidermis (VE) after 24 h topical application of zinc pyrithione that increased significantly by ~250 fold after 48 h when compared to control skin. Confocal microscopy using a labile zinc specific dye, ZinPyr-1, showed that zinc pyrithione disrupted the skin cells zinc homeostasis and significantly increased the intracellular zinc concentration leading to cell toxicity. Overall, this study demonstrates that topical application of zinc pyrithione formulations leads to an increase in zinc penetration in human skin, consequently, raising concerns for potential localised toxicity to occur.
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.JID.2018.08.024
Abstract: Zinc oxide is a widely used broad-spectrum sunscreen, but concerns have been raised about the safety of its nanoparticle (NP) form. We studied the safety of repeated application of agglomerated zinc oxide (ZnO) NPs applied to human volunteers over 5 days by assessing the skin penetration of intact ZnO-NPs and zinc ions and measuring local skin toxicity. Multiphoton tomography with fluorescence lifetime imaging microscopy was used to directly visualize ZnO-NP skin penetration and viable epidermal metabolic changes in human volunteers. The fate of ZnO-NPs was also characterized in excised human skin in vitro. ZnO-NPs accumulated on the skin surface and within the skin furrows but did not enter or cause cellular toxicity in the viable epidermis. Zinc ion concentrations in the viable epidermis of excised human skin were slightly elevated. In conclusion, repeated application of ZnO-NPs to the skin, as used in global sunscreen products, appears to be safe, with no evidence of ZnO-NP penetration into the viable epidermis nor toxicity in the underlying viable epidermis. It was associated with the release and penetration of zinc ions into the skin, but this did not appear to cause local toxicity.
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.JCONREL.2009.06.029
Abstract: Dry-coated microprojections (MPs) deliver vaccine to abundant immunogenic cells within the skin to induce immune responses. Success in this targeted vaccine delivery relies on overcoming the challenges of dry-coating the vaccine onto the very small (<or=90 microm length) and densely packed (approximately 20,000 cm(-2)) MPs. In this paper, we show that a gas-jet drying coating method achieves the desired uniform coating. The coating approach is robustly demonstrated on compounds representative of a range of immunotherapeutics (e.g. DNA, proteins), with each uniformly coated on thousands of MPs. Furthermore, the dry-coating remains intact during skin insertion, and then releases within the wet skin cellular environment within 3 min. Finally, we applied ovalbumin protein coated MP patches to immunise mice, achieving comparable antibody levels (p=0.08) with needle and syringe intramuscular injection. In summary, this paper presents a simple, practical and versatile method to achieve uniform coating on very small and densely packed MPs for a needle-free and targeted vaccine delivery technology.
Publisher: Elsevier BV
Date: 03-2023
Publisher: Elsevier BV
Date: 07-2001
DOI: 10.1046/J.1523-1747.2001.01398.X
Abstract: The effect of adding thickening agents on the penetration of a sunscreen benzophenone-3 through epidermal and a high-density polyethylene membrane was studied using both very thick (infinite dose) and thin (in use) applications. Contradictory results were obtained. Thickening agents retard skin penetration, in a manner consistent with a diffusional resistance in the formulation, when applied as an infinite dose. In contrast, when applied as in thin (in use) doses, thickening agents promote penetration, most likely through greater stratum corneum diffusivity arising from an enhanced hydration by the thicker formulations. The two key implications from this work are (i) a recognition of the danger in the potential extrapolation of infinite dosing to in use situations, and (ii) to recognize that thicker formulations may sometimes enhance the penetration of other topical agents when applied "in use".
Publisher: Elsevier BV
Date: 08-2008
DOI: 10.1002/JPS.21253
Publisher: Springer Science and Business Media LLC
Date: 08-1989
DOI: 10.1007/BF01061455
Abstract: The incorporation of rigid aromatic linkers into β-diketiminate ligands creates a binucleating scaffold that holds two metals near each other. This paper discloses the synthesis, characterization, and reactivity of mBin(2-), which has a meta-substituted xylylene spacer, and pBin(2-), which has a para-substituted xylylene spacer. Lithium, aluminum, and zinc complexes of each ligand are isolated, and in some cases are characterized by X-ray crystallography. The lithium complexes are coordinated to solvent-derived THF ligands, while the zinc and aluminum complexes have alkyl ligands. Complexes of the mBin(2-) ligand have an anti conformation in which the metals are on opposite sides of the macrocycle, while pBin(2-) complexes prefer a syn conformation. The (1)H NMR spectra of the complexes demonstrate that the conformations rapidly interconvert in the lithium complexes, and less rapidly in the zinc and aluminum complexes.
Publisher: Springer Science and Business Media LLC
Date: 2001
Abstract: This study sought to determine whether multidisciplinary case conference reviews improved outcomes for nursing home residents, and the effects of this team approach to resident care on carers, including the hands-on carers employed by the nursing home, and health professionals. 245 residents of three Canberra nursing homes were enrolled in this non-randomised controlled trial. The intervention consisted of sessions of three case conference reviews held between 10/4/96 and 4/12/96. These sessions were attended by the General Practitioners (GPs) of the residents discussed, the GP project officer from the ACT Division of General Practice, a clinical pharmacist, senior nursing staff, other health professionals e.g. physiotherapist, and occasionally the resident concerned or their representative. At each review, a case presentation by the resident's GP was followed by a multidisciplinary discussion of all aspects, medical and non-medical, of the resident's care. The review concluded with a management plan for the resident. In total 75 residents were reviewed. Medication use and cost, and mortality. One month after the reviews were completed comparisons between those who were reviewed and those who were not showed non-significant reductions in medication orders, medication cost, and mortality in the reviewed group. Many of the 92 recommendations in the management plans that were carried out benefited the residents (n = 37) and/or carers (n = 24). The responses of the GPs and the Directors of Nursing to the reviews were overwhelmingly positive. Recommendations arising from multidisciplinary case conferences were carried out to the benefit of patients and carers. Given the support shown by key stakeholders, multidisciplinary conferences should be used more.
Publisher: IOP Publishing
Date: 07-07-2020
Publisher: Oxford University Press (OUP)
Date: 03-2002
Abstract: The purpose of this study was to determine the pharmacokinetics of [14C]diclofenac, [14C]salicylate and [3H]clonidine using a single pass rat head perfusion preparation. The head was perfused with 3-[N-morpholino] propane-sulfonic acid-buffered Ringer's solution. 99mTc-red blood cells and a drug were injected in a bolus into the internal carotid artery and collected from the posterior facial vein over 28 min. A two-barrier stochastic organ model was used to estimate the statistical moments of the solutes. Plasma, interstitial and cellular distribution volumes for the solutes ranged from 1.0 mL (diclofenac) to 1.6 mL (salicylate), 2.0 mL (diclofenac) to 4.2 mL (water) and 3.9 mL (salicylate) to 20.9 mL (diclofenac), respectively. A comparison of these volumes to water indicated some exclusion of the drugs from the interstitial space and salicylate from the cellular space. Permeability-surface area (PS) products calculated from plasma to interstitial fluid permeation clearances (CLPI) (range 0.02-0.40 mL s−1) and fractions of solute unbound in the perfusate were in the order: diclofenac & salicylate & clonidine & sucrose (from 41.8 to 0.10 mL s−1). The slow efflux of diclofenac, compared with clonidine and salicylate, may be related to its low average unbound fraction in the cells. This work accounts for the tail of disposition curves in describing pharmacokinetics in the head.
Publisher: Wiley
Date: 28-01-2010
DOI: 10.1111/J.1440-1746.2009.05981.X
Abstract: Compound Astragalus and Salvia miltiorrhiza extract (CASE) is made up of astragalosides, astragalus polysaccharide and salvianolic acids extracted from Astragalus membranaceus Bunge (Leguminosae) and Salvia miltiorhiza Bunge (Lamiaceae) with a standard ratio. Previous reports showed that CASE inhibited hepatic fibrosis by mediating transforming growth factor (TGF)-beta/Smad signaling. This study further investigated the effect of CASE on hepatoma HepG2 cells stimulated by TGF-beta(1) and its potential action mechanisms by TGF-beta/Smad signaling. Cell proliferation was studied by MTT assay and cell invasion was evaluated by measuring cell migration through Matrigel. Protein expression in hepatoma HepG2 cells stimulated by TGF-beta(1) was analyzed by western blotting and plasminogen activator inhibitor type 1 (PAI-1) transcriptional activity in HepG2 cells was evaluated. CASE (40 microg/mL) markedly suppressed cell invasion triggered by TGF-beta(1). Smad3 phosphorylation at the linker region (pSmad3L) and Samd2 phosphorylation at the C-terminal region (pSmad2C) were significantly reduced by CASE. Mild elevated Smad3 phosphorylation at C-terminal (pSmade3C) region was enhanced by CASE at 20 microg/mL. In addition, treatment of CASE decreased the level of Smad2/3/4 complex at 80 microg/mL, but upregulated the expression of Smad7 in a dose-dependent manner. CASE also showed inhibitory effect on PAI-1 transcriptional activity. All these results suggest that CASE exerts anti-HepG2 cell invasion effect by modulating TGF-beta/Smad signaling.
Publisher: Springer Science and Business Media LLC
Date: 1998
Abstract: To study epidermal and polyethylene membrane penetration and retention of the sunscreen benzophenone-3 (BP) from a range of single solvent vehicles and evaluate solvent effects on permeability parameters. The solubility of BP was measured in a number of solvents. Penetration of BP across human epidermis and high density polyethylene (HDPE) membranes was studied from 50% saturated solutions in each solvent. Maximal BP fluxes from the solvents across the two membranes varied widely. Highest fluxes were observed from 90% ethanol (EtOH) for epidermis and from isopropyl myristate (IPM) and C12-15 benzoate alcohols (C12-15 BA) for HDPE membrane. Both the flux and estimated permeability coefficient and skin-vehicle partitioning of BP appeared to be related to the vehicle solubility parameter (delta(v)). The major effects of solvents on BP flux appear to be via changes in BP diffusivity through the membranes. Minimal penetration of sunscreens such as BP is best achieved by choosing vehicles with a delta(v) substantially different to the solubility parameter of the membrane.
Publisher: Elsevier BV
Date: 06-1993
Publisher: Wiley
Date: 04-2002
DOI: 10.1046/J.1365-2125.2002.01554.X
Abstract: Morphine-6-glucuronide (M6G), one of the active metabolites of morphine, has attracted considerable interest as a potent opioid analgesic with an apparently superior therapeutic index. To date studies have used the intravenous route, which is generally unacceptable in the treatment of cancer related pain. The aim of this study was to define the pharmacokinetics, toxicity and cardio-respiratory effects of three alternative routes of administration of M6G. Ten healthy volunteers participated in an open randomized study. Subjects received M6G 2 mg as an intravenous bolus, 20 mg orally, 2 mg subcutaneously and 4 mg by the nebulized route. Pulse, blood pressure, respiratory rate and peak flow rate were monitored and subjective toxicity recorded on rating and visual analogue scales. After i.v. M6G the mean (+/- s.d.) AUC(0,infinity) standardized to a dose of 1 mg was 223 +/- 57 nmol l(-1) h, mean elimination half-life was 1.7 +/- 0.7 h and the mean clearance was 157 +/- 46 ml min(-1). These parameters were virtually identical after subcutaneous administration which had a bioavailability (F(0,infinity)) of 102 +/- 35% (90% CI 82, 117%) and t(max) of 0.5 +/- 0.2 h. The mean bioavailability of nebulized M6G was 6 +/- 2% (90% CI 4, 7%) with a t(max) of 1.2 +/- 0.8 h. Following oral M6G two plasma M6G peaks were seen in 7 of the 10 subjects, the first with a t(max) of 3.1 (+/- 0.9) h. The second peak had a t(max) of 13.4 (+/-5.0) h, started approximately 4 h after dosing, and was associated with the detection of plasma M3G and morphine, suggesting that M6G was significantly hydrolysed in the gut to morphine, which was then glucuronidated following absorption. Although the overall mean bioavailability was 11 +/- 3% (90% CI 9, 12%), confining the analysis to data from the first peak suggested a bioavailability of directly absorbed M6G of only 4 +/- 4%. Apart from a characteristic dysphoria following intravenous and subcutaneous M6G, there was no significant toxicity. With the minimal toxicity reported in this and previous studies, subcutaneous infusion of M6G may potentially provide clinically useful analgesia for advanced cancer pain. Nebulized M6G is not significantly absorbed via the lungs, and if opiates are shown to have a local effect in the lung, reducing the sensation of breathlessness, then nebulized administration is likely to minimize systemic effects. Oral M6G has poor bioavailability, but is significantly hydrolysed in the gut to morphine, which is subsequently glucuronidated following absorption. This circuitous route accounts for the majority of systemically available M6G after oral administration.
Publisher: Informa UK Limited
Date: 03-2010
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 05-11-2021
Abstract: Clearance is one of the most widely quoted and applied pharmacokinetic concepts in drug development and therapy. Its foundations and associated models of drug elimination are well embedded and accepted within the scientific community. Recently, however, the prevailing views that have held us in good stead for the past almost 50 years have been challenged with the argument that organ clearance should not be based on elimination rate, now defined by extraction across the liver ided by incoming or systemic concentration, as in current practice, but rather, by the mean concentration of drug within the blood in the organ, which is model-dependent. We argue that all needed parameters already exist, and that the proposed new approach to organ clearance is confusing and unnecessary. SIGNIFICANCE STATEMENT: Clearance concepts are widely applied in drug development and therapy. Historically, hepatic clearance has been defined as the ratio of rate of elimination ided by ingoing blood concentration. Recently, this approach has been challenged arguing that clearance should be referenced to blood concentration within the liver extrapolation (IVIVE). There is no need for additional, a feature that corresponds to intrinsic clearance of the chosen clearance model, a widely accepted parameter in physiologically based pharmacokinetic (PBPK) and in vitro to in vivo extrapolation (IVIVE). There is no need for additional, confusing clearance terms, which offer no material benefit.
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.EJPS.2013.06.006
Abstract: A better understanding of the role of hepatic transporters in drug elimination is of crucial importance for drug development and therapy. This study examined the usefulness of intravital microscopy to quantitatively evaluate the function of hepatic transporters in the exposed liver of anesthetized rats. In one experiment the function of the organic anion transporting polypeptide (Oatp) in sinusoidal uptake was investigated by administering an Oatp inhibitor, rif icin, prior to the probe substrate Na-fluorescein. In another experiment, rhodamine 123 was used to quantify the biliary canalicular transporter P-glycoprotein (P-gp, Abcb1a/b) with cyclosporin A as an inhibitor of P-gp activity. Calibrated fluorescence intensity time curves measured in sinusoids and hepatocytes together with cumulative biliary excretion data from control and inhibitor treated animals were analyzed with a three-compartment model. A robust parameter estimation was achieved using nonlinear mixed effects modeling. Rif icin reduced the hepatic uptake clearance of Na-fluorescein to 25% of the control (p<0.05) without affecting other parameters. In the presence of cyclosporin A, biliary excretion of rhodamine 123 decreased to 7% of the control (p<0.01). The novelty of this approach is that it allows a quantitative evaluation of transporter function in the in vivo rat liver.
Publisher: Elsevier BV
Date: 11-1996
Abstract: Conditions which influence the viability, integrity, and extraction efficiency of the isolated perfused rat liver were examined to establish optimal conditions for subsequent work in reperfusion injury studies including the choice of buffer, use of oncotic agents, hematocrit, perfusion flow rate, and pressure. Rat livers were perfused with MOPS-buffered Ringer solution with or without erythrocytes. Perfusates were collected and analyzed for blood gases, electrolytes, enzymes, radioactivity in MID studies, and lignocaine in extraction studies. Liver tissue was s led for histological examinations, and wet:dry weight of the liver was also determined. MOPS-buffered Ringer solution was found to be superior to Krebs bicarbonate buffer, in terms of pH control and buffering capacity, especially during any prolonged period of liver perfusion. A pH of 7. 2 is chosen for perfusion since this is the physiological pH of the portal blood. The presence of albumin was important as an oncotic agent, particularly when erythrocytes were used in the perfusate. Perfusion pressure, resistance, and vascular volume are flow-dependent and the inclusion of erythrocytes in the perfusate substantially altered the flow characteristics for perfusion pressure and resistance but not vascular volume. Lignocaine extraction was relatively flow-independent. Perfusion injury as defined by enzyme release and tissue fine structure was closely related to the supply of O2. The optimal conditions for liver perfusion depend upon an adequate supply of oxygen. This can be achieved by using either erythrocyte-free perfusate at a flow rate greater than 6 ml/min/g liver or a 20% erythrocyte-containing perfusate at 2 ml/min/g.
Publisher: Springer Science and Business Media LLC
Date: 04-02-2020
Publisher: American Physiological Society
Date: 2011
Abstract: It has been reported that the adjuvant-induced inflammation could affect drug metabolism in liver. Here we further investigated the effect of inflammation on drug transport in liver using taurocholate as a model drug. The hepatic disposition kinetics of [ 3 H]taurocholate in perfused normal and adjuvant-treated rat livers were investigated by the multiple indicator dilution technique and data were analyzed by a previously reported hepatobiliary taurocholate transport model. Real-time RT-PCR was also performed to determine the mRNA expression of liver bile salt transporters in normal and diseased livers. The uptake and biliary excretion of taurocholate were impaired in the adjuvant-treated rats as shown by decreased influx rate constant k in (0.65 ± 0.09 vs. 2.12 ± 0.30) and elimination rate constant k be (0.09 ± 0.02 vs. 0.17 ± 0.04) compared with control rat group, whereas the efflux rate constant k out was greatly increased (0.07 ± 0.02 vs. 0.02 ± 0.01). The changes of mRNA expression of liver bile salt transporters were found in adjuvant-treated rats. Hepatic taurocholate extraction ratio in adjuvant-treated rats (0.86 ± 0.05, n = 6) was significantly reduced compared with 0.93 ± 0.05 ( n = 6) in normal rats. Hepatic extraction was well correlated with altered hepatic ATP content ( r 2 = 0.90). In conclusion, systemic inflammation greatly affects hepatic ATP content roduction and associated transporter activities and causes an impairment of transporter-mediated solute trafficking and pharmacokinetics.
Publisher: Elsevier BV
Date: 10-2018
Publisher: Informa UK Limited
Date: 08-01-2013
DOI: 10.1517/17425255.2013.754009
Abstract: The process of drug disposition in the lung after pulmonary delivery is complex involving absorptive and non-absorptive mechanisms. The lung has also been suggested to be a trapping and metabolizing organ, especially after intravenous administration of drug. A key challenge is to define the most suitable models for the evaluation of pulmonary drug disposition. This review provides an overview of the anatomy and physiology of the lung and sites of action. The authors follow this with a description of the processes associated with pulmonary disposition (deposition, absorption, distribution, metabolism, and non-absorptive clearance). The article also summarizes and compares models and techniques for the assessment of drug disposition in the lung, in terms of characteristic features, advantages and disadvantages. Finally, the authors review pharmaceutical science implications of these findings. In vivo models are preferred for studying drug deposition, absorption, disposition, and response in the lung. In vitro models may be useful in the initial screening for new compounds and in drug lead optimization. The labor-intensive isolated perfused lung models are most suitable for in-depth studies on drug pulmonary disposition for lead compounds. In the future, engineered lungs may become a more convenient means of evaluating drug disposition in the lung.
Publisher: Elsevier BV
Date: 12-1992
Publisher: Springer Science and Business Media LLC
Date: 05-11-2013
DOI: 10.1007/S13346-013-0181-8
Abstract: The transdermal route offers advantages for delivery of peptides and proteins. However, these polar and large molecules do not permeate the skin barrier well. Various enhancement methods have been employed to address this problem. Iontophoresis is one of the methods that shows promise but its application to peptide delivery has yet to be fully explored. This study investigates the effects of different molecular properties and iontophoretic conditions on the skin permeation of peptides. In this study, the permeation of alanine-tryptophan dipeptide (MW 276 Da), alanine-alanine-proline-valine tetrapeptide (MW 355 Da), Argireline® (Acetyl hexapeptide-3, MW 889 Da) and Triptorelin acetate (decapeptide, MW 1311 Da) through excised human skin under passive or iontophoretic current of 0.4 mA was investigated. The effects of pH change (3.0-7.4, to provide different net negative, neutral, and positive charges) to the peptide, donor concentration (1-10 mg/ml), background electrolyte (34-137 mM NaCl and/or 5-20 mM HEPES) and current direction (anodal vs cathodal) were also studied. Peptides were analysed by high-performance liquid chromatography or liquid scintillation counting. Iontophoresis led up to a 30 times increase in peptide permeation relative to passive permeation for the peptides. Electroosmosis was an important determinant of the total flux for the high molecular weight charged peptides. Electrorepulsion was found to be considerable for low molecular weight charged moieties. Permeation was decreased at lower pH, possibly due to decreased electroosmosis. Results also showed that 10 times increase in donor peptide concentration increases permeation of peptides by about 2-4 times and decreases iontophoretic permeability coefficients by about 2.5-5 times. The addition of extra background electrolyte decreased the iontophoretic permeation coefficient of peptides by 2-60 times. This study shows that iontophoretic permeation of peptides is affected by a number of parameters that can be optimized for effective transdermal peptide delivery.
Publisher: Wiley
Date: 16-03-2015
DOI: 10.1111/HDI.12293
Abstract: Isoniazid is a rare overdose that causes seizures and there is limited evidence to guide treatment. We report a 20-year-old female migrant who presented with recurrent seizures after ingesting 25 g of isoniazid. She was treated with activated charcoal, repeated doses of midazolam for the seizures, and given multiple doses of pyridoxine (14 mg), limited by availability. She was admitted to intensive care, and 5.5 hours post-ingestion, she was commenced on continuous veno-venous hemodiafiltration (CVVHDF). She was extubated after 24 hours and CVVHDF was ceased 6 hours later (30 hours post-overdose). Her renal function remained normal and her initial lactate was the highest at 2.3. She made a full recovery. Five plasma s les were collected before, during, and after CVVHDF, and isoniazid was quantified with liquid chromatography-tandem mass spectrometry. A pharmacokinetic analysis of time-isoniazid concentration data was fitted to a two-compartment model with first-order input (with fixed ka ) with the effect of CVVHDF modeled as a time-dependent covariate. This suggested that there was initially good clearance with CVVHDF (4 times endogenous clearance), which rapidly declined within hours.
Publisher: SPIE-Intl Soc Optical Eng
Date: 2006
DOI: 10.1117/1.2166086
Abstract: A miniature fiber optic spectrometer enclosed within a semipermeable (dialysis) membrane is proposed for in vivo interstitial sensing applications. The semipermeable membrane acts as a molecular filter, allowing only small molecules to pass through to the s ling volume. This filtering, in principle, should enable continuous in vivo drug sensing, removing the necessity for complex microdialysis systems. We use a biological phantom to examine the reliable detection of a fluorescence signal from small dye molecules in the presence of large fluorophores and scatterers. We find that spectral artefacts arising from scatterers and large fluorophores are substantially suppressed, simplifying the spectral analysis. In addition, the measured s ling rate of 157 s is superior to existing in vivo tissue assaying techniques such as microdialysis, which can take tens of minutes.
Publisher: Springer Science and Business Media LLC
Date: 16-08-2005
DOI: 10.1007/S11095-005-7248-2
Abstract: The hepatic transmembrane flux of long-chain fatty acids (LCFA) occurs through passive and fatty acid transport protein facilitated processes from blood. The extent that these transport processes can be related to the unbound and protein-bound fractions of LCFA in blood is not clear. We used hepatocyte suspensions, hepatoma monolayers, and perfused rat livers to quantitate the transport of purified [(3)H]palmitate ([(3)H]PA) and 12-(N-methyl)-N-[(7-nitrobenz-2oxa-1,3-diazol-4yl-)amino]octadecanoicacid (12-NBDS) from solutions with a constant unbound LCFA concentration with varying bovine serum albumin (BSA) concentrations and in the presence and absence of antisera raised against cytosolic liver fatty acid binding protein (L-FABP). In the absence of L-FABP antisera, using an unbound ligand concentration that was adjusted to remain constant at each BSA concentration, hepatocyte [(3)H]PA and 12-NBDS uptake rates increased linearly with an increase in BSA concentration (p < 0.0001). In the presence of L-FABP antisera, [(3)H]PA uptake showed a greater reduction in the presence of 100 muM BSA than 5 muM BSA. The calculated permeability surface area product (PS) confirmed that both unbound and bound fractions of LCFA contributed to the overall flux, but only the PS for the protein-bound fraction was reduced in the presence of L-FABP antisera. In situ rat liver perfusion studies showed that the only rate process for the disposition of [(3)H]PA in the liver inhibited by L-FABP antisera was that for influx, as defined by PS, and that it reduced PS in the perfused liver by 42%. These results suggest that, at physiological albumin concentrations, most of the LCFA uptake is mediated from that bound to albumin by a hepatocyte basolateral membrane transport protein, and uptake of unbound LCFA occurring by passive diffusion contributes a minor component.
Publisher: eLife Sciences Publications, Ltd
Date: 09-07-2018
DOI: 10.7554/ELIFE.35800
Abstract: Intravital microscopy can provide unique insights into the function of biological processes in a native context. However, physiological motion caused by peristalsis, respiration and the heartbeat can present a significant challenge, particularly for functional readouts such as fluorescence lifetime imaging (FLIM), which require longer acquisition times to obtain a quantitative readout. Here, we present and benchmark Galene, a versatile multi-platform software tool for image-based correction of s le motion blurring in both time resolved and conventional laser scanning fluorescence microscopy data in two and three dimensions. We show that Galene is able to resolve intravital FLIM-FRET images of intra-abdominal organs in murine models and NADH autofluorescence of human dermal tissue imaging subject to a wide range of physiological motions. Thus, Galene can enable FLIM imaging in situations where a stable imaging platform is not always possible and rescue previously discarded quantitative imaging data.
Publisher: SPIE-Intl Soc Optical Eng
Date: 2008
DOI: 10.1117/1.3041492
Abstract: Zinc oxide (ZnO-nano) and titanium dioxide nanoparticles (20 to 30 nm) are widely used in several topical skin care products, such as sunscreens. However, relatively few studies have addressed the subdermal absorption of these nanoparticles in vivo. We report on investigation of the distribution of topically applied ZnO in excised and in vivo human skin, using multiphoton microscopy (MPM) imaging with a combination of scanning electron microscopy (SEM) and an energy-dispersive x-ray (EDX) technique to determine the level of penetration of nanoparticles into the sub-dermal layers of the skin. The good visualization of ZnO in skin achieved appeared to result from two factors. First, the ZnO principal photoluminescence at 385 nm is in the "quiet" spectral band of skin autofluorescence dominated by the endogenous skin fluorophores, i.e., NAD[P]H and FAD. Second, the two-photon action cross section of ZnO-nano [sigma(ZnO) ((TPEF)) approximately 0.26 GM diameter, 18 nm] is high: approximately 500-fold of that inferred from its bulk third-order nonlinear susceptibility [Im chi(ZnO) ((3))], and is favorably compared to that of NAD[P]H and FAD. The overall outcome from MPM, SEM, and EDX studies was that, in humans in vivo, ZnO nanoparticles stayed in the stratum corneum (SC) and accumulated into skin folds and/or hair follicle roots of human skin. Given the lack of penetration of these nanoparticles past the SC and that the outermost layers of SC have a good turnover rate, these data suggest that the form of ZnO-nano studied here is unlikely to result in safety concerns.
Publisher: Springer Science and Business Media LLC
Date: 09-10-2013
DOI: 10.1007/S11096-012-9704-5
Abstract: There is a large amount of research into and promotion of rational prescribing, but there is a comparative lack of investigation into deprescribing. The success of deprescribing is likely to be dependent on both medical and patient factors. The aim of this study was to develop and validate a tool to capture the views and beliefs of patients regarding cessation of medications. Setting Participants were recruited from a multidisciplinary clinic at the Royal Adelaide Hospital and H stead Rehabilitation Centre. The patients' attitudes towards deprescribing (PATD) questionnaire was developed through expert opinion and piloting. Psychometric testing included face, content and criterion validity, sensitivity and test-retest reliability. A final 15 item questionnaire was produced. Through piloting, expert review and gamma rank correlation with the previously validated beliefs about medicines questionnaire, the PATD was determined to be valid. Test-retesting resulted in a total concordance of 71.3 % (95 % confidence interval, 64.1-78.5 %). The PATD has acceptable psychometric properties and has potential for future use in research and practice to not only determine patients' willingness towards deprescribing, but also uncover what beliefs may influence this.
Publisher: Elsevier BV
Date: 08-1999
Publisher: Springer Science and Business Media LLC
Date: 19-10-2006
DOI: 10.1007/S10928-006-9031-3
Abstract: Current physiologically based pharmacokinetic (PBPK) models are inductive. We present an additional, different approach that is based on the synthetic rather than the inductive approach to modeling and simulation. It relies on object-oriented programming. A model of the referent system in its experimental context is synthesized by assembling objects that represent components such as molecules, cells, aspects of tissue architecture, catheters, etc. The single pass perfused rat liver has been well described in evaluating hepatic drug pharmacokinetics (PK) and is the system on which we focus. In silico experiments begin with administration of objects representing actual compounds. Data are collected in a manner analogous to that in the referent PK experiments. The synthetic modeling method allows for recognition and representation of discrete event and discrete time processes, as well as heterogeneity in organization, function, and spatial effects. An application is developed for sucrose and antipyrine, administered separately and together. PBPK modeling has made extensive progress in characterizing abstracted PK properties but this has also been its limitation. Now, other important questions and possible extensions emerge. How are these PK properties and the observed behaviors generated? The inherent heuristic limitations of traditional models have hindered getting meaningful, detailed answers to such questions. Synthetic models of the type described here are specifically intended to help answer such questions. Analogous to wet-lab experimental models, they retain their applicability even when broken apart into sub-components. Having and applying this new class of models along with traditional PK modeling methods is expected to increase the productivity of pharmaceutical research at all levels that make use of modeling and simulation.
Publisher: SPIE-Intl Soc Optical Eng
Date: 2011
DOI: 10.1117/1.3647597
Abstract: Ischemia-reperfusion (I/R) injury is a common occurrence in liver surgery. In orthotopic transplantation, the donor liver is exposed to periods of ischemia and when oxygenated blood is reintroduced to the liver, oxidative stress may develop and lead to graft failure. The aim of this project was to investigate whether noninvasive multiphoton and fluorescence lifetime imaging microscopy, without external markers, were useful in detecting early liver damage caused by I/R injury. Localized hepatic ischemia was induced in rats for 1 h followed by 4 h reperfusion. Multiphoton and fluorescence lifetime imaging microscopy was conducted prior to ischemia and up to 4 h of reperfusion and compared to morphological and biochemical assessment of liver damage. Liver function was significantly impaired at 2 and 4 h of reperfusion. Multiphoton microscopy detected liver damage at 1 h of reperfusion, manifested by vacuolated cells and heterogeneous spread of damage over the liver. The damage was mainly localized in the midzonal region of the liver acinus. In addition, fluorescence lifetime imaging showed a decrease in cellular metabolic activity. Multiphoton and fluorescence lifetime imaging microscopy detected evidence of early I/R injury both structurally and functionally. This provides a simple noninvasive technique useful for following progressive liver injury without external markers.
Publisher: Oxford University Press (OUP)
Date: 24-12-2015
DOI: 10.1093/JAC/DKV412
Abstract: The objectives of this study were to determine the effects of obesity on unbound trough concentrations and on the achievement of pharmacokinetic (PK) harmacodynamic (PD) targets of piperacillin and meropenem in critically ill patients. This study retrospectively analysed therapeutic-drug-monitoring data from ICU databases in Australia, Germany and Spain, as well as from a large PK study. The presence of obesity was defined as a BMI ≥30 kg/m(2), and patients were also categorized based on level of renal function. The presence of obesity was compared with unbound piperacillin and meropenem trough concentrations. We also used logistic regression to describe factors associated with the achievement of the PK/PD targets, an unbound concentration maintained above the MIC breakpoint (100% fT>MIC and 100% fT>4×MIC) of Pseudomonas aeruginosa. In all, 1400 patients were eligible for inclusion in the study. The median age and weight were 67 years (IQR 52-76 years) and 79 kg (69-90 kg), respectively, and 65% of participants were male. Significantly lower median piperacillin trough concentrations [29.4 mg/L (IQR 17.0-58.0 mg/L)] were found in obese patients compared with non-obese patients [42.0 mg/L (21.5-73.5 mg/L)] (P = 0.001). There was no difference for meropenem trough concentrations [obese 10.3 mg/L (IQR 4.8-16.0 mg/L) versus non-obese 11.0 mg/L (4.3-18.5 mg/L) P = 0.296]. Using logistic regression, we found that the presence of obesity was not associated with achievement of 100% fT>MIC, but the use of prolonged infusion, a creatinine clearance ≤100 mL/min, increasing age and female gender were for various PK/PD targets for both piperacillin and meropenem (P < 0.05). This large dataset has shown that the presence of obesity in critically ill patients may affect piperacillin, but not meropenem, unbound trough concentrations.
Publisher: Elsevier BV
Date: 09-1997
Publisher: Oxford University Press (OUP)
Date: 20-01-2015
DOI: 10.1093/JAC/DKU564
Abstract: The objective of this study was to describe the population pharmacokinetics of cefazolin in plasma and the interstitial fluid of subcutaneous tissue of post-trauma critically ill patients and provide clinically relevant dosing recommendations that result in optimal concentrations at the target site. This was a pharmacokinetic study in a tertiary referral ICU. We recruited 30 post-trauma critically ill adult patients and collected serial total and unbound plasma cefazolin concentrations. Interstitial fluid concentrations were determined using in vivo microdialysis. Population pharmacokinetic analysis and Monte Carlo simulations were undertaken with Pmetrics®. Fractional target attainment against an MIC distribution for Staphylococcus aureus isolates was calculated. The mean (SD) age, weight, APACHE II score and CLCR were 37.0 (14.1) years, 86.8 (22.7) kg, 16.9 (5.3) and 163 (44) mL/min, respectively. A three-compartment linear population pharmacokinetic model was most appropriate. Covariates included in the model were CLCR on drug clearance and serum albumin concentration and body weight on the volume of the central compartment. The fractional target attainment for a 1 g intravenous 8-hourly dose for a CLCR of 50 mL/min was 88%, whereas for a patient with a CLCR of 215 mL/min, a dose of 2 g 6-hourly achieved 84% fractional target attainment. Clinicians should be mindful of the effects of elevated CLCR and serum albumin concentrations on dosing requirements for post-trauma critically ill patients.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Elsevier BV
Date: 06-2021
Publisher: Springer Science and Business Media LLC
Date: 06-1990
DOI: 10.1007/BF01062200
Publisher: Springer Science and Business Media LLC
Date: 06-1990
DOI: 10.1007/BF01062201
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.EJPB.2009.06.012
Abstract: This study documents drug-excipient incompatibility studies of acyclovir in physical mixtures with lactose and in different tablet brands. Differential scanning calorimetry (DSC) was initially used to assess compatibility of mixtures. The Fourier-transform infrared (FTIR) spectrum was also compared with the spectra of pure drug and excipient. Although DSC results indicated incompatibility with lactose, FTIR spectra were mostly unmodified due to overlapping peaks. S les of isothermally stressed physical mixture were stored at 95 degrees C for 24 h. The residual drug was monitored using a validated high-performance liquid chromatography (HPLC) assay and data fitting to solid-state kinetic models was performed. The drug loss kinetics followed a diffusion model. The aqueous mixture of drug and excipient was heated in order to prepare an adduct mixture. HPLC analysis revealed one extra peak that was fractionated and subsequently injected into the liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) system. The MRM (Multiple Reaction Monitoring) chromatograms characterized the peak with molecular mass corresponding to an acyclovir-lactose Maillard reaction product. The presence of lactose in commercial tablets was checked using a new TLC method. Overall, the incompatibility of acyclovir with lactose was successfully evaluated using a combination of thermal methods and LC-MS/MS.
Publisher: Informa UK Limited
Date: 11-06-2015
DOI: 10.3109/15563650.2015.1054504
Abstract: To describe the clinical effects, pharmacokinetics, and pharmacodynamics of plasma and acetylcholinesterase in an aldicarb overdose. A 57-year-old female was found unconscious and incontinent of urine after ingesting aldicarb. She was bradycardic, hypotensive, hypersalivating, clammy, had small pupils, and generalized weakness. She was intubated, ventilated, and treated with large atropine doses (50 mg and 20 mg/h infusion) and adrenaline. She improved hemodynamically over 24 h, but remained comatose for another 24 h, before recovering without sequela. Aldicarb concentration at admission was 2.18 μg/ml and concentration-time data best fitted a two compartmental model with first order absorption and a time of ingestion 4.5 h preadmission. The half-life of distribution was 0.4 h and half-life of elimination, 13 h. Plasma cholinesterase concentration at admission was 0.3 kU/L (Reference range[RR]:4.3-10.6 kU/L) and red cell cholinesterase was 10 U/gHb (RR:38-66 U/gHb). The IC50 was 0.15 μg/ml and 0.26 μg/ml for plasma and red cell cholinesterase, respectively. Aldicarb poisoning causes rapid onset severe toxicity with muscarinic and nicotinic excess, seizures, and decreased consciousness. Cholinesterases rapidly recover once aldicarb concentrations decrease and precede clinical recovery.
Publisher: Elsevier BV
Date: 06-1994
Abstract: The deep-tissue penetration of lidocaine below a dermally applied site was quantified in a rat model. The concentrations of lidocaine in tissues below the applied site were measured and compared with plasma concentrations and concentrations in similar tissues on the contralateral side. The direct penetration of lidocaine was predominant for the first 2 h up to a depth of about 1 cm below the applied site. A physiologically based pharmacokinetic model based on apparent tissue-tissue clearances and local blood flow to tissues is presented which adequately describes the concentration-time profiles of lidocaine in underlying tissues after dermal application. The apparent tissue-tissue clearances were estimated by nonlinear regression assuming first-order diffusional mass transfer of lidocaine between the various tissue compartments below the applied site in anesthetized rats. Tissue levels of lidocaine were estimated using simulations from the model with and without direct penetration and tissue blood supply. Dermal microcirculation is not a perfect sink for lidocaine.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2011
DOI: 10.1007/S11095-011-0437-2
Abstract: To model and interpret drug distribution in the dermis and underlying tissues after topical application which is relevant to the treatment of local conditions. We created a new physiological pharmacokinetic model to describe the effect of blood flow, blood protein binding and dermal binding on the rate and depth of penetration of topical drugs into the underlying skin. We used this model to interpret literature in vivo human biopsy data on dermal drug concentration at various depths in the dermis after topical application of six substances. This interpretation was facilitated by our in vitro human dermal penetration studies in which dermal diffusion coefficient and binding were estimated. The model shows that dermal diffusion alone cannot explain the in vivo data, and blood and/or lymphatic transport to deep tissues must be present for almost all of the drugs tested. Topical drug delivery systems for deeper tissue delivery should recognise that blood/lymphatic transport may dominate over dermal diffusion for certain compounds.
Publisher: Elsevier BV
Date: 06-1994
Abstract: The effects of the local vasoconstrictor phenylephrine on the dermal absorption kinetics and local tissue distribution of compounds were investigated in rats. Phenylephrine (0.0025% -0.1%) and tracer quantities of salicylic acid, lidocaine, and water were applied in an aqueous solution to the exposed rat dermis. The disappearance of salicylic acid from the solution into the rat dermis and its appearance in blood, local underlying tissues, and similar tissues on the contralateral side was quantified. The clearance of salicylic acid into the dermis decreased and the concentrations of salicylic acid in underlying tissues increased with an increase in phenylephrine concentration (up to 0.01%). The concentrations of salicylic acid in plasma and contralateral issues decreased with increasing phenylephrine concentrations. At higher phenylephrine concentrations, no significant increase in local tissue concentrations of salicylic acid was observed. The effects of phenylephrine on local tissue levels of lidocaine and tritiated water paralleled those found for salicylic acid. The concentration-depth profiles for solutes in underlying tissues with variable blood flows were described by a compartment-in-series pharmacokinetic model in which each tissue's blood flows to and from a central compartment were incorporated. The values predicted under varying degrees of vasoconstriction were found to compare well with the experimentally determined concentrations of salicylic acid, lidocaine, and water in issues below a dermal application site, in the presence of phenylephrine. Phenylephrine can significantly increase quantities of solutes delivered to local tissues after dermal application, the observed effects being due to the vasoconstrictive properties of phenylephrine. Blood flow changes in skin can have profound effects on dermal pharmacokinetics and relative processes of local and systemic solute distribution.
Publisher: Springer Science and Business Media LLC
Date: 02-2012
DOI: 10.1007/S11095-012-0690-Z
Abstract: To explore how liver damage arising from cardio-hepatic syndromes in RHF affect the hepatic pharmacokinetics of basic drugs. The hepatic pharmacokinetics of five selected basic drugs with different physicochemical properties were studied in IPRL from control rats and rats with RHF. Hepatic pharmacokinetic modelling was performed with a two-phase physiologically-based organ pharmacokinetic model with the vascular space and dispersion evaluated with the MID technique. The liver damage arising from RHF was assessed by changes in liver biochemistry and histopathology. The expression of various CYP isoforms was evaluated by real-time RT-PCR analysis. Four of the five basic drugs had a significantly lower E in RHF rat livers compared to the control rat livers. Hepatic pharmacokinetic analysis showed that both the CL int and PS were significantly decreased in the RHF rat livers. Stepwise regression analysis showed that the alterations in the pharmacokinetic parameters (E, CL int and PS) can be correlated to the observed histopathological changes (NI, CYP concentration and FI) as well as to the lipophilicity of the basic drugs (logP app). Serious hepatocellular necrosis and fibrosis induced by RHF affects both hepatic microsomal activity and hepatocyte wall permeability, leading to significant impairment in the hepatic pharmacokinetics of basic drugs.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 18-01-2011
Abstract: The hepatic pharmacokinetics of five selected cationic drugs (propranolol, labetalol, metoprolol, antipyrine, and atenolol) was studied in the liver from control rats and from those with high-fat emulsion-induced nonalcoholic steatohepatitis (NASH). Studies were undertaken using an in situ-perfused rat liver and multiple indicator dilution, and outflow data were analyzed with a physiologically based organ pharmacokinetic model. Hepatic extraction (E) was significantly lower in the NASH model, and lipophilicity was the main solute structural determinant of the observed differences in intrinsic elimination clearance (CL(int)) and permeability-surface area product (PS) with pK(a) defining the extent of sequestration in the liver [apparent distribution ratio (K(v))]. The main pathophysiological determinants were liver fibrosis, leading to a decreased PS, liver fat causing an increase in K(v), and an increase in both total liver cytochrome P450 (P450) concentration and P450 isoform expression for Cyp3a2 and Cyp2d2, causing an increase CL(int) in NASH rat livers compared with control livers. Changes in hepatic pharmacokinetics (PS, K(v), CL(int), and E ratio) as a result of NASH were related to the physicochemical properties of drugs (lipophilicity or pK(a)) and hepatic histopathological changes (fibrosis index, steatosis index, and P450 concentration) by stepwise regression analysis. Thus, it appears that in NASH, counteracting mechanisms to facilitate hepatic removal are created in NASH-induced P450 expression, whereas NASH-induced fibrosis and steatohepatitis inhibit E by decreasing hepatocyte permeability through fibrosis and hepatic sequestration.
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.JPBA.2012.01.007
Abstract: A simple and rapid high performance liquid chromatographic method was developed, validated and applied for the simultaneous determination of marbofloxacin (MBX) and trovafloxacin (TVX) in sheep plasma. S les were extracted with 20% perchloric acid and MBX and TVX were separated on a C(18) column using a gradient mobile phase system consisting of 17.5mM of NaH(2)PO(4) and 1.5mM of tetrabutylammonium hydroxide aqueous solution, pH 3 (A) and 50% acetonitrile and 50% methanol (B), with UV detection at 293 and 270 nm. The retention times of MBX and TVX were 4.9 and 6.6 min respectively. The detection and quantification limits for MBX and TVX were 2 ng/mL and 10 ng/mL respectively for both compounds. The calibration curves were linear over a concentration range of 10-50,000 ng/mL for both antibiotics. The linearity, precision, accuracy, recovery and stability of the assay were evaluated from spiked sheep plasma. The method was successfully applied to sheep plasma s les obtained from MBX and TVX pharmacokinetic studies.
Publisher: Springer Science and Business Media LLC
Date: 11-2018
Publisher: SAGE Publications
Date: 07-2012
DOI: 10.1345/APH.1Q694
Abstract: The elderly population is at a high risk of medication misadventure, with many studies reporting a high number of medication-related problems (MRPs) in this group. To quantify MRPs in residential facilities routinely reviewed by pharmacists and compare these results with other published findings. This cross-sectional study included deidentified residents' health and medication data from 6 aged-care facilities. Regular medication reviews had been conducted over 20 years in these facilities. Two hundred ninety-six pharmacist intervention report forms were completed by 3 accredited clinical pharmacists over a 2-year period. These data were then used as a baseline in analyzing other published data for residential aged-care facilities and for patients at home. A total of 802 (range 0-12 per review) MRPs were identified in patients who were prescribed 2-29 medicines per patient, with a mean of 2.7 MRPs per review (95% CI 2.43 to 2.98). An analysis of the literature showed that the length of treatment, inclusion criteria used, and the definition of MRPs greatly affected the results obtained. However, application of the different inclusion criteria used in other published studies to our data resulted in findings similar to the published Australian average for residents of aged-care facilities and patients living independently at home (3.9 and 4.8 MRPs per patient, respectively). All medicines can potentially lead to MRPs. MRPs identified during pharmacist medication reviews vary widely between studies but can be normalized by inclusion criteria, length of stay, and the nature of the identified problem. It is recommended that a minimum benchmark for best practice in a patient population receiving at least yearly reviews be less than 3 MRPs per patient. Higher benchmarks of 4 MRPs per patient should apply when the patient population is restricted to include those receiving more than 9 medications and with more than 2 MRPs.
Publisher: Elsevier BV
Date: 07-1999
Publisher: S. Karger AG
Date: 31-10-2018
DOI: 10.1159/000491758
Abstract: b i Aim: /i /b We evaluated the effects of the incorporation of zinc oxide (ZnO) nanoparticles in a mesoporous matrix, aiming to improve the textural, structural and morphological properties and verify their safety so that they can be applied in sunscreen cosmetics. b i Materials and Methods: /i /b ZnO nanoparticles were incorporated into an ordered mesoporous silica matrix known as Santa Barbara Amorphous-15 (SBA-15), using post-synthesis methodology. The resulting nanocomposites were characterized using X-ray diffraction, small angle X-ray scattering, N sub /sub adsorption-desorption isotherms, Fourier transform infrared spectroscopy, scanning electron microscopy and predicted in vitro sun protector factor (SPF) estimation. Effectiveness and safety were evaluated by antimicrobial activity, in vitro cell toxicity and non-invasive multi-photon tomography with fluorescence lifetime imaging. b i Results: /i /b The structure of the nanocomposites was similar to that of SBA-15, with little perturbation caused by ZnO incorporation. Nanocomposites had an increased in vitro SPF, reduced cytotoxic activity and favourable antimicrobial properties compared to ZnO. ZnO:SBA-15 nanocomposites exhibited no measurable toxicity when applied to human skin in vivo. b i Conclusion: /i /b Due to their suitable physicochemical properties and improved safety compared to bare ZnO nanoparticles, the ZnO:SBA-15 nanocomposites show promise for use in cosmetic applications.
Publisher: Elsevier BV
Date: 02-2004
DOI: 10.1002/JPS.10567
Publisher: Bentham Science Publishers Ltd.
Date: 09-2013
DOI: 10.2174/1381612811319350011
Abstract: Exposure of human skin to nanoparticles (NPs) is increasing with the development of nanotechnology and new applications of NPs in medicine. Safety concerns have sparked debate on the capacity of NPs to penetrate through skin and enter into the body. This article attempts to summarize the recent evidence on whether NPs penetrate human skin and the factors that may affect the penetration. Skin structure and penetration mechanisms are reviewed to provide background information. Size, shape, formulation, surface properties and application methods and their effects on skin penetration are specifically discussed. Finally, the relationship between skin penetration and nanotoxicity is reviewed to further emphasise the importance of the research in this area.
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.JCHROMB.2014.04.029
Abstract: There is strong evidence in literature supporting the benefit of monitoring plasma concentrations of β-lactam antibiotics in the critically ill to ensure appropriateness of dosing. The objective of this work was to develop a method for the simultaneous determination of total concentrations piperacillin, benzylpenicillin, flucloxacillin, meropenem, ertapenem, cephazolin and ceftazidime in human plasma. S le preparation involved protein precipitation with acetonitrile containing 0.1% formic acid and subsequent dilution of supernatant with 0.1% formic acid in water. Chromatographic separation was achieved on a reversed phase column (C18, 2.6 μm, 2.1 × 50 mm) via gradient elution using water and acetonitrile, each containing 0.1% formic acid, as mobile phase. Tandem mass spectrometry (MSMS) analysis was performed, after electrospray ionization in the positive mode, with multiple reaction monitoring (MRM). The method is accurate with the inter-day and intra-day accuracies of quality control s les (QCs) ranging from 95 to 107% and 95 to 108%, respectively. It is also precise with intra-day and inter-day coefficient of variations ranging from 4 to 12% and 5 to 14%, respectively. The lower limit of quantification was 0.1 μg/mL for each antibiotic except flucloxacillin (0.25 μg/mL). Recovery was greater than 96% for all analytes except for ertapenem (78%). Coefficients of variation for the matrix effect were less than 10% over the six batches of plasma. Analytes were stable over three freeze-thaw cycles, and for reasonable hours on the bench top as well as post-preparation. This novel liquid chromatography tandem mass spectrometry method proved accurate, precise and applicable for therapeutic drug monitoring and pharmacokinetic studies of the selected β-lactam antibiotics.
Publisher: Wiley
Date: 07-06-2012
DOI: 10.1111/J.1600-0846.2012.00640.X
Abstract: 5-Aminolevulinate (ALA) is an important photodynamic therapy drug for the treatment of actinic keratoses and other non-melanoma skin cancers in cosmetically sensitive areas. One limitation of this drug is a relatively high recurrence rate. Our aim was to evaluate the feasibility of ultrasound augmented ALA delivery in excised human skin. An ultrasonic delivery device was used to enhance radiolabelled ALA into excised skin. Quantification of ALA was performed after passive and ultrasonic ALA delivery. Transepidermal water loss was used as a measure of barrier function before and after ultrasonic treatment. We found that ultrasonic treatment dramatically increased the mean cumulative amount of ALA to P< 0.0001 from 4 to 8 h when compared to passive ALA treatment. The flux was calculated to be 54.8 ± 8.0 μg/cm(2) h with ultrasound treatment. TEWL increased nearly two-fold, from 12.3 to 21.0, after ultrasound treatment. Our study supports the use of ultrasound for improved ALA delivery by showing significant improvements in the cumulative drug load and flux via combined ultrasound and ALA treatment.
Publisher: Informa UK Limited
Date: 11-03-2011
DOI: 10.3109/03602532.2011.560607
Abstract: Pharmacokinetics, pharmacology, and toxicology are the major determinants of the success or failure of candidates during drug development. Because inappropriate pharmacokinetics often leads to inefficacy, even toxicity, pharmacokinetics studies have been regarded as crucial components in drug preclinical and clinical research. However, new data increasingly reveal that drug concentrations in plasma or tissues cannot totally explain the efficacy of drug on the target organ. For most drugs that interact with targets localized in cells, intracellular penetration, accumulation, distribution, and elimination are important parameters governing the efficacy in the target cells. So, there is a pressing need to clarify the cellular pharmacokinetics and thus evaluate the efficacy of drugs in the target cells. This review provides a general overview regarding current knowledge about cellular pharmacokinetics in some specific cells and also summarizes the factors that can influence cellular pharmacokinetics. It concludes by discussing potential strategies for optimizing cellular pharmacokinetics and advocating that global cellular pharmacokinetics studies be conducted in future research toward improving drug efficacy.
Publisher: Elsevier BV
Date: 02-2009
DOI: 10.1002/JPS.21461
Publisher: Springer Science and Business Media LLC
Date: 03-2016
Publisher: Springer New York
Date: 2009
Publisher: Springer Science and Business Media LLC
Date: 2001
Abstract: In the present study we examined the relationship between solvent uptake into a model membrane (silicone) with the physical properties of the solvents (e.g., solubility parameter, melting point, molecular weight) and its potential predictability. We then assessed the subsequent topical penetration and retention kinetics of hydrocortisone from various solvents to define whether modifications to either solute diffusivity or partitioning were dominant in increasing permeability through solvent-modified membranes. Membrane sorption of solvents was determined from weight differences following immersion in in idual solvents, corrected for differences in density. Permeability and retention kinetics of 3H-hydrocortisone, applied as saturated solutions in the various solvents, were determined over 48 h in horizontal Franz-type glass diffusion cells. Solvent sorption into the membrane could be related to differences in solubility parameters, MW and hydrogen bonding (r2=0.76). The actual and predicted volume of solvent sorbed into the membrane was also found to be linearly related to Log hydrocortisone flux, with changes in both diffusivity and partitioning of hydrocortisone observed for the different solvent vehicles. A simple structure-based predictive model can be applied to the sorption of solvents into silicone membranes. Changes in solute diffusivity and partitioning appeared to contribute to the increased hydrocortisone flux observed with the various solvent vehicles. The application of this predictive model to the more complex skin membrane remains to be determined.
Publisher: American Society for Microbiology
Date: 11-2016
DOI: 10.1128/AAC.01088-16
Abstract: Our objective was to describe the population pharmacokinetics of fluconazole in a cohort of critically ill nonobese, obese, and morbidly obese patients. Critically ill patients prescribed fluconazole were recruited into three body mass index (BMI) cohorts, nonobese (18.5 to 29.9 kg/m 2 ), obese (30.0 to 39.9 kg/m 2 ), and morbidly obese (≥40 kg/m 2 ). Serial fluconazole concentrations were determined using a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Twenty-one critically ill patients (11 male) were enrolled, including obese ( n = 6) and morbidly obese ( n = 4) patients. The patients mean ± standard deviation (SD) age, weight, and BMI were 54 ± 15 years, 90 ± 24 kg, and 31 ± 9 kg/m 2 , respectively. A two-compartment linear model described the data adequately. The mean ± SD population pharmacokinetic parameter estimates were clearance (CL) of 0.95 ± 0.48 liter/h, volume of distribution of the central compartment ( V c ) of 15.10 ± 11.78 liter, intercompartmental clearance from the central to peripheral compartment of 5.41 ± 2.28 liter/h, and intercompartmental clearance from the peripheral to central compartment of 2.92 ± 4.95 liter/h. A fluconazole dose of 200 mg daily was insufficient to achieve an area under the concentration-time curve for the free, unbound drug fraction/MIC ratio of 100 for pathogens with MICs of ≥2 mg/liter in patients with BMI of kg/m 2 . A fluconazole loading dose of 12 mg/kg and maintenance dose of 6 mg/kg/day achieved pharmacodynamic targets for higher MICs. A weight-based loading dose of 12 mg/kg followed by a daily maintenance dose of 6 mg/kg, according to renal function, is required in critically ill patients for pathogens with a MIC of 2 mg/liter.
Publisher: Copernicus GmbH
Date: 08-09-2015
Abstract: Abstract. Soil erosion is a major threat to soil functioning. The use of vegetation to control erosion has long been a topic for research. Much of this research has focused on the above-ground properties of plants, demonstrating the important role that canopy structure and cover plays in the reduction of water erosion processes. Less attention has been paid to plant roots. Plant roots are a crucial yet under-researched factor for reducing water erosion through their ability to alter soil properties, such as aggregate stability, hydraulic function and shear strength. However, there have been few attempts to specifically manipulate plant root system properties to reduce soil erosion. Therefore, this review aims to explore the effects that plant roots have on soil erosion and hydrological processes, and how plant root architecture might be manipulated to enhance its erosion control properties. We demonstrate the importance of root system architecture for the control of soil erosion. We also show that some plant species respond to nutrient-enriched patches by increasing lateral root proliferation. The erosional response to root proliferation will depend upon its location: at the soil surface dense mats of roots may reduce soil erodibility but block soil pores thereby limiting infiltration, enhancing runoff. Additionally, in nutrient-deprived regions, root hair development may be stimulated and larger amounts of root exudates released, thereby improving aggregate stability and decreasing erodibility. Utilizing nutrient placement at specific depths may represent a potentially new, easily implemented, management strategy on nutrient-poor agricultural land or constructed slopes to control erosion, and further research in this area is needed.
Publisher: Informa UK Limited
Date: 10-2016
DOI: 10.2147/CPAA.S64788
Publisher: S. Karger AG
Date: 2013
DOI: 10.1159/000353647
Abstract: An appreciation of solute-vehicle-skin interactions underpins our current understanding of the processes of percutaneous absorption as well as in the prediction of the extent of absorption. This understanding has been reached through principles developed and validated over the last century through the work of a number of authors, including Dale Wurster, Takeru Higuchi, Irvin Blank, Robert Scheuplein, Gordon Flynn, Boyd Poulsen and Tom Franz, as well as by many scientists from my and younger generations. Their work has led to an appreciation of the rate-limiting steps in percutaneous penetration, the role played by the physicochemical properties of the solute, vehicle and skin and the variability that may arise from using various experimental/mathematical harmacokinetic models to quantify absorption as well as enabling the prediction of local and systemic efficacy and toxicity. In addition, unexpected behaviour may result from non-ideality in solute-vehicle-skin effects, including dehydration, chemical enhancement, supersaturation, metabolism, sequestration and vascular effects, including those of nanosystems on the local vasculature. In general, in vitro skin penetration profiles are predictive of in vivo profiles but a number of exceptions also exist.
Publisher: Springer Science and Business Media LLC
Date: 12-1993
DOI: 10.1007/BF01113500
Abstract: Gene regulatory network is a complicated set of interactions between genetic materials, which dictates how cells develop in living organisms and react to their surrounding environment. Robust comprehension of these interactions would help explain how cells function as well as predict their reactions to external factors. This knowledge can benefit both developmental biology and clinical research such as drug development or epidemiology research. Recently, the rapid advance of single-cell sequencing technologies, which pushed the limit of transcriptomic profiling to the in idual cell level, opens up an entirely new area for regulatory network research. To exploit this new abundant source of data and take advantage of data in single-cell resolution, a number of computational methods have been proposed to uncover the interactions hidden by the averaging process in standard bulk sequencing. In this article, we review 15 such network inference methods developed for single-cell data. We discuss their underlying assumptions, inference techniques, usability, and pros and cons. In an extensive analysis using simulation, we also assess the methods' performance, sensitivity to dropout and time complexity. The main objective of this survey is to assist not only life scientists in selecting suitable methods for their data and analysis purposes but also computational scientists in developing new methods by highlighting outstanding challenges in the field that remain to be addressed in the future development.
Publisher: Informa UK Limited
Date: 28-10-2017
DOI: 10.1080/15563650.2016.1249795
Abstract: Poisoning due to chloroform ingestion is rare. The classic features of acute chloroform toxicity include central nervous system (CNS) and respiratory depression, and delayed hepatotoxicity. A 30-year-old female ingested 20-30 mL of 99% chloroform solution, which caused rapid loss of consciousness, transient hypotension and severe respiratory depression requiring endotracheal intubation and ventilation. She was alert by 12 h and extubated 16 h post-overdose. At 38-h post-ingestion, her liver function tests started to rise and she was commenced on intravenous acetylcysteine. Her alanine transaminase (1283 U/L), aspartate transaminase (734 U/L) and international normalized ratio (2.3) peaked 67- to 72-h post-ingestion. She also developed severe abdominal pain, vomiting and diarrhoea. An abdominal CT scan was consistent with severe enterocolitis, and an upper gastrointestinal endoscopy showed erosive oesophagitis, severe erosive gastritis and ulceration. She was treated with opioid analgesia, proton pump inhibitors, sucralfate and total parenteral nutrition. Secretions caused a contact dermatitis of her face and back. Nine days post-ingestion she was able to tolerate food. Her liver function tests normalized and the dermatitis resolved. Chloroform was measured using headspace gas chromatograph mass spectrometry, with a peak concentration of 2.00 μg/mL, 4 h 20 min post-ingestion. The concentration-time data fitted a 1-compartment model with elimination half-life 6.5 h. In addition to early CNS depression and delayed hepatotoxicity, we report severe gastrointestinal injury and dermatitis with chloroform ingestion. Recovery occurred with good supportive care, acetylcysteine and management of gastrointestinal complications.
Publisher: Springer Science and Business Media LLC
Date: 2011
DOI: 10.1186/CC9966
Publisher: Pharmaceutical Society of Japan
Date: 2005
DOI: 10.1248/BPB.28.383
Abstract: The uptake and metabolism profiles of ginsenoside Rh2 and its aglycon protopanaxadiol (ppd) were studied in the human epithelial Caco-2 cell line. High-performance liquid chromatography-mass spectrometry was applied to determine Rh2 and its aglycon ppd concentration in the cells at different pH, temperature, concentration levels and in the presence or absence of inhibitors. Rh2 uptake was time and concentration dependent, and its uptake rates were reduced by metabolic inhibitors and influenced by low temperature, thus indicating that the absorption process was energy-dependent. Drug uptake was maximal when the extracellular pH was 7.0 for Rh2 and 8.0 for ppd. Rh2 kinetic analysis showed that a non-saturable component (Kd 0.17 nmol x h(-1) x mg(-1) protein) and an active transport system with a Km of 3.95 micromol x l(-1) and a Vmax of 4.78 nmol x h(-1) x mg(-1)protein were responsible for the drug uptake. Kinetic analysis of ppd showed a non-saturable component (Kd 0.78 nmol x h(-1) x mg(-1) protein). It was suggested that active extrusion of P-glycoprotein and drug degradation in the intestine may influence Rh2 bioavailability.
Publisher: Elsevier BV
Date: 11-2001
DOI: 10.1016/S0006-8993(01)03011-6
Abstract: The purpose of this study was to develop a newborn piglet model of hypoxia/ischaemia which would better emulate the clinical situation in the asphyxiated human neonate and produce a consistent degree of histopathological injury following the insult. One-day-old piglets (n=18) were anaesthetised with a mixture of propofol (10 mg/kg/h) and alfentinal (55.5 microg/kg/h) i.v. The piglets were intubated and ventilated. Physiological variables were monitored continuously. Hypoxia was induced by decreasing the inspired oxygen (FiO(2)) to 3-4% and adjusting FiO(2) to maintain the cerebral function monitor peak litude at < or =5 microV. The duration of the mild insult was 20 min while the severe insult was 30 min which included 10 min where the blood pressure was allowed to fall below 70% of baseline. Control piglets (n=4 of 18) were subjected to the same protocol except for the hypoxic/ischaemic insult. The piglets were allowed to recover from anaesthesia then euthanased 72 h after the insult. The brains were perfusion-fixed, removed and embedded in paraffin. Coronal sections were stained by haematoxylin/eosin. A blinded observer examined the frontal and parietal cortex, hippoc us, basal ganglia, thalamus and cerebellum for the degree of damage. The total mean histology score for the five areas of the brain for the severe insult was 15.6+/-4.4 (mean +/-S.D., n=7), whereas no damage was seen in either the mild insult (n=4) or control groups. This 'severe damage' model produces a consistent level of damage and will prove useful for examining potential neuroprotective therapies in the neonatal brain.
Publisher: S. Karger AG
Date: 2005
DOI: 10.1159/000085861
Abstract: Sunscreen skin penetration and safety assessment should be considered together in order to ensure that in vitro cytotoxicity studies examine relevant doses of these organic chemical UV filters to which viable epidermal cells are realistically exposed. In this study, we sought to determine whether sufficient topically applied sunscreens penetrated into human viable epidermis to put the local keratinocyte cell populations at risk of toxicity. The penetration and retention of five commonly used sunscreen agents (avobenzone, octinoxate, octocrylene, oxybenzone and padimate O) in human skin was evaluated after application in mineral oil to isolated human epidermal membranes. Sunscreen concentration–human keratinocyte culture response curves were then defined using changes in cell morphology and proliferation (DNA synthesis using radiolabelled thymidine uptake studies) as evidence of sunscreens causing toxicity. Following 24 h of human epidermal exposure to sunscreens, detectable amounts of all sunscreens were present in the stratum corneum and viable epidermis, with epidermal penetration most evident with oxybenzone. The concentrations of each sunscreen found in human viable epidermis after topical application, adjusting for skin partitioning and binding effects, were at least 5-fold lower, based on levels detected in viable epidermal cells, than those appearing to cause toxicity in cultured human keratinocytes. It is concluded that the human viable epidermal levels of sunscreens are too low to cause any significant toxicity to the underlying human keratinocytes.
Publisher: Springer Science and Business Media LLC
Date: 02-1992
DOI: 10.1007/BF01143185
Publisher: Springer Science and Business Media LLC
Date: 1997
Abstract: Absorption kinetics of solutes given with the subcutaneous administration of fluids is ill-defined. The gamma emitter, technitium pertechnetate, enabled estimates of absorption rate to be estimated independently using two approaches. In the first approach, the counts remaining at the site were estimated by imaging above the subcutaneous administration site, whereas in the second approach, the plasma technetium concentration-time profiles were monitored up to 8 hr after technetium administration. Boluses of technetium pertechnetate were given both intravenously and subcutaneously on separate occasions with a multiple dosing regimen using three doses on each occasion. The disposition of technetium after i.v. administration was best described by biexponential kinetics with a Vss of 0.30 +/- 0.11 L/kg and a clearance of 30.0 +/- 13.1 ml/min. The subcutaneous absorption kinetics was best described as a single exponential process with a half-life of 18.16 +/- 3.97 min by image analysis and a half-life of 11.58 +/- 2.48 min using plasma technetium time data. The bioavailability of technetium by the subcutaneous route was estimated to be 0.96 +/- 0.12. The absorption half-life showed no consistent change with the duration of the subcutaneous infusion. The amount remaining at the absorption site with time was similar when analyzed using image analysis, and plasma concentrations assuming multiexponential disposition kinetics and a first-order absorption process. Profiles of fraction remaining at the absorption site generated by deconvolution analysis, image analysis, and assumption of a constant first-order absorption process were similar. Slowing of absorption from the subcutaneous administration site is apparent after the last bolus dose in three of the subjects and can be associated with the stopping of the infusion. In a fourth subject, the retention of technetium at the subcutaneous site is more consistent with accumulation of technetium near the absorption site as a result of systemic recirculation.
Publisher: Elsevier BV
Date: 11-2000
DOI: 10.1046/J.1523-1747.2000.00151.X
Abstract: The efficacy of topical allergy screening systems relies on the ability of test agents to effectively penetrate the stratum corneum from applied vehicles and reach the viable cells involved in the cutaneous immune response system. There is very little evidence in the dermatologic literature to justify the choice and suitability of vehicles used in many allergy test systems and the effectiveness of occlusion, reported to have variable effects on solute penetration, often employed in combination with these systems. In this study we evaluated the in vitro human epidermal penetration of a mixture of paraben ester preservatives from a commercially available test ointment and two commonly employed solvent vehicles (acetone and ethanol), together with the effect of occlusion on the rate of delivery from these systems. Parabens were applied as finite doses (5 mg per cm2) to epidermal membranes mounted in horizontal Franz-type diffusion cells. At intervals of 2 h for a total of 10 h the receptor phase (20% ethanol in distilled water) was completely removed and replaced. Occlusion was effected by the placement of a piece of high density polyethylene (20 microm) over the application site immediately after dosing. Concentrations of parabens in receptor fluid and remaining in the epidermis at the end of the study were determined by high-performance liquid chromatography. There was a significant change in the epidermal flux of parabens from each of the vehicles following occlusion. Whereas increases were observed for the acetone and ethanol vehicles a decrease was seen following occlusion of the ointment formulation. Changes in flux appeared to result from a significant decrease in the epidermal partitioning of the esters following occlusion of the ointment and primarily by an increase in paraben epidermal diffusivity (estimated from changes in flux/retention) following occlusion of the solvent vehicles. These studies show that the effects of occlusion are strongly vehicle dependent, having wide implications for optimization of this technique with a range of topically applied solutes.
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.EJPB.2018.01.019
Abstract: The mathematical model describing drug flux through microporated skin was previously developed. Based on this model, two mathematical equations can be used to predict the microporatio-enhanced transdermal drug flux: the complex primal equation containing a variety of experimentally-determined variables, and the simplified straightforward equation. In this study, experimental transdermal fluxes of three corticosteroids through split-thickness human skin treated with a microneedle roller were measured, and the values of fluxes compared with those predicted using both the more complex and simplified equations. According to the results of the study, both equations demonstrated high accuracy in the prediction of the fluxes of corticosteroids. The simplified equation was validated and confirmed as robust using regression analysis of literature data. Further, its capability and ease of use was exemplified by predicting the flux of methotrexate through the skin microporated with laser and comparing with published experimental data.
Publisher: Elsevier BV
Date: 08-2000
DOI: 10.1016/S0928-0987(00)00095-6
Abstract: The tissue distribution kinetics of a highly bound solute, propranolol, was investigated in a heterogeneous organ, the isolated perfused limb, using the impulse-response technique and destructive s ling. The propranolol concentration in muscle, skin, and fat as well as in outflow perfusate was measured up to 30 min after injection. The resulting data were analysed assuming (1) vascular, muscle, skin and fat compartments as well mixed (compartmental model) and (2) using a distributed-in-space model which accounts for the noninstantaneous intravascular mixing and tissue distribution processes but consists only of a vascular and extravascular phase (two-phase model). The compartmental model adequately described propranolol concentration-time data in the three tissue compartments and the outflow concentration-time curve (except of the early mixing phase). In contrast, the two-phase model better described the outflow concentration-time curve but is limited in accounting only for the distribution kinetics in the dominant tissue, the muscle. The two-phase model well described the time course of propranolol concentration in muscle tissue, with parameter estimates similar to those obtained with the compartmental model. The results suggest, first that the uptake kinetics of propranolol into skin and fat cannot be analysed on the basis of outflow data alone and, second that the assumption of well-mixed compartments is a valid approximation from a practical point of view (as, e.g., in physiological based pharmacokinetic modelling). The steady-state distribution volumes of skin and fat were only 16 and 4%, respectively, of that of muscle tissue (16.7 ml), with higher partition coefficient in fat (6.36) than in skin (2.64) and muscle (2.79).
Publisher: Springer Science and Business Media LLC
Date: 1998
Abstract: An in vitro study was carried out to determine the iontophoretic permeability of local anesthetics through human epidermis. The relationship between physicochemical structure and the permeability of these solutes was then examined using an ionic mobility-pore model developed to define quantitative relationships. The iontophoretic permeability of both ester-type anesthetics (procaine, butacaine, tetracaine) and amide-type anesthetics (prilocaine, mepivacaine, lidocaine, bupivacaine, etidocaine, cinchocaine) were determined through excised human epidermis over 2 hrs using a constant d.c. current and Ag/AgCl electrodes. In idual ion mobilities were determined from conductivity measurements in aqueous solutions. Multiple stepwise regression was applied to interrelate the iontophoretic permeability of the solutes with their physical properties to examine the appropriateness of the ionic mobility-pore model and to determine the best predictor of iontophoretic permeability of the local anesthetics. The logarithm of the iontophoretic permeability coefficient (log PC(j,iont)) for local anesthetics was directly related to the log ionic mobility and MW for the free volume form of the model when other conditions are held constant. Multiple linear regressions confirmed that log PC(j,iont) was best defined by ionic mobility (and its determinants: conductivity, pKa and MW) and MW. Our results suggest that of the properties studied, the best predictors of iontophoretic transport of local anesthetics are ionic mobility (or pKa) and molecular size. These predictions are consistent with the ionic mobility pore model determined by the mobility of ions in the aqueous solution, the total current, epidermal permselectivity and other factors as defined by the model.
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.EJPB.2010.12.023
Abstract: New multiphoton and confocal microscope technologies and fluorescence lifetime imaging techniques are now being used to non-invasively image, in space (three dimensions),in time, in spectra, in lifetime and in fluorescence anisotropy (total of 7 dimensions), fluorescent molecules in in situ and in vivo biological tissue, including skin. The process involves scanning a 2D area and measuring fluorescence at a given tissue depth below the surface after excitation by a laser beam with a wavelength within the one-photon or two-photon absorption band of the fluorophores followed by the stacking together of a series of 2D images from different depths to reconstruct the full spatial structure of the s le. Our aim in this work is to describe the principles, opportunities, limitations and applications of this new technology and its application in defining skin morphology, disease and skin penetration in vitro and in vivo by drugs, chemicals and nanoparticles. A key emphasis is in the use of fluorescence lifetime imaging to add additional specificity and quantitation to the detection of the various exogenous chemicals and nanoparticles that may be applied to the skin as well as endogenous fluorescent species in the skin. Ex les given include equipment configuration components in skin autofluorescence in various skin strata imaging and quantification of coexisting drugs and their metabolites skin pH nanoparticle zinc oxide skin penetration liposome delivery of drugs to deeper tissues and observations in skin ageing and in various skin diseases.
Publisher: Elsevier BV
Date: 06-2008
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2001
DOI: 10.1097/00008390-200108000-00014
Abstract: Isolated limb infusion (ILI) is an attractive, less complex alternative to isolated limb perfusion (ILP). It has a lower morbidity in treating localized recurrences and in transit metastases of the limb for tumours such as melanoma, Merkel cell tumour and Kaposi's sarcoma, allowing administration of high concentrations of cytotoxic agent to the affected limb under hypoxic conditions. Melphalan is the preferred cytotoxic agent for the treatment of melanoma by ILP or ILI. We report pharmacokinetic data from 12 patients treated by ILI for tumours of the limb in Brisbane. The kinetics of drug distribution in the limb was calculated using a two-compartment vascular model, where both tissue and infusate act as well-stirred compartments. Analysis of melphalan concentrations in the perfusate during ILI showed good agreement between the values measured and the concentrations predicted by the model. Recirculation and wash-out flow rates, tissue concentrations and the permeability surface area product (PS) were calculated. Correlations between the PS value and the drug concentrations in the perfusate and tissue were supported by the results. These data contribute to a better understanding of the distribution of melphalan during ILI in the limb, and offer the opportunity to optimize the drug regimen for patients undergoing ILI.
Publisher: Wiley
Date: 19-02-2017
DOI: 10.1111/EXD.13274
Abstract: Skin cancer is associated with abnormal cellular metabolism which if identified early introduces the possibility of intervention to prevent its progress to a deadly metastatic stage. This study combines multiphoton microscopy with fluorescence lifetime imaging (FLIM) using a syngeneic melanoma mouse model, to detect changes in metabolic state of single epidermal cells as a metabolic marker to monitor the progress of tumor growth. This method utilizes imaging of the ratio of the amounts of the free and protein-bound forms of the intracellular autofluorescent metabolic co-enzyme nicotinamide adenine dinucleotide (NADH). Here, we investigate the impact of the primary tumor lesion on the epidermal layers at three different growth stages of melanoma lesion compared to normal skin as a control. We showed a significant increase in the free-to-bound NADH ratio with the growth of the solid melanoma tumor, while concurrently the short and the long lifetime components of NADH remained constant. These results demonstrate the ability of FLIM for rapid, non-invasive and sensitive assessment of melanoma progression revealing its potential as a diagnostic tool for melanoma detection and as an aid for melanoma staging.
Publisher: Informa UK Limited
Date: 08-2012
DOI: 10.1586/EDM.12.32
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.MEATSCI.2022.108910
Abstract: This study investigated the effect of superchilling (-30 °C until the core temperature achieved -3 °C, and - 1 °C until 24 h, SC) on shelf-life and bacterial community dynamics of beef loins, with a typical very fast chilling (-30 °C until the core temperature achieved 0 °C, and - 1 °C until 24 h, VFC) and conventional chilling (0- 4 °C for 24 h, CC) as controls. The super-chilled storage (-1 °C) was adopted after each chilling procedure, and physicochemical traits and microbiological quality were evaluated during a long-term storage. No remarkable adverse impact on meat color and lipid oxidation were observed in SC treatment. The bacterial composition results showed that Carnobacterium spp. were the main bacteria in SC treatment in the late storage period (63- 84 days). The loss of Lactobacillus spp., due to the "ultra-low temperature" during the superchilling, might be the reason that the SC did not result in a longer shelf-life compared with CC s les.
Publisher: Springer Science and Business Media LLC
Date: 06-2004
DOI: 10.1023/B:PHAR.0000026803.89436.A8
Abstract: To identify determinants of PRN (as needed) drug use in nursing homes. Decisions about the use of these medications are made expressly by nursing home staff when general medical practitioners (GPs) prescribe medications for PRN use. Cross-sectional drug use data were collected during a 7-day window from 13 Australian nursing homes. Information was collected on the size, staffing-mix, number of visiting GPs, number of medication rounds, and mortality rates in each nursing home. Resident specific measures collected included age, gender, length of stay, recent hospitalisation and care needs. The number of PRN orders prescribed per resident and the number of PRN doses given per week averaged over the number of PRN medications given at all in the seven-day period. Approximately 35% of medications were prescribed for PRN use. Higher PRN use was found for residents with the lower care needs, recent hospitalisation and more frequent doses of regularly scheduled medications. With increasing length of stay, PRN medication orders initially increased then declined but the number of doses given declined from admission. While some resident-specific characteristics did influence PRN drug use, the key determinant for PRN medication orders was the specific nursing home in which a resident lived. Resident age and gender were not determinants of PRN drug use. The determinants of PRN drug use suggest that interventions to optimize PRN medications should target the care of in idual residents, prescribing and the nursing home processes and policies that govern PRN drug use.
Publisher: Springer Science and Business Media LLC
Date: 06-1988
DOI: 10.1007/BF01062135
Abstract: Motivation plays an important role in a variety of behaviors, including smoking cessation, and is integral to theory and treatment of smoking. For many women, pregnancy offers a motivational shift that helps them stop smoking and maintain abstinence during pregnancy. However, women's motivation to maintain smoking abstinence postpartum is not well-understood and may play a role in high postpartum relapse rates. The current study utilized multiple measures of prepartum motivation to maintain smoking abstinence to predict postpartum smoking abstinence. As part of a randomized clinical trial on postpartum smoking relapse prevention, pregnant women who quit smoking during pregnancy reported their motivation to continue smoking abstinence at a prepartum baseline session. Biochemically verified continued smoking abstinence was assessed at 8 and 26 weeks postpartum. Direct relationships among multiple measures of motivation were significant, and ranged in strength from weak to moderate. All motivation measures in idually predicted continuous smoking abstinence, after controlling for treatment group, demographics, and prequit tobacco use. When tested simultaneously, a global motivation measure and parenthood motives for quitting remained significant predictors of abstinence. Backward selection modeling procedures resulted in a reduced model of prepartum predictors of postpartum abstinence including global motivation, parenthood motives, and stage of change. Global motivation for smoking abstinence and parenthood motives for quitting are particularly important motivational constructs for pregnant women's continued smoking abstinence.
Publisher: SPIE-Intl Soc Optical Eng
Date: 28-06-2013
Publisher: Elsevier BV
Date: 1985
Publisher: Elsevier BV
Date: 02-1996
DOI: 10.1016/0378-4347(95)00368-1
Abstract: This paper describes a simple and more sensitive reversed-phase HPLC method for the quantification of phenol, 4-nitrophenol and beta-naphthol and some of their glucuronide and sulphate conjugates in aqueous solution and liver perfusate buffer. Methanol-water mobile phases with ion-pairing agents for each phenolic group are detailed. The assay showed good recovery, accuracy and precision and is suitable for the quantification of these phenolic compounds in liver perfusion experiments.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 06-2002
Abstract: The disposition kinetics of six cationic drugs in perfused diseased and normal rat livers were determined by multiple indicator dilution and related to the drug physicochemical properties and liver histopathology. A carbon tetrachloride (CCl(4))-induced acute hepatocellular injury model had a higher fibrosis index (FI), determined by computer-assisted image analysis, than did an alcohol-induced chronic hepatocellular injury model. The alcohol-treated group had the highest hepatic alpha(1)-acid glycoprotein, microsomal protein (MP), and cytochrome P450 (P450) concentrations. Various pharmacokinetic parameters could be related to the octanol-water partition coefficient (log P(app)) of the drug as a surrogate for plasma membrane partition coefficient and affinity for MP or P450, the dependence being lower in the CCl(4)-treated group and higher in the alcohol-treated group relative to controls. Stepwise regression analysis showed that hepatic extraction ratio, permeability-surface area product, tissue-binding constant, intrinsic clearance, partition ratio of influx (k(in)) and efflux rate constant (k(out)), and k(in)/k(out) were related to physicochemical properties of drug (log P(app) or pK(a)) and liver histopathology (FI, MP, or P450). In addition, hepatocyte organelle ion trapping of cationic drugs was evident in all groups. It is concluded that fibrosis-inducing hepatic disease effects on cationic drug disposition in the liver may be predicted from drug properties and liver histopathology.
Publisher: Springer Science and Business Media LLC
Date: 28-09-2007
DOI: 10.1007/S00403-007-0789-Y
Abstract: Transepidermal water loss (TEWL), mainly regulated by the stratum corneum, was quantitatively correlated to percutaneous absorption of compounds in human and suggested for the ex vivo assessment of skin integrity. The present study investigated qualitatively and quantitatively the relevance of 100-microm heat separated epidermis (HSE) in percutaneous absorption studies as compared to 500-microm dermatomed skin by dual complementary approaches. Percutaneous absorption of caffeine delivered from aqueous solution through dermatomed skin or HSE specimens (n = 9) was measured using vertical static diffusion cells coupled with an unventilated evaporimeter enabling the assessment of TEWL and skin integrity for 21 h. Permeation of caffeine exhibited different finite dose-like profiles ranged according to the thickness of skin specimens (cumulative dose absorbed up to 21 h: 11.5 +/- 11.5 microg/cm(2) and 29.4 +/- 36.2 microg/cm(2) through dermatomed skin and HSE, respectively). Normalized TEWL and caffeine fluxes were similar through dermatomed skin and HSE suggesting that the intrinsic permeability properties of both models were undifferentiated over time. Interestingly, a significant relationship was shown between TEWL and caffeine fluxes, suggesting the usefulness of TEWL measurement as an element in the estimation of percutaneous drug absorption. In conclusion, the present showed that percutaneous absorption through HSE was qualitatively and quantitatively similar to dermatomed skin when TEWL as endogenous standard and skin thickness were considered in permeability data comparisons.
Publisher: Oxford University Press (OUP)
Date: 07-2003
Publisher: Elsevier BV
Date: 07-2021
DOI: 10.1016/J.PHRS.2021.105608
Abstract: The past decade has seen many advancements in the development of three-dimensional (3D) in vitro models in pharmaceutical sciences and industry. Specifically, organoids present a self-organising, self-renewing and more physiologically relevant model than conventional two-dimensional (2D) cell cultures. Liver organoids have been developed from a variety of cell sources, including stem cells, cell lines and primary cells. They have potential for modelling patient-specific disease and establishing personalised therapeutic approaches. Additionally, liver organoids have been used to test drug efficacy and toxicity. Herein we summarise cell sources for generating liver organoids, the advantages and limitations of each cell type, as well as the application of the organoids in modelling liver diseases. We focus on the use of liver organoids as tools for drug validation and toxicity assessment.
Publisher: Springer Science and Business Media LLC
Date: 10-11-2017
Publisher: American Society for Microbiology
Date: 03-2017
DOI: 10.1128/AAC.01276-16
Abstract: The treatment of infections in critically ill obese and morbidly obese patients is challenging because of the combined physiological changes that result from obesity and critical illness. The aim of this study was to describe the population pharmacokinetics of piperacillin in a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients who received piperacillin-tazobactam were classified according to their body mass index (BMI) as nonobese, obese, and morbidly obese. Plasma s les were collected, and piperacillin concentrations were determined by a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were performed using Pmetrics software. Thirty-seven critically ill patients (including 12 obese patients and 12 morbidly obese patients) were enrolled. The patients' mean ± standard deviation age, weight, and BMI were 50 ± 15 years, 104 ± 35 kg, and 38.0 ± 15.0 kg/m 2 , respectively. The concentration-time data were best described by a two-compartment linear model. The mean ± SD parameter estimates for the final covariate model were a clearance of 14.0 ± 7.1 liters/h, a volume of distribution of the central compartment of 49.0 ± 19.0 liters, an intercompartmental clearance from the central compartment to the peripheral compartment of 0.9 ± 0.6 liters · h −1 , and an intercompartmental clearance from the peripheral compartment to the central compartment of 2.3 ± 2.8 liters · h −1 . A higher measured creatinine clearance and shorter-duration infusions were associated with a lower likelihood of achieving therapeutic piperacillin exposures in patients in all BMI categories. Piperacillin pharmacokinetics are altered in the presence of obesity and critical illness. As with nonobese patients, prolonged infusions increase the likelihood of achieving therapeutic concentrations.
Publisher: Springer Science and Business Media LLC
Date: 1982
DOI: 10.1007/BF00542462
Abstract: Theiler's murine encephalomyelitis virus (TMEV) infection of the central nervous system (CNS) induces a chronic, progressive demyelinating disease in susceptible mouse strains characterized by inflammatory mononuclear infiltrates and spastic hind limb paralysis. Our lab has previously demonstrated a critical role for TMEV- and myelin-specific CD4(+) T cells in initiating and perpetuating this pathology. It has however, also been shown that the MHC class I loci are associated with susceptibility/resistance to TMEV infection and persistence. For this reason, we investigated the contribution of CD8(+) T cells to the TMEV-induced demyelinating pathology in the highly susceptible SJL/J mouse strain. Here we show that beta2M-deficient SJL mice have similar disease incidence rates to wild-type controls, however beta2M-deficient mice demonstrated earlier onset of clinical disease, elevated in vitro responses to TMEV and myelin proteolipid (PLP) epitopes, and significantly higher levels of CNS demyelination and macrophage infiltration at 50 days post-infection. beta2M-deficient mice also displayed a significant elevation in persisting viral titers, as well as an increase in macrophage-derived pro-inflammatory cytokine mRNA expression in the spinal cord at this same time point. Taken together, these results indicate that CD8(+) T cells are not required for clinical or histologic disease initiation or progression in TMEV-infected SJL mice. Rather, these data stress the critical role of CD4(+) T cells in this capacity and further emphasize the potential for CD8(+) T cells to contribute to protection from TMEV-induced demyelination.
Publisher: MDPI AG
Date: 20-11-2018
DOI: 10.3390/PHARMACEUTICS10040244
Abstract: A major impediment to the long-term in vivo vascular imaging is a lack of suitable probes and contrast agents. Our developed mercaptosuccinic acid (MSA) capped cadmium telluride/cadmium sulfide (CdTe/CdS) ultrasmall quantum dots (QDs) have high fluorescent quantum yield, long fluorescence lifetime and long half-life in blood, allowing high resolution long-term intravital vascular imaging. In this study, we showed that these QDs can be used to visualize the in vivo the vasculature in normal and cancerous livers in mice using multiphoton microscopy (MPM) coupled with fluorescence lifetime imaging (FLIM), with cellular resolution (~1 µm) up to 36 h after intravenous injection. Compared to highly regulated and controlled sinusoids in normal liver tissue, disordered, tortuous, and immature neovessels were observed in tumors. The utilized imaging methods have great potential as emerging tools in diagnosis and monitoring of treatment response in cancer.
Publisher: Springer Science and Business Media LLC
Date: 10-12-2018
DOI: 10.1038/S41598-018-36009-8
Abstract: Microscale medical devices are being developed for targeted skin delivery of vaccines and the extraction of biomarkers, with the potential to revolutionise healthcare in both developing and developed countries. The effective clinical development of these devices is dependent on understanding the macro-molecular diffusion properties of skin. We hypothesised that diffusion varied according to specific skin layers. Using three different molecular weights of rhodamine dextran (RD) (MW of 70, 500 and 2000 kDa) relevant to the vaccine and therapeutic scales, we deposited molecules to a range of depths (0–300 µm) in ex vivo human skin using the Nanopatch device. We observed significant dissipation of RD as diffusion with 70 and 500 kDa within the 30 min timeframe, which varied with MW and skin layer. Using multiphoton microscopy, image analysis and a Fick’s law analysis with 2D cartesian and axisymmetric cylindrical coordinates, we reported experimental trends of epidermal and dermal diffusivity values ranging from 1–8 µm 2 s −1 to 1–20 µm 2 s −1 respectively, with a significant decrease in the dermal-epidermal junction of 0.7–3 µm 2 s −1 . In breaching the stratum corneum (SC) and dermal-epidermal junction barriers, we have demonstrated practical application, delivery and targeting of macromolecules to both epidermal and dermal antigen presenting cells, providing a sound knowledge base for future development of skin-targeting clinical technologies in humans.
Publisher: Elsevier BV
Date: 1987
DOI: 10.1016/0378-4347(87)80308-0
Abstract: We analyzed the spike discharge patterns of two types of neurons in the rodent peripheral gustatory system, Na specialists (NS) and acid generalists (AG) to lingual stimulation with NaCl, acetic acid, and mixtures of the two stimuli. Previous computational investigations found that both spike rate and spike timing contribute to taste quality coding. These studies used commonly accepted computational methods, but they do not provide a consistent statistical evaluation of spike trains. In this paper, we adopted a new computational framework that treated each spike train as an in idual data point for computing summary statistics such as mean and variance in the spike train space. We found that these statistical summaries properly characterized the firing patterns (e. g. template and variability) and quantified the differences between NS and AG neurons. The same framework was also used to assess the discrimination performance of NS and AG neurons and to remove spontaneous background activity or "noise" from the spike train responses. The results indicated that the new metric system provided the desired decoding performance and noise-removal improved stimulus classification accuracy, especially of neurons with high spontaneous rates. In summary, this new method naturally conducts statistical analysis and neural decoding under one consistent framework, and the results demonstrated that in idual peripheral-gustatory neurons generate a unique and reliable firing pattern during sensory stimulation and that this pattern can be reliably decoded.
Publisher: Springer Science and Business Media LLC
Date: 12-1989
DOI: 10.1007/BF01062125
Publisher: Oxford University Press (OUP)
Date: 09-1998
Publisher: Wiley
Date: 26-10-2021
Publisher: Elsevier BV
Date: 03-2005
DOI: 10.1002/JPS.20229
Location: Australia
No related grants have been discovered for Michael Roberts.