ORCID Profile
0000-0002-7051-2023
Current Organisations
Monash Institute of Pharmaceutical Sciences
,
Monash University
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Publisher: Elsevier BV
Date: 2006
Publisher: American Society for Microbiology
Date: 08-2009
DOI: 10.1128/AAC.00363-09
Abstract: Peroxide antimalarials, including artemisinin, are important for the treatment of multidrug-resistant malaria. These peroxides are known to react with iron or heme to produce reactive intermediates that are thought to be responsible for their antimalarial activities. This study investigated the potential interaction of selected peroxide antimalarials with oxyhemoglobin, the most abundant form of iron in the human body. The observed stability of artemisinin derivatives and 1,2,4-trioxolanes in the presence of oxyhemoglobin was in contrast to previous reports in the literature. Spectroscopic analysis of hemoglobin found it to be unstable under the conditions used for previous studies, and it appears likely that the artemisinin reactivity reported in these studies may be attributed to free heme released by protein denaturation. The stability of peroxide antimalarials with intact oxyhemoglobin, and reactivity with free heme, may explain the selective toxicity of these antimalarials toward infected, but not healthy, erythrocytes.
Publisher: Elsevier BV
Date: 12-1986
Publisher: Springer Science and Business Media LLC
Date: 02-2004
DOI: 10.1023/B:PHAM.0000016283.87709.A9
Abstract: The purpose of this study was to characterize the solubilization and precipitation characteristics of a range of poorly water-soluble drugs during the in vitro digestion of long-chain or medium-chain triglyceride (TG) lipid suspension formulations. TG suspensions of model drugs (present at double their equilibrium solubilities in the respective lipid) were digested in vitro and the drug solubilization and precipitation pattern in the resulting digests analyzed. For griseofulvin, diazepam, and danazol, solubilization of the small mass of drug originally presented in the TG lipid was efficient with only a small proportion of the dose precipitating and being recovered in the pellet phase after digestion of the TG lipid. For the more lipophilic and lipid-soluble drugs (cinnarizine, halofantrine), in which higher drug loadings were possible, significant enhancement in drug solubilization in the postdigestion aqueous phase was not apparent compared with simple TG lipid solutions. Suspensions of drugs, which are poorly soluble in water and TG lipid, may prove beneficial as the relatively high solubilizing capacity of the colloidal phases produced on TG digestion will likely exceed the mass of drug that could have been administered as a simple lipid solution. However, for more lipid-soluble drugs, suspension formulations may offer little benefit as sufficiently high drug loadings can otherwise be achieved with simple solution formulations that still provide for adequate solubilization after TG digestion.
Publisher: Elsevier BV
Date: 23-08-2001
Publisher: Elsevier BV
Date: 10-1998
Publisher: Springer Science and Business Media LLC
Date: 12-2002
DOI: 10.1208/PS040440
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-1995
DOI: 10.1097/00000539-199504000-00016
Abstract: We evaluated the utility of medium molecular weight hyaluronic acid for prolonging the local anesthetic activity of lidocaine in a rabbit model of epidural analgesia. Equiviscous formulations were prepared as either a physical mixture of lidocaine hydrochloride and sodium hyaluronate (where drug release occurred via diffusion) or as a lidocaine-hyaluronate complex (where drug release occurred via diffusional and electrostatic processes). The novel hyaluronic acid formulations were functionally evaluated, relative to lidocaine solution, in an intact, conscious rabbit model. The hyaluronate formulations were well tolerated. The duration of sensory block and loss of weight-bearing was prolonged twofold by the lidocaine-hyaluronate complex relative to the solution (P < 0.05). In terms of motor block, flaccid paresis occurred after administration of the solution formulation, whereas only partial motor block was evident after administration of the viscous formulations. Pharmacokinetic modeling of the lidocaine plasma concentration-time data indicated that the rate of drug absorption from the lidocaine-hyaluronate complex was decreased fourfold relative to the solution (P < 0.05). These observations indicate that ionic complexes of local anesthetics with medium molecular weight hyaluronic acid may offer advantages for the prolongation of epidural analgesia.
Publisher: Elsevier BV
Date: 09-1994
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 04-08-2015
Abstract: Drug receptor kinetics is as a key component in drug discovery, development, and efficacy however, determining kinetic parameters has historically required direct radiolabeling or competition with a labeled tracer. Here we present a simple approach to determining the kinetics of competitive antagonists of G protein-coupled receptors by exploiting the phenomenon of hemi-equilibrium, the state of partial re-equilibration of agonist, antagonist, and receptor in some functional assays. Using functional [Ca(2+)]i-flux and extracellular kinases 1 and 2 phosphorylation assays that have short incubation times and therefore are prone to hemi-equilibrium "behaviors," we investigated a wide range of structurally and physicochemically distinct muscarinic acetylcholine receptor antagonists. Using a combined operational and hemi-equilibrium model of antagonism to both simulate and analyze data, we derived estimates of association and dissociation rates for the test set of antagonists, identifying both rapidly dissociating (4-DAMP, himbacine) and slowly dissociating (tiotropium, glycopyrrolate) ligands. The results demonstrate the importance of assay incubation time and the degree of receptor reserve in applying the analytical model. There was an excellent correlation between estimates of antagonist pK(B), k(on), and k(off) from functional assays and those determined by competition kinetics using whole-cell [(3)H]N-methylscopolamine binding, validating this approach as a rapid and simple method to functionally profile receptor kinetics of competitive antagonists in the absence of a labeled tracer.
Publisher: Wiley
Date: 09-2006
Publisher: Elsevier BV
Date: 10-2001
Publisher: Springer Science and Business Media LLC
Date: 02-2004
DOI: 10.1023/B:PHAM.0000016282.77887.1F
Abstract: The purpose of this study was to characterize the solubilization and precipitation characteristics of a range of poorly water-soluble drugs during digestion of either long-chain or medium-chain triglyceride (TG) lipid formulations. TG solution formulations of five selected drugs (griseofulvin, diazepam, danazol, cinnarizine, and halofantrine) were digested in ritro and drug distribution/solubilization behavior in the resulting digests assessed. For the less lipophilic drugs, the mass of drug dissolved in either medium or long-chain TG was low and the drugs partitioned rapidly into the aqueous digestion phase. For the higher log P drugs, drug transfer to the aqueous phase was limited by accumulation in undigested long-chain TG. In contrast, medium-chain TG was digested completely producing a dispersed aqueous phase that was capable, at least in the case of the high log P drugs, of supporting supersaturated drug concentrations. The solubilization behavior of lipophilic drugs on digestion of simple TG lipid formulations is a function of the lipophilicity of the drug (which dictates the drug dose and the partitioning behavior), the nature of the colloidal phases produced on digestion of the different formulation lipids, and the kinetics of drug transfer between the digesting formulation and the colloidal phases produced.
Publisher: Springer Science and Business Media LLC
Date: 1993
Abstract: Three denaturing techniques have been evaluated for their ability to induce irreversible aggregation and precipitation of recombinant porcine growth hormone (pGH). The denaturing stimuli included thermal denaturation, interfacial denaturation through the introduction of a high air/water interface by vortex agitation, and a guanidine (Gdn) HCl technique which involved rapid dilution of a partially unfolded state of pGH to nondenaturing conditions. Soluble and insoluble pGH fractions were evaluated for the presence of covalently modified species and soluble aggregates by size exclusion chromatography (SEC), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and isoelectric focusing (IEF). In each of the three denaturation methods, precipitation was found to be irreversible, as the precipitated pellet could not be solubilized upon resuspending in buffer. The soluble pGH fractions consisted of only monomeric material and the insoluble protein pellet could be completely solubilized with Gdn HCl or SDS. There was no evidence of detectable covalent modifications in the precipitated protein pellet following any of the three denaturation techniques. Three excipients, Tween 20, hydroxypropyl-beta-cyclodextrin (HPCD), and sorbitol were evaluated for their stabilizing ability using each of the three denaturation methods and the degree of stabilization was found to be dependent upon the denaturing stimulus incorporated. Tween 20 was found to be highly effective in preventing pGH precipitation using the interfacial and Gdn techniques and was moderately effective using the thermal denaturation method. Inclusion of HPCD in the s le buffer significantly reduced precipitation using the thermal and interfacial methods but was ineffective in the Gdn technique.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: SAGE Publications
Date: 19-10-2018
Abstract: The present study compares career choice motives of future early childhood educators studying for a tertiary qualification. Suitable analyses of this kind are still missing. Diverging training systems, traditions and professional images in the different countries are related to certain motives. These motives are categorised according to a theory that is used as a theoretical framework. The study takes into account 468 student teachers from Germany, Sweden, Switzerland and Romania and is methodologically based on variance analyses. Overall, intrinsic motives were found to be of greater significance. This applies equally to all countries. Furthermore, addressee-related motives are more pronounced among Swiss and German prospective early childhood educators than among those from Sweden or Romania. On the contrary, extrinsic motives have a stronger presence among Romanian student teachers. Income and prestige, as the only exceptions, are important for students from Sweden and Switzerland. The results are discussed referring to country-specific working conditions and the current status of professionalisation processes existing in problem areas.
Publisher: American Chemical Society (ACS)
Date: 12-05-2011
DOI: 10.1021/JM200265B
Publisher: Springer Netherlands
Date: 2009
Publisher: Routledge
Date: 31-03-2020
Publisher: Elsevier BV
Date: 15-09-2006
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.IJPHARM.2017.06.040
Abstract: We report on the successful incorporation of the antimalarial drug, halofantrine, into laboratory based soybean oil emulsions which were designed to mimic the commercially available parenteral fat emulsion, Intralipid
Publisher: SAGE Publications
Date: 04-2020
Abstract: The present study compares student teachers’ career choice motives and their relationship with stress-inducing thoughts across five European countries. A previously established factorial structure for career choice motives embedded within self-determination theory was supported. The factors consist of intrinsic motives, such as interest in educational work with children, and extrinsic motives, such as financial security. Furthermore, differences in the importance of these factors in choosing the teaching profession across countries were found. Results further revealed evidence for a link between extrinsic motives and stress-inducing cognitions. Conclusions and implications for teaching practice are discussed.
Publisher: Springer Science and Business Media LLC
Date: 16-07-2010
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 25-10-2006
Publisher: Springer Science and Business Media LLC
Date: 1992
Abstract: Self-emulsifying drug delivery systems (SEDDSs) represent a possible alternative to traditional oral formulations of lipophilic compounds. In the present study, a lipophilic compound, WIN 54954, was formulated in a medium chain triglyceride oil/nonionic surfactant mixture which exhibited self-emulsification under conditions of gentle agitation in an aqueous medium. The efficiency of emulsification was studied using a laser diffraction sizer to determine particle size distributions of the resultant emulsions. An optimized formulation which consisted of 25% (w/w) surfactant, 40% (w/w) oil, and 35% (w/w) WIN 54954 emulsified rapidly with gentle agitation in 0.1 N HCl (37 degrees C), producing dispersions with mean droplet diameters of less than 3 microns. The self-emulsifying preparation was compared to a polyethylene glycol 600 (PEG 600) solution formulation by administering each as prefilled soft gelatin capsules to fasted beagle dogs in a parallel crossover study. Pharmacokinetic parameters were determined and the absolute bioavailability of the drug was calculated by comparison to an i.v. injection. The SEDDS improved the reproducibility of the plasma profile in terms of the maximum plasma concentration (Cmax) and the time to reach the maximum concentration (tmax). There was no significant difference in the absolute bioavailability of WIN 54954 from either the SEDDS or the PEG formulations.
Publisher: Springer US
Date: 2005
Publisher: Oxford University Press (OUP)
Date: 10-2004
Abstract: The trypanocide berenil was assessed for chemical stability over the pH range 1–8 at 37°C and 0.2 m ionic strength. It was found to be sufficiently unstable under acid conditions that its therapeutic efficacy is most likely severely compromised when administered orally. At pH 3, the half-life was 35 min, decreasing to 1.5 min at pH 1.75. Reaction rate constants were corrected for the effects of buffer catalysis and were found to range from 2.00 min−1 at pH 1 to 6.1 × 10−6 min−1 at pH 8. The pH-rate profile displayed a region (pH 1–4) where specific acid catalysis was dominant, followed by a transitional region (pH 5–7), and finally a region (pH & 7) where uncatalysed degradation was most important. It is recommended that berenil be enteric coated for formulations to be used in treating Third World parasitic diseases.
Publisher: Springer International Publishing
Date: 2018
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.JCONREL.2013.12.031
Abstract: A lipophilic prodrug approach has been used to promote the delivery of a model immunomodulator, mycophenolic acid (MPA), to the lymphatic system after oral administration. Lymphatic transport was employed to facilitate enhanced drug uptake into lymphocytes, as recent studies demonstrate that targeted drug delivery to lymph resident lymphocytes may enhance immunomodulatory effects. Two classes of lymph-directing prodrugs were synthesised. Alkyl chain derivatives (octyl mycophenolate, MPA-C8E octadecyl mycophenolate, MPA-C18E and octadecyl mycophenolamide, MPA-C18AM), to promote passive partitioning into lipids in lymphatic transport pathways, and a triglyceride mimetic prodrug (1,3-dipalmitoyl-2-mycophenoloyl glycerol, 2-MPA-TG) to facilitate metabolic integration into triglyceride deacylation-reacylation pathways. Lymphatic transport, lymphocyte uptake and plasma pharmacokinetics were assessed in mesenteric lymph and carotid artery cannulated rats following intraduodenal infusion of lipid-based formulations containing MPA or MPA prodrugs. Patterns of prodrug hydrolysis in rat digestive fluid, and cellular re-esterification in vivo, were evaluated to examine the mechanisms responsible for lymphatic transport. Poor enzyme stability and low absorption appeared to limit lymphatic transport of the alkyl derivatives, although two of the three alkyl chain prodrugs - MPA-C18AM (6-fold) and MPA-C18E (13-fold) still increased lymphatic drug transport when compared to MPA. In contrast, 2-MPA-TG markedly increased lymphatic drug transport (80-fold) and drug concentrations in lymphocytes (103-fold), and this was achieved via biochemical incorporation into triglyceride deacylation-reacylation pathways. The prodrug was hydrolysed rapidly to 2-mycophenoloyl glycerol (2-MPA-MG) in the presence of rat digestive fluid, and 2-MPA-MG was subsequently re-esterified in the enterocyte with oleic acid (most likely originating from the co-administered formulation) prior to accessing the lymphatics and lymphocytes. Importantly, after administration of 2-MPA-TG, the concentrations of free MPA in the mesenteric lymph nodes were significantly enhanced (up to 28 fold) when compared to animals administered equimolar quantities of MPA, suggesting the efficient conversion of the esterified prodrug back to the pharmacologically active parent drug. The data suggest that triglyceride mimetic prodrugs have potential as a means of enhancing immunotherapy via drug targeting to lymphocytes and lymph nodes.
Publisher: Elsevier BV
Date: 1987
DOI: 10.1016/S0021-9673(01)94499-1
Abstract: A method for characterization of the melanin biopolymer has been developed and validated by the use of synthetic melanins derived from tyrosine, dopamine or hydroquinone. The technique involved pyrolysis gas-liquid chromatography with capillary columns. A back-flushing technique is described which improves pyrogram reproducibility such that closely related melanins can be distinguished with the aid of principal components analysis and non-metric multidimensional scaling.
Publisher: Elsevier BV
Date: 1996
Publisher: Springer Science and Business Media LLC
Date: 08-2004
DOI: 10.1023/B:PHAM.0000036914.22132.CC
Abstract: To investigate the impact of lipidic formulation type on in vitro dispersion and digestion properties and the relationship to oral bioavailability, using danazol as a model lipophilic poorly water-soluble drug. Three lipid-based danazol formulations [a long-chain triglyceride solution (LCT-solution) and self-microemulsifying drug delivery systems (SMEDDS) based on long-chain (C18) lipids (LC-SMEDDS) and medium-chain (C8-C10) lipids (MC-SMEDDS)] were administered to fasted beagle dogs and compared with a micronized danazol formulation administered postprandially and in the fasted state. In vitro dispersion and particle size data for the two SMEDDS were compared, and the distribution/solubilization patterns of danazol across the various phases produced during in vitro digestion quantified. The LCT-solution and LC-SMEDDS formulations significantly enhanced the oral bioavailability of danazol when compared to fasted administration of the powder formulation. In contrast, and despite displaying excellent dispersion properties, the MC-SMEDDS resulted in little enhancement in danazol bioavailability. In support of the in vivo findings, in vitro digestion of the medium-chain formulation resulted in significant drug precipitation when compared with the long-chain lipid formulations. Digestion of microemulsion preconcentrate formulations based on medium-chain lipids may limit in vivo utility when compared with similar formulations based on long chain lipids.
Publisher: Springer Science and Business Media LLC
Date: 08-2004
DOI: 10.1038/NATURE02779
Publisher: Elsevier BV
Date: 12-1992
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1002/JPS.20568
Publisher: OsloMet - Oslo Metropolitan University
Date: 12-01-2018
DOI: 10.7577/NJCIE.1967
Abstract: This comparative case study addresses a timely issue engaging researchers involved in the internationalisation of Nordic Higher Education, in the context of Sweden and Finland. The study examines a hypothetical imaginary in the transition between university international policy statements and their understandings from the position of a globalised episteme. The investigation forms a tag-project as part of a funded large international research project examining ethical internationalism in times of global crises, involving a partnership between more than twenty higher education institutions in excess of ten countries across five continents. The data was collected using a mixed-methods design, whilst being controlled across the matched data collection period in 2013-2014. Data consisted of policy texts, surveys and interviews. The current research inquiry reports on a within and across comparative analyses of certain policy texts and follow-up interviews with university management. The results yield logical support for a global higher education imaginary driving internationalisation in ways which reveal paradoxical associations between the imagined and the real worlds of international scholar-practitioners.
Publisher: American Geophysical Union (AGU)
Date: 04-1996
DOI: 10.1021/JS9502229
Publisher: Springer Science and Business Media LLC
Date: 12-03-2009
DOI: 10.1007/S11095-009-9860-Z
Abstract: To examine the effect of food on the oral bioavailability of a highly lipophilic, cannabinoid receptor agonist (CRA13) and to explore the basis for the food effect in lymph-cannulated and non-cannulated dogs. Oral bioavailability was assessed in fasted and fed human volunteers and in lymph-cannulated dogs. In fasted dogs, the extent of absorption and oral bioavailability was also examined following administration of radiolabelled CRA13. Food had a substantial positive effect on the oral bioavailability of CRA13 in human volunteers (4.3-4.9 fold increase in AUC(0 - infinity)) and in dogs. The absolute bioavailability of parent drug was low in fasted dogs (8-20%), in spite of good absorption (72-75% of radiolabelled CRA13 recovered in the systemic circulation). In post-prandial lymph-cannulated dogs, bioavailability increased to 47.5% and the majority (43.7%) of the dose was absorbed via the intestinal lymphatic system. The positive food effect for CRA13 does not appear to result from increased post-prandial absorption. Rather these data provide one of the first ex les of a significant increase in bioavailability for a highly lipophilic drug, which is stimulated via almost complete post-prandial transport into the lymph, in turn resulting in a reduction in first-pass metabolism.
Publisher: Springer Science and Business Media LLC
Date: 21-02-2013
Publisher: Elsevier BV
Date: 06-2001
Publisher: American Chemical Society (ACS)
Date: 18-01-2017
DOI: 10.1021/ACS.JMEDCHEM.6B01586
Abstract: Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pK
Publisher: Informa UK Limited
Date: 2001
Publisher: Elsevier BV
Date: 09-2004
Publisher: Proceedings of the National Academy of Sciences
Date: 07-02-2011
Abstract: Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC 50 values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures Plasmodium berghei -infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. The outstanding efficacy and prolonged blood concentrations of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death.
Publisher: Elsevier BV
Date: 05-2004
DOI: 10.1002/JPS.20039
Publisher: Elsevier BV
Date: 11-1986
Publisher: Elsevier BV
Date: 04-2016
Publisher: American Geophysical Union (AGU)
Date: 04-1996
DOI: 10.1021/JS950221G
Publisher: Springer Netherlands
Publisher: Elsevier BV
Date: 03-2005
DOI: 10.1002/JPS.20260
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 21-01-2003
Abstract: P-glycoprotein (P-gp)-mediated drug efflux from the apical membrane of enterocytes is believed to modulate intestinal cytochrome P450 3A (CYP3A) metabolism by altering substrate access to the CYP3A enzyme. This interplay between P-gp and CYP3A was investigated in a rat in situ model of intestinal permeation, where a recirculating luminal perfusion of the jejunum was coupled with mesenteric vein blood collection to simultaneously monitor the uptake, transport, and metabolism of the P-gp and CYP3A substrate, verapamil. Transport of intact verapamil into the venous blood was increased by 160, 84, and 160%, and the intestinal extraction ratio on passage across the jejunum was reduced by 15, 24, and 97% by inhibitors of P-gp [PSC833 ([3'-keto-Me-Bmt(1)]-[Val(2)]-cyclosporin)], CYP3A (midazolam), or P-gp and CYP3A (ketoconazole), respectively, when present in the luminal perfusate and compared with control experiments. Compartmental kinetic analysis of the data revealed that inhibition of P-gp did not affect the rate constant describing verapamil metabolism but, rather, increased the intestinal uptake of verapamil and stimulated a disproportionate increase in verapamil transport into the venous blood. The increase in verapamil transport, in the absence of changes to metabolism, reduced the intestinal extraction ratio. This finding may be explained by saturation of intracellular verapamil binding sites within the intestinal tissue in response to increased verapamil uptake resulting from P-gp inhibition. The current findings confirm previous in vitro and theoretical approaches which suggest that P-gp can modulate the extent of intestinal extraction of P-gp/CYP3A substrates.
Publisher: Springer Science and Business Media LLC
Date: 2003
Publisher: CSIRO Publishing
Date: 1993
DOI: 10.1071/CH9930377
Abstract: The concentration-dependent self-association of nicotinamide in solution has been studied by 1H and 13C n.m.r. spectroscopy, attendant relaxation time measurements, and osmometric techniques. N-Methylnicotinamide and N,N- dimethylnicotinamide were also studied to evaluate the role of the amide group in the association process. The osmometric studies indicated that the dimethyl -substituted analogue underwent little (if any) self-association, whereas nicotinamide and N- methylnicotinamide did self-associate. The concentration-dependent 1H and 13C chemical shift profiles of nicotinamide and the monosubstituted analogue indicated that the association involved the amide group and did not occur through stacking of the pyridine rings. Spin lattice relaxation (T1) studies indicated that the T1( ortho C)/T1( para C) ratio of nicotinamide decreased with increasing concentration, and that loss of a preferred axis of rotation had occurred due to formation of a large associated species. The T1 ratios of either substituted amide analogue were not concentration-dependent. The extent of self-association of the monosubstituted derivative was insufficient to affect the measured T1 ratios. These data indicate that the self-association of nicotinamide in aqueous solution occurs primarily through interamide hydrogen bonding.
Publisher: Elsevier BV
Date: 11-2003
DOI: 10.1002/JPS.10479
Publisher: Elsevier BV
Date: 23-08-2001
Publisher: Elsevier BV
Date: 02-1998
Publisher: Oxford University Press (OUP)
Date: 12-2001
Abstract: P-glycoprotein (P-gp) can limit the intestinal permeability of a number of compounds and may therefore influence their exposure to metabolizing enzymes within the enterocyte (e.g. cytochrome P450 3A, CYP 3A). In this study, the intestinal metabolic profile of verapamil, the influence of P-gp anti-transport on the cellular residence time of verapamil, and the impact of this change in residence time on the extent of enterocyte-based metabolism have been investigated in-vitro, utilizing segments of rat jejunum and side-by-side diffusion chambers. Verapamil exhibited concentration-dependent P-gp efflux and CYP 3A metabolism. The P-gp efflux of verapamil (1 μm) increased the cellular residence time across the intestinal membrane (approximately 3-fold) in the mucosal to serosal (m to s) direction relative to serosal to mucosal (s to m), yielding significantly greater metabolism (approximately 2-fold), presumably as a result of the prolonged exposure to CYP 3A. Intestinal metabolism of verapamil generated not only norverapamil, but resulted also in the formation of an N-dealkylated product (D-617). Norverapamil and D-617 accumulated significantly in mucosal chambers, relative to serosal chambers, over the time course of the experiment. Based on these in-vitro data, it was apparent that P-gp efflux prolonged the cellular residence time of verapamil (m to s) and therefore increased the extent of intestinal metabolism, and also played a role in metabolite secretion from within the enterocyte.
Publisher: SAGE Publications, Inc.
Date: 2007
Publisher: American Chemical Society (ACS)
Date: 12-11-2010
DOI: 10.1021/MP100259A
Publisher: Oxford University Press (OUP)
Date: 03-2006
Abstract: Much research has focussed on the development of novel therapeutic agents to target various central nervous system disorders, however less attention has been given to determining the potential of such agents to permeate the blood-brain barrier (BBB), a factor that will ultimately govern the effectiveness of these agents in man. In order to assess the potential for novel compounds to permeate the BBB, various in-vitro, in-vivo and in-silico methods may be employed. Although in-vitro models (such as primary cell culture and immortalized cell lines) are useful as a screening method and can appropriately rank compounds in order of BBB permeability, they often correlate poorly to in-vivo brain uptake due to down-regulation of some BBB-specific transporters. In-vivo models (such as the internal carotid artery single injection or perfusion, intravenous bolus injection, brain efflux index and intracerebral microdialysis) provide more accurate information regarding brain uptake, and these can be complemented with novel imaging techniques (such as magnetic resonance imaging and positron emission tomography), although such methods are not suited to high-throughput permeability assessment. This paper reviews current methods used for assessing BBB permeability and highlights the particular advantages and disadvantages associated with each method, with a particular focus on methods suitable for moderate- to high-throughput screening.
Publisher: Elsevier BV
Date: 10-2001
DOI: 10.1002/JPS.1110
Abstract: Postprandial administration of halofantrine (Hf), an important antimalarial, leads to 3- and 12-fold increases in oral bioavailability in humans and beagles, respectively, and corresponding 2.4-fold and 6.8-fold decreases in metabolic conversion to desbutylhalofantrine (Hfm). Factors contributing to the decreased postprandial metabolism of Hf could include inhibition of presystemic CYP3A metabolism by food components and/or recruitment of the intestinal lymphatics as an absorption pathway. Although previous rat studies confirmed Hf base is a substrate for lymphatic transport, it is difficult to extrapolate such data to higher species, as the largely constant bile flow in a rat precludes attainment of representative pre- and postprandial states, and formulations administered to rats are often not relevant to higher species. These limitations have now been addressed by development of a conscious dog model that allows simultaneous study of intestinal lymphatic and nonlymphatic drug absorption and aspects of enterocyte-based drug metabolism. After oral administration of 100 mg Hf base, the mean fasted and postprandial lymphatic transport was 1.3% and 54% of the administered dose, respectively. Comparison of portal and systemic plasma Hfm concentration profiles suggested enterocyte-based conversion of Hf to Hfm however, the proportion of Hf metabolized to Hfm was similar after fasted or postprandial administration. Hence, it appears that the previously observed decrease in the postprandial metabolism of Hf is largely a consequence of significant postprandial intestinal lymphatic transport (which bypasses first pass hepatic metabolism). This new dog model will facilitate identification of the key factors that impact bioavailability, lymphatic transport, and metabolic profiles of highly lipophilic drugs.
Publisher: Elsevier BV
Date: 05-1985
Publisher: Elsevier BV
Date: 03-2003
DOI: 10.1002/JPS.10329
Publisher: Springer Science and Business Media LLC
Date: 15-06-2013
Publisher: Proceedings of the National Academy of Sciences
Date: 03-10-2012
Abstract: Malarial dihydrofolate reductase (DHFR) is the target of antifolate antimalarial drugs such as pyrimethamine and cycloguanil, the clinical efficacy of which have been compromised by resistance arising through mutations at various sites on the enzyme. Here, we describe the use of cocrystal structures with inhibitors and substrates, along with efficacy and pharmacokinetic profiling for the design, characterization, and preclinical development of a selective, highly efficacious, and orally available antimalarial drug candidate that potently inhibits both wild-type and clinically relevant mutated forms of Plasmodium falciparum (Pf) DHFR. Important structural characteristics of P218 include pyrimidine side-chain flexibility and a carboxylate group that makes charge-mediated hydrogen bonds with conserved Arg122 (PfDHFR-TS amino acid numbering). An analogous interaction of P218 with human DHFR is disfavored because of three species-dependent amino acid substitutions in the vicinity of the conserved Arg. Thus, P218 binds to the active site of PfDHFR in a substantially different fashion from the human enzyme, which is the basis for its high selectivity. Unlike pyrimethamine, P218 binds both wild-type and mutant PfDHFR in a slow-on/slow-off tight-binding mode, which prolongs the target residence time. P218, when bound to PfDHFR-TS, resides almost entirely within the envelope mapped out by the dihydrofolate substrate, which may make it less susceptible to resistance mutations. The high in vivo efficacy in a SCID mouse model of P. falciparum malaria, good oral bioavailability, favorable enzyme selectivity, and good safety characteristics of P218 make it a potential candidate for further development.
Publisher: American Chemical Society (ACS)
Date: 11-02-2004
DOI: 10.1021/JM030947M
Abstract: New fluoroartemisinin derivatives containing polar or water-soluble functionalities at C-16 (11a-j, 12a-g) were synthesized using the key intermediate 16-bromo-10-trifluoromethyl anhydrodihydroartemisinin 10. The substitution reaction from 10 was more selective than that from the nonfluorinated parent bromide the allylic bromide 10 underwent no allylic rearrangement and provided only nucleophilic substitution products in high yields with N-, O-, and C-nucleophiles. Among them, amines 11a-c appeared to be highly in vivo efficient antimalarials on mice infected with Plasmodium berghei, more than the reference sodium artesunate 1d. In particular, the most effective piperazinoethanol derivative 11b cured all mice after oral treatment at a dose lower than 10 mg/kg. Further pharmacokinetic studies showed that the bioavailability in rats following oral administration was 25 times greater for 11b than for artemether 1b.
Publisher: Elsevier BV
Date: 04-1992
Abstract: Methods of analyzing drug absorption data from rat intestinal-perfusion experiments are discussed in terms of mass-transfer resistances, or reciprocal permeabilities, and mass balances. Typically, a two-resistance model is used to determine the dimensionless effective permeability (P*eff) by measuring the disappearance of drug from the perfusing solution. Unstated assumptions in two-resistance models are (1) the portal blood is under sink conditions and (2) complete transfer of drug occurs from the intestinal perfusate to the portal vein. The assumption of sink conditions is generally acceptable, because the drug concentration in portal blood is approximately two orders of magnitude less than in the perfusate. Single-pass intestinal-perfusion experiments were performed on rats with theophylline as a model compound. The drug mass leaving the intestinal perfusate was substantially less than the drug mass appearing in the portal plasma that is, the assumption of complete transfer did not hold for theophylline in this experimental system. These data indicate that models based on the two-resistance theory can lead to overestimation of P*eff by the ratio of the drug mass leaving the perfusate to the drug mass appearing in the plasma. For compounds for which the assumption of complete transfer does not hold, a more accurate estimate of P*eff may be determined by iding the value derived from perfusate data by the mass balance ratio (i.e., the drug mass leaving the perfusate ided by the drug mass appearing in the plasma).
Publisher: Wiley
Date: 2003
DOI: 10.1002/BDD.351
Publisher: American Geophysical Union (AGU)
Date: 09-1999
DOI: 10.1021/JS980382V
Publisher: Springer Science and Business Media LLC
Date: 23-09-2006
Publisher: Oxford University Press (OUP)
Date: 06-2006
Abstract: Exogenous surfactants are increasingly used to enhance the dispersion properties of lipid-based formulations of poorly water-soluble drugs, yet their possible effects on formulation digestion and oral bioavailability in-vivo are not well documented. In this study, in-vitro dispersion and digestion experiments were conducted using formulations comprising a blend of long-chain glycerides, ethanol, a model poorly water-soluble drug (atovaquone), and a series of surfactants including Cremophor EL and a range of Pluronic surfactants (Pluronics L121, L61, L72, L43 and F68). Inclusion of Cremophor EL, a surfactant with a high hydrophilic-lipophilic balance (HLB), promoted complete digestion of the formulation and effective dispersion and solubilisation of the lipolytic products and co-administered drug. Surprisingly, formulations containing the Pluronic (L121) with the lowest HLB (0.5) equally effectively promoted digestion and drug solubilisation and a trend towards decreased digestion and drug solubilisation was observed with Pluronics of increasing HLB values. All formulations effectively prevented drug precipitation, suggesting possible utility in-vivo, and no correlation was evident between the ability of the formulations to self-emulsify on dispersion and to promote drug solubilisation on digestion. Subsequent assessment of the oral bioavailability of atovaquone after administration of formulations containing Cremophor EL or Pluronic L121 or a simple solution of atovaquone in long-chain glycerides confirmed the utility of lipid-based formulations for enhancing the oral bioavailability of poorly water-soluble drugs such as atovaquone, but also indicated that in some cases microemulsion preconcentrate formulations may not provide additional bioavail-ability benefits beyond that achievable using simple lipid solutions.
Publisher: American Chemical Society (ACS)
Date: 27-03-2013
DOI: 10.1021/MP3006566
Abstract: The oral bioavailability of poorly water-soluble drugs (PWSD) is often significantly enhanced by coadministration with lipids in food or lipid-based oral formulations. Coadministration with lipids promotes drug solubilization in intestinal mixed micelles and vesicles, however, the mechanism(s) by which PWSD are absorbed from these dispersed phases remain poorly understood. Classically, drug absorption is believed to be a product of the drug concentration in free solution and the apparent permeability across the absorptive membrane. Solubilization in colloidal phases such as mixed micelles increases dissolution rate and total solubilized drug concentrations, but does not directly enhance (and may reduce) the free drug concentration. In the absence of changes to cellular permeability (which is often high for lipophilic, PWSD), significant changes to membrane flux are therefore unexpected. Realizing that increases in effective dissolution rate may be a significant driver of increases in drug absorption for PWSD, we explore here two alternate mechanisms by which membrane flux might also be enhanced: (1) collisional drug absorption where drug is directly transferred from lipid colloidal phases to the absorptive membrane, and (2) supersaturation-enhanced drug absorption where bile mediated dilution of lipid colloidal phases leads to a transient increase in supersaturation, thermodynamic activity and absorption. In the current study, collisional uptake mechanisms did not play a significant role in the absorption of a model PWSD, cinnarizine, from lipid colloidal phases. In contrast, bile-mediated dilution of model intestinal mixed micelles and vesicles led to drug supersaturation. For colloids that were principally micellar, supersaturation was maintained for a period sufficient to promote absorption. In contrast, for primarily vesicular systems, supersaturation resulted in rapid drug precipitation and no increase in drug absorption. This work suggests that ongoing dilution by bile in the gastrointestinal tract may invoke supersaturation in intestinal colloids and promote absorption, and thus presents a new mechanism by which lipids may enhance the oral absorption of PWSD.
Publisher: Elsevier BV
Date: 10-1994
Publisher: Informa UK Limited
Date: 1991
Publisher: Elsevier BV
Date: 05-2005
Publisher: Elsevier BV
Date: 02-2006
DOI: 10.1002/JPS.20534
Publisher: Elsevier BV
Date: 07-1995
Publisher: American Chemical Society (ACS)
Date: 19-11-2010
DOI: 10.1021/JM901473S
Publisher: Wiley
Date: 04-1993
DOI: 10.1002/J.1552-4604.1993.TB04673.X
Abstract: The bioavailability of a single 100-mg dose of danazol delivered from the commercial formulation (hard gelatin capsule) and from an experimental lipid emulsion formulation of danazol was studied in 11 healthy female volunteers in both fed and fasted states. The emulsion formulation (fasted) increased bioavailability fourfold compared with the capsule (P = .0001) the difference, however, was not significant in the fed state. Food increased the bioavailability of the capsule formulation more than threefold over fasted administration (P = .0001). In a separate study of 12 female volunteers, single doses of the emulsion formulation of danazol administered with food demonstrated essentially dose-proportional pharmacokinetics over the dose range studied (50-200 mg). The authors conclude that factors that increase the extent of solubilization lead to significant enhancement in the bioavailability of danazol.
Publisher: American Chemical Society (ACS)
Date: 20-06-2012
DOI: 10.1021/JM3002795
Abstract: A new bispyrroloiminoquinone alkaloid, tsitsikammamine C (1), displayed potent in vitro antimalarial activity with IC(50) values of 13 and 18 nM against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum, respectively. Tsitsikammamine C (1) displayed selectivity indices of >200 against HEK293 cells and inhibited both ring and trophozoite stages of the malaria parasite life cycle. Previously reported compounds makaluvamines J (2), G (3), L (4), K (5) and damirones A (6) and B (7) were also isolated from the same marine sponge (Zyzzya sp.). Compounds 2-4 displayed potent growth inhibitory activity (IC(50) < 100 nM) against both P. falciparum lines and only moderate cytotoxicity against HEK293 cells (IC(50) = 1-4 μM). Makaluvamine G (3) was not toxic to mice and suppressed parasite growth in P. berghei infected mice following subcutaneous administration at 8 mg kg(-1) day(-1).
Publisher: Elsevier BV
Date: 02-2017
Abstract: Osteoclasts are multinuclear cells that degrade bone under both physiological and pathophysiological conditions. Osteoclasts are therefore a major target of osteoporosis therapeutics aimed at preserving bone. Consequently, analytical methods for osteoclast activity are useful for the development of novel biomarkers and/or pharmacological agents for the treatment of osteoporosis. The nucleation state of an osteoclast is indicative of its maturation and activity. To date, activity is routinely measured at the population level with only approximate consideration of the nucleation state (an 'osteoclast population' is typically defined as cells with ≥3 nuclei). Using a fluorescent substrate for tartrate-resistant acid phosphatase (TRAP), a routinely used marker of osteoclast activity, we developed a multi-labelled imaging method for quantitative measurement of osteoclast TRAP activity at the single cell level. Automated image analysis enables interrogation of large osteoclast populations in a high throughput manner using open source software. Using this methodology, we investigated the effects of receptor activator of nuclear factor kappa-B ligand (RANK-L) on osteoclast maturation and activity and demonstrated that TRAP activity directly correlates with osteoclast maturity (i.e. nuclei number). This method can be applied to high throughput screening of osteoclast-targeting compounds to determine changes in maturation and activity.
Publisher: Elsevier BV
Date: 2010
Publisher: Cold Spring Harbor Laboratory
Date: 23-07-2020
DOI: 10.1101/2020.07.22.215509
Abstract: Adenosine A 1 receptors (A 1 R) are a potential target for cardiac injury treatment due to their cardioprotective/antihypertrophic actions, but drug development has been h ered by on-target side effects such as bradycardia and altered renal haemodynamics. Biased agonism has emerged as an attractive mechanism for A 1 R-mediated cardioprotection that is haemodynamically safe. Here we investigate the pre-clinical pharmacology, efficacy and side-effect profile of the A 1 R agonist neladenoson, shown to be safe but ineffective in phase IIb trials for the treatment of heart failure. We compare this agent with the well-characterised, pan-adenosine receptor (AR) agonist NECA, capadenoson, and the A 1 R biased agonist VCP746, previously shown to be safe and cardioprotective in pre-clinical models of heart failure. We show that like VCP746, neladenoson is biased away from Ca 2+ influx relative to NECA and the cAMP pathway at the A 1 R, a profile predictive of a lack of adenosine-like side effects. Additionally, neladenoson was also biased away from the MAPK pathway at the A 1 R. In contrast to VCP746, which displays more ‘adenosine-like’ signalling at the A 2B R, neladenoson was a highly selective A 1 R agonist, with biased, weak agonism at the A 2B R. Together these results show that unwanted haemodynamic effects of A 1 R agonists can be avoided by compounds biased away from Ca 2+ influx relative to cAMP, relative to NECA. The failure of neladenoson to reach primary endpoints in clinical trials suggests that A 1 R-mediated cAMP inhibition may be a poor indicator of effectiveness in chronic heart failure. This study provides additional information that can aid future screening and/or design of improved AR agonists that are safe and efficacious in treating heart failure in patients. Biased agonists that preference against calcium influx relative to the cyclic AMP pathway, when compared to a conventional agonist, confer clinical safety to A 1 adenosine receptor ligands.
Publisher: Springer Science and Business Media LLC
Date: 1991
Abstract: The steady-state flux (SSF) of nicotinamide from an aqueous donor phase across a model Silastic membrane did not increase proportionally with increasing donor phase concentration. The suspected self-association of the drug in aqueous solution was evaluated by studying the concentration-dependent changes in (i) the molal osmotic coefficient of nicotinamide (freezing-point depression studies) and (ii) the partition coefficient between water and n-octanol. The freezing points of aqueous solutions of nicotinamide were measured and a plot of osmolality vs molality was nonlinear. The partition coefficient of nicotinamide, studied at 15, 25, and 32 degrees C, also decreased with increasing concentration of drug. Mathematical models describing dimerization and higher orders of association were applied to the data. The results indicated the involvement of higher orders of association and it was found that an isodesmic (step-association) model was an adequate description of the freezing-point depression and partition coefficient data. The association constant, K, ranged between 1.59 +/- 0.02 M-1 at the freezing point and 0.48 +/- 0.01 M-1 as estimated from the partition coefficient data at 32 degrees C. These models for the self-association of nicotinamide allowed estimation of the apparent concentration of "monomeric" nicotinamide in the donor phase solutions studied in the SSF experiments. When the SSF data were analyzed with regard to the concentration of monomeric nicotinamide in the donor phase, a relationship close to linearity was observed.
Publisher: Wiley
Date: 03-1999
DOI: 10.1002/(SICI)1098-2299(199903/04)46:3/4<316::AID-DDR18>3.0.CO;2-E
Publisher: American Chemical Society (ACS)
Date: 06-2011
DOI: 10.1021/MP100462D
Abstract: Elevated systemic levels of triglyceride-rich lipoproteins (TRL) are a risk factor for the development of atherosclerosis. In patients with metabolic syndrome (MetS), intestinal TRL overproduction contributes to high systemic TRL levels, and recent studies suggest that systemic changes in MetS such as increases in plasma fatty acids and insulin resistance stimulate intestinal TRL production. The current study has examined whether increases in systemic TRL influence intestinal lipid transport and lipoprotein assembly pathways and evaluates the impact of these changes on the absorption and lymphatic transport of lipids and a model lipophilic drug (halofantrine). Mesenteric lymph-duct or bile-duct cannulated rats were administered IV saline or (14)C-labeled chylomicron (CM) (to increase systemic TRL) and intraduodenal (3)H lipids and drug. Changes to biliary lipid output and lymphatic lipid and drug transport were subsequently examined. Increasing systemic TRL concentrations stimulated a significant increase in lymphatic lipid and drug transport. The increased lipids in lymph were not derived from bile or the intestinal blood supply (fatty acid or IV infused (14)C-CM). Rather, an increase in lymphatic transport of duodenally sourced lipids was evident. Increasing plasma levels of TRL therefore stimulated lipid absorption and lymphatic transport via a positive feedback process. The data also suggest that the changes to intestinal TRL formation that result from raised systemic TRL levels may impact on the absorption of highly lipophilic drugs and therefore the reproducibility of drug treatments.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 2013
Abstract: Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.
Publisher: Elsevier BV
Date: 09-1999
Publisher: Elsevier BV
Date: 08-2005
DOI: 10.1002/JPS.20400
Publisher: Springer Science and Business Media LLC
Date: 2003
Abstract: To examine whether the small quantities of lipid present in unit-dose microemulsion formulations comprising medium- (C8-10) or long-chain (C18) glyceride lipids can stimulate the intestinal lymphatic transport of halofantrine (Hf), a model lymphatically transported drug. Hf (50 mg) was administered to thoracic lymph duct- and cephalic vein-cannulated fasted greyhound dogs. Drug was formulated as a single soft gelatin capsule containing approximately 1 g of a microemulsion preconcentrate based on either medium- or long-chain glycerides. Thoracic lymph was collected, and systemic plasma s les taken over 10 h postdose. The extent of lymphatic transport of Hf after administration of the long-chain lipid formulation was high (28.3% of dose), and significantly higher than that seen after administration of the medium-chain formulation (5.0% of dose). Plasma levels of Hf were not significantly different across the two formulations when assessed by AUC0-10h. This is the first study to demonstrate that the small amounts of lipid present within a single lipid-based dose form can support substantial intestinal lymphatic transport in the fasted state. Furthermore, microemulsions based on long-chain glycerides appear to be more effective with respect to lymphatic transport than the equivalent medium-chain formulation.
Publisher: Elsevier BV
Date: 23-08-2001
Publisher: Elsevier BV
Date: 11-1986
Publisher: Elsevier BV
Date: 09-2003
DOI: 10.1016/S0928-0987(03)00174-X
Abstract: The potential for lipidic self-microemulsifying drug delivery systems (SMEDDS) containing triglycerides with a defined structure, where the different fatty acids on the glycerol backbone exhibit different metabolic fate, to improve the lymphatic transport and the portal absorption of a poorly water-soluble drug, halofantrine, were investigated in fasted lymph cannulated canines. Two different structured triglycerides were incorporated into the SMEDDS 1,3-dioctanoyl-2-linoleyl-sn-glycerol (C8:0-C18:2-C8:0) (MLM) and 1,3-dilinoyl-2-octanoyl-sn-glycerol (C18:2-C8:0-C18:2) (LML). A previously optimised SMEDDS formulation for halofantrine, comprising of triglyceride, Cremophor EL, Maisine 35-1 and ethanol was selected for bioavailability assessment. The extent of lymphatic transport via the thoracic duct was 17.9% of the dose for the animals dosed with the MLM SMEDDS and 27.4% for LML. Also the plasma availability was affected by the triglyceride incorporated into the multi-component delivery system and availabilities of 56.9% (MLM) and 37.2% (LML) were found. These data indicate that the pharmaceutical scientist can use the structure of the lipid to affect the relative contribution of the two absorption pathways. The MLM formulation produced a total bioavailability of 74.9%, which is higher than the total absorption previously observed after post-prandial administration. This could indicate the utility of disperse lipid-base formulations based on structured triglycerides for the oral delivery of halofantrine, and potentially other lipophilic drugs.
Publisher: American Geophysical Union (AGU)
Date: 05-1996
DOI: 10.1021/JS950472P
Publisher: American Chemical Society (ACS)
Date: 07-02-2014
DOI: 10.1021/JM401540F
Abstract: Peptide inhibitors of insulin-regulated aminopeptidase (IRAP) enhance fear avoidance and spatial memory and accelerate spatial learning in a number of memory paradigms. Using a virtual screening approach, a series of benzopyran compounds was identified that inhibited the catalytic activity of IRAP, ultimately resulting in the identification of potent and specific inhibitors. The present study describes the medicinal chemistry c aign that led to the development of the lead candidate, 3, highlighting the key structural features considered as critical for binding. Furthermore, the in vivo pharmacokinetics and brain uptake of compounds (1 and 3) were assessed in rats and were complemented with in vitro human and rat microsomal stability studies. Following intravenous administration to rodents, 3 exhibits brain exposure, albeit it is rapidly converted to 1, a compound which also exhibits potent inhibition of IRAP.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 07-02-2006
Publisher: Informa UK Limited
Date: 11-02-2009
Publisher: Elsevier BV
Date: 2006
DOI: 10.1002/JPS.20525
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.ADDR.2016.04.007
Abstract: Lipid based formulations (LBF) provide well proven opportunities to enhance the oral absorption of drugs and drug candidates that sit close to, or beyond, the boundaries of Lipinski's 'rule-of-five' chemical space. Advantages in permeability, efflux and presystemic metabolism are evident however, the primary benefit is in increases in dissolution and apparent intestinal solubility for lipophilic, poorly water soluble drugs. This review firstly details the inherent advantages of LBF, their general properties and classification, and provides a brief retrospective assessment of the development of LBF over the past fifty years. More detailed analysis of the ability of LBF to promote intestinal solubilisation, supersaturation and absorption is then provided alongside review of the methods employed to assess formulation performance. Critical review of the ability of simple dispersion and more complex in vitro digestion methods to predict formulation performance subsequently reveals marked differences in the correlative ability of in vitro tests, depending on the properties of the drug involved. Notably, for highly permeable low melting drugs e.g. fenofibrate, LBF appear to provide significant benefit in all cases, and sustained ongoing solubilisation may not be required. In other cases, and particularly for higher melting point drugs such as danazol, where re-dissolution of crystalline precipitate drug is likely to be slow, correlations with ongoing solubilisation and supersaturation are more evident. In spite of their potential benefits, one limitation to broader use of LBF is low drug solubility in the excipients employed to generate formulations. Techniques to increase drug lipophilicity and lipid solubility are therefore explored, and in particular those methods that provide for temporary enhancement including lipophilic ionic liquid and prodrug technologies. The transient nature of these lipophilicity increases enhances lipid solubility and LBF viability, but precludes enduring effects on receptor promiscuity and off target toxicity. Finally, recent efforts to generate solid LBF are briefly described as a means to circumvent the need to encapsulate in soft or hard gelatin capsules, although the latter remain popular with consumers and a proven means of LBF delivery.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 13-06-2003
Publisher: American Chemical Society (ACS)
Date: 13-10-2011
DOI: 10.1021/MP2004862
Publisher: Public Library of Science (PLoS)
Date: 19-01-2016
Publisher: American Geophysical Union (AGU)
Date: 02-1998
DOI: 10.1021/JS970279Q
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 18-11-2016
Abstract: The human histamine H
Publisher: Wiley
Date: 12-1993
DOI: 10.1002/J.1552-4604.1993.TB03921.X
Abstract: The absorption of danazol (100 mg) after oral or intraintestinal administration to the proximal jejunum or proximal ileum has been studied in healthy female subjects. The extent of danazol absorption after administration as a solubilized glycerol mono-oleate emulsion formulation was approximately twofold and fourfold greater after oral dosing when compared with jejunal or ileal administration, respectively. Although not statistically significant in this study, the extent of absorption after jejunal administration was generally greater than after ileal administration. After oral dosing, qualitative assessment identified the presence of double peaks or major shouldering characteristics in 14 of the 16 in idual danazol plasma concentration-time profiles, whereas only single peaks were present after intraintestinal administration. These data are consistent with the double peaking phenomena after oral administration of the emulsion formulation being stomach-related. The double peaking effect may be explained in terms of a probable combination of gastric emptying regulated absorption (due to the presence of the lipid in the emulsion formulation) and the dependence of danazol solubility on bile salt solubilization within the upper small intestine.
Publisher: Elsevier BV
Date: 05-1994
Publisher: Springer Singapore
Date: 2020
Publisher: Springer Science and Business Media LLC
Date: 21-07-2006
Publisher: Elsevier BV
Date: 08-1999
DOI: 10.1016/S0168-3659(99)00115-7
Abstract: 50 h) were detected for the transport and release of a model protein (ribonuclease A) compared with that for the translucent region which showed no lag time. The results highlight the importance of carefully controlling matrix formation to ensure reproducible transport and release characteristics from polymer matrices.
Publisher: Elsevier BV
Date: 03-1995
DOI: 10.1016/0731-7085(95)01256-K
Abstract: The development of a new and simplified, validated LC assay for the quantitation of halofantrine and desbutylhalofantrine in plasma is described. The methodology employs an inexpensive, rapid and simple liquid-liquid extraction procedure in combination with previously reported chromatographic conditions. The method has been employed to study aspects of the pharmacokinetics of orally administered halofantrine in beagle dogs and some preliminary data are presented. During development of the extraction procedure, degradation of desbutylhalofantrine was observed under non-acidic conditions in the extraction solvent (tert-butyl methyl ether) and we also report the structural elucidation of the breakdown product and the conditions required to avoid this degradation.
Publisher: Springer Science and Business Media LLC
Date: 16-08-2005
Publisher: Springer Netherlands
Date: 2005
Publisher: Informa UK Limited
Date: 06-1998
Publisher: American Chemical Society (ACS)
Date: 25-06-2005
DOI: 10.1021/JM049040U
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.ADDR.2016.02.005
Abstract: The physicochemical properties of some contemporary drug candidates are moving towards higher molecular weight, and coincidentally also higher lipophilicity in the quest for biological selectivity and specificity. These physicochemical properties move the compounds towards beyond rule-of-5 (B-r-o-5) chemical space and often result in lower water solubility. For such B-r-o-5 compounds non-traditional delivery strategies (i.e. those other than conventional tablet and capsule formulations) typically are required to achieve adequate exposure after oral administration. In this review, we present the current status of computational tools for prediction of intestinal drug absorption, models for prediction of the most suitable formulation strategies for B-r-o-5 compounds and models to obtain an enhanced understanding of the interplay between drug, formulation and physiological environment. In silico models are able to identify the likely molecular basis for low solubility in physiologically relevant fluids such as gastric and intestinal fluids. With this baseline information, a formulation scientist can, at an early stage, evaluate different orally administered, enabling formulation strategies. Recent computational models have emerged that predict glass-forming ability and crystallisation tendency and therefore the potential utility of amorphous solid dispersion formulations. Further, computational models of loading capacity in lipids, and therefore the potential for formulation as a lipid-based formulation, are now available. Whilst such tools are useful for rapid identification of suitable formulation strategies, they do not reveal drug localisation and molecular interaction patterns between drug and excipients. For the latter, Molecular Dynamics simulations provide an insight into the interplay between drug, formulation and intestinal fluid. These different computational approaches are reviewed. Additionally, we analyse the molecular requirements of different targets, since these can provide an early signal that enabling formulation strategies will be required. Based on the analysis we conclude that computational biopharmaceutical profiling can be used to identify where non-conventional gateways, such as prediction of 'formulate-ability' during lead optimisation and early development stages, are important and may ultimately increase the number of orally tractable contemporary targets.
Publisher: American Chemical Society (ACS)
Date: 18-03-2009
DOI: 10.1021/JM801343R
Publisher: American Chemical Society (ACS)
Date: 14-07-2011
DOI: 10.1021/JM200592F
Publisher: Elsevier BV
Date: 09-1996
Publisher: American Chemical Society (ACS)
Date: 27-05-2004
DOI: 10.1021/JM030475B
Publisher: Elsevier BV
Date: 02-2004
DOI: 10.1002/JPS.10554
Publisher: Springer Science and Business Media LLC
Date: 1993
Abstract: A reverse-phase HPLC method for the analysis of tryptic digests of recombinant porcine growth hormone (pGH) has been developed and validated. Digestion was performed at 4 degrees C for a 20-hr period with TPCK-treated trypsin at a 1:20 (w/w) trypsin:pGH ratio. Gradient elution HPLC, using an Aquapore RP300 C8 column, was incorporated for separation of the digestion products and peak identification was carried out by mass spectrometry (MS). The digestion procedure and subsequent chromatography were linear in the initial concentration range of 4.55-45.46 microM (100 to 1000 micrograms/mL) pGH. The variability in the fragment retention times was low and the normalized peak area variability was less than 5% for all but three of the fragments. The utility of the trypsin digestion and chromatography procedures has been demonstrated by assessing chemical changes in pGH induced by incubation at elevated pH. Upon incubation of pGH in 0.2 M Tris buffer at pH 9 (ionic strength adjusted to 0.5 with NaCl) and 37 degrees C over a period of 400 hr, significant degradation in the regions corresponding to the digestion fragments T23-T25 (residues 181-182 linked by a disulfide bond to residues 184-191), T9 (residues 96-108), and T5-T18 (residues 43-64 linked by a disulfide bond to residues 158-166) was observed. The disappearance of the peaks corresponding to fragments T23-T25 and T9 both displayed apparent first-order degradation kinetics over the time period investigated with half-lives of 131 and 154 hr, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Elsevier BV
Date: 09-2008
DOI: 10.5688/AJ7206131
Publisher: Elsevier BV
Date: 04-1997
Publisher: Elsevier BV
Date: 09-1998
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1002/JPS.23179
Publisher: Informa UK Limited
Date: 03-10-2017
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1002/JPS.23211
Publisher: Elsevier BV
Date: 11-1986
Publisher: Springer Netherlands
Publisher: American Society for Microbiology
Date: 07-2009
DOI: 10.1128/AAC.01568-08
Abstract: High-throughput screening of 100,000 lead-like compounds led to the identification of nine novel chemical classes of trypanothione reductase (TR) inhibitors worthy of further investigation. Hits from five of these chemical classes have been developed further through different combinations of preliminary structure-activity relationship rate probing and assessment of antiparasitic activity, cytotoxicity, and chemical and in vitro metabolic properties. This has led to the identification of novel TR inhibitor chemotypes that are drug-like and display antiparasitic activity. For one class, a series of analogues have displayed a correlation between TR inhibition and antiparasitic activity. This paper explores the process of identifying, investigating, and evaluating a series of hits from a high-throughput screening c aign.
Publisher: Springer Netherlands
Publisher: Elsevier BV
Date: 05-1985
No related grants have been discovered for William Charman.