ORCID Profile
0000-0002-3255-9242
Current Organisation
University of South Australia
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Animal Physiology - Systems | Zoology | Animal Developmental and Reproductive Biology | Cell Development, Proliferation and Death
Publisher: Informa UK Limited
Date: 02-11-2021
DOI: 10.1080/17425255.2021.1839413
Abstract: Age-associated physiological changes can alter the disposition of drugs, however, pathophysiological changes associated with geriatric syndromes in older adults may lead to even greater heterogeneity in pharmacokinetics. Geriatric syndromes are common health problems in older adults which have multifactorial causes and do not fit into distinct organ-based disease categories. With older adults being the greatest users of medications, understanding both age- and geriatric syndrome-related changes is important clinically to ensure safe and effective medication use. This review provides an overview of current evidence regarding pharmacokinetic alterations that occur with aging and in common geriatric syndromes, including frailty, sarcopenia, dementia, polypharmacy and enteral feeding. The evidence is presented according to the four primary pharmacokinetic processes (Absorption, Distribution, Metabolism and Excretion). There is some evidence to inform our understanding of the impact of chronological aging and various geriatric syndromes on drug disposition. However, many areas require more research, including drug induced inhibition and induction of cytochrome P450 enzymes and the clinical utility of emerging methods for estimating renal function. There is a need to develop tools to predict alterations in drug disposition in subgroups of older adults, particularly where the currently available clinical information is sparse.
Publisher: Elsevier BV
Date: 09-2020
Publisher: Springer Science and Business Media LLC
Date: 18-11-2020
Publisher: Elsevier BV
Date: 09-2008
DOI: 10.1016/J.ABB.2008.05.014
Abstract: Venom of the Australian ant species Myrmecia pilosula contains a number of allergenic peptides including pilosulins. To obtain novel cDNA clones that encode the pilosulin-related bioactive peptides, mRNA of M. pilosula species complex was subjected to RT-PCR in which the forward primer corresponds to a nucleotide sequence in the leader sequences of pilosulins. We isolated a cDNA clone encoding the novel bioactive peptide pilosulin 5. Tandem mass analysis was entirely consistent with the cDNA derived sequence, and indicated that pilosulin 5 is connected by a single disulfide bridge to create a dimmer peptide of 8546Da. Synthetic pilosulin 5 peptide caused a significant histamine release in a dose-dependent manner, and the mastoparan homologous region of pilosulin 5 was responsible for the activity.
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.LFS.2022.120521
Abstract: Maternal undernutrition during pregnancy disrupts both fetal growth and development with perturbations to certain physiological processes within the maternal-fetal-placental unit, including metabolic function. However, it is unknown if hypoglycemia during pregnancy alters maternal-fetal-placental drug metabolism as mediated by cytochrome P450 (CYP) enzymes. Despite this, hypoglycemia reduces CYP enzyme activity in non-pregnant animals. We therefore hypothesised that in a sheep model of hypoglycemia induced by late gestation undernutrition (LGUN), maternal-fetal-placental CYP activity would be reduced, and that fetal glucose infusion (LGUN+G) would rescue reduced CYP activity. At 115d gestation (term, 150d), ewes were allocated to control (100% metabolic energy requirement (MER) n = 11), LGUN (50% MER n = 7) or LGUN+G (50% MER + fetal glucose infusion n = 6) and maintained on their diets until post-mortem. Maternal-fetal-placental CYP activity assays were performed at 131-133d gestation. Microsomes were isolated from placenta and fetal liver collected at 139-142d gestation and incubated with CYP-specific probe drugs. Metabolite concentrations were measured using Liquid Chromatography - tandem mass spectrometry (LC-MS/MS). CYP2C19 and CYP3A were undetectable in placenta or fetal liver, and CYP1A2 was undetectable in the fetal liver. Placental-specific CYP1A2 and CYP2D6 activity and hepatic-specific CYP2D6 activity were unaffected by LGUN. Maternal-fetal-placental CYP1A2 activity was reduced in response to LGUN in the maternal compartment only. Reduced maternal-fetal-placental CYP1A2 activity, but not placental-specific CYP1A2 activity, may lead to the developing fetus being exposed to increased concentrations of CYP1A2-specific substrates and suggests further consideration of drug dosing is required in instances of late gestation maternal undernutrition.
Publisher: Wiley
Date: 11-01-2018
DOI: 10.1111/BCP.13480
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: Elsevier BV
Date: 11-2020
Publisher: Wiley
Date: 22-04-2015
DOI: 10.1111/BCP.12553
Publisher: Future Medicine Ltd
Date: 09-2012
DOI: 10.2217/PGS.12.118
Abstract: Aim: Leflunomide is a disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis. Not all patients respond to leflunomide and, as it has potentially serious side effects, targeting only those most likely to benefit would address a clinical need. We aimed to determine whether variations in the gene encoding DHODH, the molecular target of leflunomide, might include biomarkers that could be used to rationalize provision of this drug. Materials & methods: We analyzed six haplotype-tagging SNPs in DHODH in 56 patients with rheumatoid arthritis treated with leflunomide. Clinical response was determined by assessing the change in 28 joint disease activity score over the first 3 months of treatment. Results & conclusion: Carriage of a six-marker DHODH haplotype was associated with a reduced treatment response (p = 0.008). This suggests that a functional variant in strong linkage disequilibrium with this haplotype may predispose to reduced leflunomide efficacy. Original submitted 2 April 2012 Revision submitted 13 July 2012
Publisher: Informa UK Limited
Date: 11-2018
DOI: 10.2147/PGPM.S170557
Publisher: SAGE Publications
Date: 2021
DOI: 10.1177/1759720X211009020
Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease associated with increased risk of cardiovascular disease (CVD). Treatment for CVD may involve pharmacological agents that antagonise beta adrenergic receptors. These receptors may play an important role in immunology, and the effects of beta-blockers (BB) in RA is unknown. The aim of this study was to investigate the association between BB use and remission in patients with RA initiating tocilizumab +/− conventional synthetic (cs-) DMARD therapy. Data was pooled from five randomised trials investigating tocilizumab and/or csDMARD treatment in RA (primarily methotrexate). The association between BB use and remission according to the Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) was assessed by Cox proportional hazard analysis. Sensitivity analysis in patients with pre-existing CVD and an exploratory analysis of the impact of other CVD drugs were conducted. Data were available from 5502 participants, 594 (10.8%) of whom were using systemic BB. BB use was associated with less frequent SDAI remission in the total [adjusted hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.57–0.87, p = 0.001] and CVD cohort [adjusted HR 0.72 (0.57–0.90, p = 0.005)]. The association was consistent between trials (interaction p = 0.44) and treatment arms (interaction p = 0.06). No significant association between remission and β1-receptor selectivity was identified ( p = 0.16), and the association was independent from other cardiovascular drug use. Similar associations between BB use and CDAI remission were observed. In a large, pooled cohort of RA patients initiating csDMARDs and/or tocilizumab, BB use was independently associated with less frequent remission.
Publisher: SAGE Publications
Date: 27-05-2014
Abstract: Background: Medication-related problems and adverse drug events are leading causes of preventable hospitalizations. Few previous studies have investigated the possible association between medication regimen complexity and unplanned rehospitalization. Objective: To investigate the association between discharge medication regimen complexity and unplanned rehospitalization over a 12-month period. Method: The prospective study comprised patients aged ≥70 years old consecutively admitted to a Geriatrics Evaluation and Management (GEM) unit between October 2010 and December 2011. Medication regimen complexity at discharge was calculated using the 65-item validated Medication Regimen Complexity Index (MRCI). Cox proportional-hazards regression was used to compute unadjusted and adjusted hazard ratios (HRs) with 95% CIs for factors associated with rehospitalization over a 12-month follow-up period. Result: Of 163 eligible patients, 99 patients had one or more unplanned hospital readmissions. When adjusting for age, sex, activities of daily living, depression, comorbidity, cognitive status, and discharge destination, MRCI (HR = 1.01 95% CI = 0.81-1.26), number of discharge medications (HR = 1.01 95% CI = 0.94-1.08), and polypharmacy (≥9 medications HR = 1.12 95% CI = 0.69-1.80) were not associated with rehospitalization. In patients discharged to nonhome settings, there was an association between rehospitalization and the number of discharge medications (HR = 1.12 95% CI = 1.01-1.25) and polypharmacy (HR = 2.24 95% CI = 1.02-4.94) but not between rehospitalization and MRCI (HR = 1.32 95% CI = 0.98-1.78). Conclusion: Medication regimen complexity was not associated with unplanned hospital readmission in older people. However, in patients discharged to nonhome settings, the number of discharge medications and polypharmacy predicted rehospitalization. A patient’s discharge destination is an important factor in unplanned medication-related readmissions.
Publisher: Hindawi Limited
Date: 14-03-2016
DOI: 10.1111/IJCP.12785
Abstract: While the introduction of the treat-to-target (T2T) strategy has been an important advance in the management of rheumatoid arthritis (RA), the potential for increased toxicity due to use of concurrent drugs could adversely affect patient reported outcomes (PROs). The objective was to determine whether the cessation of therapy due to toxicity affects long-term improvement in PROs in patients treated according to T2T strategy. A total of 149 patients from an inception cohort of early RA were included. The occurrence and severity of toxicity were monitored at each visit over 3 years. PROs studied were function (measured using health assessment questionnaire) pain, fatigue and patient global assessment (PtGA) all assessed using a 100 mm visual analogue scale helplessness and health-related quality of life (HRQoL). For each PRO, effect of drug withdrawal was measured by comparing mean change in PROs among patients with no/temporary vs. permanent withdrawal. In addition, effects of frequency of drug withdrawals, weeks to withdrawal and number of drugs withdrawn were analysed using linear regression. After 3 years, 56 (37.4%) patients ceased at least one drug permanently due to toxicity. Patients with no/temporary withdrawal (n = 93) achieved significantly greater improvement in function (mean change = -0.54 vs. -0.31, p = 0.033), pain (mean change = -39.82 vs. -5.02, p = 0.018), fatigue (mean change = -29.14 vs. -14.76, p = 0.015) and PtGA (mean change = -29.64 vs. -17.00, p = 0.018) compared with their counterparts. Higher frequency of withdrawals was associated with lesser improvements in function, pain, fatigue and PtGA, while the number of drugs withdrawn and the weeks to withdrawal had lesser effects. However, the cessation of the drugs due to their toxicity did not have a significant association with HRQoL and helplessness. Improvements in function, pain, fatigue and PtGA at 3 years were diminished for patients who ceased drugs due to toxicity while broader measures of HRQoL were not affected.
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.LFS.2021.120133
Abstract: Non-alcoholic fatty liver disease (NAFLD) is characterised by accumulation of triglycerides and cholesterol within the liver and dysregulation of specific hepatic cytochrome P450 (CYPs) activity. CYPs are involved in the metabolism of endogenous and exogenous chemicals. Hepatic CYP activity is dysregulated in human studies and animal models of a Western diet (WD) or low birth weight (LBW) independently, but the additive effects of LBW and postnatal WD consumption are unknown. As such, the aim of this study was to determine the independent and combined effect of birthweight and postnatal diet on hepatic CYP activity in a guinea pig model. LBW was generated via uterine artery ablation at mid gestation (term = 70 days gestation). Normal birthweight (NBW) and LBW pups were allocated either a control diet (CD) or WD at weaning. After 4 months of dietary intervention, guinea pigs were humanely killed, and liver tissue collected for biochemical and functional hepatic CYP activity analyses. Independent of birthweight, functional activity of CYP3A was significantly reduced in female and male WD compared to CD animals (female, P < 0.0001 male, P = 0.004). Likewise, CYP1A2 activity was significantly reduced in male WD compared to CD animals (P = 0.020) but this same reduction was not observed in females. Diet, but not birthweight, significantly altered hepatic CYP activity in both sexes, and the effect of diet appeared to be greater in males. These findings may have clinical implications for the management of NAFLD and associated co-morbidities between the sexes.
Publisher: Wiley
Date: 07-2022
DOI: 10.1002/EJP.1992
Abstract: Negative experiences of needle procedures in childhood can lead to medical avoidance and vaccine hesitancy into adulthood. We evaluated the feasibility of two new interventions provided by clinical nurses to reduce the negative impact of vaccinations: ided attention (DA) and positive memory reframing (PMR). Children (8–12 years) were randomized into four groups: usual care (UC), DA, PMR or combined (DA + PMR). To evaluate feasibility, we undertook in‐depth analysis of video‐recorded interventions, nurse experiences (phone interviews) and child arent memory recall of interventions (phone interviews at 2 weeks post‐vaccination). Key clinical outcomes included child and parent ratings of needle‐related pain intensity and fear assessed at baseline, immediately post‐vaccination and 2 weeks post‐vaccination (recalled). A total of 54 child–parent dyads were screened, with 41 included (10/group, except PMR [ n = 11]). The interventions were not always completed as intended: 10%–22% of participants received complete interventions and two had adverse events related to protocol breach. Preliminary within‐group analyses showed no effects on child arent pain ratings. However, children in DA + PMR had reduced recalled fear ( p = 0.008), and PMR ( p = 0.025) and DA + PMR ( p = 0.003) had reduced fear of future needles. Parent ratings of child fear were also reduced immediately post‐vaccination for UC ( p = 0.035) and PMR ( p = 0.035). The interventions were feasible, although enhanced nurse training is required to improve fidelity. Preliminary clinical results appear promising, particularly for reducing needle‐related fear. Protocol registration: Protocol number ACTRN12618000687291 at ANZCTR.org.au Two new nurse‐led interventions to reduce negative impacts of vaccinations in children, ided attention and positive memory reframing, were feasible and may reduce needle‐related fear. Nurses were able to deliver the interventions in various environments including non‐clinical settings (schools). These interventions have potential to facilitate broader dissemination of vaccinations for children in a manner that minimizes distress.
Publisher: Elsevier BV
Date: 07-2012
DOI: 10.1016/J.JACI.2012.02.022
Abstract: Venom immunotherapy can be initiated by different schedules, but randomized comparisons have not been performed. We aimed to compare the safety of 2 initiation schedules. Patients of any age with prior immediate generalized reactions to jack jumper ant (Myrmecia pilosula) stings were randomized to venom immunotherapy initiation by a semirush schedule over 10 visits (9 weeks) or an ultrarush schedule over 3 visits (2 weeks). In a concurrent treatment efficacy study, the target maintenance dose was randomized to either 50 μg or 100 μg. The primary outcome was the occurrence of 1 or more objective systemic reactions during venom immunotherapy initiation. Analyses were by intention to treat. We also assessed outcomes in patients who declined randomization. Of 213 eligible patients, 93 were randomized to semirush (44 patients) or ultrarush (49 patients) initiation. Objective systemic reactions were more likely during ultrarush initiation (65% vs 29% P < .001), as were severe reactions (12% vs 0% P= .029). Times to maximal increases in venom-specific IgG(4) were no different between treatments, whereas the maximal increase in venom-specific IgE occurred earlier with ultrarush treatment. Similar differences between methods were observed in patients who declined randomization. One hundred seventy-eight patients were randomized to maintenance doses of either 50 μg (90 patients) or 100 μg (88 patients). The target maintenance dose had no effect on the primary outcome, but multiple-failure-per-subject analysis found that the 50 μg dose reduced the likelihood of reactions. Ultrarush initiation increases the risk of systemic reactions. A lower maintenance dose reduces the risk of repeated reactions, but the effect on treatment efficacy is unknown.
Publisher: Elsevier BV
Date: 07-2021
DOI: 10.1016/J.NEURO.2021.05.015
Abstract: Parkinson's disease (PD) is the second most common neurodegenerative disease, characterised by the loss of dopaminergic neurons in the substantia nigra. Mounting evidence indicates a crucial role of inflammation and concomitant oxidative stress in the disease progression. Therefore, the aim of this study was to investigate the ability of systemically administered lipopolysaccharide (LPS) to induce motor and non-motor symptoms of PD, inflammation, oxidative stress and major neuropathological hallmarks of the disease in regions postulated to be affected, including the olfactory bulb, hippoc us, midbrain and cerebellum. Twenty-one male C57BL/6 mice, approximately 20 weeks old, received a dose of 0.3 mg/kg/day of LPS systemically on 4 consecutive days and behavioural testing was conducted on days 14-18 post-treatment, followed by tissue collection. Systemically administered LPS increased latency time in the buried food seeking test (indicative of olfactory impairment), and decreased time spent in central zone of the open field (anxiety-like behaviour). However, there was no change in latency time in the rotarod test or the expression of tyrosine hydroxylase (TH) in the midbrain. Systemically administered LPS induced increased glial markers GFAP and Iba-1 and oxidative stress marker 3-nitrotyrosine (3-NT) in the olfactory bulb, hippoc us, midbrain and cerebellum, and there were region specific changes in the expression of NFκB, IL-1β, α-synuclein, TH and BDNF proteins. The model could be useful to further elucidate early non-motor aspects of PD and the possible mechanisms contributing to the non-motor deficits.
Publisher: Wiley
Date: 08-1999
Publisher: BMJ
Date: 20-08-2012
Publisher: Elsevier BV
Date: 02-2004
Publisher: Elsevier BV
Date: 04-2020
Publisher: Informa UK Limited
Date: 09-06-2014
DOI: 10.1517/17425255.2014.925880
Abstract: A number of disease-modifying therapies have become available to treat multiple sclerosis (MS) in recent years. As the effects of these medications are unpredictable and they are generally used for a number of years, the selection of the most appropriate disease-modifying agent must be based on the long-term efficacy and toxicity profile, thus strategies to personalise treatment to optimise responses may be potentially very useful. This review provides an overview of the efficacy and toxicity of disease-modifying agents used in MS and specifically discusses any metabolic side effects and advances in personalising the use of each of these agents. Medline and EMBASE were searched for any articles regarding the efficacy, toxicity and personalised use of the medicines discussed in this review. Disease-modifying agents used to treat MS differ substantially in their efficacy and toxicity profile, but metabolic side effects appear to be limited to alemtuzumab, teriflunomide and IFN-β. Although personalised treatment strategies to assist in selection of the most appropriate disease-modifying agent for MS are limited, there is substantial potential to use genetic sub-studies of the many recent trials investigating disease-modifying agents to develop personalised treatment strategies.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.JPBA.2011.01.034
Abstract: The clinical activity of leflunomide, a drug used in the treatment of rheumatoid arthritis, is due to its active metabolite, teriflunomide. In vitro studies indicate that at least 99% of teriflunomide is expected to be protein bound in human plasma in vivo, leaving<1% in the unbound or 'free' state for clinical activity. To examine details of the relationships between leflunomide dosing and patient response, it is necessary to have an assay that is sufficiently sensitive to measure the minor fraction of free teriflunomide in patient s les. Therefore, we aimed to develop and validate an LC-MS/MS method for the measurement of teriflunomide, and use it to determine the total and free teriflunomide concentration in patients with rheumatoid arthritis. Teriflunomide and its deuterated internal standard were extracted from human plasma and separated using a reversed phase method with a C18 column. Detection was conducted with an API 3000 LC-MS/MS System by monitoring selected ions in negative ion MRM. Optimal detection occurred at m/z 269.1/160.0 (teriflunomide) and m/z 273.1/164.0 (teriflunomide-D4). Over a linear range of 5-500 μg/L, the inter-batch precision ranged from 1.9 to 8.8% and accuracy from -8.4 to 8.0%. The intra- and inter-batch assay precision for quality control s les ranged from 2.1-5.4% and 5.7-7.1% respectively. The procedure was applied to assess total and free plasma concentrations of teriflunomide in patients with rheumatoid arthritis. Free teriflunomide was approximately 0.11% of total teriflunomide, and there was a significant correlation (r2=0.724) between free and total teriflunomide concentrations. A validated, accurate and sensitive method was developed and successfully applied for the measurement of total and free teriflunomide concentration in human plasma s les. This method has been shown to be reproducible and sensitive and can be applied to clinical s les.
Publisher: Wiley
Date: 31-08-2017
DOI: 10.1111/CEA.12987
Abstract: Allergen immunotherapy uses pharmaceutical preparations derived from naturally occurring source materials, which contain water-soluble allergenic components responsible for allergic reactions. The success of in vivo and in vitro diagnoses in allergen sensitization and allergen immunotherapy largely depends on the quality, composition and uniformity of allergenic materials used to produce the active ingredients, and the formulation employed to prepare finished products. We aimed to examine the factors influencing batch-to-batch consistency of Jack Jumper (Myrmecia pilosula) ant venom (JJAV) in the form of active pharmaceutical ingredient (AI) and informed whether factors such as temperature, artificial light and container materials influence the quality of JJAV AIs. We also aimed to establish handling and storage requirements of JJAV AIs to ensure preservation of allergenic activities during usage in the diagnosis of allergen sensitization and in allergen immunotherapy. The quality and consistency of JJAV AIs were analysed using a combination of bicinchoninic acid assay for total protein quantification, HPLC-UV for JJAV allergen peptides quantification, ELISA inhibition for total allergenic potency, SDS-PAGE, AU-PAGE and immunoblot for qualitative assessment of JJAV components, and Limulus Amebocyte Lysate assay for the quantification of endotoxin concentration. API-ZYM and Zymogram assays were used to probe the presence of enzymatic activities in JJAV. Pharmaceutical-grade JJAV for allergen immunotherapy has good batch-to-batch consistency. Temporary storage at 4°C and light exposure do not affect the quality of JJAV. Exposure to temperature above 40°C degrades high MW allergens in JJAV. Vials containing JJAV must be stored frozen and in upright position during long-term storage. We have identified factors, which can influence the quality and consistency of JJAV AIs, and provided a framework for appropriate handling, transporting and storage of JJAV to be used for the diagnosis of allergen sensitization and in AIT.
Publisher: SAGE Publications
Date: 08-2017
Abstract: Methotrexate (MTX) treatment in rheumatoid arthritis (RA) has been associated with lower cardiovascular risk compared to other disease-modifying antirheumatic drugs (DMARDs). We sought to identify whether the MTX-associated cardioprotection involves changes in blood pressure (BP) and/or arterial function. Clinic and 24-hour peripheral and central systolic and diastolic BP (SBP and DBP), augmentation index (AIx), pulse wave velocity (PWV) and plasma asymmetric dimethylarginine (ADMA) were assessed in RA patients on stable treatment with either MTX ± other DMARDs (MTX group, n = 56, age 61 ± 13 years, 70% females) or other DMARDs (non-MTX group, n = 30, age 63 ± 12 years, 76% females). Measurements were performed at baseline and after 8 months. After adjusting for visit, age, gender, body mass index, folic acid use and 28-joint disease activity score, the MTX group had significantly lower clinic peripheral SBP (−7.7 mmHg, 95% CI −13.2 to −2.3, p = 0.006) and DBP (−6.1 mmHg, 95% CI −9.8 to −2.4, p = 0.001) and clinic central SBP (−7.8 mmHg, 95% CI −13.1 to −2.6, p = 0.003) and DBP (−5.4 mmHg, 95% CI −9.1 to −1.6, p = 0.005) versus the non-MTX group. Furthermore, the MTX group had significantly lower 24-hour peripheral and central SBP and DBP and PWV versus the non-MTX group ( p 0.01 for all comparisons). By contrast, there were no significant between-group differences in AIx and ADMA. RA patients on MTX treatment had significantly lower clinic and 24-hour peripheral and central BP compared to those who did not take MTX. The lower BP with MTX may be related to differences in PWV, but not in AIx or ADMA concentrations. Further longitudinal studies including randomized controlled trials are warranted to confirm these findings, to identify other possible mechanisms responsible for the effects of MTX on BP and PWV, and to establish whether these effects might account for the reduced cardiovascular risk with MTX.
Publisher: SAGE Publications
Date: 2022
DOI: 10.1177/1759720X221111613
Abstract: Rheumatoid arthritis (RA) is an inflammatory autoimmune condition associated with an increased risk of developing depression and anxiety. Depression and anxiety are associated with worse outcomes in RA, but the magnitude of the effect of each condition on RA outcomes is unclear. It is also unknown how pharmacological treatment of depression affects RA outcomes. The primary aim of this study was to investigate the association of comorbid depression and anxiety with remission in patients with RA. Secondary aims were to determine the association between comorbid depression and anxiety on patient-reported outcomes and the relationship between concomitant use of antidepressants and remission in patients with depression. Data from patients with moderate to severe RA were pooled from five randomised controlled trials investigating tocilizumab and conventional synthetic disease-modifying agents. Remission was defined as a clinical disease activity index (CDAI) of ⩽2.8 and simple disease activity index (SDAI) of ⩽3.3. The association between the time to reach remission and depression and anxiety was analysed using Cox proportional hazard analysis. In idual patient data were available from 5502 subjects, of whom 511 had depression, 236 had anxiety and 387 were using antidepressants. Depression was significantly associated with reduced remission [adjusted HR (95% CI): 0.62 (0.48–0.80), p 0.001 and adjusted HR (95% CI): 0.59 (0.44–0.79), p 0.001] using CDAI and SDAI, respectively. Depression was associated with a lower likelihood of achieving more subjective outcomes (⩽1 physician global assessment, ⩽1 patient global assessment) and ⩽1 28-swollen joint count, but not ⩽1 28-tender joint count or C-reactive protein measurement. Treatment with antidepressants did not improve outcomes for patients with depression. Anxiety was not significantly associated with RA remission. Comorbid depression, but not anxiety, was associated with less frequent remission. Concomitant antidepressant use was not associated with improvements in RA outcomes in patients with depression.
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.JPBA.2010.08.024
Abstract: Allergy to Myrmecia pilosula (Jack Jumper Ant) venom is common in Australia, affecting ∼2.7% of some communities. Venom immunotherapy is a highly effective treatment, but for the venom to be widely distributed for clinical use, the stability and shelf-life of formulated Jack Jumper Ant venom must be demonstrated. HPLC-UV, ELISA Inhibition, SDS-PAGE and SDS-PAGE Immunoblot were used to assess venom stability under conditions of varying temperature, pH and in the presence of various stabilising agents. Optimal stability occurred between pH 8 and 10, however the presence of benzyl alcohol within this pH range resulted in a cloudy appearance within 3 days, so a pH of 6 was used. Increasing polysorbate 80 concentrations accelerated the degradation of allergenic peptides in 100 μg/mL venom, but improved stability at concentrations of 1 μg/mL or less. Sucrose reduced degradation of allergens Myr p 1 and Myr p 3, whilst glycerol was destabilizing. In the presence of 22% sucrose, 1.1mg/mL Jack Jumper Ant venom was stable at -18 °C and 4 °C for 12 months following dilution to 100 μg/mL with 0.9% sodium chloride, 10mM phosphate (pH 6), 0.05% polysorbate 80 and 0.9% benzyl alcohol (giving 2% sucrose), venom was stable for 7 days when stored at 4 °C. Concentrated Jack Jumper Ant venom can be stored in 22% sucrose for 12 months, and after dilution to 100 μg/mL for clinical use, it should be discarded after 7 days.
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.JPBA.2007.08.028
Abstract: Ant sting allergy is relatively common within south-eastern Australia and is predominantly due to Myrmecia pilosula (Jack Jumper Ant, JJA). Venom immunotherapy has been shown to be effective in preventing anaphylaxis to the sting of the JJA, but analytical techniques to standardise the venom have not been validated. The purpose of this study was to develop assays to analyse JJA venom and apply these to the standardisation of venom prior to new batches being used for the diagnosis and treatment of JJA sting allergy. Venom was analysed by protein content, HPLC-UV, enzyme-linked immunosorbent assay (ELISA) inhibition, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and SDS-PAGE immunoblot. The protein content in JJA venom was adjusted so that all batches were equivalent. A HPLC-UV assay was used to quantify the relative amount of the major allergen Myr p 2 and two minor allergens Myr p 1 and Myr p 3 and allergenic potency was determined by ELISA inhibition. SDS-PAGE and SDS-PAGE immunoblot were used as qualitative tools to determine the protein profile and presence or absence of additional high molecular weight allergens not quantifiable by HPLC-UV. A standardisation procedure has been developed that complies with the requirements described in the European Pharmacopoeia. Techniques used to determine the content of some of the other minor allergens could be developed, which would further improve the standardisation methodology.
Publisher: Elsevier BV
Date: 08-2019
Publisher: Wiley
Date: 19-12-2016
DOI: 10.1111/JGS.14682
Abstract: To systematically review clinical outcomes associated with medication regimen complexity in older people. Systematic review of EMBASE, MEDLINE, International Pharmaceutical Abstracts, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane library. Hospitals, home, and long-term care. English-language peer-reviewed original research published before June 2016 was eligible if regimen complexity was quantified using a metric that considered number of medications and at least one other parameter, regimen complexity was calculated for participants' overall regimen, at least 80% of participants were aged 60 and older, and the study investigated a clinical outcome associated with regimen complexity. Quality assessment was conducted using an adapted version of the Joanna Briggs Institute critical appraisal tool. Sixteen observational studies met the inclusion criteria. Regimen complexity was associated with medication nonadherence (2/6 studies) and higher rates of hospitalization (2/4 studies). One study found that participants with less-complex medication administration were more likely to stop medications when feeling worse. One study each identified an association between regimen complexity and higher ability to administer medications as directed, medication self-administration errors, caregiver medication administration hassles, hospital discharge to non-home settings, postdischarge potential adverse drug events, all-cause mortality, and lower patient knowledge of their medication. Regimen complexity had no association with postdischarge medication modification, change in medication- and health-related problems, emergency department visits, or quality of life as rated by nursing staff. Research into whether medication regimen complexity is associated with nonadherence and hospitalization has produced inconsistent results. Moderate-quality evidence from four studies (two each for nonadherence and hospitalization) suggests that medication regimen complexity is associated with nonadherence and higher rates of hospitalization.
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: 12-05-2016
DOI: 10.1111/CEA.12740
Abstract: Current peanut oral immunotherapy is h ered by frequent adverse events. It has been shown that boiling can reduce peanut allergenicity. Hypoallergenic peanut products have the potential to reduce treatment-related reactions during desensitization. To show that extended boiling (for up to 12 h) can progressively reduce peanut allergenicity while retaining T cell reactivity. Raw peanuts were boiled for half, 1, 2, 4 and 12 h in deionized water. After dehydration, boiled and raw peanuts were ground, defatted and soluble proteins extracted in PBS and cooking water (leachate) retained. SDS-PAGE, Western blot, inhibition ELISA, mass spectrometry and skin prick test were used to characterize changes to peanut allergens and human IgE reactivity. T cell responses to raw and boiled peanut extracts were determined by proliferation of CD4+/CD25+/CD134+ T cells in peanut-allergic and non-allergic in iduals. Extended boiling progressively reduced peanut allergenicity through a combination of leaching of allergens into cooking water, fragmentation of allergens and denaturation of conformational epitopes. Two-hour boiling led to an eightfold reduction in IgE binding capacity of boiled peanuts as determined by inhibition ELISA, while 12-h boiling led to a 19-fold reduction. Mass spectrometry revealed an increasing number of unique allergen peptides with longer boiling times. Raw, 2- and 12-h boiled peanut extracts were equivalent in their ability to stimulate T cell activation and proliferation. Progressive reduction in peanut allergenicity with extended boiling does not affect T cell reactivity. Boiled peanuts may be a candidate for oral immunotherapy.
Publisher: Future Medicine Ltd
Date: 10-2016
Abstract: Aims: Oxaliplatin-based chemotherapy for colorectal cancer demonstrates interin idual variability in response, and polymorphisms of ERCC1, ERCC2, XRCC1, GSTP1 and GSTM1 genes may be contributing factors. Additionally, the effect of these genotypes may differ between ethnic groups. Material & Methods: A meta-analysis of the association between these genotypes and response, progression-free survival and overall survival (OS) for patients with colorectal cancer treated with oxaliplatin-based therapy is reported. Results: ERCC1 C118T (TT vs CC OS [hazard ratio (HR): 2.59 p = 0.001]), ERCC2 A2251C (CC or AC vs AA OS [HR: 1.53 p = 0.04]) and GSTP1 A313G (GG vs AA OS, [HR: 0.47 p 0.001]) polymorphisms were associated with survival. The effect size may be larger for ERCC1 C118T and XRCC1 G1196A in Asian compared with Caucasian populations. No association was apparent for the GSTM1 genotype. Conclusion: ERCC1 C118T, ERCC2 A2251C and GSTP1 A313G polymorphisms were associated with clinical outcomes
Publisher: Wiley
Date: 19-09-2014
DOI: 10.1111/BCP.12386
Publisher: Elsevier BV
Date: 09-2021
Publisher: Elsevier BV
Date: 03-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2014
DOI: 10.1161/CIRCGENETICS.114.000669
Abstract: The degree to which cytochrome P450 (CYP) 2C19 genotype influences the effectiveness of clopidogrel remains uncertain because of considerable heterogeneity in results between studies and potential publication bias. Clopidogrel indication and ethnic population have been proposed to influence the effect of CYP2C19 genotype. A systematic review was undertaken up to 14 November 2013. Meta-analysis of the CYP2C19 genotype effect was stratified by the predominant clopidogrel indication (percutaneous coronary intervention [PCI] versus non-PCI) and ethnic population (white versus Asian) of each primary study. The primary analysis was restricted to studies with ≥500 participants, which comprised 24 studies and a total of 36 076 participants. The association between carriage of ≥1 CYP2C19 loss-of-function (LoF) allele and major cardiovascular outcomes differed significantly ( P .001) between studies of whites not undergoing PCI (relative risk 0.99 [95% confidence interval, 0.84–1.17] n=7043), whites undergoing PCI (1.20 [1.10–1.31] n=19,016), and Asians undergoing PCI (1.91 [1.61–2.27] n=10,017). Similar differences were identified in secondary analyses of 2 CYP2C19 LoF alleles, stent thrombosis outcomes, and studies with ≥200 participants. Minimal heterogeneity was apparent between studies of Asian populations. The reported association between CYP2C19 LoF allele carriage and major cardiovascular outcomes differs based on the ethnic population of the study and, to a lesser extent, the clopidogrel indication. This is potentially of major importance given that over 50% of Asians carry ≥1 CYP2C19 LoF alleles.
Publisher: Wiley
Date: 15-03-2013
Publisher: Springer Science and Business Media LLC
Date: 07-01-2014
DOI: 10.1038/TPJ.2013.45
Abstract: Sulphasalazine (SSA) is a disease modifying anti-rheumatic drug (DMARD) that is commonly used to treat rheumatoid arthritis (RA). Plasma levels of SSA and its metabolite sulphapyridine are influenced by common polymorphisms in genes that encode N-acetyl transferase 2 (NAT2) and ATP-binding cassette protein G2 (ABCG2). Study participants had early RA that was treated with a combination DMARD regimen that included SSA. Toxicity was defined by cessation of SSA due to adverse effects and response as remission after 12 months of treatment. The effect of variables on toxicity was assessed by a Cox-proportional Hazard model and response by logistic regression. After correction for conventional variables, toxicity in 229 participants was influenced by NAT2 phenotype (hazard ratio=1.74 (95% confidence interval (CI) 1.01-3.21), P=0.044) and remission in 141 participants was associated with ABCG2 genotype (odds ratio=3.34 (95% CI 1.18-9.50), P=0.024). In our s le of early RA patients who were primarily treated with a combination of DMARDs, common variants in genes that encode NAT2 and ABCG2 were associated respectively with toxicity and response to SSA.
Publisher: Informa UK Limited
Date: 09-2016
DOI: 10.1080/17425255.2016.1229303
Abstract: Small molecule protein kinase inhibitors (KIs) are a class of drugs with complex and unconventional physiochemical and pharmacokinetic characteristics. Cytochrome P450 mediated metabolism and transporter-mediated uptake and efflux are important processes that determine KI disposition and exposure. Areas covered: We provide an overview of KI pharmacology, with a comprehensive summary of KI physiochemical and pharmacokinetic properties and description of the major sources of variability in KI pharmacokinetics focusing on common pathways involved in determining exposure. We also consider the strategies proposed to optimize KI dosing, appraise the current evidence for their use and analyze the challenges and knowledge gaps for KI dose optimization. Expert opinion: A number of strategies to optimize KI dosing have been proposed, but evidence underpinning their use is limited. The major challenge for optimized KI dosing is the development of high-quality evidence to demonstrate a significant improvement in therapeutic outcomes and /or reduction in adverse events through appropriately designed trials in a setting where the limited KI prescribing restricts capacity to undertake prospective randomized studies. If precision KI dosing can facilitate a fraction of the reported observational benefits, then substantial gains in patient outcomes will be derived in a cost-effective manner.
Publisher: Oxford University Press (OUP)
Date: 26-12-2016
Publisher: American Medical Association (AMA)
Date: 09-2022
DOI: 10.1001/JAMAONCOL.2022.2867
Abstract: Emerging policies drafted by the pharmaceutical industry indicate that they will transparently share clinical trial data. These data offer an unparalleled opportunity to advance evidence-based medicine and support decision-making. To evaluate the eligibility of independent, qualified researchers to access in idual participant data (IPD) from oncology trials that supported US Food and Drug Administration (FDA) approval of new anticancer medicines within the past 10 years. In this quality improvement study, a cross-sectional analysis was performed of pivotal clinical trials whose results supported FDA-approved anticancer medicines between January 1, 2011, and June 30, 2021. These trials’ results were identified from product labels. Eligibility for IPD sharing was confirmed by identification of a public listing of the trial as eligible for sharing or by receipt of a positive response from the sponsor to a standardized inquiry. The main outcome was frequency of IPD sharing eligibility. Reasons for data sharing ineligibility were requested and collated, and company-, drug-, and trial-level subgroups were evaluated and presented using χ 2 tests and forest plots. During the 10-year period examined, 115 anticancer medicines were approved by the FDA on the basis of evidence from 304 pharmaceutical industry–sponsored trials. Of these trials, 136 (45%) were eligible for IPD sharing and 168 (55%) were not. Data sharing rates differed substantially among industry sponsors, with the most common reason for not sharing trial IPD being that the collection of long-term follow-up data was still ongoing (89 of 168 trials [53%]). Of the top 10 anticancer medicines by global sales, nivolumab, pembrolizumab, and pomalidomide had the lowest eligibility rates for data sharing (& % of trials). There has been a substantial increase in IPD sharing for industry-sponsored oncology trials over the past 5 years. However, this quality improvement study found that more than 50% of queried trials for FDA-approved anticancer medicines were ineligible for IPD sharing. Data accessibility would be substantially improved if, at the time of FDA registration of a medicine, all data that support the registration were made available.
Publisher: Wiley
Date: 28-06-2021
DOI: 10.1002/ACR.24236
Abstract: Leflunomide is a commonly used disease‐modifying drug in the treatment of rheumatoid arthritis (RA). Its effects are mediated via inhibition of dihydroorotate dehydrogenase (DHODH) by its active metabolite teriflunomide, and the pharmacokinetics of teriflunomide are highly variable. Our objective was to examine the association between the DHODH haplotype and plasma teriflunomide concentration with response to leflunomide in patients with RA where leflunomide was added to an existing disease‐modifying drug regimen after failure to achieve an adequate response with conventional triple therapy. Patients with RA who were taking, or were about to initiate, leflunomide were included. Participant characteristics, including the DHODH haplotype, were determined. Up to 5 plasma s les were collected after leflunomide was initiated for assays of total and free teriflunomide concentration. Disease activity was determined via the 28‐joint Disease Activity Score (DAS28). The association between DAS28 scores and patient covariates was determined by linear mixed‐effects modeling. A total of 67 patients were included in the study. The DAS28 score after initiation of leflunomide was associated with the baseline DAS28 score (β = 0.70, P 0.001) and was higher in those who carried the DHODH haplotype 2 (β = 0.56. P = 0.01) and did not carry the shared epitope (β = 0.56, P = 0.013). As total and free plasma teriflunomide concentration increased, the DAS28 score was significantly lower ( P 0.001 and P = 0.001, respectively). When considering threshold concentrations, teriflunomide concentrations mg/liter were associated with a DAS28 score that was 0.33 lower, and when free teriflunomide concentration was µg/liter, the DAS28 score was 0.32 lower. Teriflunomide concentration and carriage of the DHODH haplotype 2 are associated with response to leflunomide in patients with RA, and a total plasma teriflunomide concentration of at least 16 mg/liter is needed to maximize the likelihood of response.
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: Elsevier BV
Date: 2023
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.PHRS.2018.06.003
Abstract: The effects of intrauterine growth restriction (IUGR) extend well into postnatal life. IUGR is associated with an increased risk of adverse health outcomes, which often leads to greater medication usage. Many medications require hepatic metabolism for activation or clearance, but hepatic function may be altered in IUGR fetuses. Using a sheep model of IUGR, we determined the impact of IUGR on hepatic drug metabolism and drug transporter expression, both important mediators of fetal drug exposure, in late gestation and in neonatal life. In the late gestation fetus, IUGR decreased the gene expression of uptake drug transporter OATPC and increased P-glycoprotein protein expression in the liver, but there was no change in the activity of the drug metabolising enzymes CYP3A4 or CYP2D6. In contrast, at 3 weeks of age, CYP3A4 activity was reduced in the livers of lambs born with low birth weight (LBW), indicating that LBW results in changes to drug metabolising capacity in neonatal life. Together, these results suggest that IUGR may reduce hepatic drug metabolism in fetal and neonatal life through different mechanisms.
Publisher: Wiley
Date: 06-2023
DOI: 10.14814/PHY2.15749
Abstract: Babies born growth restricted are at an increased risk of both poor short‐and long‐term outcomes. Current interventions to improve fetal growth are ineffective and do not lower the lifetime risk of poor health status. Maternal resveratrol (RSV) treatment increases uterine artery blood flow, fetal oxygenation, and fetal weight. However, studies suggest that diets high in polyphenols such as RSV may impair fetal hemodynamics. We aimed to characterize the effect of RSV on fetal hemodynamics to further assess its safety as an intervention strategy. Pregnant ewes underwent magnetic resonance imaging (MRI) scans to measure blood flow and oxygenation within the fetal circulation using phase contrast‐MRI and T 2 oximetry. Blood flow and oxygenation measures were performed in a basal state and then repeated while the fetus was exposed to RSV. Fetal blood pressure and heart rate were not different between states. RSV did not impact fetal oxygen delivery (DO 2 ) or consumption (VO 2 ). Blood flow and oxygen delivery throughout the major vessels of the fetal circulation were not different between basal and RSV states. As such, acute exposure of the fetus to RSV does not directly impact fetal hemodynamics. This strengthens the rationale for the use of RSV as an intervention strategy against fetal growth restriction.
Publisher: Elsevier BV
Date: 09-2023
Publisher: Informa UK Limited
Date: 17-04-2020
Publisher: Wiley
Date: 13-07-2020
DOI: 10.1002/PRP2.625
Publisher: Springer Science and Business Media LLC
Date: 04-02-2020
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.TOXICON.2015.02.013
Abstract: Myrmecia pilosula is an endemic Australian ant whose sting is a frequent cause of insect allergy in southeast Australia, and several deaths due to M. pilosula sting envenomation have been documented. In this review, we discuss the composition and bioactivity of M. pilosula venom. In addition to various enzymes and pharmacologically active constituents, the venom contains four families of highly basic low molecular weight peptides trivially named Pilosulins. These peptides are unique and have low structural homology to other Hymenoptera venom peptides. Moreover, M. pilosula venom is relatively simple in its composition with 5 predominant peptides making up about 90% by weight. These peptides display cytotoxic, hypotensive, histamine-releasing and antimicrobial activities. Within the M. pilosula venom, Pilosulin 3 has been classified as a major allergen and [Ile(5)]pilosulin 1 and Pilosulin 4.1 are classified as minor allergens. Several uncharacterised higher molecular weight components with allergenic activities have also been identified. The revised naming of M. pilosula venom peptides according to the International Union of Immunological Societies (IUIS) criteria for allergen nomenclature is discussed in this review.
Publisher: Springer Science and Business Media LLC
Date: 08-03-2015
Publisher: Wiley
Date: 07-04-2016
DOI: 10.1111/BCP.12891
Publisher: Cambridge University Press (CUP)
Date: 25-01-2021
DOI: 10.1017/S2040174420001403
Abstract: Medical care is predicated on ‘do no harm’, yet the urgency to find drugs and vaccines to treat or prevent COVID-19 has led to an extraordinary effort to develop and test new therapies. Whilst this is an essential cornerstone of a united global response to the COVID-19 pandemic, the absolute requirements for meticulous efficacy and safety data remain. This is especially pertinent to the needs of pregnant women a group traditionally poorly represented in drug trials, yet a group at heightened risk of unintended adverse materno-fetal consequences due to the unique physiology of pregnancy and the life course implications of fetal or neonatal drug exposure. However, due to the complexities of drug trial participation when pregnant (be they vaccines or therapeutics for acute disease), many clinical drug trials will exclude them. Clinicians must determine the best course of drug treatment with a dearth of evidence from either clinical or preclinical studies, where at least in the short term they may be more focused on the outcome of the mother than of her offspring.
Publisher: Springer Science and Business Media LLC
Date: 11-2012
Publisher: Wiley
Date: 10-11-2017
DOI: 10.1002/MUS.25222
Abstract: The aim of this study was to determine whether a single-nucleotide polymorphism (SNP 1858CT, R620W) in the protein tyrosine phosphatase N22 (PTPN22) gene confers susceptibility to idiopathic inflammatory myopathy (IIM) in South Australian patients with IIM. Genotyping was performed on stored DNA from 199 patients with histologically confirmed polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM), and then compared with 455 matched controls. Associations with the 8.1 ancestral haplotype (AH), and myositis-specific (MSA) and myositis-associated (MAA) autoantibodies were investigated. The PTPN22 R620W minor allele frequency was increased in IIM patients (50 of 398, 12.6%) compared with controls (75 of 910, 8.2%) (odds ratio 1.6, 95% confidence interval 1.1-2.3, P = 0.016). In IIM patients, there was no association between the R620W minor allele and detection of any MSA/MAA (P = 0.70), nor any evidence of epistasis with the 8.1 AH (P = 0.69). The PTPN22 R620W minor allele is associated with susceptibility to IIM in SA patients, independent of the 8.1 AH. Muscle Nerve, 2016 Muscle Nerve 55: 270-273, 2017.
Publisher: Springer Science and Business Media LLC
Date: 27-05-2014
DOI: 10.1007/S40266-014-0185-1
Abstract: Older people often take multiple medications. It is a policy priority to facilitate older people to stay at home longer. Three-quarters of nursing home placements in the US are preceded by a hospitalization. To investigate the association between polypharmacy and medication regimen complexity with hospital discharge destination among older people. This prospective cohort study comprised patients aged ≥70 years consecutively admitted to the Geriatric Evaluation and Management unit at a tertiary hospital in Adelaide, Australia, between October 2010 and December 2011. Medication regimen complexity at discharge was calculated using the 65-item validated Medication Regimen Complexity Index (MRCI). Unadjusted and adjusted relative risks (RRs) with 95 % confidence intervals (CIs) were calculated for medication-related factors associated with discharge directly to home versus non-community settings (rehabilitation, transition care, and residential aged care). From 163 eligible patients, 87 were discharged directly to home (mean age 84.6 years, standard deviation [SD] 6.9 mean MRCI 26.1, SD 9.7), while 76 were discharged to non-community settings (mean age 85.8 years, SD 5.8 mean MRCI 29.9, SD 13.2). After adjusting for age, sex, comorbidity, and activities of daily living, having a high medication regimen complexity (MRCI >35) was inversely associated with discharge directly to home (RR 0.39 95 % CI 0.20-0.73), whereas polypharmacy (≥9 medications) was not significantly associated with discharge directly to home (RR 0.97 95 % CI 0.53-1.58). Having high medication regimen complexity was inversely associated with discharge directly to home, while polypharmacy was not associated with discharge destination.
Publisher: Elsevier BV
Date: 11-2021
Publisher: Springer Science and Business Media LLC
Date: 24-02-2017
DOI: 10.1007/S11095-017-2128-0
Abstract: Pharmacogenetic testing aims to personalize drug therapy with a view to optimising drug efficacy and minimise toxicity. However, despite the potential benefits, pharmacogenetic testing is mostly confined to specialised medical areas, laboratories and centres. Widespread integration into routine clinical practice has been limited by a complex set of issues including regulatory and reimbursement frameworks, evidence of clinical utility and clinician perspectives, practices and education. Here we assess the current barriers to widespread clinical uptake and identify the key issue necessary to address to accelerate routine testing.
Publisher: Springer Science and Business Media LLC
Date: 17-11-2014
DOI: 10.1007/S11096-013-9871-Z
Abstract: Deprescribing is a holistic process of medication cessation that encompasses gaining a comprehensive medication list, identifying potentially inappropriate medications, deciding if the identified medication can be ceased, planning the withdrawal regimen and monitoring, support and follow-up. It is currently being investigated as a mechanism to reduce unnecessary or redundant medications. However, given the systematic and patient-centred nature of the deprescribing process, it is possible that it may also confer additional benefits such as improving adherence to medications, even if there is no net reduction in overall medication use. Specifically, deprescribing may improve adherence via reducing polypharmacy, reducing the financial costs associated with medication taking, increasing the patient's medication knowledge through education, increasing patient engagement in medication management and resolution of adverse drug reactions. More research into deprescribing must be conducted to establish if these potential benefits can be realised, in addition to establishing any negative consequences.
Publisher: Wiley
Date: 06-2012
DOI: 10.1111/J.1445-5994.2011.02601.X
Abstract: Urticaria, angioedema and anaphylaxis are common adverse reactions to non-steroidal anti-inflammatory drugs (NSAIDs). To investigate the clinical characteristics of NSAID-induced acute hypersensitivity reactions with structured oral drug challenges. Patients with NSAID-induced urticaria, angioedema or anaphylaxis were challenged with either the homologous NSAID to confirm diagnosis or a heterologous NSAID to investigate cross-reactivity. Data were analysed retrospectively and supplemented by a telephone questionnaire. Sixty-eight patients (mean age 48.3, 53 females) reported a total of 75 instances of NSAID-induced reactions of which 64% were purely cutaneous and 36% were systemic anaphylaxis. Ibuprofen was the most frequent cause of reactions (35%), however, diclofenac was the most frequent cause of anaphylaxis (48%). Seventeen out of 40 (43%) homologous NSAID challenges were positive presentation with anaphylaxis or reaction to diclofenac predicted a positive challenge. Only 7 of 28 (25%) of heterologous NSAID challenges were positive. Structured challenges enabled us to identify 23 (34%) patients with selective reactivity to a single NSAID, 19 (28%) patients with cross-reactivity to multiple NSAIDs and 23 (34%) patients in whom NSAID hypersensitivity was not reproduced. Selective reactors presented most often with anaphylaxis and some had a background of beta-lactam antibiotic allergy. Cross-reactive patients often had a background of chronic urticaria and presented with milder reactions. In the absence of a reliable in vitro test, structured drug challenges allow identification of selective and cross-reactive NSAID hypersensitivity syndromes. NSAID-induced anaphylaxis is often associated with selective hypersensitivity and patients may not need to avoid other NSAIDs.
Publisher: BMJ
Date: 04-2016
Publisher: Elsevier BV
Date: 11-2021
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: 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: Wiley
Date: 16-09-2021
Abstract: Intrauterine growth restriction (IUGR) is a result of limited substrate supply to the developing fetus in utero, and can be caused by either placental, genetic or environmental factors. Babies born IUGR can have poor long‐term health outcomes, including being at higher risk of developing cardiovascular disease. Limited substrate supply in the IUGR fetus not only changes the structure of the heart but may also affect metabolism and function of the developing heart. We have utilised two imaging modalities, two‐photon microscopy and phase‐contrast MRI (PC‐MRI), to assess alterations in cardiac metabolism and function using a sheep model of IUGR. Two‐photon imaging revealed that the left ventricle of IUGR fetuses (at 140–141 d GA) had a reduced optical redox ratio, suggesting a reliance on glycolysis for ATP production. Concurrently, the use of PC‐MRI to measure foetal left ventricular cardiac output (LVCO) revealed a positive correlation between LVCO and redox ratio in IUGR, but not control fetuses. These data suggest that altered heart metabolism in IUGR fetuses is indicative of reduced cardiac output, which may contribute to poor cardiac outcomes in adulthood.
Publisher: Springer Science and Business Media LLC
Date: 14-06-2015
DOI: 10.1007/S00228-015-1883-2
Abstract: There is a lack of population-based research about factors associated with medication regimen complexity. This study investigated factors associated with medication regimen complexity in older people, and whether factors associated with regimen complexity were similar to factors associated with number of medications. This cross-sectional population-based study included 3348 people aged ≥ 60 years. Medication regimen complexity was computed using the validated 65-item Medication Regimen Complexity Index (MRCI). Multinomial logistic regression was used to compute unadjusted and adjusted odds ratios (ORs) with 95 % confidence intervals (CIs) for factors associated with regimen complexity. Multivariable quantile regression was used to compare factors associated with regimen complexity and number of medications. In adjusted analyses, participants in the highest MRCI quintile (MRCI > 20) were older (OR = 1.04, 95 % CI 1.02 .05), less likely to live at home (OR = 0.35, 95 % CI 0.15 .86), had greater comorbidities (OR = 2.17, 95 % CI 1.89 .49), had higher cognitive status (OR = 1.06, 95 % CI 1.01 .11), a higher prevalence of self-reported pain (OR = 2.85, 95 % CI 2.16 .76), had impaired dexterity (OR = 2.39, 95 % CI 1.77 .24) and were more likely to receive help to sort their medications (OR = 4.43 95 % CI 2.39 .56) than those with low regimen complexity (MRCI > 0-5.5). Similar factors were associated with both regimen complexity and number of medications. Older people with probable difficulties managing complex regimens, including those with impaired dexterity and living in institutional settings, had the most complex medication regimens even after adjusting for receipt of help to sort medications. The strong correlation between regimen complexity and number of medications suggests that clinicians could use a person's number of medications to target interventions to reduce complexity.
Publisher: Wiley
Date: 07-2020
DOI: 10.1111/IMJ.14463
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.PHRS.2018.02.001
Abstract: A large proportion of women are prescribed a medication during pregnancy, and the conditions requiring treatment with these medicines are often also associated with placental dysfunction and abnormal fetal growth. For the fetus, exposure to maternal illness or medications can alter fetal growth trajectory, which is a key indicator of fetal and postnatal wellbeing. There is a large amount of human and animal evidence highlighting the hormonal and/or metabolic changes that occur in both the mother and the fetus as a result of maternal illness or either excessive or restricted fetal growth. These changes can affect the expression of drug metabolising enzymes and drug transporters in the both the mother and her fetus, and may ultimately alter fetal drug exposure. This review aims to explore the complex and multidirectional interplay between maternal illness, fetal growth trajectory, maternal drug treatment, and fetal drug exposure.
Publisher: Springer Science and Business Media LLC
Date: 2012
DOI: 10.1186/AR3911
Publisher: Wiley
Date: 10-2019
DOI: 10.1113/JP278110
Publisher: Wiley
Date: 28-10-2015
DOI: 10.1111/BCP.12760
Publisher: Elsevier BV
Date: 08-2005
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: SAGE Publications
Date: 17-08-2015
Publisher: Future Medicine Ltd
Date: 12-2013
DOI: 10.2217/PGS.13.164
Abstract: Aims: This study aims to assess the cost–effectiveness in Australia of screening CYP2C19 loss-of-function (LoF) alleles to guide selection of clopidogrel or ticagrelor for in iduals with acute coronary syndrome who are likely to undergo coronary stenting. Methods: Three treatment strategies were compared: universal clopidogrel therapy, universal ticagrelor therapy and genotyping CYP2C19 with use of ticagrelor for in iduals with a LoF allele and clopidogrel for in iduals without a LoF allele. Lifetime costs and quality-adjusted life years for each treatment strategy were estimated using a Markov model. The risks of events were primarily derived from the genetic substudy of the pivotal randomized controlled trial. Results: CYP2C19 genotyping resulted in greater effectiveness and was cost-effective when compared with universal use of clopidogrel. However, universal use of ticagrelor was the most effective strategy overall and the incremental cost–effectiveness compared with the genotyping strategy was generally within what is considered acceptable. Conclusion: Ticagrelor is likely to be cost-effective even for in iduals not carrying a CYP2C19 LoF allele. Original submitted 30 May 2013 Revision submitted 16 August 2013
Publisher: Springer Science and Business Media LLC
Date: 18-02-2015
DOI: 10.1007/S00228-015-1819-X
Abstract: Evidence regarding the relationship between red blood cell methotrexate polyglutamate concentration and response to treatment and adverse drug reactions in patients using methotrexate for inflammatory arthropathies is complex and in some respects appears conflicting. Accordingly, we undertook a systematic analysis of available evidence to determine the clinical utility of dosing methotrexate to a target red blood cell methotrexate polyglutamate concentration. A systematic literature review was conducted to identify all studies that had reported an association between red blood cell methotrexate polyglutamate concentration and disease activity or adverse drug reactions in users of methotrexate for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis or psoriatic arthritis. No randomised controlled trials were identified. Thirteen studies (ten in patients with rheumatoid arthritis and three in patients with juvenile idiopathic arthritis) were identified. All studies evaluated an association between red blood cell methotrexate polyglutamate concentration and response to treatment, and eight evaluated an association with toxicity. Eight studies identified lower disease activity with at least one higher red blood cell methotrexate polyglutamate concentration, although there was at least moderate potential for bias in all of these studies. Relatively large increases in concentration appeared to be required to produce a meaningful reduction in disease activity. Only one study identified an association between red blood cell methotrexate polyglutamate concentration and methotrexate-induced side effects, although studies were likely underpowered to detect this type of association. The manner in which data were presented in the included studies had many limitations that h ered its conclusive assessment, but red blood cell methotrexate polyglutamate concentrations appear to be a potentially useful guide to treatment in patients with inflammatory arthropathies, but the specific polyglutamate that should be monitored and how monitoring could be integrated into treat-to-target approaches should be clarified before it can be routinely implemented.
Publisher: Wiley
Date: 06-1999
Publisher: Springer Science and Business Media LLC
Date: 15-02-2022
Publisher: AME Publishing Company
Date: 06-2016
Publisher: AMPCo
Date: 02-2016
DOI: 10.5694/MJA15.00716
Abstract: Biological disease-modifying antirheumatic drugs (bDMARDs) for rheumatoid arthritis (RA) treatment were among the first high-cost medicines to be subsidised in Australia. High-cost medicines pose several challenges to the Australian National Medicines Policy, which aims to provide timely access to effective medicines at a cost in iduals and the community can afford. Thus, novel restriction criteria were developed to encourage cost-effective use of bDMARDs. Government expenditure on bDMARD subsidies for RA treatment grew to about $383 million in 2014. Evidence that initiation and continuation criteria for bDMARDs meet usually applied cost-benefit criteria is lacking. The combined expenditure on tocilizumab, certolizumab pegol and golimumab (added to the Australian Government's Pharmaceutical Benefits Scheme in 2010) was $93 million in 2014, which is 210% over the initial estimate. Present and future challenges with regard to bDMARDs for RA and other high-cost drugs include improved expenditure predictions, monitoring of cost-effectiveness in relation to actual use and strategic development, regulation and use of biosimilars. Ten years of documentation on clinical and laboratory findings indicating eligibility to initiate and continue on bDMARDs remains un-used. These data represent an untapped opportunity to promote quality of use of bDMARDs and biosimilars and to improve cost predictions for high-cost drugs.
Publisher: Wiley
Date: 14-02-2013
DOI: 10.1002/PDS.3417
Abstract: To determine the validity of sequence symmetry analysis (SSA) method to detect adverse drug reactions from an administrative claims database. Published randomised controlled trials (RCTs) of 19 medicines were identified through search databases, product information (PI) or the US Food and Drug Administration Web site. All adverse events (AEs) in the RCTs and the PI for the medicines were extracted. AEs were considered 'gold standard positive events' if they were reported as being statistically significant events in adequately powered RCTs. The remaining AEs were considered 'gold standard negative events' if the event was not listed as an AE in the PI for that medicine or any other medicine in its class. Indicators of AEs were identified by consensus from two clinical researchers. SSA was run for each medicine-indicator pair using four different time windows: 3, 6, 9 and 12 months. A total of 120 randomised placebo controlled trials were reviewed for the 19 tested medicines. A total of 165 medicine-indicator pairs (44 positive and 121 negative events) were identified and tested by SSA. At the 12-month time window, the sensitivity, specificity, positive and negative predictive values of SSA were 61% (95%CI 0.46-0.74), 93% (95%CI 0.87-0.96), 77% (95%CI 0.61-0.88) and 87% (95%CI 0.80-0.92), respectively. Using a 3-month time window, the SSA had a lower sensitivity (52%). The SSA technique was found to have moderate sensitivity and high specificity for detecting ADRs. These results suggest that SSA is a potential tool for detecting ADRs using administrative claims data that could complement existing pharmacosurveillance methods.
Publisher: Elsevier BV
Date: 03-2016
DOI: 10.1016/J.EJCA.2015.11.025
Abstract: Metastatic colorectal cancer (mCRC) tumours harbouring a RAS mutation are associated with a lack of treatment benefit from anti-EGFR monoclonal antibodies (mAbs). However, observational evidence has led to speculation that mCRC patients with KRAS G13D mutant (MT) tumours may derive a benefit from treatment with anti-EGFR mAbs. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate whether the efficacy of anti-EGFR mAbs for mCRC differs between tumours harbouring a KRAS G13D mutation (KRAS G13D) and KRAS mutations other than G13D (other KRAS MT). Eight RCTs (n = 5967) met the inclusion criteria for assessment of both overall survival (OS) and progression-free survival (PFS). For other KRAS MT the hazard ratio for OS benefit with addition of anti-EGFR mAb therapy was 1.06 (95% confidence interval [CI] 0.96, 1.17), compared to 1.08 (95% CI 0.73, 1.60) for KRAS G13D [test for interaction p=0.99]. In contrast, the hazard ratio for KRAS wild-type (WT) tumours was 0.85 (95% CI 0.76, 0.95). Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 1.07 (95% CI 0.92, 1.26) for other KRAS MT, 0.96 (95% CI 0.73, 1.27) for KRAS G13D, and 0.68 (95% CI 0.54, 0.85) for KRAS WT. Again, the test for interaction (p=0.46) demonstrated no significant difference in PFS benefit for anti-EGFR mAb therapy between KRAS G13D and other KRAS MT. This meta-analysis demonstrates no significant difference between KRAS G13D and other KRAS MT tumours in terms of treatment benefit from anti-EGFR mAbs for mCRC.
Publisher: Elsevier BV
Date: 02-2006
DOI: 10.1016/J.TOXICON.2005.10.018
Abstract: Ant sting allergy in Australia is predominantly due to the Myrmecia pilosula species complex. Gel separation of M. pilosula venom is necessary so that the allergenic importance of each component can be defined by western blotting. However, previous PAGE methods produced suboptimal resolution and the components of each band were not precisely defined. Venom was resolved in both non-reduced and reduced form by one-dimensional acid urea PAGE, SDS-PAGE and two-dimensional acid urea-SDS PAGE. Resolved peptides were extracted and analysed by HPLC-MS. Acid urea PAGE and acid urea-SDS PAGE proved more effective than SDS-PAGE for resolution of peptides smaller than 10 kDa. All of the major peptides previously observed in M. pilosula venom were observed in gel resolved venom. Venom was found to primarily consist of peptides with molecular weight <10 kDa, most of which contain disulfide bridges. SDS-PAGE of non-reduced venom clearly defined six higher molecular weight proteins between 26 and 90 kDa. An 8546 Da dimer named pilosulin 5 was observed, but pilosulin 4, a peptide recently proposed to be present in venom was not. A variant of pilosulin 4 here named pilosulin 4.1a, existing as an 8198 Da dimer, was observed and has been characterised.
Publisher: Oxford University Press (OUP)
Date: 21-07-2013
Publisher: Informa UK Limited
Date: 17-05-2013
DOI: 10.1517/17425255.2013.800483
Abstract: Teriflunomide is an immunomodulatory drug that received FDA approval for the treatment of relapsing forms of multiple sclerosis (MS) in September 2012. Its primary mode of action is inhibition of dihydroorotate dehydrogenase which inhibits the proliferation of activated T cells, but it also has a number of other actions that may be important contributors to its efficacy in MS. This review covers a basic pathophysiology of MS and the current treatment options, including a discussion of the needs for additional treatments. The main focus of the review is the pharmacokinetics and pharmacodynamics of teriflunomide, including a brief comparison with the disease-modifying antirheumatic drug leflunomide. The authors discuss the clinical efficacy and toxicity profile of teriflunomide and make some comparisons with treatments that are currently, or soon to be available. While teriflunomide is no more effective than a number of other agents that are used in the treatment of MS, it has a favorable side-effect profile and the convenience of once a day oral administration. As such, it is likely to be a popular agent in the treatment of MS over the next 5 years.
Publisher: Future Medicine Ltd
Date: 04-2014
DOI: 10.2217/PGS.14.24
Publisher: Wiley
Date: 02-2020
DOI: 10.14814/PHY2.14365
Publisher: Wiley
Date: 14-07-2015
Publisher: CSIRO Publishing
Date: 2017
DOI: 10.1071/PY16153
Abstract: During the terminal phase, access to medicines is critical for people wishing to spend their last days of life at home. Yet, access to medicines can be problematic. The aim of this study was to report the perspectives of specialist and generalist health professionals (HPs) on the issues of community access to medicines for this vulnerable group. A qualitative descriptive study design investigated the views of HPs working in palliative care roles in South Australia. Nurses, doctors and pharmacists described their experiences of accessing medicines for management of terminal phase symptoms during semi-structured focus group discussions. Content analysis identified six themes including: ‘Medication Supply’, ‘Education and Training’, ‘Caregiver Burden’, ‘Safety’, ‘Funding’ and ‘Clinical Governance’. Future projects should aim to address these themes when developing strategies for the management of people wishing to die at home.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Wiley
Date: 10-2015
DOI: 10.1002/PSP4.12036
Publisher: Hindawi Limited
Date: 08-07-2014
DOI: 10.1111/JCPT.12189
Abstract: A common polymorphism (C1858T) in the gene that encodes the protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with altered T-cell responses and increased susceptibility to rheumatoid arthritis (RA) and other autoimmune diseases. Teriflunomide, the active metabolite of leflunomide, reduces T-cell responses through inhibition of tyrosine kinase p56LCK. We examined a potential association between PTPN22 genotype and response or toxicity to leflunomide in Caucasian RA patients taking leflunomide in combination with other disease-modifying antirheumatic drugs (DMARDs). Patients enrolled in the Royal Adelaide Hospital RA inception cohort and taking leflunomide were eligible for inclusion. Participants were followed for 12 months after leflunomide initiation or until either another DMARD was added or leflunomide was ceased. Clinical response according to change in 28-joint Disease Activity Score (DAS28) and cessation due to toxicity were assessed. A total of 94 participants were included in the study, 75 of whom carried the CC genotype, 18 the CT, whereas one in idual carried the TT genotype. Over the first 12 months of leflunomide treatment, there was no statistically significant relationship between carrying the T allele and change in DAS28 (-0·84 vs. -1·15, P = 0·446) nor with cessation of leflunomide treatment due to side effects (P = 0·433). These results indicate that PTPN22 C1858T genotype has no effect on response or toxicity outcomes in leflunomide-treated RA patients. This is the first study to evaluate the biologically plausible hypothesis that PTPN22 genotype might be a predictor of response/toxicity to leflunomide therapy. Despite this, PTPN22 genotype was not associated with leflunomide response or toxicity in patients with RA.
Publisher: SAGE Publications
Date: 03-2013
DOI: 10.1345/APH.1R542
Abstract: To study the pharmacokinetics and pharmacogenetics of leflunomide and document its efficacy and safety in the treatment of inflammatory arthritis in a patient with end-stage renal disease (ESRD) who was on peritoneal dialysis. Therapy for a 78-year-old man with ESRD who required peritoneal dialysis was started with leflunomide 10 mg/day for psoriatic arthritis. The dosage was increased to 20 mg/day after 3 months. Monitoring was continued until the patient's unexpected death from myocardial infarction at 8 months. Total and unbound teriflunomide (the active metabolite of leflunomide) concentrations were measured by liquid-chromatography-tandem mass spectrometry. Genotyping for CYP2C19 and ABCG2 polymorphisms, both known to influence teriflunomide pharmacokinetics, was also performed. Total concentrations of teriflunomide varied between 5.2 and 23.2 mg/L, while unbound concentrations varied between 0.0306 and 0.1468 mg/L. The unbound fraction varied between 0.367% and 0.71%. Teriflunomide was found in the dialysate at a concentration of 0.0981 mg/L. A single CYP2C19 loss of function allele was present, as was wild-type ABCG2. Leflunomide appeared to be therapeutically effective, as evidenced by a reduction in daily prednisolone dosage from 20 mg to 6mg the Disease Activity Score in 28 joints (DAS28) was 5.46 at enrollment and 4.03 after 7 months. Health Assessment Questionnaire—Disability Index improved from 0.5 to 0.125 at 7 months. Numerous significant adverse events that were considered unrelated to leflunomide occurred. Dose adjustment for leflunomide does not appear to be required in the context of ESRD requiring peritoneal dialysis. We present novel evidence that a small amount of teriflunomide is removed by peritoneal dialysis. This case suggests that leflunomide is safe to use as therapy for inflammatory arthritis despite the presence of ESRD requiring peritoneal dialysis.
Publisher: Springer Science and Business Media LLC
Date: 25-04-2017
DOI: 10.1208/S12248-017-0082-8
Abstract: Infliximab is an anti-tumour necrosis factor alpha monoclonal antibody used to treat inflammatory diseases. Many patients fail during induction and others respond initially but relapse during maintenance therapy. Although anti-drug antibodies (ADA) are associated with some clinical failures, there is evidence that some failures may be due to subtherapeutic exposure. Adapting doses based on clinical outcomes and trough concentrations can improve response and reduce the proportion that develop ADA, but identification of appropriate doses in the presence of time-varying patient factors is complicated. Several adaptive dosing strategies (label recommendations versus therapeutic drug monitoring with an established stepwise algorithm or proportional dose adjustments or Bayesian population pharmacokinetic model-based dosing) were simulated on a virtual population (constructed with time-varying covariates and random effects on in idual pharmacokinetic parameters) using R to assess their relative performance. Strategies were evaluated on their ability to maintain trough infliximab concentrations above an established target, 3 mg/L, during maintenance phase. Model-based dosing was superior in maintaining target trough concentrations, showing in iduals in maintenance achieving concentrations above the target faster and a lower proportion of in iduals who developed ADA. Model-based dosing results were consistent across a range of baseline covariate groups. This in silico assessment of adaptive dosing strategies demonstrated that, when challenged with dynamic covariate and random effect changes occurring in in idual pharmacokinetic parameters, model-based approaches were superior to other strategies. Model-based dosing has not been tested clinically however, the potential benefits of model-based dosing for infliximab suggest that it should be investigated to reduce subtherapeutic exposure.
Publisher: Springer Science and Business Media LLC
Date: 22-03-2021
DOI: 10.1038/S41523-021-00241-9
Abstract: While many studies have evaluated the relationship between BMI and breast cancer outcomes, it is unclear whether this relationship is consistent between early breast cancer (BC) and advanced BC. The study included 5099 patients with HER2 positive early BC (EBC) and 3496 with HER2 positive advanced BC (ABC). In the EBC cohort, higher BMI was associated with worse overall survival (OS) (HR [95% CI]: overweight = 1.30 [1.13–1.51] obese = 1.37 [1.14–1.64], P = 0.001), and worse disease-free survival (overweight = 1.10 [0.98–1.24] obese = 1.20 [1.04–1.39], P = 0.061). In contrast, for the ABC cohort, higher BMI was significantly associated with improved OS (overweight = 0.85 [0.76–0.96] obese = 0.82 [0.72–0.95], P = 0.014), and progression-free survival (overweight = 0.91 [0.83–1.01] obese = 0.87 [0.77–0.98], P = 0.034). In this large high-quality dataset, higher BMI was independently associated with worse survival in EBC, paradoxically in ABC higher BMI was independently associated with improved survival.
Publisher: MDPI AG
Date: 08-07-2022
DOI: 10.3390/BIOM12070960
Abstract: The regulation of vitamin D3 actions in humans occurs mainly through the Cytochrome P450 24-hydroxylase (CYP24A1) enzyme activity. CYP24A1 hydroxylates both 25-hydroxycholecalciferol (25(OH)D3) and 1,25-dihydroxycholecalciferol (1,25(OH)2D3), which is the first step of vitamin D catabolism. An abnormal status of the upregulation of CYP24A1 occurs in many diseases, including chronic kidney disease (CKD). CYP24A1 upregulation in CKD and diminished activation of vitamin D3 contribute to secondary hyperparathyroidism (SHPT), progressive bone deterioration, and soft tissue and cardiovascular calcification. Previous studies have indicated that CYP24A1 inhibition may be an effective strategy to increase endogenous vitamin D activity and decrease SHPT. This study has designed and synthesized a novel C-24 O-methyloxime analogue of vitamin D3 (VD1-6) to have specific CYP24A1 inhibitory properties. VD1-6 did not bind to the vitamin D receptor (VDR) in concentrations up to 10−7 M, assessed by a VDR binding assay. The absence of VDR binding by VD1-6 was confirmed in human embryonic kidney HEK293T cultures through the lack of CYP24A1 induction. However, in silico docking experiments demonstrated that VD1-6 was predicted to have superior binding to CYP24A1, when compared to that of 1,25(OH)2D3. The inhibition of CYP24A1 by VD1-6 was also evident by the synergistic potentiation of 1,25(OH)2D3-mediated transcription and reduced 1,25(OH)2D3 catabolism over 24 h. A further indication of CYP24A1 inhibition by VD1-6 was the reduced accumulation of the 24,25(OH)D3, the first metabolite of 25(OH)D catabolism by CYP24A1. Our findings suggest the potent CYP24A1 inhibitory properties of VD1-6 and its potential for testing as an alternative therapeutic candidate for treating SHPT.
Publisher: Elsevier BV
Date: 2015
Abstract: Monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) prolong survival in metastatic colorectal cancer (mCRC) Kirsten rat sarcoma viral oncogene (KRAS) exon 2 wild-type tumors. Recent evidence has suggested that other RAS mutations (in exons 3 and 4 of KRAS and exons 2, 3 and 4 of a related gene, NRAS) may also be predictive of resistance. Systematic review and meta-analysis of randomized, controlled trials (RCTs) evaluating anti-EGFR mAbs that have assessed tumors for new RAS mutations. Tumors with the new RAS mutations were compared with both tumors without any RAS mutations and tumors with KRAS exon 2 mutations with respect to anti-EGFR treatment progression-free survival (PFS) and overall survival (OS) benefit. Nine RCTs comprising a total of 5948 participants evaluated for both KRAS exon 2 and new RAS mutations met the inclusion criteria. Approximately 20% of KRAS exon 2 wild-type tumors harbored one of the new RAS mutations. Tumors without any RAS mutations (either KRAS exon 2 or new RAS mutations) were found to have significantly superior anti-EGFR mAb PFS (P 0.05). Tumors harboring one of the new RAS mutations are unlikely to significantly benefit from anti-EGFR mAb therapy in mCRC.
Publisher: Wiley
Date: 09-2023
DOI: 10.1111/IMJ.16217
Publisher: SAGE Publications
Date: 17-12-2016
Abstract: Objectives: To investigate whether medication regimen complexity and/or polypharmacy are associated with all-cause mortality in older people. Methods: This was a population-based cohort study among community-dwelling and institutionalized people ≥60 years old (n = 3348). Medication regimen complexity was assessed using the 65-item Medication Regimen Complexity Index (MRCI) in 10-unit steps. Polypharmacy was assessed as a continuous variable (number of medications). Mortality data were obtained from the Swedish National Cause of Death Register. Cox proportional hazard models were used to compute unadjusted and adjusted hazard ratios (HRs) and 95% CIs for the association between regimen complexity and polypharmacy with all-cause mortality over a 3-year period. Subanalyses were performed stratifying by age (≤80 and years), sex, and cognition (Mini-Mental State Examination [MMSE] and ≥26). Results: During follow-up, 14% of the participants (n = 470) died. After adjusting for age, sex, comorbidity, educational level, activities of daily living, MMSE, and residential setting, a higher MRCI was associated with mortality (adjusted HR = 1.12 95% CI = 1.01-1.25). Polypharmacy was not associated with mortality (adjusted HR = 1.03 95% CI = 0.99-1.06). When stratifying by sex, both MRCI and polypharmacy were associated with mortality in men but not in women. MRCI was associated with mortality in participants ≤80 years old and in participants with MMSE ≥26 but not in participants years old or with MMSE . Conclusion: Regimen complexity was a better overall predictor of mortality than polypharmacy. However, regimen complexity was not predictive of mortality in women, in participants years old, or in those with MMSE . These different associations with mortality deserve further investigation.
Publisher: Informa UK Limited
Date: 19-01-2015
DOI: 10.1517/17425255.2015.1004310
Abstract: The worldwide population is aging, and several age-associated physiological and pathophysiological changes can affect drug disposition. This is particularly important in view of the extensive medication prescribing and exposure in older adults. Using a framework of the four primary pharmacokinetic processes (Absorption, Distribution, Metabolism and Elimination), this review discusses the current evidence of the pharmacokinetic changes that occur with aging, particularly 'healthy aging,' focusing on developments in this field over the last 10 years. A substantial amount of work has been conducted to address whether advancing age significantly affects drug disposition in humans. Despite significant advances in the field, particularly regarding drug metabolism and elimination, a number of issues remain unsolved. In particular, lack of inclusion of older adults with multimorbidity and those aged > 80 and minimal evidence in relation to new drugs limits the applicability of findings to current clinical practice.
Publisher: Springer Science and Business Media LLC
Date: 19-05-2015
DOI: 10.1038/BJC.2015.173
Publisher: S. Karger AG
Date: 2022
DOI: 10.1159/000526972
Abstract: b i Introduction: /i /b Newborns exposed to sildenafil citrate (SC) in utero have increased rates of persistent pulmonary hypertension. The mechanism behind this has not yet been fully elucidated. We aimed to utilize a combination of clinically relevant MRI techniques to comprehensively characterize the haemodynamics of the fetal sheep whilst under the influence of SC. We hypothesized that these MRI techniques would detect SC-induced increases in pulmonary blood flow and oxygen delivery prior to birth. b i Methods: /i /b At 116–117 days gestational age (term, 150 days), pregnant Merino ewes ( i n /i = 9) underwent fetal catheterization surgery. MRI scans were performed during a basal state and then repeated during a constant umbilical vein infusion of SC to measure blood flow and oxygenation within the major vessels of the fetal circulation using phase-contrast-MRI and T sub /sub oximetry. b i Results: /i /b Right and left ventricular cardiac outputs were not different between states. Pulmonary blood flow increased during the SC state resulting in elevated pulmonary oxygen delivery. Right to left heart shunting through the foramen ovale was reduced without reducing cerebral oxygen delivery. b i Conclusion: /i /b SC induces alterations to pulmonary haemodynamics i in utero /i a characteristic that if maintained may underlie or act as a precursor towards the elevated rates of poor pulmonary outcomes after birth. These MRI techniques are the first to comprehensively characterize sildenafil’s direct impact on the pulmonary vasculature and its indirect detriment to the flow of oxygen-rich blood through the foramen ovale.
Publisher: Hindawi Limited
Date: 05-06-2019
DOI: 10.1111/IJCP.13375
Abstract: Identification of key determinants of medication adherence may assist with designing interventions to improve this important parameter. The aim of the study was to determine the rate and predictors of self-reported medication adherence in patients with rheumatoid arthritis (RA) over one-year follow-up. Socio-demographic, disease, therapy and patient-related factors were obtained from a longitudinal observational cohort of RA patients between May 2014 and June 2016. Medication adherence was measured using self-reported Compliance Questionnaire for Rheumatology (CQR) at baseline, 6 and 12 months. Mixed-effects modelling was used to investigate the relationship between adherence and potential predictors. Of 185 patients invited, 110 were included in the study. The median level of adherence was 71%-74% during the study period. Around 27%-30% of patients achieved > 80% adherence, while roughly one-fifth reported a CQR score within the lower quartile (CQR < 63%). After adjustment for potential confounders, increased age (β = 0.19, P = 0.010), higher self-efficacy (β = 0.89, P = 0.039) and higher medication necessity belief (β = 1.12, P < 0.0001) were associated with better self-reported adherence. We found a moderate level of self-reported adherence over time and significant association with age, self-efficacy and medication necessity belief. The modifiable predictors of adherence found in this study can be used as a potential target for adherence-improving interventions.
Publisher: Wiley
Date: 26-09-2017
Publisher: Wiley
Date: 03-08-2018
DOI: 10.1111/CEA.13224
Abstract: The venomous stings of Jack Jumper ant (JJA species of the Myrmecia pilosula taxonomic group) are a significant public health issue in parts of south-eastern and south-western Australia, causing anaphylaxis in approximately 3% of the population. Three allergenic peptides, Myr p 1, Myr p 2 and Myr p 3, and one histamine-releasing peptide, pilosulin 5, have been fully described, but there are at least 5 additional high molecular weight IgE-binding components that have not been identified. To identify IgE-binding components in JJA venom (JJAV) and to relate the IgE recognition of these components to relevant clinical parameters. Identification of IgE-binding components and determination of their sensitizing prevalence was performed using SDS-PAGE immunoblot assay and sera from 90 patients with confirmed allergy to JJAV. Tandem mass spectrometry was used for identification of novel JJAV components fractionated by size exclusion chromatography (SEC) and SDS-PAGE. Using SDS-PAGE immunoblot, 10 IgE-binding bands were identified in JJAV, two of which were recognized by 81% and 47% of the population studied. Mass spectrometry identified 17 novel JJAV proteins, including 2 glycoproteins, and confirmed the presence of 4 known Myr p and pilosulin peptides in JJAV. Most of the newly identified IgE-binding proteins were enzymes, including phospholipase A This study has for the first time revealed the identity of various proteins with IgE-binding capacity in the venom of JJA and demonstrated their clinical relevance in the diagnosis and treatment of JJAV allergy.
Publisher: Springer Science and Business Media LLC
Date: 25-11-2016
DOI: 10.1007/S10067-016-3488-2
Abstract: Leflunomide is the most recently introduced conventional disease-modifying anti-rheumatic drugs in Australia. It has several unique methods for initiation, unique monitoring recommendations and a distinctive cessation protocol in the event of serious toxicity. The aim of this study was to evaluate initiation and monitoring practices of Australian rheumatologists using leflunomide. A survey was emailed twice, approximately 3 months apart to 332 rheumatologist members of the Australian Rheumatology Association. Wave analysis was used to assess evidence of non-response bias. The response rate to the survey was 20% and there was no difference between the responses of waves 1 and 2. Fifty percent of the respondents indicated that 20 mg once daily was the initial dose of leflunomide that they most commonly prescribed, 45% indicated 10 mg once daily, whilst only 3% preferred to initiate leflunomide at 100 mg daily for 2-3 days followed by 10 mg once a day as recommended when first marketed. Of the responders, 12% had used doses above 20 mg daily and 70% had used alternate daily dosing with leflunomide. In a patient taking leflunomide with an ALT or AST >3 times the ULN on two or more blood tests, 75% of responders indicated they would stop leflunomide immediately and 20% would follow cessation by administering a cholestyramine washout. The choice of initial leflunomide dose among responding Australian rheumatologists varied considerably, although most preferred not to use the loading dose. Despite the recommendation of clinical guidelines, the use of a cholestyramine washout procedure for hepatic toxicity is not universal.
Publisher: Wiley
Date: 20-06-2014
DOI: 10.1111/BCP.12297
Publisher: Wiley
Date: 21-09-2017
DOI: 10.1111/JEP.12620
Abstract: Development of the treat-to-target (T2T) strategy, the process whereby drug therapy is adjusted until the therapeutic goal is achieved, has revolutionized how rheumatoid arthritis (RA) patients are treated. With the advent of T2T, the management of RA is more effective than ever, with the possibility of remission and other favorable clinical and patient-reported outcomes. Effective implementation of a T2T strategy in routine clinical practice mainly depends on the long-term commitment of physician and patient to T2T treatment recommendations. However, as T2T is a complex process involving aggressive early management with several steps of therapy modifications requiring frequent close monitoring of disease activity and drug toxicities, it may be more liable to suboptimal adherence in real-life clinical practice. The aim of the review is to present key issues related to patient medication adherence and physician adherence to the current RA treatment recommendations and their importance in optimizing the outcome of treatment in RA treated according to T2T strategy.
Publisher: Oxford University Press (OUP)
Date: 25-06-2019
DOI: 10.1093/AF/VFZ019
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 14-10-2016
Abstract: Leflunomide's active metabolite teriflunomide inhibits dihydro-oroate dehydrogenase, an enzyme essential to proliferation of T lymphocytes. As teriflunomide must reach the target site to have this effect, this study assessed the distribution of teriflunomide into T lymphocytes, as intracellular concentrations may be a superior response biomarker to plasma concentrations. CD3 MicroBeads (Miltenyi Biotec, Bergisch Gladbach, Germany) were used to extract CD3
Publisher: Wiley
Date: 12-03-2007
DOI: 10.1111/J.1398-9995.2007.01320.X
Abstract: The 'Jack Jumper Ant' (JJA Myrmecia pilosula species complex) is the major cause of ant sting anaphylaxis in Australia. Our aims were to determine the allergenicity of previously described venom peptides in their native forms, identify additional allergens and if necessary, update nomenclature used to describe the allergens according to International Union of Immunological Societies criteria. Various polyacrylamide gel electrophoresis methods were used to separate JJA venom. Gel resolved venom was Western-blotted and probed with in idual sera taken from patients with a history of JJA sting anaphylaxis and immunoglobulin E radioallergosorbent test (IgE RAST) tracer uptakes of >1% to whole venom. Of 67 available sera, 54 had RAST uptakes >1%. Thirteen IgE binding bands were identified using these sera. Pilosulin 3, [Ile(5)]pilosulin 1, and pilosulin 4.1 were recognized by 42 (78%), 18 (33%) and nine (17%) of the 54 sera that were tested. Immunoglobulin E-binding proteins with estimated molecular masses of 6.6, 22.8, 25.6, 30.4, 32.1, 34.4 and 89.8 kDa were each recognized by three or more in idual sera. Two of these (25.6 and 89.8 kDa) were recognized by 46% and 37% of sera, respectively. Nomenclature used to describe JJA venom allergens has been revised. Pilosulin 3 (Myr p 2) is the only major allergen, whilst [Ile(5)]pilosulin 1 (Myr p 1), and pilosulin 4.1 (Myr p 3) are minor allergens. There are an additional five IgE-binding proteins that require further characterization before they can be named as allergens. These findings provide a framework for standardizing venom extracts for diagnosis and immunotherapy.
Publisher: Elsevier BV
Date: 04-2020
DOI: 10.1016/J.CLBC.2019.10.001
Abstract: Thrombocytopenia is a common and potentially serious adverse event of ado-trastuzumab emtansine (T-DM1) use in patients with advanced breast cancer. However, the risk factors have been minimally explored. Our aim was to develop a clinical prediction model from the clinicopathologic data that would allow for quantification of the personalized risks of thrombocytopenia from T-DM1 usage. Data from 3 clinical trials, EMILIA (a study of trastuzumab emtansine versus capecitabine + lapatinib in participants with HER2 [human epidermal growth factor receptor 2]-positive locally advanced or metastatic breast cancer), TH3RESA (a study of trastuzumab emtansine in comparison with treatment of physician's choice in participants with HER2-positive breast cancer who have received at least two prior regimens of HER2-directed therapy), and MARIANNE [a study of trastuzumab emtansine (T-DM1) plus pertuzumab ertuzumab placebo versus trastuzumab (Herceptin) plus a taxane in participants with metastatic breast cancer], were pooled. Cox proportional hazard analysis was used to assess the association between the pretreatment clinicopathologic data and grade ≥ 3 thrombocytopenia occurring within the first 365 days of T-DM1 use. A multivariable clinical prediction model was developed using a backward elimination process. Of the 1620 participants, 141 (9%) had experienced grade ≥ 3 thrombocytopenia. On univariable analysis, the body mass index, race, presence of brain metastasis, platelet count, white blood cell count, and concomitant corticosteroid use were significantly associated with the occurrence of grade ≥ 3 thrombocytopenia (P 300 × 10 A clinical prediction model, defined by race and pretreatment platelet count, was able to discriminate subgroups with a significantly different risk of grade ≥ 3 thrombocytopenia after T-DM1 initiation. The model allows for improved interpretation of the personalized risks and risk/benefit ratio of T-DM1.
Publisher: Wiley
Date: 22-12-2017
Publisher: Springer Science and Business Media LLC
Date: 10-09-2015
DOI: 10.1038/BJC.2015.325
Publisher: Springer Science and Business Media LLC
Date: 24-08-2017
DOI: 10.1038/BJC.2017.274
Publisher: Springer Science and Business Media LLC
Date: 29-10-2020
DOI: 10.1038/S41598-020-75673-7
Abstract: The aim of this study was to investigate the association between body-mass index (BMI) and remission in RA patients receiving conventional synthetic (cs-) or the biological Disease-Modifying Antirheumatic Drug (DMARD), tocilizumab. In idual participant data (IPD) were pooled from five trials investigating tocilizumab and/or csDMARDs therapy (primarily methotrexate) for RA. Time to first remission was recorded according to the Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI). BMI was classified according to WHO definitions. Associations between baseline BMI and remission were assessed by Cox-proportional hazard analysis. IPD were available from 5428 patients treated with tocilizumab ± csDMARDs (n = 4098) or csDMARDs alone (n = 1330). Of these, 1839 (33.9%) had normal BMI, 1780 (32.8%) overweight, 1652 (30.4%) obese and 157 (2.9%) were underweight. Obesity, compared to normal BMI, was associated with less frequent remission using SDAI (adjusted HR 0.80 [95% CI 0.70–0.92]) and CDAI (adjusted HR 0.77 [0.68–0.87]). As continuous variable, increased BMI was associated with less frequent SDAI (P = 0.001) and CDAI (P = 0.001) defined remission. No heterogeneity in identified associations was observed between studies (P = 0.08) or treatments (P = 0.22). Obesity was negatively associated with RA disease remission regardless of RA therapy, suggesting that baseline BMI should be considered as a stratification factor in future RA trials.
Publisher: Wiley
Date: 12-06-2023
DOI: 10.1002/ACR.25141
Abstract: Methotrexate (MTX) is effective in controlling disease activity in rheumatoid arthritis (RA). Parenteral MTX may have benefits over oral MTX, but it is rarely used in practice. To better understand this low usage rate, it is necessary to explore the barriers and enablers of therapy from the perspective of RA patients. The objectives of this scoping review were to describe RA patients’ perspectives on the barriers and enablers in the use of parenteral MTX and to identify the research gaps in this field. The search was performed in Medline, Embase, Scopus, and Cochrane Library from inception to May 2021. Data synthesis was conducted using the Theoretical Framework of Acceptability. This scoping review included any type of study that explored the use of parenteral MTX by adult RA patients from the patients’ perspective, written in English. Fifteen studies were included findings related to the constructs “affective attitude,” “burden,” “intervention coherence,” and “self‐efficacy” were explored the most, while some were rarely (“opportunity cost” and “perceived effectiveness”) or not (“ethicality”) reported. RA patients were generally satisfied with MTX injections (“affective attitude”). From the burden construct, the requirement for dexterity for administering MTX by injection was considered a barrier, whereas the lack of significant pain from MTX injection was considered an enabler. The findings suggested that patients generally preferred parenteral MTX formulations with attributes that facilitate self‐administration. However, much of the identified research focused on prefilled pen devices, and significant gaps were identified, such as a lack of qualitative research. image
Publisher: F1000 Research Ltd
Date: 30-06-2016
DOI: 10.12688/F1000RESEARCH.9040.1
Abstract: Many patients with solid tumours are treated with targeted pharmacotherapy based on the results of genetic testing (‘precision medicine’). This study investigated the use of targeted drugs after OncoFOCUS™+ KIT screening in patients with malignant melanoma, non-small cell lung cancer and metastatic colorectal cancer, and then audited the results against the National Comprehensive Cancer Network (NCCN) guidelines. Patients who were not indicated for targeted pharmacotherapy did not receive such treatment (99%, 100/101). Of the patients indicated for targeted drugs, 79% (33/42) received treatment according to NCCN guidelines. In 48% (20/42) of these patients the results from OncoFOCUS™+ KIT screening were required for targeted drug selection. This study highlights the growing importance of precision medicine approaches in directing pharmacotherapy in medical oncology.
Publisher: Springer Science and Business Media LLC
Date: 06-2022
DOI: 10.1007/S12016-021-08858-1
Abstract: Hymenoptera venom allergy is characterised by systemic anaphylactic reactions that occur in response to stings from members of the Hymenoptera order. Stinging by social Hymenoptera such as ants, honeybees, and vespids is one of the 3 major causes of anaphylaxis along with food and drug exposure, it accounts for up to 43% of anaphylaxis cases and 20% of anaphylaxis-related fatalities. Despite their recognition as being of considerable public health significance, stinging ant venoms are relatively unexplored in comparison to other animal venoms and may be overlooked as a cause of venom allergy. Indeed, the venoms of stinging ants may be the most common cause of anaphylaxis in ant endemic areas. A better understanding of the natural history of venom allergy caused by stinging ants, their venom components, and the management of ant venom allergy is therefore required. This article provides a global view on allergic reactions to the venoms of stinging ants and the contemporary approach to diagnose and manage ant venom allergy.
Publisher: Future Medicine Ltd
Date: 06-2014
DOI: 10.2217/PME.14.23
Abstract: Leflunomide is largely considered to be a second-line treatment option for rheumatoid arthritis (RA). Those who fail to respond, tend to progress to treatment with expensive biological agents, which can also be associated with serious toxicities. Optimizing leflunomide treatment to meet the needs of in iduals would hence be beneficial in terms of patient outcomes and health care expenditure. In this respect, therapeutic drug monitoring (TDM) may be useful, as plasma concentrations of leflunomide's active metabolite, teriflunomide, correlate with response to treatment, but are highly variable between patients. A number of pharmacogenetic markers have also been identified that influence response and toxicity. Incorporation of these findings into clinical practice could facilitate more efficient use of leflunomide.
Publisher: F1000 Research Ltd
Date: 20-09-2016
DOI: 10.12688/F1000RESEARCH.9040.2
Abstract: Many patients with solid tumours are treated with targeted pharmacotherapy based on the results of genetic testing (‘precision medicine’). This study investigated the use of targeted drugs after OncoFOCUS™+ KIT screening in patients with malignant melanoma, non-small cell lung cancer and metastatic colorectal cancer, and then audited the results against the National Comprehensive Cancer Network (NCCN) guidelines. Patients who were not indicated for targeted pharmacotherapy did not receive such treatment (99%, 100/101). Of the patients indicated for targeted drugs, 79% (33/42) received treatment according to NCCN guidelines. In 48% (20/42) of these patients the results from OncoFOCUS™+ KIT screening were required for targeted drug selection, with the remaining 52% (22/42) prescribed drugs independent of the screening results for various reasons. This study highlights the growing importance of precision medicine approaches in directing pharmacotherapy in medical oncology.
Publisher: Frontiers Media SA
Date: 14-07-2020
Publisher: The Journal of Rheumatology
Date: 15-07-2016
Abstract: To investigate the association between adherence to treat-to-target (T2T) protocol and disease activity, functional outcomes, and radiographic outcomes in early rheumatoid arthritis (RA). Data from a longitudinal cohort of patients with early RA were used. Adherence was determined at each followup visit over 3 years according to predefined criteria. The primary endpoint was remission according to Disease Activity Score in 28 joints (DAS28) and Simplified Disease Activity Index (SDAI) criteria. Functional and radiographic outcomes measured by modified Health Assessment Questionnaire and modified total Sharp score, respectively, were secondary endpoints. A total of 198 patients with 3078 clinic visits over 3 years were included in this analysis. After adjusting for relevant variables, although there was no significant association between adherence to T2T and remission rate after 1 year, the associations reached significance after 3 years for both DAS28 (OR 1.71, 95% CI 1.16–2.50 p = 0.006) and SDAI criteria (OR 1.94, 95% CI 1.06–3.56 p = 0.033). After 3 years, adherence was also associated with improvement in physical function (β=0.12, 95% CI 0.06–0.18 p 0.0001). None of the radiographic outcomes were associated with adherence after either 1 or 3 years, although there was a trend for higher adherence to be associated with less radiographic progression at the end of the study (p = 0.061). Increased adherence to T2T was associated with better longterm disease activity and functional outcomes, which suggests that the benefit of a T2T protocol may be enhanced by ensuring adequate adherence.
Publisher: Public Library of Science (PLoS)
Date: 31-01-2011
Publisher: Public Library of Science (PLoS)
Date: 12-05-2020
Publisher: Wiley
Date: 06-2015
DOI: 10.1002/PSP4.46
Publisher: Oxford University Press (OUP)
Date: 08-1999
Publisher: Elsevier BV
Date: 03-2003
Publisher: Wiley
Date: 16-03-2021
DOI: 10.1113/EP089237
Publisher: Springer Science and Business Media LLC
Date: 03-04-2021
Publisher: SAGE Publications
Date: 23-01-2014
Publisher: Springer Science and Business Media LLC
Date: 13-05-2013
Abstract: From 2010 to 2012, nine systematic reviews reported highly variable conclusions regarding the association between carriage of a cytochrome P450 2C19 loss-of-function allele and the risk of adverse cardiovascular (CV) events in in iduals using clopidogrel. Possible contributors to the variable findings include differences in patient populations, CV end points, and statistical models utilized by the systematic reviews, as well as unexplained heterogeneity, inconsistent/incomplete reporting, and risk of publication bias with respect to the primary studies.
Publisher: Springer Science and Business Media LLC
Date: 03-02-2017
DOI: 10.1007/S00296-017-3655-Z
Abstract: Medication adherence is believed to be a major contributor to treatment outcomes yet studies quantifying this relationship as rare in rheumatoid arthritis (RA). To determine the association of adherence to DMARD therapy with treatment outcomes among new and existing DMARD users over 2 years. Relevant clinical parameters were obtained from a longitudinal cohort of RA patients, most of who were treated with combination therapy. Patients were classified as adherent if the proportion of days covered for each DMARD was ≥80%. Outcome measures were the change in the disease activity score in 28 joints (DAS28), simplified disease activity index (SDAI), modified health assessment questionnaires (mHAQ) and proportion of patients who achieved response criteria. An inverse propensity-score weighting method was used to estimate the association of adherence with each outcome. Of 194 patients invited, a total of 111 patients (new = 45 and existing = 66 DMARD users) met study eligibility. DMARD-naive patients demonstrated relatively higher rates of adherence compared to existing users. After controlling for confounding variables, adherence was significantly associated with reduction in DAS28 (β = -1.5, 95% CI of β = - 2.17 to -0.83, p < 0.0001), SDAI (β = -9.44, 95% CI of β = -15.53 to -3.35, p = 0.002) and mHAQ (β = -0.269, 95% CI of β, -0.462 to -0.077, p = 0.017) over 2 years among new patients and adherent patients were more likely to achieve most response criteria compared to non-adherent patients. Such associations were not replicated among existing DMARD users. Adherence to combination DMARD therapy was associated with improvements in disease activity and functional outcomes in the first 2 years of therapy.
Publisher: Springer Science and Business Media LLC
Date: 18-06-2014
Abstract: Medication-taking behavior, specifically non-adherence, is significantly associated with treatment outcome and is a major cause of relapse in the treatment of psychotic disorders. Non-adherence can be multifactorial however, the rates and associated risk factors in an Ethiopian population have not yet been elucidated. The principal aim of this study was to evaluate adherence rates to antipsychotic medications, and secondarily to identify potential factors associated with non-adherence, among psychotic patients at tertiary care teaching hospital in Southwest Ethiopia. A cross-sectional study was conducted over a 2-month period in 2009 (January 15 th to March 20 th ) at the Jimma University Specialized Hospital. Adherence was computed using both a compliant fill rate method and self-reporting via a structured patient interview (focusing on how often regular medication doses were missed altogether, and whether they missed taking their doses on time). Data were analyzed using SPSS for windows version 16.0, and chi-square and Pearsons r tests were used to determine the statistical significance of the association of variables with adherence. Three hundred thirty six patients were included in the study. A total of 75.6% were diagnosed with schizophrenia, while the others were diagnosed with other psychotic disorders. Most (88.1%) patients were taking only antipsychotics, while the remainder took more than one medication. Based upon the compliant fill rate, 57.5% of prescription fills were considered compliant, but only 19.6% of participants had compliant fills for all of their prescriptions. In contrast, on the basis of patients self-report, 52.1% of patients reported that they had never missed a medication dose, 32.0% sometimes missed their daily doses, 22.0% only missed taking their dose at the specific scheduled time, and 5.9% missed both taking their dose at the specific scheduled time and sometimes missed their daily doses. The most common reasons provided for missing medication doses were: forgetfulness (36.2%) being busy (21.0%) and a lack of sufficient information about the medication (10.0%). Pill burden, medication side-effects, social drug use, and duration of maintenance therapy each had a statistically significant association with medication adherence (P ≤ 0.05). The observed rate of antipsychotic medication adherence in this study was low, and depending upon the definition used to determine adherence, it is either consistent or low compared to previous reports, which highlights its pervasive and problematic nature. Adherence must therefore be considered when planning treatment strategies with antipsychotic medications, particularly in countries such as Ethiopia.
Publisher: Georg Thieme Verlag KG
Date: 2012
DOI: 10.1160/TH12-02-0095
Start Date: 2022
End Date: 12-2024
Amount: $686,263.00
Funder: Australian Research Council
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