Publications by authors named "Michael Wiese"

217 Publications

Intrauterine growth restriction alters the activity of drug metabolising enzymes in the maternal-placental-fetal unit.

Life Sci 2021 Oct 3;285:120016. Epub 2021 Oct 3.

Early Origins of Adult Health Research Group, Australia; Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide 5000, Australia. Electronic address:

Purpose: Ten percent of pregnancies are affected by intrauterine growth restriction (IUGR), and evidence suggests that affected neonates have reduced activity of hepatic cytochrome P450 (CYP) drug metabolising enzymes. Given that almost all pregnant individuals take medications and additional medications are often required during an IUGR pregnancy, we aimed to determine the impact of IUGR on hepatic CYP activity in sheep fetuses and pregnant ewes.

Methods: Specific probes were used to determine the impact of IUGR on the activity of several CYP isoenzymes (CYP1A2, CYP2C19, CYP2D6 and CYP3A) in sheep fetuses and pregnant ewes. Probes were administered intravenously to the ewe at 132 days (d) gestation (term 150 d), followed by blood sampling from the maternal and fetal circulation over 24 h. Maternal and fetal liver tissue was collected at 139-140 d gestation, from which microsomes were isolated and incubated with probes. Metabolite and maternal plasma cortisol concentrations were measured using Liquid Chromatography - tandem mass spectrometry (LC-MS/MS).

Results: Maternal plasma cortisol concentration and maternal hepatic CYP1A2 and CYP3A activity was significantly higher in IUGR pregnancies. Maternal hepatic CYP activity was higher than fetal hepatic CYP activity for all CYPs tested, and there was minimal CYP1A2 or CYP3A activity in the late gestation fetus when assessed using in vitro methods.

Conclusions: The physiological changes to the maternal-placental-fetal unit in an IUGR pregnancy have significant effects on maternal drug metabolism, suggesting changes in medications and/or doses may be required to optimise maternal and fetal health.
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http://dx.doi.org/10.1016/j.lfs.2021.120016DOI Listing
October 2021

Synthesis and biological assessment of new pyrimidopyrimidines as inhibitors of breast cancer resistance protein (ABCG2).

Bioorg Chem 2021 Nov 6;116:105326. Epub 2021 Sep 6.

Laboratoire de Chimie Organique et Thérapeutique, Neurosciences intégratives et cliniques EA 481, Univ. Bourgogne Franche-Comté, UFR Santé, 19, rue Ambroise Paré, F-25000 Besançon, France. Electronic address:

Multidrug resistance constitutes a serious obstacle of the treatment success of cancer by chemotherapy. Mostly it is driven by expression of ABC transport proteins that actively efflux the anticancer agents out of the cell. This work describes the design and synthesis of 12 new pyrimidopyrimidines, as well as their inhibition of ABCG2 a transporter referred also to as breast cancer resistance protein, the selectivity versus ABCB1 (P-glycoprotein/P-gp) and ABCC1 as well as the investigation of their accumulation in single cells. From these results, N-(3,5-dimethoxyphenyl)-2-methyl-7-phenyl-5-(p-tolyl)pyrimido[4,5-d]pyrimidin-4-amine 7 h was identified as promising hit that deserves further investigation showing a selective and effective inhibition of ABCG2 with IC equal to 0.493 µM only 2-fold less active than Ko143.
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http://dx.doi.org/10.1016/j.bioorg.2021.105326DOI Listing
November 2021

A review of liquid biopsy as a tool to assess epigenetic, cfDNA and miRNA variability as methotrexate response predictors in patients with rheumatoid arthritis.

Pharmacol Res 2021 Nov 16;173:105887. Epub 2021 Sep 16.

Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia.

Rheumatoid arthritis (RA) is a common autoimmune inflammatory disease affecting 0.5-1% of adults worldwide. Achieving long term remission or low disease activity is possible through early diagnosis, rapid initiation of disease modifying anti-rheumatic drugs (DMARDs) and implementation of a treat to target approach. Initial DMARD therapy usually involves methotrexate (MTX), either alone or in combination with other agents, however 40% of RA patients do not respond adequately, putting them at risk of disease progression and unnecessary exposure to MTX related adverse effects. Early predictors of MTX response would therefore enable a more personalized treatment strategy, ensuring timely access to MTX for those likely to respond and importantly, early initiation of alternative treatment for those in which MTX is unlikely to be efficacious. Predicting response to treatment will most likely require consideration of the clinical characteristics of the patient and interrogation of a number of factors including genetic, epigenetic, cell free DNA (cfDNA) and microRNA (miRNA), all of which can be investigated through blood derived liquid biopsies. This review will summarize the existing literature examining the use of epigenetic factors, cfDNA and miRNA as response predictors among RA patients treated with MTX.
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http://dx.doi.org/10.1016/j.phrs.2021.105887DOI Listing
November 2021

Redox ratio in the left ventricle of the growth restricted fetus is positively correlated with cardiac output.

J Biophotonics 2021 Sep 9:e202100157. Epub 2021 Sep 9.

Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia.

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.
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http://dx.doi.org/10.1002/jbio.202100157DOI Listing
September 2021

Impact of maternal late gestation undernutrition on surfactant maturation, pulmonary blood flow and oxygen delivery measured by magnetic resonance imaging in the sheep fetus.

J Physiol 2021 Oct 22;599(20):4705-4724. Epub 2021 Sep 22.

Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia.

Restriction of fetal substrate supply has an adverse effect on surfactant maturation in the lung and thus affects the transition from in utero placental oxygenation to pulmonary ventilation ex utero. The effects on surfactant maturation are mediated by alteration in mechanisms regulating surfactant protein and phospholipid synthesis. This study aimed to determine the effects of late gestation maternal undernutrition (LGUN) and LGUN plus fetal glucose infusion (LGUN+G) compared to Control on surfactant maturation and lung development, and the relationship with pulmonary blood flow and oxygen delivery ( ) measured by magnetic resonance imaging (MRI) with molecules that regulate lung development. LGUN from 115 to 140 days' gestation significantly decreased fetal body weight, which was normalized by glucose infusion. LGUN and LGUN+G resulted in decreased fetal plasma glucose concentration, with no change in fetal arterial compared to control. There was no effect of LGUN and LGUN+G on the mRNA expression of surfactant proteins (SFTP) and genes regulating surfactant maturation in the fetal lung. However, blood flow in the main pulmonary artery was significantly increased in LGUN, despite no change in blood flow in the left or right pulmonary artery and to the fetal lung. There was a negative relationship between left pulmonary artery flow and to the left lung with SFTP-B and GLUT1 mRNA expression, while their relationship with VEGFR2 was positive. These results suggest that increased pulmonary blood flow measured by MRI may have an adverse effect on surfactant maturation during fetal lung development. KEY POINTS: Maternal undernutrition during gestation alters fetal lung development by impacting surfactant maturation. However, the direction of change remains controversial. We examined the effects of maternal late gestation maternal undernutrition (LGUN) on maternal and fetal outcomes, signalling pathways involved in fetal lung development, pulmonary haemodynamics and oxygen delivery in sheep using a combination of molecular and magnetic resonance imaging (MRI) techniques. LGUN decreased fetal plasma glucose concentration without affecting arterial . Surfactant maturation was not affected; however, main pulmonary artery blood flow was significantly increased in the LGUN fetuses. This is the first study to explore the relationship between in utero MRI measures of pulmonary haemodynamics and lung development. Across all treatment groups, left pulmonary artery blood flow and oxygen delivery were negatively correlated with surfactant protein B mRNA and protein expression in late gestation.
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http://dx.doi.org/10.1113/JP281292DOI Listing
October 2021

Scaffold fragmentation and substructure hopping reveal potential, robustness, and limits of computer-aided pattern analysis ([email protected]).

Comput Struct Biotechnol J 2021 10;19:3269-3283. Epub 2021 May 10.

Department of Pharmaceutical and Cellbiological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.

Computer-aided pattern analysis ([email protected]) was recently presented as a powerful tool to predict multitarget ABC transporter inhibitors. The backbone of this computational methodology was the statistical analysis of frequently occurring molecular features amongst a fixed set of reported small-molecules that had been evaluated toward ABCB1, ABCC1, and ABCG2. As a result, negative and positive patterns were elucidated, and secondary positive substructures could be suggested that complemented the multitarget fingerprints. Elevating [email protected] to a non-statistical and exploratory level, the concluded secondary positive patterns were extended with potential positive substructures to improve [email protected]'s prediction capabilities and to explore its robustness. A small-set compound library of known ABCC1 inhibitors with a known hit rate for triple ABCB1, ABCC1, and ABCG2 inhibition was taken to virtually screen for the extended positive patterns. In total, 846 potential broad-spectrum ABCB1, ABCC1, and ABCG2 inhibitors resulted, from which 10 have been purchased and biologically evaluated. Our approach revealed 4 novel multitarget ABCB1, ABCC1, and ABCG2 inhibitors with a biological hit rate of 40%, but with a slightly lower inhibitory power than derived from the original [email protected] This is the very first report about discovering novel broad-spectrum inhibitors against the most prominent ABC transporters by improving [email protected]
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http://dx.doi.org/10.1016/j.csbj.2021.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193046PMC
May 2021

Efficacy and safety of statins in ethnic differences: a lesson for application in Indigenous Australian patient care.

Pharmacogenomics 2021 06 14;22(9):553-571. Epub 2021 Jun 14.

UniSA Clinical & Health Science, University of South Australia, Adelaide, SA 5000, Australia.

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.
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http://dx.doi.org/10.2217/pgs-2020-0152DOI Listing
June 2021

The efficacy of systemic administration of lipopolysaccharide in modelling pre-motor Parkinson's disease in C57BL/6 mice.

Neurotoxicology 2021 07 13;85:254-264. Epub 2021 Jun 13.

Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia. Electronic address:

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, hippocampus, 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, hippocampus, 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.
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http://dx.doi.org/10.1016/j.neuro.2021.05.015DOI Listing
July 2021

Simultaneous LC-MS/MS quantification of oxycodone, tramadol and fentanyl and their metabolites (noroxycodone, oxymorphone, O- desmethyltramadol, N- desmethyltramadol, and norfentanyl) in human plasma and whole blood collected via venepuncture and volumetric absorptive micro sampling.

J Pharm Biomed Anal 2021 Sep 27;203:114171. Epub 2021 May 27.

UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, Australia; Health and Biomedical Innovation, University of South Australia, Adelaide, Australia.

Introduction: A range of opioids are commonly prescribed to manage chronic pain, but individual patient responses vary greatly, especially in older populations. One source of that variability are differences in absorption, metabolism and excretion, i.e. pharmacokinetics. Blood, plasma and serum concentrations of opioids allow that variability to be quantified and may be used to optimise opioid dosing. As an aid to that process, there is an unmet need to rapidly quantify several opioids and their metabolites in a single analytical method.

Aims: To develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of tramadol, oxycodone, fentanyl and their major metabolites in various human matrices.

Methods: Sample preparation involved adding three deuterated internal standards followed by protein precipitation with 100 % acetonitrile, evaporation and reconstitution. Separation of analytes via LC was achieved on a reversed phase column via binary gradient elution using 0.005 % formic acid in water and 100 % acetonitrile as mobile phases. Analytes were detected via MS/MS with multiple reaction monitoring (MRM).

Results: The method was accurate with the inter-day and intra-day accuracy of quality control samples (QCs) below 15 %. It was also precise with inter-day and intra-day coefficient of variation below 15 %. The lower limit of quantification (LLOQ) was 0.2 ng/mL for all analytes except tramadol and its metabolites, where the LLOQ was 10 ng/mL. Recovery was greater than 88 % for all analytes, except for O-desmethyltramadol (81 %). Analytes were stable over four freeze-thaw cycles, for 24 h on the bench top and for 24 h post-preparation. The inter- and intra-day variability of concentrations determined in blood and plasma were within 84-124%, whereas the inter- and intra-day variability for blood samples prepared using volumetric absorptive micro-sampling (VAMS) compared to those prepared from whole blood ranged between 83-122%.

Conclusion: A LC-MS/MS method is described that is able to accurately and precisely quantify a number of commonly prescribed opioids and their major metabolites in plasma and whole blood, including whole blood collected using VAMS.
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http://dx.doi.org/10.1016/j.jpba.2021.114171DOI Listing
September 2021

Global View on Ant Venom Allergy: from Allergenic Components to Clinical Management.

Clin Rev Allergy Immunol 2021 Jun 1. Epub 2021 Jun 1.

School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, GPO Box 24715001, Australia.

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.
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http://dx.doi.org/10.1007/s12016-021-08858-1DOI Listing
June 2021

Concomitant beta-blocker use is associated with a reduced rate of remission in patients with rheumatoid arthritis treated with disease-modifying anti-rheumatic drugs: a multicohort analysis.

Ther Adv Musculoskelet Dis 2021 12;13:1759720X211009020. Epub 2021 Apr 12.

Discipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia.

Background: 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.

Methods: 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.

Results: 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,  = 0.001] and CVD cohort [adjusted HR 0.72 (0.57-0.90,  = 0.005)]. The association was consistent between trials (interaction  = 0.44) and treatment arms (interaction  = 0.06). No significant association between remission and β1-receptor selectivity was identified ( = 0.16), and the association was independent from other cardiovascular drug use. Similar associations between BB use and CDAI remission were observed.

Conclusion: In a large, pooled cohort of RA patients initiating csDMARDs and/or tocilizumab, BB use was independently associated with less frequent remission.
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http://dx.doi.org/10.1177/1759720X211009020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047969PMC
April 2021

LC-MS/MS analysis of vitamin D metabolites in human serum using a salting-out based liquid-liquid extraction and DAPTAD derivatization.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Mar 12;1173:122654. Epub 2021 Mar 12.

Clinical and Health Sciences Academic Unit, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, Australia. Electronic address:

LC-MS/MS has recently emerged as the best-practice for simultaneous analysis of vitamin D metabolites. We have developed and validated an LC-MS/MS method for simultaneous quantification of 25(OH)D, 24,25(OH)D, and 3-epi-25(OH)D in human serum. These three metabolites were extracted from 50 μL of serum by acetonitrile protein precipitation followed by salting-out of acetonitrile. DAPTAD (4-(4'-dimethylaminophenyl)-1,2,4-triazoline-3,5-dione) was used to derivatize the extracted metabolites and their deuterated isotope internal standards. Chromatographic separation was achieved on a UPLC C18 column (Waters® ACQUITY 100 × 2.1 mm, 1.7 µm) utilizing 0.1% formic acid and acetonitrile as mobile phases. Limits of quantification were 1 ng/mL for 25(OH)D and 0.1 ng/mL for 24,25(OH)D and 3-epi-25(OH)D. In-house and external Vitamin D External Quality Assessment Scheme (DEQAS) quality control sample analysis revealed satisfactory method accuracy. Within-analytical batch and between analytical batches precision were <15%. Extraction recovery for the three analytes were all ˃ 85% and all showed adequate autosampler, bench-top and freeze-thaw stability. Inter-methodological comparison of 25(OH)D results in patient serum samples revealed systematic and proportional differences between our method and DiaSorin® Liaison immunoassay, however a good agreement with an independent LC-MS/MS method was found.
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http://dx.doi.org/10.1016/j.jchromb.2021.122654DOI Listing
March 2021

Population pharmacokinetic model of subcutaneous fentanyl in older acute care patients.

Eur J Clin Pharmacol 2021 Sep 3;77(9):1357-1368. Epub 2021 Apr 3.

UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, Australia.

Purpose: Subcutaneous fentanyl injection is commonly prescribed to manage acute pain in older patients; however, there is a gap in the literature describing the pharmacokinetic parameters for this route of administration in this population. The aim of this study was to develop and evaluate a population pharmacokinetic model for subcutaneous fentanyl injection in older patients.

Methods: Twenty-one patients who received subcutaneous fentanyl injections (50 to 75 μg) were recruited. Fentanyl concentrations were determined using a validated liquid chromatography/tandem mass spectrometry method. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. A base model was selected based on the Akaike information criterion. Age, sex, body weight, number of previous fentanyl doses, number of prescribed medications, creatinine clearance, Charlson Comorbidity Index, Identification of Seniors at Risk score and concurrent use of CYP3A4 inhibitors were covariates considered for inclusion. A p value of < 0.05 was considered statistically significant for inclusion of covariates in the final model by stepwise addition. The simulation performance of the model was assessed by visual predictive check.

Results: A one-compartment, first-order absorption with lag time and linear elimination model was the best to fit to the fentanyl concentration data. The absorption rate constant was 0.136 h (between subject variability (BSV), 46%), lag time 0.66 h (BSV 51%), apparent volume of distribution 6.28 L (BSV 30%), and apparent clearance 16.3 L.h (BSV 54%). The Charlson Comorbidity Index was the only covariate included in the final model, where a higher value of the index increased fentanyl exposure and C.

Conclusion: This is the first report of subcutaneous fentanyl population pharmacokinetic model to evaluate fentanyl pharmacokinetic in older patients. The between subject variability in clearance and subcutaneous absorption rate was relatively high, and some patients recorded high fentanyl concentrations in the context of their titration to effect.
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http://dx.doi.org/10.1007/s00228-021-03126-9DOI Listing
September 2021

The obesity paradox in early and advanced HER2 positive breast cancer: pooled analysis of clinical trial data.

NPJ Breast Cancer 2021 Mar 22;7(1):30. Epub 2021 Mar 22.

College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.

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.
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http://dx.doi.org/10.1038/s41523-021-00241-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985140PMC
March 2021

[email protected]: Computer-Aided Pattern Analysis to Predict Multitarget ABC Transporter Inhibitors.

J Med Chem 2021 03 16;64(6):3350-3366. Epub 2021 Mar 16.

Department of Pharmaceutical and Cellbiological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.

Based on literature reports of the last two decades, a computer-aided pattern analysis ([email protected]) was implemented for the discovery of novel multitarget ABCB1 (P-gp), ABCC1 (MRP1), and ABCG2 (BCRP) inhibitors. [email protected] included basic scaffold identification, substructure search and statistical distribution, as well as novel scaffold extraction to screen a large virtual compound library. Over 45,000 putative and novel broad-spectrum ABC transporter inhibitors were identified, from which 23 were purchased for biological evaluation. Our investigations revealed five novel lead molecules as triple ABCB1, ABCC1, and ABCG2 inhibitors. [email protected] is the very first successful computational approach for the discovery of promiscuous ABC transporter inhibitors.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041314PMC
March 2021

Impact of resveratrol-mediated increase in uterine artery blood flow on fetal haemodynamics, blood pressure and oxygenation in sheep.

Exp Physiol 2021 May 16;106(5):1166-1180. Epub 2021 Mar 16.

Early Origins of Adult Health Research Group, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia.

New Findings: What is the central question of this study? Uterine artery blood flow helps to maintain fetal oxygen and nutrient delivery. We investigated the effects of increased uterine artery blood flow mediated by resveratrol on fetal growth, haemodynamics, blood pressure regulation and oxygenation in pregnant sheep. What is the main finding and its importance? Fetuses from resveratrol-treated ewes were significantly larger and exhibited a haemodynamic profile that might promote peripheral growth. Absolute uterine artery blood flow was positively correlated with umbilical vein oxygen saturation, absolute fetal oxygen delivery and fetal growth. Increasing uterine artery blood flow with compounds such as resveratrol might have clinical significance for pregnancy conditions in which fetal growth and oxygenation are compromised.

Abstract: High placental vascular resistance hinders uterine artery (UtA) blood flow and fetal substrate delivery. In the same group of animals as the present study, we have previously shown that resveratrol (RSV) increases UtA blood flow, fetal weight and oxygenation in an ovine model of human pregnancy. However, the mechanisms behind changes in growth and the effects of increases in UtA blood flow on fetal circulatory physiology have yet to be investigated. Twin-bearing ewes received s.c. vehicle (VEH, n = 5) or RSV (n = 6) delivery systems at 113 days of gestation (term = 150 days). Magnetic resonance imaging was performed at 123-124 days to quantify fetal volume, blood flow and oxygen saturation of major fetal vessels. At 128 days, i.v. infusions of sodium nitroprusside and phenylephrine were administered to study the vascular tone of the fetal descending aorta. Maternal RSV increased fetal body volume (P = 0.0075) and weight (P = 0.0358), with no change in brain volume or brain weight. There was a positive relationship between absolute UtA blood flow and umbilical vein oxygen saturation, absolute fetal oxygen delivery and combined fetal twin volume (all P ≤ 0.05). There were no differences between groups in fetal haemodynamics or blood pressure regulation except for higher blood flow to the lower body in RSV fetuses (P = 0.0170). The observed increase in fetal weight might be helpful in pregnancy conditions in which fetal growth and oxygen delivery are compromised. Further preclinical investigations on the mechanism(s) accounting for these changes and the potential to improve growth in complicated pregnancies are warranted.
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http://dx.doi.org/10.1113/EP089237DOI Listing
May 2021

COVID-19: can we treat the mother without harming her baby?

J Dev Orig Health Dis 2021 Jan 25:1-11. Epub 2021 Jan 25.

Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia.

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.
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http://dx.doi.org/10.1017/S2040174420001403DOI Listing
January 2021

Rational drug design of 6-substituted 4-anilino-2-phenylpyrimidines for exploration of novel ABCG2 binding site.

Eur J Med Chem 2021 Feb 3;212:113045. Epub 2020 Dec 3.

Pharmaceutical and Cellbiological Chemistry, Pharmaceutical Institute, Rheinische Friedrich-Wilhelms-University of Bonn, An der Immenburg 4, 53121, Bonn, Germany. Electronic address:

In the search for novel, highly potent, and nontoxic adjuvant chemotherapeutics to resolve the major issue of ABC transporter-mediated multidrug resistance (MDR), pyrimidines were discovered as a promising compound class of modern ABCG2 inhibitors. As ABCG2-mediated MDR is a major obstacle in leukemia, pancreatic carcinoma, and breast cancer chemotherapy, adjuvant chemotherapeutics are highly desired for future clinical oncology. Very recently, docking studies of one of the most potent reversers of ABCG2-mediated MDR were reported and revealed a putative second binding pocket of ABCG2. Based on this (sub)pocket, a series of 16 differently 6-substituted 4-anilino-2-phenylpyrimidines was designed and synthesized to explore the potential increase in inhibitory activity of these ABCG2 inhibitors. The compounds were assessed for their influence on the ABCG2-mediated pheophorbide A transport, as well as the ABCB1- and ABCC1-mediated transport of calcein AM. They were additionally evaluated in MDR reversal assays to determine their half-maximal reversal concentration (EC). The 6-substitution did not only show increased toxicity against ABCG2-overexpressing cells in combination with SN-38 but also a negative influence on cell viability in general. Nevertheless, several candidates had EC values in the low double-digit nanomolar concentration range, qualifying them as some of the most potent reversers of ABCG2-mediated MDR. In addition, five novel multitarget ABCB1, ABCC1, and ABCG2 inhibitors were discovered, four of them exerting their inhibitory power against the three stated transporters at least in the single-digit micromolar concentration range.
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http://dx.doi.org/10.1016/j.ejmech.2020.113045DOI Listing
February 2021

Opioid prescribing and risk of drug-opioid interactions in older discharged patients with polypharmacy in Australia.

Int J Clin Pharm 2021 Apr 18;43(2):365-374. Epub 2020 Nov 18.

UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, Australia.

Background Opioids are commonly prescribed to managing chronic pain in older persons. However, these patients are often at risk of drug-opioid interactions due to polypharmacy. Objectives To identify the prevalence of opioid prescribing and drug-opioid interactions in poly-medicated older patients and factors associated with opioid prescribing. Setting Patients were included if they were admitted to the Royal Adelaide Hospital between September 2015 and August 2016, aged ≥ 75 years and took ≥ 5 medications at discharge. Methods After ethics approval, data of were retrospectively collected from case notes. The Charlson Comorbidity Index and Drug Burden Index were determined and opioids were classified as strong or weak. The association between opioid use and concurrent medications was computed using logistic regression and the results presented as odds ratios (OR) and 95% confidence intervals (95% CI), adjusted for age, sex, Charlson Comorbidity Index, number of prescribed medications and modified-Drug Burden Index. Main outcome measure Association between concurrent medications and opioid prescribing. Results 15,000 geriatric admissions were identified, of which 1192 were included. A total of 283 (23.7%) patients were prescribed opioids, with oxycodone accounting for 56% of these prescriptions. Opioid users were prescribed more medications (11.2 vs. 9.0, P < 0.001) and had higher Drug Burden Index (1.2 vs. 0.14, P < 0.001) compared to non-users. Opioid use was associated with concurrent prescription of antiepileptics (OR = 1.7, 95% CI 1.1-2.6), and negatively associated with Charlson Comorbidity Index (OR = 0.9, 95% CI 0.8-0.98) and concurrent use of antipsychotics (OR = 0.5, 95% CI 0.3-0.9) and beta blocking agents (OR = 0.4, 95% CI 0.3-0.6). Conclusions Strong opioids were prescribed more often than weak opioids and opioid users presented with characteristics and concurrent medications which increased the risk of opioid related adverse drug effects.
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http://dx.doi.org/10.1007/s11096-020-01191-1DOI Listing
April 2021

Association between obesity and remission in rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs.

Sci Rep 2020 10 29;10(1):18634. Epub 2020 Oct 29.

Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia.

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. Individual 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.
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http://dx.doi.org/10.1038/s41598-020-75673-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596471PMC
October 2020

Development of a method to determine cytochrome P450 1A2, 2C9, 2D6 and 3A4 activity sheep hepatic microsomes.

J Pharmacol Toxicol Methods 2020 Nov - Dec;106:106934. Epub 2020 Oct 18.

UniSA: Clinical and Health Sciences, University of South Australia, Adelaide 5000, Australia. Electronic address:

Introduction: Ex vivo studies of human fetal hepatic drug metabolism are uncommon as it requires access to functional liver tissue and therefore raises practical and ethical concerns. Large animal models provide an alternative opportunity to study changes in cytochrome P450 (CYP) activity in the mother and fetus during pregnancy. We aimed to develop methods to determine the activity of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in sheep hepatic microsomes.

Methods: We identified optimal conditions to determine the activity of CYP1A2 (using the probe drug phenacetin), CYP2C9 (diclofenac), CYP2D6 (dextromethorphan) and CYP3A4 (midazolam) by varying techniques for microsome extraction, probe drug concentration, incubation time and microsome concentration. The specificity of each probe drug was assessed by determining the rate of metabolism when specific CYP enzyme inhibitors were included in the reaction.

Results: The optimum incubation time and probe drug concentration was six hours with 5 μM phenacetin (CYP1A2), four hours with 10 μM diclofenac (CYP2C9), 30 min with 1 μM of midazolam (CYP3A4) and 10 min with 1 μM dextromethorphan (CYP2D6). For both CYP2D6 and CYP3A4 reactions required 20 μg of microsomal protein, whereas for CYP1A2 and CYP2C9, reactions required 40 μg of microsomal protein. Metabolism of phenacetin, dextromethorphan and midazolam was reduced by specific enzyme inhibitors, but the specific CYP2C9 inhibitor sulfaphenazole did not substantially inhibit diclofenac metabolism.

Discussion: This study identifies the optimal conditions for determining CYP activity in maternal sheep hepatic microsomes. In doing so, we have developed a standardised protocol for assessment of microsomal activity of CYP3A4, CYP1A2 and CYP2D6, but we were unable to optimise conditions for assessment of CYP2C9. This approach can be applied to investigate the impact of pregnancy complications on maternal and fetal hepatic drug metabolism.
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http://dx.doi.org/10.1016/j.vascn.2020.106934DOI Listing
August 2021

Alterations in drug disposition in older adults: a focus on geriatric syndromes.

Expert Opin Drug Metab Toxicol 2021 Jan 2;17(1):41-52. Epub 2020 Nov 2.

Quality Use of Medicines and Pharmacy Research Centre, UniSA: Clinical and Health Sciences, University of South Australia , Australia.

Introduction: 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.

Areas Covered: 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).

Expert Opinion: 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.
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http://dx.doi.org/10.1080/17425255.2021.1839413DOI Listing
January 2021

An Outbreak of COVID-19 Associated with a Recreational Hockey Game - Florida, June 2020.

MMWR Morb Mortal Wkly Rep 2020 Oct 16;69(41):1492-1493. Epub 2020 Oct 16.

On June 16, 2020, a recreational ice hockey game was played at an ice rink in the Tampa Bay, Florida, metropolitan area. Teams A and B, each consisting of 11 players (typically six on the ice and five on the bench at any given time), included men aged 19-53 years. During the 5 days after the game, 15 persons (14 of the 22 players and a rink staff member) experienced signs and symptoms compatible with coronavirus disease 2019 (COVID-19)*; 13 of the 15 ill persons had positive laboratory test results indicating infection with SARS-CoV-2, the virus that causes COVID-19. Widespread transmission of SARS-CoV-2 has been documented at a choir practice (1) and at meat processing plants (2,3); however, apart from an outbreak involving 57 infected dancers that has been linked to high-intensity fitness dance classes in South Korea (4) and a cluster of five infected persons at a squash facility in Slovenia (5), few published reports are available regarding transmission associated with specific sports games or practices. In addition, outbreaks of COVID-19 infections among amateur hockey players in the United States have recently been reported in the news..
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http://dx.doi.org/10.15585/mmwr.mm6941a4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561093PMC
October 2020

Superior Pyrimidine Derivatives as Selective ABCG2 Inhibitors and Broad-Spectrum ABCB1, ABCC1, and ABCG2 Antagonists.

J Med Chem 2020 09 11;63(18):10412-10432. Epub 2020 Sep 11.

Pharmaceutical and Cellbiological Chemistry, Pharmaceutical Institute, Rheinische Friedrich-Wilhelms-University Bonn, An der Immenburg 4, 53121 Bonn, Germany.

In the search for highly effective modulators addressing ABCG2-mediated MDR, 23 pyrimidines were synthesized and biologically assessed. Seven derivatives with (a) nitrogen- and/or halogen-containing residue(s) had extraordinary potencies against ABCG2 (IC < 150 nM). The compounds competitively inhibited ABCG2-mediated Hoechst 33342 transport but were not substrates of ABCG2. The most potent MDR reverser, compound , concentration-dependently increased SN-38-mediated cancer cell death at 11 nM (EC), time-dependently doubled SN-38 toxicity in a period of 7 days at 10 nM, and half-maximally accelerated cell death combined with SN-38 at 17 nM. No induction of ABCG2 was observed. Furthermore, 11 pyrimidines were revealed as triple ABCB1/ABCC1/ABCG2 inhibitors. Five possessed IC values below 10 μM against each transporter, classifying them as some of the 50 most potent multitarget ABC transporter inhibitors. The most promising representative, compound , reversed ABCB1-, ABCC1-, and ABCG2-mediated MDR, making it one of the three most potent ABC transporter inhibitors and reversers of ABC transporters-mediated MDR.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00961DOI Listing
September 2020

The Influence of Pre-Existing Beta-Blockers Use on Survival Outcomes in HER2 Positive Advanced Breast Cancer: Pooled Analysis of Clinical Trial Data.

Front Oncol 2020 14;10:1130. Epub 2020 Jul 14.

College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.

Beta-blockers (BB) are commonly used to manage cardiovascular disease and may have benefits in controlling complications of anti-HER2 therapies. This study aimed to evaluate the association of pre-existing BB use with survival outcomes in patients initiating anti-HER2 therapy for advanced breast cancer (ABC). Data from clinical trials EMILIA, TH3RESA, MARIANNE, and CLEOPATRA was pooled. Cox proportional analysis was used to assess the association between pre-existing BB use with survival outcomes in patients initiating anti-HER2 therapies. Of the 2,777 patients with HER2 positive ABC, 266 were using a BB at the time of anti-HER2 therapy initiation. BB use was associated with worse overall survival (OS) (adjusted HR = 1.27, 95% CI: 1.04-1.55). Sensitivity analysis in patients with pre-existing cardiovascular disease (CVD) also indicated that BB use was associated with worse OS (1.29, 1.02-1.63). In large high-quality data, BB use at the time of anti-HER2 therapy initiation for ABC was independently associated with worse OS, regardless of CVD status. The finding is contrary to pre-study hypotheses and findings in other BC subtypes. Future research should aim to gain a deeper understanding of the effects of BBs on specific BC subtypes, cancer types, and cancer treatments.
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http://dx.doi.org/10.3389/fonc.2020.01130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373122PMC
July 2020

The impact of intrauterine growth restriction on cytochrome P450 enzyme expression and activity.

Placenta 2020 09 25;99:50-62. Epub 2020 Jul 25.

Early Origins of Adult Health Research Group, Australia; UniSA Clinical and Health Sciences, University of South Australia, Adelaide, 5000, Australia. Electronic address:

With the increased prevalence of non-communicable disease and availability of medications to treat these and other conditions, a pregnancy free from prescribed medication exposure is rare. Up to 99% of women take at least one medication during pregnancy. These medications can be divided into those used to improve maternal health and wellbeing (e.g., analgesics, antidepressants, antidiabetics, antiasthmatics), and those used to promote the baby's wellbeing in either fetal (e.g., anti-arrhythmics) or postnatal life (e.g., antenatal glucocorticoids). These medications are needed for pre-existing or coincidental illnesses in the mother, maternal conditions induced by the pregnancy itself through to conditions that arise in the fetus or that will be encountered by the newborn. Thus, medications administered to the mother may be used to treat the mother, the fetus or both. Metabolism of medications is regulated by a range of physiological processes that change during pregnancy. Other pathological processes such as placental insufficiency can in turn have both immediate and lifelong adverse health consequences for babies. Individuals born growth restricted are more likely to require medications but may also have an altered ability to metabolise these medications in fetal and postnatal life. This review aims to determine the effect of suboptimal fetal growth on the fetal expression of the drug metabolising enzymes (DMEs) that convert medications into active or inactive metabolites, and the transporters that remove both these medications and their metabolites from the fetal compartment.
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http://dx.doi.org/10.1016/j.placenta.2020.07.012DOI Listing
September 2020

Nuances to precision dosing strategies of targeted cancer medicines.

Pharmacol Res Perspect 2020 08;8(4):e00625

College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia.

Selecting the dose of a targeted cancer medicine that is most appropriate for a specific individual is a rational approach to maximize therapeutic outcomes and minimize toxicity. There are many different options for optimizing the dose of targeted cancer medicines and the purpose of this review is to provide a comprehensive comparison of the main options explored in prospective studies. Precision initial dose selection of targeted cancer therapies has been minimally explored to date; however, concentration, toxicity, and therapeutic outcome markers are used to guide on-therapy dose adaption of targeted cancer therapies across several medicines and cancers. While a specific concentration, toxicity, or therapeutic outcome marker commonly dominates an investigated precision on-therapy dose adaption strategy, greater attention to simultaneously account for exposure, toxicity, therapeutic outcomes, disease status, time since treatment initiation and patient preferences are required for optimal patient outcomes. To enable successful implementation of precision dosing strategies for targeted cancer medicines into clinical practice, future prospective studies aiming to develop strategies should consider these elements in their design.
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http://dx.doi.org/10.1002/prp2.625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358594PMC
August 2020

Repeat serological testing for anti-citrullinated peptide antibody after commencement of therapy is not helpful in patients with seronegative rheumatoid arthritis.

Intern Med J 2020 07;50(7):818-822

Department of Rheumatology, The Royal Adelaide Hospital, Adelaide, South Australia, Australia.

Aim: To Investigate the prevalence of seroconversion to ACPA after commencement of triple disease-modifying anti-rheumatic drug (DMARD) treat-to-target therapy.

Background: Anti-citrullinated peptide antibody (ACPA) and rheumatoid factor (RF) define 'seropositive' rheumatoid arthritis (RA). Both predict unfavourable disease course, development of extra-articular features and treatment outcomes. We investigated the prevalence of seroconversion to ACPA after commencement of triple disease-modifying anti-rheumatic drug (DMARD) treat-to-target therapy.

Methods: DMARD-naïve patients with RA according to the 1987 American College of Rheumatology criteria and disease duration of <96 weeks were enrolled. RF and ACPA levels were recorded at baseline and sequentially during triple DMARD therapy.

Results: A total of 368 patients were followed for a median of 272 weeks. Of 154 patients seronegative for ACPA at recruitment, 10 (6.5%) seroconverted at some point. Nine of these were positive for RF at baseline and baseline RF titre was predictive of seroconversion. Four (2.6%) patients remained seropositive. No patients seroconverted from negative to positive for both RF and ACPA. Median time to seroconversion for ACPA was 29 months.

Conclusion: Persistent seroconversion of ACPA from negative to positive after diagnosis in patients with RA is uncommon. ACPA and RF double negative patients are highly unlikely to ever develop ACPA positivity with a risk <1%. It is therefore unlikely to be helpful or cost effective to perform serial ACPA measurements in patients with seronegative RA after commencement of a treat-to-target strategy.
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http://dx.doi.org/10.1111/imj.14463DOI Listing
July 2020

Methamphetamine administration increases hepatic CYP1A2 but not CYP3A activity in female guinea pigs.

PLoS One 2020 12;15(5):e0233010. Epub 2020 May 12.

Department of Paediatrics and Child Health, Brain Health Research Centre and Brain Research New Zealand, University of Otago, Dunedin, New Zealand.

Methamphetamine use has increased over the past decade and the first use of methamphetamine is most often when women are of reproductive age. Methamphetamine accumulates in the liver; however, little is known about the effect of methamphetamine use on hepatic drug metabolism. Methamphetamine was administered on 3 occassions to female Dunkin Hartley guinea pigs of reproductive age, mimicking recreational drug use. Low doses of test drugs caffeine and midazolam were administered after the third dose of methamphetamine to assess the functional activity of cytochrome P450 1A2 and 3A, respectively. Real-time quantitative polymerase chain reaction was used to quantify the mRNA expression of factors involved in glucocorticoid signalling, inflammation, oxidative stress and drug transporters. This study showed that methamphetamine administration decreased hepatic CYP1A2 mRNA expression, but increased CYP1A2 enzyme activity. Methamphetamine had no effect on CYP3A enzyme activity. In addition, we found that methamphetamine may also result in changes in glucocorticoid bioavailability, as we found a decrease in 11β-hydroxysteroid dehydrogenase 1 mRNA expression, which converts inactive cortisone into active cortisol. This study has shown that methamphetamine administration has the potential to alter drug metabolism via the CYP1A2 metabolic pathway in female guinea pigs. This may have clinical implications for drug dosing in female methamphetamine users of reproductive age.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233010PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217439PMC
July 2020

Precision Medicine With Leflunomide: Consideration of the DHODH Haplotype and Plasma Teriflunomide Concentration and Modification of Outcomes in Patients With Rheumatoid Arthritis.

Arthritis Care Res (Hoboken) 2021 07;73(7):983-989

Royal Adelaide Hospital and The University of Adelaide, Adelaide Medical School, Adelaide, South Australia, Australia.

Objective: 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.

Methods: 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 samples 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.

Results: 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 >16 mg/liter were associated with a DAS28 score that was 0.33 lower, and when free teriflunomide concentration was >35 µg/liter, the DAS28 score was 0.32 lower.

Conclusion: 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.
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http://dx.doi.org/10.1002/acr.24236DOI Listing
July 2021
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