Utilization and associated factors of TPMT testing among Australian adults receiving thiopurines: A national retrospective data-linkage study.

Introduction: Thiopurine drugs are metabolized by thiopurine methyltransferase (TPMT) and low TPMT activity can result in severe adverse drug reactions. Therefore, TPMT testing is recommended for individuals receiving thiopurines to reduce the risk of toxicity.

Objectives: The objectives of this study were to assess the rate of TPMT testing among individuals receiving thiopurines and explore factors associated with undergoing TPMT testing in Australia.

Consumer and multidisciplinary clinician experiences after implementation of the Drug Burden Index intervention bundle to facilitate deprescribing in older inpatients: A mixed method study.

Rationale: The Drug Burden Index (DBI) measures exposure to anticholinergic and sedative drugs, which are associated with harm in older adults. To facilitate deprescribing in older Australian inpatients, we piloted an intervention bundle integrating the DBI in Electronic Medical Records, clinician deprescribing guides, consumer information leaflets and a stewardship pharmacist.

Objectives: To understand (i) hospital clinician experiences of using the bundle and (ii) consumer (patient and carer) and General Practitioner (GP) experiences of in-hospital deprescribing, following bundle implementation.

Metabolic activation of WHO-congeners PCB28, 52, and 101 by human CYP2A6: evidence from in vitro and in vivo experiments.

Despite extensive research on the metabolism of polychlorinated biphenyls (PCBs), knowledge gaps persist regarding their isoform-specific biotransformation pathways. This study aimed to elucidate the role of different cytochrome P450 enzymes in PCB metabolism, focusing on WHO-congeners 2,4,4'-trichlorobiphenyl (PCB28), 2,2',5,5'-tetrachlorobiphenyl (PCB52), and 2,2',4,5,5'-pentachlorobiphenyl (PCB101). Utilizing engineered HEK293 cell lines, we investigated the in vitro metabolism of these PCBs by CYP1A2, CYP2C8, CYP2C9, CYP3A4, CYP2A6, and CYP2E1, revealing robust production of hydroxylated metabolites.

The Causal Effect of Gut Microbiota and Plasma Metabolome on Lung Cancer and the Heterogeneity across Subtypes: A Mendelian Randomization Study.

The causal effect and pathways of gut microbiota and plasma metabolome on lung cancer have been important topics for personalized medicine; however, the heterogeneity of lung cancer subtypes has not gained enough attention in previous studies. This study sought to employ a Mendelian randomization analysis to screen the specific gut microbiota and plasma metabolome, which may have a causal effect on lung cancer. We further extended our analysis to estimate the effects of these exposures on various pathological subtypes of lung cancer.

A physiologically-based pharmacokinetic precision dosing approach to manage dasatinib drug-drug interactions.

Dasatinib, a second-generation tyrosine kinase inhibitor, is approved for treating chronic myeloid and acute lymphoblastic leukemia. As a sensitive cytochrome P450 (CYP) 3A4 substrate and weak base with strong pH-sensitive solubility, dasatinib is susceptible to enzyme-mediated drug-drug interactions (DDIs) with CYP3A4 perpetrators and pH-dependent DDIs with acid-reducing agents. This work aimed to develop a whole-body physiologically-based pharmacokinetic (PBPK) model of dasatinib to describe and predict enzyme-mediated and pH-dependent DDIs, to evaluate the impact of strong and moderate CYP3A4 inhibitors and inducers on dasatinib exposure and to support optimized dasatinib dosing.

A high performance liquid chromatography-tandem mass spectrometry assay for therapeutic drug monitoring of 10 drug compounds commonly used for antimicrobial therapy in plasma and serum of critically ill patients: Method optimization, validation, cross-validation and clinical application.

Background And Aims: Intensive care antibiotic treatment faces challenges due to substantial pharmacokinetic differences in critically ill patients. Individualized antibiotic dosing guided by therapeutic drug monitoring (TDM) is considered to minimize the risk of treatment failure and toxicity. This study aimed to develop a valid method for simultaneous LC-MS/MS quantification of 10 drugs frequently used in intensive care antibiotic therapy for which TDM-guided dosing is recommended: piperacillin, meropenem, flucloxacillin, cefuroxime, vancomycin, colistin A and B, linezolid, ciprofloxacin and tazobactam.

Trial of Lixisenatide in Early Parkinson's Disease.

Background: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease.

Methods: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period.

Polypharmacy and precision medicine.

Precision medicine is an approach to maximise the effectiveness of disease treatment and prevention and minimise harm from medications by considering relevant demographic, clinical, genomic and environmental factors in making treatment decisions. Precision medicine is complex, even for decisions about single drugs for single diseases, as it requires expert consideration of multiple measurable factors that affect pharmacokinetics and pharmacodynamics, and many patient-specific variables. Given the increasing number of patients with multiple conditions and medications, there is a need to apply lessons learned from precision medicine in monotherapy and single disease management to optimise polypharmacy.

Nonlinear Mixed-Effects Model of Z-Endoxifen Concentrations in Tamoxifen-Treated Patients from the CEPAM Cohort.

Tamoxifen is widely used in patients with hormone receptor-positive breast cancer. The polymorphic enzyme CYP2D6 is primarily responsible for metabolic activation of tamoxifen, resulting in substantial interindividual variability of plasma concentrations of its most important metabolite, Z-endoxifen. The Z-endoxifen concentration thresholds below which tamoxifen treatment is less efficacious have been proposed but not validated, and prospective trials of individualized tamoxifen treatment to achieve Z-endoxifen concentration thresholds are considered infeasible.

Physiologically based pharmacokinetic modeling of imatinib and N-desmethyl imatinib for drug-drug interaction predictions.

The first-generation tyrosine kinase inhibitor imatinib has revolutionized the development of targeted cancer therapy and remains among the frontline treatments, for example, against chronic myeloid leukemia. As a substrate of cytochrome P450 (CYP) 2C8, CYP3A4, and various transporters, imatinib is highly susceptible to drug-drug interactions (DDIs) when co-administered with corresponding perpetrator drugs. Additionally, imatinib and its main metabolite N-desmethyl imatinib (NDMI) act as inhibitors of CYP2C8, CYP2D6, and CYP3A4 affecting their own metabolism as well as the exposure of co-medications.

Patient-perceived progression in multiple system atrophy: natural history of quality of life.

Background: Health-related quality of life (Hr-QoL) scales provide crucial information on neurodegenerative disease progression, help improve patient care and constitute a meaningful endpoint for therapeutic research. However, Hr-QoL progression is usually poorly documented, as for multiple system atrophy (MSA), a rare and rapidly progressing alpha-synucleinopathy. This work aimed to describe Hr-QoL progression during the natural course of MSA, explore disparities between patients and identify informative items using a four-step statistical strategy.

Protocol for a randomized, placebo-controlled, double-blind phase IIa study of the safety, tolerability, and symptomatic efficacy of the ROCK-inhibitor Fasudil in patients with Parkinson's disease (ROCK-PD).

Background: The Rho-kinase (ROCK) inhibitor Fasudil has shown symptomatic and disease-modifying effects in Parkinson's disease (PD) models and . In Japan, Fasudil has been approved for the treatment of subarachnoid haemorrhage since 1995 and shows a favourable safety profile.

Objectives/design: To investigate the safety, tolerability, and symptomatic efficacy of ROCK-inhibitor Fasudil in comparison to placebo in a randomized, national, multicenter, double-blind phase IIa study in patients with PD.

The effect of genetic variants in the transcription factor TSPYL family on the CYP3A4 mediated cyclosporine metabolism in kidney transplant patients.

CYP3A4 activity shows considerable interindividual variability. Although studies indicate 60%-80% is heritable, common single nucleotide variants (SNVs) in CYP3A4 together only explain ~10%. Transcriptional factors, such as the testis-specific Y-encoded-like proteins (TSPYLs) family, have been reported to regulate the expression of CYP enzymes including CYP3A4 in vitro.

Determination of sulfadoxine and pyrimethamine in microvolume human plasma using ultra high performance liquid chromatography-tandam mass spectrometry.

To support the pharmacokinetic study of sulfadoxine (SD) and pyrimethamine (PM) in pregnant women and children, sensitive methods with small sample volume are desirable. Here we report a method to determine SD and PM with microvolume plasma samples: 5 µL plasma samples were cleaned up by protein precipitation with acetonitrile. The deuterated analytes were used as the internal standards.

The Carer Assessment of MedicaTion Management GuidanCe for People With Dementia at Hospital Discharge (CATCH) Tool: Exploratory Factor Analysis.

Purpose: The Carer Assessment of medicaTion management guidanCe for people with dementia at Hospital discharge (CATCH) tool was developed to examine the carer's experiences of medication management guidance delivery at discharge. This study explored its factor structure, characterized carers' experiences at discharge, and identified predictors of carer preparedness to manage medications at discharge.

Methods: A cross-sectional survey of carers across Australia was distributed.

Personalized Chronomodulated 5-Fluorouracil Treatment: A Physiologically-Based Pharmacokinetic Precision Dosing Approach for Optimizing Cancer Therapy.

The discovery of circadian clock genes greatly amplified the study of diurnal variations impacting cancer therapy, transforming it into a rapidly growing field of research. Especially, use of chronomodulated treatment with 5-fluorouracil (5-FU) has gained significance. Studies indicate high interindividual variability (IIV) in diurnal variations in dihydropyrimidine dehydrogenase (DPD) activity - a key enzyme for 5-FU metabolism.

Analysis of the immunological markers BTLA, TIM-3, and PD-L1 at the invasion front and tumor center in clear cell renal cell carcinoma.

Purpose: Immune checkpoint inhibitors (ICI) are then backbone in the therapy of metastatic renal cell carcinoma (RCC). The aim of this analysis was to explore the different expression of the ICI PD-L1, BTLA, and TIM-3 at the different tumor locations of the invasion front and the tumor center.

Methods: Large-area sections of the tumor center and invasion front of 44 stage pT1-4 clear cell RCCs were examined immunohistochemically using antibodies against BTLA, TIM-3, and PD-L1 and subsequently correlated with clinicopathologic data.

The outcomes of considering goals of care in medication reviews for older adults: a systematic review.

Introduction: This is a systematic review of prescribing, clinical, patient-reported, and health utilization outcomes of goal-directed medication reviews in older adults.

Methods: A systematic review was conducted using MEDLINE, EMBASE, SCOPUS and CINAHL databases to identify studies examining outcomes of goal-directed medication reviews in humans, with mean/median age ≥ 60 years and in English.

Results: Seventeen out of 743 articles identified were included.

Nutrimetric Validation of Solanidine as Dietary-Derived CYP2D6 Activity Marker In Vivo.

CYP2D6 is involved in the metabolism of many drugs. Its activity is affected by pharmacogenetic variability leading to highly polymorphic phenotypes between individuals, affecting safety and efficacy of drugs. Recently, solanidine, a steroidal alkaloid from potatoes, and its metabolites, has been identified as a dietary-derived activity marker for CYP2D6.

Development of a maturity matrix to assess organizational readiness of community pharmacies for implementation of guideline recommendations in diabetes care.

Objectives: Pharmaceutical care for people with diabetes mellitus type 2 (DMT2) has been described in professional guidelines. To apply their recommendations, organizational changes are needed. We aimed to describe, for the first time, the development of a maturity matrix for community pharmacy teams (MM-CP) to assess organizational readiness in implementing the guideline recommendations on pharmaceutical DMT2 care.