British journal of clinical pharmacology最新文献

Mitotane is an adrenolytic drug with cytotoxic effects, registered for the treatment of advanced adrenocortical carcinoma (ACC), a rare but aggressive tumour type with a poor prognosis despite treatment. Recently, the oral multi-kinase inhibitor cabozantinib has shown promising results as a potential second-line treatment option. Unfortunately, first-line mitotane therapy complicates subsequent treatments due to its strong and long-lasting inducing effects on drug-metabolizing enzymes resulting in persistent subtherapeutic concentrations. This is also relevant for subsequent cabozantinib treatment, and therefore only patients with mitotane concentration ≤2 mg/L were eligible to enter the cabozantinib study. However, ACC is often too aggressive to await mitotane effects to diminish. In this case report, we describe different pharmacokinetic interventions to potentiate cabozantinib efficacy in a patient with rapidly progressive ACC who had persistent subtherapeutic cabozantinib concentrations after previous mitotane treatment. First, we recommended co-administration with a high-fat meal and grapefruit juice to increase cabozantinib absorption. Second, we aimed to reduce cabozantinib clearance through co-administration of the CYP3A4 inhibitor cobicistat (150 mg once daily). Pharmacokinetic sampling revealed that cobicistat enhanced cabozantinib absorption, but had insufficient impact on metabolic enzymes and thereby failed to normalize the mitotane-induced clearance of cabozantinib. Therefore, doubling the dose is deemed necessary in order to reach therapeutic cabozantinib concentrations. Our findings suggest that an aggressive approach, combining pharmacokinetic boosting, dose escalation and frequent pharmacokinetic monitoring is required to prevent undertreatment and toxicity. By mitigating mitotane-induced subtherapeutic concentrations, this pharmacokinetic strategy may facilitate more effective use and earlier initiation of cabozantinib as second-line treatment in ACC.

Levofloxacin is a widely used antibiotic included in rifampicin-resistant tuberculosis (RR-TB) treatment. Data describing levofloxacin concentrations in breastmilk and infant exposure are limited. We analysed data from two South African studies of breastfeeding women receiving levofloxacin (750-1000 mg daily) for RR-TB. Plasma and breastmilk samples were collected over eight hours, ≥5 weeks postpartum. A single plasma sample was obtained from breastfed infants. Twenty women contributed paired plasma-breastmilk samples, 15 plasma concentrations from breastfed infants were available. Using nonlinear mixed-effects modelling, levofloxacin equilibrated rapidly between plasma and breastmilk (7.50 min half-life; 95% CI: 3.89-11.5), with a breastmilk: plasma ratio of 1.46 (95% CI: 1.40-1.52). The relative infant dose through breastfeeding was 6-8% of the recommended 15-20 mg/kg/day adult and paediatric dose, confirmed by low (but detectable) concentrations in some infants. It is unclear whether these low infant concentrations may be prophylactic or instead contribute to the development of drug resistance.

The majority of penicillin allergy labels are incorrect and a label of penicillin allergy is associated with worse outcomes and increased use of healthcare services. Penicillin allergy assessment and de-labelling may be considered in critically ill patients. An oral penicillin challenge is a common component of most penicillin allergy protocols. In critical illness, the enteral route may not be an option and is less reliable due to altered absorption kinetics. In this study, simulations were undertaken to determine an intravenous infusion dosing schedule for critically ill patients that matches the concentration-time profile of an oral penicillin drug provocation test in the general population. These simulations may help clinicians develop procedures for intravenous infusion penicillin drug provocation tests for critically ill patients.

Objective: Kidney stones affect approximately 10% of adults globally, with increasing prevalence and significant associated morbidity. While ibuprofen and paracetamol are widely used over-the-counter analgesics, their associations with kidney stone risk remain unclear. This study aimed to investigate whether regular use of paracetamol or ibuprofen is associated with incident kidney stones.

Methods: A prospective cohort analysis was conducted including 483 692 participants from the UK Biobank without prior kidney stones. Regular use of paracetamol or ibuprofen was defined as use on most days of the week in the past 4 weeks. The study outcome was incident kidney stones. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs), adjusting for demographic, lifestyle, genetic and clinical factors.

Results: During a median follow-up of 13.6 years, 6613 (1.4%) incident kidney stones cases were recorded. Regular paracetamol usage was significantly associated with increased stone risk (adjusted HR, 1.17, 95%CI: 1.10-1.23), with a stronger effect in non-diabetic individuals (vs. with diabetes, P interaction = 0.006). Regular ibuprofen usage showed no significant association (adjusted HR, 1.05, 95%CI: 0.98-1.13). Sensitivity analyses and propensity score matching supported these findings. Analysis of changes in usage showed that initiating or consistently using paracetamol was linked to significantly higher risk, while consistent ibuprofen users also showed an elevated risk.

Conclusions: Regular paracetamol usage, but not ibuprofen usage, was associated with an increased risk of incident kidney stones. These findings suggest that caution is warranted regarding regular paracetamol usage, particularly in individuals at risk for kidney stones.

Aims: The aim of this study was to introduce a new assessment method for pharmacy students' real-life competence in reviewing medications after obligatory advanced-level practical internship in Finland.

Methods: The new medication review (MR) competence assessment method consisted of (1) a self-assessment by pharmacy students and (2) a performance assessment by their MR specialized preceptors at the completion of the advanced-level pharmacy internship during the third study year at the University of Helsinki, Finland. The assessment applied a structured and validated electronic evaluation tool based on national MR competence recommendations for pharmacists (31 items).

Results: Altogether 378 students and their MR preceptors assessed students' MR competence during the period of November 2020-December 2023. Majority of the students self-assessed their MR competence as very good (25%) or good (70%). Preceptors' estimates for students' MR competence were higher, as they graded 54% of the students with the grade very good and 43% with the grade good. Differences between students' and preceptors' assessments were statistically significant (p < .05) in all other statements except for 'Understands the importance of medication reconciliation and prescription review in improving medication safety and outcomes' (p = .829). The preceptors tended to assess students' MR competence as better than students themselves.

Conclusions: Combining self-assessment and assessment by an MR specialized preceptor forms a feasible method for assessing the real-life MR competence of students after advanced-level pharmacy internship. The involvement of the students' and preceptors' assessments can balance the effect of over- and under-estimation of the competence.

Background: Observational studies indicate an association between antihypertensive drugs and the risk of acute pancreatitis (AP) and chronic pancreatitis (CP). This study aims to utilize Mendelian randomization (MR) analysis to assess the causal impact of antihypertensive drugs on the risk of AP and CP.

Method: Protein target information for eight commonly used antihypertensive drugs was collected from the DrugBank database. The inverse variance-weighted (IVW) method was the primary approach used to investigate the association between genetic instruments from the discovery cohorts and the risk of AP and CP. The presence of heterogeneity was determined using Cochran's Q test.

Result: The genetic proxies of angiotensin-converting enzyme inhibitors (ACEIs) were identified as risk factors for AP. Genetic proxies for potassium-sparing diuretics (PSDs) were found to have a positive causal relationship with the occurrence of AP. In contrast, β-blockers (BBs) and loop diuretics were identified as protective factors against AP. Genetic proxies of ACEIs were identified as risk factors for CP, whereas BBs were found to be protective factors for CP. Additionally, genetic proxies for PSDs showed a protective effect on CP, while loop diuretics were identified as risk factors for CP.

Conclusion: BBs may have a protective effect on AP, whereas ACEIs and PSDs may have negative effects. The genetic proxies of PSDs and BBs are protective factors for CP, while the genetic proxies of ACEIs and loop diuretics are risk factors for CP.