British journal of clinical pharmacology最新文献

Aims: Valproic acid is an inhibitor of histone deacetylases (HDACs) and is used for the treatment of epileptic seizures. The drug (sodium valproate) has antihypertensive effects, and HDACs modulate renal Na⁺-transporting ATPases. The aim was to investigate whether valproate could be repositioned as an adjunctive drug for the prevention of acute kidney injury (AKI).

Methods: AKI due to ischemia followed by reperfusion (I/R) was induced by clamping of the renal arteries in rats that had received valproate or a vehicle for 20 days. Plasma creatinine and urea concentrations, and glomerular filtration rate (colorimetrically); plasma and urinary Na⁺ and K⁺ concentrations, and urinary excretion of Na⁺ and K⁺ (spectrophotometrically); proximal tubules (Na⁺+K⁺)ATPase activity (release of P_i from ATP); and blood pressure (pletismography) were measured 48 h later.

Results: AKI increases plasma creatinine and returns to baseline values observed in non-operated animals when I/R rats are pretreated with valproate. Its decrease in urine is significantly prevented by valproate administration. The elevated plasma urea concentration is significantly reduced. Urinary excretion of Na⁺ and K⁺ decreases in I/R, but while the former is recovered by valproate, this does not occur with K⁺. The plasma levels of both ions remain ~10% below those of Sham controls. The decrease in (Na⁺+K⁺)ATPase activity in I/R rats is totally prevented by valproate. The AKI-provoked hypertension is prevented by valproate.

Conclusions: Valproate has pharmacological properties that point to its potential repositioning as an adjuvant in improving several outcomes in AKI and potentially avoiding progression to chronic kidney disease.

Aims: The study aims to develop a physiologically-based pharmacokinetic (PBPK) model to quantitatively evaluate the role of ATP-binding cassette sub-family B member 1 (ABCB1) and ATP-binding cassette super-family G member 2 (ABCG2) in the drug-drug interaction (DDI) between rifampin and linezolid and to predict the impact of high-dose rifampin on linezolid pharmacokinetics (PK).

Methods: We developed a PBPK model of linezolid and verified this using published clinical PK data. The built-in PK-SIM PBPK model for rifampin was used as a perpetrator model, which incorporate ABCB1 and ABCG2 transporter activity, along with inhibition and induction kinetic parameters. Using the developed PBPK models, linezolid PK was predicted when co-administered with rifampin and verified using published data. Based on the developed DDI model, linezolid exposure when co-administered with high-dose rifampin at steady state was predicted.

Results: The developed linezolid PBPK model had acceptable predictive performance for 36 different PK arms from 13 individual clinical studies. The PBPK-predicted DDI effect of standard dose rifampin on linezolid, with AUC and C_max ratios of 0.77 and 0.87, respectively, aligned well with observed DDI ratio. PBPK simulations indicated that both ABCG2 and ABCB1 contributed to the DDI between linezolid and rifampin, with ABCB1 playing the major role in the interaction. Increasing the daily dose of rifampin from 10 mg/kg to 20-40 mg/kg resulted in a similar linezolid exposure.

Conclusions: Our study suggested that ABCB1 is the primary transporter responsible for the interaction between rifampin and linezolid. The DDI effect of high-dose rifampin on linezolid plasma exposure is similar to that of standard-dose rifampin.

Aims: Amoxicillin, a widely used β-lactam antibiotic, requires improved pharmacokinetic characterization during breastfeeding. This study used a population pharmacokinetic (PopPK) approach to model amoxicillin concentrations in breast milk, identify variability sources and estimate infant exposure, applying worst-case scenarios.

Methods: Breastfeeding mothers receiving amoxicillin for at least 2 days were enrolled. At steady state, three (nearly) paired blood and milk samples were collected between two doses: 15-30 min, 1-2 h and 3-4 h post-dose. Samples were analysed using LC-MS/MS. PopPK modelling was performed with Monolix. Milk-to-plasma (M/P) concentrations ratios and relative infant dose (RID) were evaluated. RID was calculated relative to both adult and paediatric dosing regimens. Monte Carlo simulations estimated infant exposure at high maternal doses (6 g/day).

Results: Twenty-five mother-infant pairs were included. All plasma and milk samples (n = 75/matrix) contained quantifiable amoxicillin. A two-compartment model described the data, with drug transfer from plasma to milk and elimination from milk. Simulated M/P concentrations ratios were 4.1%-5.4%, while observed values ranged from 4.5% to 9.6%. RID based on adult or paediatric dosages remained <0.4%, regardless of measured or simulated concentrations. No adverse effects were reported in breastfed infants.

Conclusions: These findings support the low transfer of amoxicillin into breast milk and align with the absence of adverse effects in breastfed infants, reinforcing its safety during lactation.

Aim: Elexacaftor/tezacaftor/ivacaftor (ETI) has markedly improved cystic fibrosis (CF) outcomes. However, its long-term impact on nutrition, metabolism and liver health remains underexplored. We assessed 30-month changes in pulmonary, nutritional, metabolic and inflammatory markers in people with CF (PwCF) homozygous for F508del.

Methods: We retrospectively analysed 112 PwCF (median age-31 years) treated with ETI from July 2021 to December 2024. Clinical, spirometric and biochemical data were collected at baseline and at 6, 12, 24 and 30 months.

Results: ETI produced sustained lung function gains (percent predicted FEV₁ + 15 points at 24 months, p < 0.001), BMI increase (+1.7 kg/m² in year-one, p < 0.001) and marked C-reactive protein reduction (-80% at 6 months), with an 85% decrease in pulmonary exacerbations. Nutritional recovery shifted BMI distribution: underweight prevalence declined from 12.5% to 1.8%, while overweight rose from 15.2% to 27.7%. Adolescents improved in weight-for-age Z-scores (+0.42, p = 0.01). Total and LDL cholesterol increased but remained within reference ranges; HDL, triglycerides and glycaemic control stayed stable, with no new cystic fibrosis-related diabetes (CFRD). Vitamin D improved; vitamin B12 fluctuated with supplementation. Mild, transient transaminase elevations occurred in 4.5% of PwCF, with no fibrosis progression (APRI/FIB-4 below risk thresholds).

Conclusion: ETI provides durable multisystem benefits, preserving lung function and improving nutritional and metabolic profiles. However, the shift towards overweight/obesity and biochemical signs of hepatic stress suggests evolving cardiometabolic risks. These findings support early ETI initiation and reinforce the need for ongoing monitoring of nutrition, lipid profile and liver function, together with updated CF care strategies to mitigate long-term cardiometabolic complications.

Aims: Chemical Adherence Testing (CAT) is gaining prominence as a reliable and valid clinical method to detect whether antihypertensive agents are being taken as prescribed. This study aimed to explore clinicians' attitudes and perspectives on the clinical use of CAT.

Methods: Clinicians involved in hypertension care were recruited through purposive and snowball sampling (N = 9). Participants represented general practice, cardiology, geriatric medicine, clinical pharmacology, nephrology and internal medicine. Semi-structured interviews were carried out, and transcripts were analysed using reflexive thematic analysis with an inductive, constructivist approach. Theme development was peer-reviewed by a health psychologist and clinical pharmacologist to enhance reflexivity.

Results: Three themes were developed: (1) The impactful weight of new evidence- CAT was perceived as a valuable, more objective tool for checking for non-adherence and informing treatment, especially in cases of suspected treatment-resistant hypertension; (2) CAT meets clinical reality- participants highlighted practical barriers such as test availability, workflow disruption, staffing needs and costs that could impact implementation in an overburdened healthcare system; (3) The human side of CAT- while CAT supported discussions around adherence, clinicians highlighted the need for trust, consent and sensitive communication to avoid perceptions of policing or blame.

Conclusion: Clinicians viewed CAT as a promising tool for improving diagnostic clarity and prompting adherence discussions. However, concerns about logistical feasibility, ethical use and potential strain on patient relationships were evident. Successful implementation requires clinician training, clear communication and system-level support to ensure CAT is integrated in an ethical, patient-centred way that preserves trust and supports collaborative care.

Aims: Prescribing is a complex, essential skill that doctors must acquire to practice medicine safely and effectively. The British Pharmacological Society has historically provided a core curriculum to guide clinical pharmacology and prescribing education in UK medical schools. This study aimed to update the 2012 curriculum to reflect contemporary practice, regulatory requirements and the evolving needs of medical education.

Methods: A modified Delphi was undertaken. A steering committee of six clinical and educational experts reviewed the previous curriculum and oversaw the process. Forty experts, comprising clinical and academic pharmacologists, medical educators and pharmacists from across the UK, participated in three Delphi rounds. Round 1 involved item-level review of existing learning outcomes; Round 2 incorporated feedback and new proposals; Round 3 convened expert panels to resolve outstanding disagreements. Consensus was defined as ≥75% agreement.

Results: The updated curriculum comprises four sections: (I) Principles of Clinical Pharmacology, (II) Drugs, (III) Therapeutics and (IV) Prescribing and related skills. Key changes include consistent application of clearly defined command verbs, updates to reflect current practice and a reduction in learning outcomes (226 to 205), particularly in Section I. The core drug list remained stable, with minor revisions and reorganization.

Conclusion: This updated British Pharmacological Society curriculum provides a robust, evidence-based framework for clinical pharmacology and prescribing education. Its structured approach supports curriculum design, mapping and quality assurance, while alignment with national assessments and regulatory expectations ensures relevance for undergraduate education and early clinical practice. It aims to enhance safe, effective and responsible prescribing by future doctors.

Aim: Induction of cytochrome P450 (CYP) enzymes is one of the major mechanisms for drug-drug interactions (DDIs), which requires accurate assessment for dose adjustments. This study aimed to develop a reliable method for isolating exosomes from rat and human plasma samples, quantifying several CYP enzymes in the isolated exosomes at the mRNA level, and further validating their utility for studying enzyme induction in both preclinical and clinical settings.

Methods: We evaluated and validated exosome isolation methods from human plasma and serum samples using nanoparticle tracking analysis (NTA) for physical characterization and RT-qPCR for exosomal mRNA quantification. CYP mRNA induction was quantified in plasma-derived exosomes from rats and humans following dexamethasone or modafinil treatment.

Results: Among six exosome isolation methods, the ExoQuick kit was selected and further optimized based on the high yield and purity of isolated exosomes. This workflow of exosome isolation and RNA extraction exhibited high precision and reproducibility, and demonstrated excellent assay linearity, with gene detectability and expression levels increasing in a volume-dependent manner from 0.5, 1 and 2 mL plasma samples. Following dexamethasone treatment in rats, significant induction of Cyp3a23/3a1 mRNA was observed in both plasma-derived exosomes and liver tissues. Additionally, CYP3A4, CYP3A5 and CYP1A2 mRNA in human plasma-derived exosomes were induced in clinical studies following 200 mg and 400 mg modafinil administration.

Conclusion: We present a robust workflow for detecting several CYP mRNAs in plasma-derived exosomes and demonstrate proof-of-concept induction in preclinical and clinical samples. However, larger prospective studies are required to validate clinical utility.

Aims: Long-term use of medications with anticholinergic properties has been associated with cognitive and functional decline among older adults, yet these measures are typically assessed in isolation-potentially overlooking their interrelated nature. This study investigated the longitudinal association between anticholinergic burden and integrated cognitive-functional measures in older adults.

Methods: Participants were drawn from S.AGES (France, 2009-2012). The total daily anticholinergic burden was assessed using the Anticholinergic Burden Scale (ACB) and the Anticholinergic and Sedative Burden Catalogue (ACSBC). We combined the Mini-Mental State Examination (MMSE) with basic activities of daily living (BADLs), with instrumental activities of daily living (IADLs) or with both. Exploratory factor analyses (EFAs) and confirmatory factor analyses (CFAs) were conducted to explore dimensionality and model fit. The associations between the total burden and outcomes were estimated using generalized linear mixed models (GLMMs).

Results: Among 983 participants, a higher total daily ACB score was associated with poorer MMSE-BADLs-IADLs performance (OR = 1.25; 95% CI = [1.06-1.47]; p = 0.004) and MMSE-IADLs (OR = 1.56; 95% CI = [1.30-1.88]; p < 0.001). Higher ACSBC scores showed similar associations with the MMSE-BADLs-IADLs (OR = 1.23; 95% CI = [1.08-1.40]; p < 0.001) and MMSE-IADLs (OR = 1.40; 95% CI = [1.16-1.70]; p < 0.001). The three cognitive-functional measures showed high internal consistency with comparative fit indexes (CFIs) of 0.9 and 0.95 and root mean squared error of approximations (RMSEAs) < 0.08, supporting a one-factor model.

Conclusions: Our findings, based on combined measures in assessing cognitive-functional decline in older adults, support incorporating anticholinergic burden assessment into routine care, particularly for patients aged ≥85 or those with CNS diseases and depression.

Levothyroxine (LT4) is the standard treatment for hypothyroidism and the most widely prescribed medication worldwide. Although generally safe, regulatory reports list potential cardiac, neuropsychiatric and musculoskeletal adverse events (AEs). Clarifying their clinical relevance is essential. We systematically searched MEDLINE, Embase, CENTRAL and Google Scholar for randomized controlled trials (RCTs) and observational studies reporting predefined AEs. Eligible comparators included placebo, no treatment, liothyronine (LT3), usual-dose LT4 or LT4 monotherapy when LT4/T3 combination therapy was studied. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated. TSH values at baseline and post-treatment were recorded to contextualize AEs by thyroid status (euthyroid, suppressed or hypothyroid). Twelve studies (n = 1817) were included: seven RCTs, two crossover trials, two case-control studies and one quasi-experimental study. Cardiac AEs (tachycardia, palpitations, angina, atrial fibrillation), neuropsychiatric AEs (headache, tremor, insomnia, anxiety, depression) and musculoskeletal AEs (myalgia) were reported; however, most comparisons were statistically nonsignificant and clinically not meaningful, indicating that LT4 at replacement doses is generally safe. AEs primarily occurred when TSH was suppressed, whereas in euthyroid patients, blinded placebo-controlled trials showed no significant differences, confirming a very low risk of LT4-related side effects. Some subjective symptoms may reflect placebo or nocebo effects rather than true drug toxicity. LT4 at replacement doses is safe, and AEs are predominantly associated with suppressed TSH or subjective effects. Interpretation of AEs should always consider thyroid status, highlighting the importance of maintaining euthyroidism.