British journal of clinical pharmacology最新文献

{"title":"Epigenetic modifications in drug-induced liver injury: A systematic review.","authors":"Romina Lorena de Los Santos-Fernández, Antonio Segovia-Zafra, Guillermo Paz-López, Gonzalo Matilla-Cabello, Hao Niu, Ismael Álvarez-Álvarez, Camilla Stephens, Andrés González-Jiménez, M Isabel Lucena, Raúl J Andrade, Inmaculada Medina-Cáliz","doi":"10.1002/bcp.70053","DOIUrl":"https://doi.org/10.1002/bcp.70053","url":null,"abstract":"<p><p>Genetic susceptibility has been identified in idiosyncratic drug-induced liver injury, a potentially severe adverse reaction towards drugs, herbal products and dietary supplements. However, its occurrence cannot be fully explained by the presence of genetic variants in specific genes, suggesting that other factors are involved. Drug-induced liver injury epigenetic signatures could help explain genetic regulatory mechanisms behind this disease and might provide disease biomarkers. This systematic review aims to analyse all available information on epigenetic risk association studies in drug-induced liver injury. The main inclusion criterion was population studies on idiosyncratic drug-induced liver injury with significant risk association analysis between drug-induced liver injury and an epigenetic regulation mechanism. Out of the 7 included articles, 6 focused on DNA methylation and 1 on long noncoding RNA. All of the studies were on antituberculosis drug-induced liver injury and came from Asia. CpG site methylation in the CYP2D6 (odds ratio: 9.19, 95% confidence interval: 3.26-25.89, P < .001) and NAT2 (odds ratio: 8.37, 95% confidence interval: 2.39-29.32, P = .001) promoters conferred the highest risk. Hypomethylation of LINE-1 and Alu transposable elements has potential as antituberculosis drug-induced liver injury biomarkers, showing an area under the curve value of 0.94. To conclude, the studies mainly focused on DNA methylation modifications associated with antituberculosis drug-induced liver injury, with all of them coming from Asia, where tuberculosis is a public health burden. Despite the lack of knowledge in this area, the evidence has shown that DNA methylation alterations in antituberculosis drug-induced liver injury could have potential as a new diagnostic and therapeutic target.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety of sulfamethoxazole-trimethoprim for the treatment of bacterial infection in outpatient settings: A systematic review and meta-analysis with active comparator disproportionality analysis.","authors":"Rebecca Preyra, Lujain Ez Eddin, Fatemeh Ahmadi, Atefeh Jafari, Flory T Muanda","doi":"10.1002/bcp.70051","DOIUrl":"https://doi.org/10.1002/bcp.70051","url":null,"abstract":"<p><strong>Aims: </strong>Sulfamethoxazole-trimethoprim (SMX-TMP) is a widely used antibiotic for treating bacterial infections, but its safety in adult outpatients remains understudied. This systematic review and meta-analysis evaluated the safety profile of SMX-TMP and identified critical research gaps. The pharmacovigilance study aimed to validate and extend findings from meta-analyses to better understand the real-world safety of SMX-TMP.</p><p><strong>Methods: </strong>We searched MEDLINE and Embase up to 12 August 2024, to identify studies comparing adverse drug events (ADEs) following SMX-TMP vs. other antibiotics in adult outpatients. Meta-analyses were performed where data allowed. A pharmacovigilance study using the Food and Drug Administration Adverse Event Reporting System was conducted to supplement our findings.</p><p><strong>Results: </strong>Our review, which included 43 studies, found SMX-TMP had a nearly 3-fold higher risk of rash compared to other antibiotics (pooled risk ratio 2.56, 95% confidence interval [1.69, 3.89], I² = 0%, n = 4458 participants, 24 randomized control trials). Pharmacovigilance data confirmed a higher frequencies of skin disorders and other ADEs compared to various comparator drugs. Compared to azithromycin, SMX-TMP was associated with a 5-fold increase in Stevens-Johnson syndrome, a 3-fold increase in toxic epidermal necrolysis, and a 10-fold increase in drug reaction with eosinophilia and systemic symptoms. Additionally, SMX-TMP showed a 10-fold increase in reports of pancytopenia, a 6-fold increase in neutropenia, a 4-fold increase in both thrombocytopenia and aplastic anaemia, a 56-fold increase in hyperkalaemia, and a 10-fold increase in hyponatraemia.</p><p><strong>Conclusion: </strong>Our meta-analyses and pharmacovigilance study suggested SMX-TMP was associated with increased risk of ADEs compared to other antibiotics including amoxicillin/clavulanate, azithromycin and nitrofurantoin. Further robust research is essential to confirm these safety signals and guide clinical practice.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Education about deprescribing for pre-licensed and licensed healthcare professionals: A scoping review.","authors":"Brian J Chow, Alexi M Yuzwenko, Liz Dennett, Cheryl A Sadowski","doi":"10.1002/bcp.70040","DOIUrl":"https://doi.org/10.1002/bcp.70040","url":null,"abstract":"<p><p>Deprescribing is complex because it involves patients' health, values, and preferences. The World Health Organization and Canadian Medication Appropriateness and Deprescribing Network have recommended that deprescribing be integrated into health curricula, prompting the need for further understanding about deprescribing education. The purpose of this research is to describe the literature regarding deprescribing education provided to healthcare professionals. We conducted a scoping review using the five-step model by Arksey and O'Malley with revisions from Levac et al. The databases searched included Medline, Scopus, Embase and ERIC. Papers were included if they were written in English and contained an educational intervention about deprescribing tailored toward physicians, pharmacists or nurses. White papers and conference abstracts were included. A total of 4853 abstracts were eligible for screening and 46 papers were included (25 full texts, 15 conference abstracts and 6 white papers). Thirty-three papers utilized group education for their intervention and of these, 20 involved interactive portions. Medicine was the most targeted profession, included in 29 papers. The most common outcomes were the number of medications deprescribed and an increase in learner knowledge and self-efficacy regarding deprescribing using self-assessment surveys or post-educational examinations. We found that there is evidence that educational interventions can increase participant knowledge regarding deprescribing and improve self-efficacy. To expand the education of deprescribing, future interventions should engage and utilize a variety of health professions and interventions could include real patients. Further research is required to determine the retention and application of deprescribing knowledge gained from single educational interventions.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"European Medicines Agency (EMA) commentary on EMA/CHMP Guideline on allergen products development for immunotherapy and allergy diagnosis in moderate to low-sized study populations.","authors":"Andreas Bonertz, Catherine Drai, Diana Hartenstein, Susanne Kaul, Milica Mitrevski, Jose M Zubeldia","doi":"10.1002/bcp.70048","DOIUrl":"https://doi.org/10.1002/bcp.70048","url":null,"abstract":"","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The tacrolimus concentration-to-dose ratio is associated with kidney function in heart transplant recipients.","authors":"Maaike R Schagen, Teun B Petersen, Boris C A Seijkens, Jasper J Brugts, Kadir Caliskan, Alina A Constantinescu, Brenda C M de Winter, Isabella Kardys, Dennis A Hesselink, Olivier Manintveld","doi":"10.1002/bcp.70041","DOIUrl":"https://doi.org/10.1002/bcp.70041","url":null,"abstract":"<p><strong>Aim: </strong>Heart transplantation (HT) is frequently complicated by chronic kidney disease, of which tacrolimus-related nephrotoxicity is an important cause. In kidney and liver transplant recipients, fast tacrolimus metabolism (defined as a low concentration-to-dose [C₀/D] ratio), negatively affects kidney function. Here, the association between the C₀/D ratio and kidney function in HT recipients was investigated.</p><p><strong>Methods: </strong>This was a retrospective study including 209 HT recipients who received an immediate-release tacrolimus formulation. The C₀/D ratio and kidney function (estimated glomerular filtration rate [eGFR]) were assessed at 3, 6, 12, 36 and 60 months post-HT. Patients were categorized as fast, intermediate and slow metabolisers, depending on their individual median C₀/D ratio as calculated over the follow-up period. A linear mixed-effects model analysis was performed, in which the time-varying eGFR was the dependent variable.</p><p><strong>Results: </strong>The distribution of the individual median C₀/D ratios ranged from 0.41 to 8.9 ng/mL/mg. At baseline, patients' kidney function was comparable. In the multivariable linear mixed-effects model, fast metabolisers (C₀/D ratio ≤1.53) had a significantly lower eGFR compared to slow metabolisers (C₀/D ratio >2.27) (-6.8 mL/min/1.73 m², 95% CI -11.2, -2.4, p = 0.002). This association was confirmed when utilizing the individual median C₀/D ratio as a continuous variable: for each 1 unit increase in the C₀/D ratio there was a 2.8 mL/min/1.73 m² (95% CI 1.0, 4.5) increase in eGFR (P = 0.002).</p><p><strong>Conclusion: </strong>Fast tacrolimus metabolism is significantly associated with worse kidney function in HT recipients in the first 5 years post-HT when compared to recipients with intermediate and slow tacrolimus metabolism.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Severe myelosuppression and alopecia after thiopurine initiation in a patient with NUDT15 deficiency.","authors":"Annie Siyu Wu, Lee Mozessohn, Richard B Kim, Jonathan S Zipursky","doi":"10.1002/bcp.70047","DOIUrl":"https://doi.org/10.1002/bcp.70047","url":null,"abstract":"<p><p>Thiopurines are a class of immunosuppressant and antineoplastic agents. They are widely used in the treatment of inflammatory bowel disease, haematological malignancies and autoimmune diseases, but can cause significant toxicity. Inherited gene mutations are now recognized as independent risk factors for severe adverse drug reactions to thiopurines even at 10-fold dose reductions. We present a case of thiopurine toxicity resulting in severe myelosuppression, hepatotoxicity and alopecia in an individual with homozygous *3/*3 loss-of-function alleles in the NUDT15 gene. Our case highlights important differences in gene mutation frequencies between races that can help guide pharmacogenomic testing.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the environmental impact of medicines in Italy using data from the Italian Medicines Agency.","authors":"Valentina Giunchi, Michele Fusaroli, Agnese Cangini, Filomena Fortinguerra, Simona Zito, Andrea Pierantozzi, Carlotta Lunghi, Elisabetta Poluzzi, Francesco Trotta","doi":"10.1002/bcp.70046","DOIUrl":"https://doi.org/10.1002/bcp.70046","url":null,"abstract":"<p><strong>Aim: </strong>This study builds on the environmental risk analysis presented in the 2022 National Report on Medicines Use in Italy by the Italian Medicines Agency and aims to assess the environmental risk posed by medicines in Italy and its regions.</p><p><strong>Methods: </strong>The analysis selected 90 medicines based on three criteria: high utilization, low predicted no effect concentration (PNEC), and inclusion or candidacy for the European Watch List. For each medicine, the environmental risk was computed as the ratio between the predicted environmental concentration (PEC) and the PNEC. The PEC was derived following the approach of the Swedish Association of Pharmaceutical Industries and Italian drug utilization data. The risk was classified high if the ratio was greater than 10 and moderate if greater than 1.</p><p><strong>Results: </strong>Overall, 13 medicines were identified as posing a high risk, including cardiovascular agents, antibiotics, analgesics, antidepressants and antiparasitic agents. The high risk was driven by either a very low PNEC (eg, estradiol and lacidipine) or high utilization (eg, amoxicillin, ibuprofen and diclofenac). Regional analysis showed higher risk due to high consumption for azithromycin and ofloxacin in central and southern Italy, and for levonorgestrel in northern Italy.</p><p><strong>Conclusion: </strong>This study points to the need for prioritizing targeted sampling in surface waters for medicines estimated at high risk. To prevent and mitigate the risk, a more conscious clinical practice coupled with appropriate waste management are required.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"General practitioner consultation for postmenopausal bleeding after COVID-19 vaccination-a self-controlled cohort study.","authors":"Rana Jajou, Eugène P van Puijenbroek, Renee Veldkamp, Jetty A Overbeek, Florence P A M van Hunsel, Agnes C Kant","doi":"10.1002/bcp.70045","DOIUrl":"https://doi.org/10.1002/bcp.70045","url":null,"abstract":"<p><strong>Aims: </strong>The incidence of postmenopausal bleeding (PMB) has been increasing over the past years. Little is known about the risk of PMB after COVID-19 vaccination. Our study aimed to investigate this based on routine general practitioner (GP) healthcare data from the Netherlands.</p><p><strong>Methods: </strong>A retrospective self-controlled cohort study was performed, which included women aged ≥50 years who received at least 1 COVID-19 vaccination in 2021 and were registered in the GP databases of Nivel (the Nivel Primary Care Database, Nivel-PCD) or PHARMO by 1 January 2021. GP consultations for PMB in the exposed period (28 days after each COVID-19 vaccination) were compared with the nonexposed period (all-time outside the exposed period). Incidence rate ratios (IRRs) were calculated using Poisson regression, adjusting for SARS-CoV-2 infection during the study follow-up period.</p><p><strong>Results: </strong>A total of 692 760 COVID-19 vaccinated women aged ≥50 years were included. No increased GP consultations for PMB was observed for all COVID-19 vaccines together, as well as when stratifying the results by vaccine type (mRNA vs. vector) and vaccine brand (Pfizer/BioNTech, Moderna, AstraZeneca, Johnson & Johnson). After the second Moderna dose an adjusted IRR of 1.47 (95% confidence interval: 0.93-2.32) was observed and after the third Pfizer/BioNTech dose an adjusted IRR of 1.33 (95% confidence interval: 0.92-1.93); however, these results were not statistically significant.</p><p><strong>Conclusion: </strong>No increased number of GP consultations for PMB in primary care was observed after COVID-19 vaccination in general, nor for any of the COVID-19 vaccine brands, vaccine doses or potential risk groups.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Janus kinase inhibitors for the treatment of lichen Sclerosus: A systematic review.","authors":"Chin-Hsuan Shen, Tzu-Yu Wang, Ching-Chi Chi","doi":"10.1002/bcp.70042","DOIUrl":"https://doi.org/10.1002/bcp.70042","url":null,"abstract":"<p><strong>Aim: </strong>The current treatment options for lichen sclerosus (LS) remain limited. We aimed to systematically assess the evidence on the effects of Janus kinase (JAK) inhibitors in treating LS.</p><p><strong>Methods: </strong>We performed a systematic review and searched PubMed, Cochrane, Embase and the Airiti Library from inception to 16 January 2025. As we expected a lack of relevant randomized trials, we also included relevant single-arm trials, case reports and case series. The risk of bias of included case reports and case series was evaluated using Murad's tool, while single-arm trials were assessed using Alsinbili's tool.</p><p><strong>Results: </strong>This systematic review included a total of nine studies, with one single-arm trial and three case reports on baricitinib, one single-arm trial and one case report on abrocitinib, two case reports on topical ruxolitinib and one case report on tofacitinib. A total of 43 LS patients (31 females and 12 males) were included, with four presenting with extragenital LS and one with bullous type affecting both genital and extragenital areas. The overall risk of bias of the included studies was low to unclear. Improvements in clinical symptoms, lesion characteristics and quality of life were observed for both genital and extragenital LS, with adverse events being tolerable.</p><p><strong>Conclusion: </strong>Single-arm trials with baricitinib and abrocitinib provide the highest current evidence for JAK inhibitors in treating genital LS. While evidence for extragenital LS remains limited to case reports, baricitinib shows therapeutic potential. These findings support baricitinib and abrocitinib as potential candidates for future randomized controlled trials.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacology and safety of TAS5315, a Bruton tyrosine kinase inhibitor, in healthy volunteers: First-in-human, randomized, ascending-dose studies.","authors":"Yuji Kumagai, Tomoe Fujita, Mika Maeda, Akiko Yamamoto, Hideki Amano","doi":"10.1002/bcp.70039","DOIUrl":"https://doi.org/10.1002/bcp.70039","url":null,"abstract":"<p><strong>Aim: </strong>TAS5315 is a Bruton tyrosine kinase (Btk) inhibitor in development for autoimmune and allergic diseases, including rheumatoid arthritis (RA) and chronic spontaneous urticaria (CSU). Two clinical studies evaluated the pharmacology and safety of single and multiple oral doses of TAS5315.</p><p><strong>Methods: </strong>Two phase 1 studies (single ascending-dose [SAD] and multiple ascending-dose [MAD]) assessed the pharmacokinetics (including effect of food), pharmacodynamics (Btk occupancy, inhibition of basophil activation) and safety of TAS5315 (up to 8 mg/day) in healthy males.</p><p><strong>Results: </strong>TAS5315 showed linear pharmacokinetics over a 0.01-8 mg dose range; maximum plasma concentration and area under the plasma concentration-time curve were reduced by ~40% by food. TAS5315 had dose dependent effects on Btk and basophil activation. In the SAD study, doses ≥2 mg resulted in mean Btk occupancy of almost 100% at 2 and 6 h, and >80% at 24 h, post-administration. TAS5315 1-8 mg/day inhibited basophil activation (mean change from baseline -55% to -89%). TAS5315 was generally tolerable. Although it dose-dependently reduced platelet aggregation (over 2-8 mg in both studies) and prolonged bleeding time (1-8 mg in the MAD study), no relationship between these effects and clinical symptoms was observed. All adverse drug reactions were mild and resolved without treatment; no noteworthy safety concerns were observed in either study.</p><p><strong>Conclusion: </strong>These data indicate TAS5315 has potential as a novel therapeutic for immunological diseases associated with aberrant Btk signalling, including RA and CSU. Further evaluation of TAS5315 is warranted.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}