European Journal of Clinical Pharmacology最新文献

Purpose: Systemic sclerosis (SSc) is a chronic connective tissue disorder characterized by skin thickening with vascular and visceral involvements. The efficacy of cyclophosphamide for SSc-related skin fibrosis remains controversial. The aim of this study was to evaluate the effectiveness of cyclophosphamide for skin fibrosis in SSc.

Methods: PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov databases were systematically searched for all published clinical trials on the treatment of SSc with cyclophosphamide until January 15, 2025.The outcome of interest was the extent of skin fibrosis, measured by the modified Rodnan skin score (mRSS). Two authors independently screened studies, extracted data, and evaluated the risk of bias. Meta-analysis was conducted with Stata/SE software.

Results: A total of 20 articles involving 869 patients met the inclusion criteria. Cyclophosphamide reduced mRSS score by 2.30 (95% CI 0.72-3.88), 4.53 (95% CI 2.91-6.14), 6.72 (95% CI 2.74-10.70), 5.70 (95% CI 4.04-7.36), and 4.60 (95% CI 3.18-6.02) at 6-, 12-, 18-, 24- and 36-month, respectively. The estimated effect size, obtained by pooling mRSS from all studies at the follow-up endpoint, decreased by 4.71 (95% CI 2.72-6.70). In diffuse cutaneous SSc (dcSSc) subtype, the pooled mRSS decreased by 3.02 (95% CI 1.46-4.58), 6.45 (95% CI 5.02-7.87), 8.03 (95% CI 5.26-10.80), and 6.34 (95% CI 6.00-6.68) at 6-, 12-, 18-, and 24-month, respectively. And the overall reduction in mRSS at the end of follow-up in dcSSc was 7.30 (95% CI 5.61-8.99) across 11 studies. Significant heterogeneity was observed among these studies, and subgroup analysis revealed that study size and disease subtype partially explained the heterogeneity. Sensitivity analysis indicated good study stability.

Conclusion: Cyclophosphamide effectively reduced mRSS scores in SSc, particularly in dcSSc. While skin thickness improvement diminishes after 24 months, it remains a viable option for patients with worsening skin fibrosis.

Trial registration: PROSPERO registration number: CRD42024502283. Registered on 25 January 2024.

Purpose: In advanced cancer patients the CYP3A4-mediated clearance of drugs is dependent on the severity of inflammation. In a study in patients with advanced cancer (n = 44) with solid tumors, prior to cancer treatment, high inter-patient variability was observed in the plasma pharmacokinetic (PK) parameters of the CYP3A4 substrate midazolam. The neutrophil-to-lymphocyte ratio (NLR) was used to categorize the degree of inflammation of each patient and in turn to correlate increases in NLR to decreases in CYP3A4 expression.

Methods: Patients with NLR ≥ 5 were categorized as having high inflammation, and patients with NLR < 5 as having low-to-moderate inflammation. A physiologically-based PK (PBPK) model of midazolam PK and a top-down approach was used to determine the reductions in CYP3A4 abundance in the liver and gut wall needed to match the PK parameters of midazolam in the NLR ≥ 5 and NLR < 5 groups of patients.

Results: The midazolam mean CL/F was 33 L/h in the NLR < 5 group, and midazolam CL/F was 20 L/h in the NLR ≥ 5 group. To match the PK of midazolam in the NLR < 5 group, the CYP3A4 expression was reduced 40% in both the liver and the gut. In the NLR ≥ 5 group, CYP3A4 expression was reduced approximately 40% in the liver and at least 90% in the gut to produce the best fit.

Conclusion: Overall, these results support that NLR may be used as an inflammatory marker that broadly correlates to inflammation-driven changes in CYP3A4 activity.

Background: The efficacy and safety of pembrolizumab in treating advanced hepatocellular carcinoma (HCC) are inconsistent across studies. This study sheds light on the efficacy and safety of pembrolizumab in advanced HCC patients.

Methods: Several databases were comprehensively searched up to January 13, 2025, to identify studies assessing pembrolizumab for advanced HCC. Outcome indicators included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), rash, adverse events (AEs), and severe adverse events (SAEs). Pooled effects were estimated through hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs). R 4.4.1. was employed for statistical analyses.

Results: Twenty-two studies involving 2964 patients were encompassed. Meta-analysis indicated that pembrolizumab demonstrated an ORR of 28% in single-arm analyses. Pembrolizumab significantly improved ORR in comparison to placebo (OR = 2.57, 95% CI: 1.32-5.03) but showed no significant advantage over nivolumab. Pembrolizumab markedly enhanced PFS (HR = 0.76, 95% CI: 0.69-0.85) and OS (HR = 0.78, 95% CI: 0.70-0.88) compared to placebo, but no significant differences were observed when compared to nivolumab. Pembrolizumab significantly raised the risk of rash in comparison to placebo (OR = 2.27, 95% CI: 1.55-3.31) but showed no significant difference versus nivolumab. The pembrolizumab group showed a higher incidence of AEs (OR = 1.94, 95% CI: 1.42-2.64) and SAEs (OR = 2.10, 95% CI: 1.04-4.25) than the placebo group, with no significant difference between pembrolizumab and nivolumab.

Conclusions: This study proves that pembrolizumab may have promising therapeutic effects in patients with advanced HCC, although no clear advantage over nivolumab was observed. The occurrence of AEs warrants attention in clinical practice.

Purpose: Opioid medications remain a common treatment for acute pain in hospitalized patients. This study aims to identify factors contributing to opioid overdose in the inpatient population, addressing the gap in data on which patients are at higher risk for opioid-related adverse events in the hospital setting.

Methods: A retrospective chart review of inpatients receiving at least one opioid medication was performed at a large academic medical center from January 1, 2022, through December 31, 2022. Patients who received naloxone were designated as the overdose group, while those who received opioids without naloxone served as the control group. Suspected risk factors were included in a multivariable direct logistic regression model to identify patients at higher risk for opioid-related adverse events.

Results: The review included 11,050 admitted patients who received an inpatient opioid, of whom 130 received naloxone. Analysis revealed that patients with creatinine clearance (CrCl) < 60 mL/min, co-administered benzodiazepine, body mass index (BMI) > 30 kg/m², underlying pulmonary disease, obstructive sleep apnea, chronic opioid use, and/or substance use disorder were at higher risk for requiring naloxone. These factors significantly influenced the likelihood and magnitude of in-hospital opioid overdose.

Conclusion: These validated risk factors should be considered when administering opioid analgesics in the inpatient setting. Consideration should be given to reducing the dose and/or frequency of opioids in addition to the use of alternative analgesic modalities for patients with these risk factors to mitigate the risk of opioid-related adverse events. Incorporating these considerations into clinical practice can enhance patient safety and outcomes.

Every drug development is a complex and long journey. Clinical pharmacology is an essential discipline in modern drug development. With its applications, computational modelling, and simulation techniques, it can significantly contribute to the efficiency in drug development today. In this perspective, we highlight why pharmacokinetics and pharmacodynamics are important, what developers need to consider in their clinical development programme, how modelling influences the development process, and discuss recent trends such as artificial intelligence and machine learning that have the potential to reshape future drug development.

Purpose: We aim to use a network meta-analysis to evaluate the efficacy and safety of antiseizure medications and provide a theoretical basis for rational drug use for children and adolescents in adjunctive treatment.

Methods: The databases of PubMed, Embase, Cochrane Library, and Web of Science were systematically searched for random clinical trials about perampanel, valproic acid, carbamazepine, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, topiramate, zonisamide, brivaracetam, cenobamate, eslicarbazepine acetate, and pregabalin from their inception until December 10, 2023. The included studies' risk of bias was evaluated by the Cochrane Collaboration's tool (RoB2). The network meta-analysis was performed using Stata 15 on the included studies.

Results: Seventeen studies were identified and of these 19 randomized controlled trials evaluating 9 different antiepileptic drugs were included. In total, 2959 patients were covered in the analysis of the outcomes. For efficacy, lacosamide (OR = 1.91, 95%CI 1.14-3.20), lamotrigine (OR = 3.82, 95%CI 1.86-7.83), levetiracetam (OR = 3.01, 95%CI 1.89-4.80), oxcarbazepine (OR = 2.75, 95%CI 1.52-4.96), perampanel (OR = 2.05, 95%CI 1.15-3.65), and zonisamide (OR = 2.27, 95%CI 1.21-4.24) were more effective than placebo in the 50% responder rate. Lamotrigine ranked first on the cumulative probability curve, followed by levetiracetam. Eslicarbazepine acetate (OR = 6.44, 95%CI 1.43-29.00) and levetiracetam (OR = 5.75, 95%CI 2.45-13.50) were better than placebo in seizure freedom. For safety, topiramate (OR = 4.11, 95%CI 1.43-11.76) and oxcarbazepine (OR = 2.72, 1.28-5.76) were more likely to cause adverse effects in children or adolescents compared to placebo.

Conclusion: In terms of efficacy and safety, lamotrigine and levetiracetam may be selected preferentially for the adjunctive treatment of focal epilepsy in children and adolescents. However, owing to the limited random clinical trials, our results need to be verified by further studies.

Purpose: The clinical benefit of up-titration of metoprolol to a guideline-recommended target dose after myocardial infarction (MI) is unknown. Our aim was to investigate whether variation in metoprolol exposure determined by cytochrome p450 enzyme 2D6 (CYP2D6) influences the occurrence of major adverse cardiovascular events (MACE) and cardiovascular death (CV death) among patients treated with metoprolol after MI.

Method: This Mendelian randomization study was performed using individual-level data from 1554 patients treated with metoprolol after an acute MI. CYPD26 genotype was applied as a binary genetic instrument assigning patients into two metoprolol exposure groups: CYP2D6 normal metabolizers (NM) (low exposure) and CYP2D6 intermediate and poor metabolizers (IM + PM) (high exposure). The null hypothesis of no association between the CYP2D6 metabolizer subgroup and MACE or CV death was tested using the Cox proportional hazards model. All-cause mortality and individual components of MACE were included as secondary outcomes.

Results: In total, 879 (56.6%) patients were classified as NM and 675 (43.4%) as IM + PM. During the 3-year follow-up, 56 patients (6.4%) in the NM group had an outcome of MACE, and 24 (2.7%) patients died from CV disease. Corresponding frequency in the IM + PM group was 47 (7.0%) and 22 (3.3%), respectively. There was no association between genotype and MACE [unadjusted HR 1.12 (CI 0.76, 1.65)] or CV death [unadjusted HR 1.20 (CI 0.67, 2.14)], or between the CYP2D6 group and any of the secondary outcomes.

Conclusion: In patients treated with metoprolol after MI, variation in metoprolol exposure determined by CYP2D6 did not impact the occurrence of cardiovascular events.

Background: The renin-angiotensin-aldosterone system (RAAS) is a vital endocrine system that plays a crucial role in maintaining homeostasis. However, excessive activation of the RAAS can contribute to the pathogenesis of certain diseases. Prolonged hyperglycemia leads to overactivation of the RAAS through the production of inflammatory factors and other mechanisms, ultimately resulting in diabetic complications. Oral antidiabetic agents are the cornerstone of diabetes treatment, and the effects of oral antidiabetic agents on the RAAS have not been clearly summarized.

Objective: To review the effects of various types of oral antidiabetic agents on the components of the RAAS.

Results: Sodium-glucose cotransporter inhibitors (SGLT2i) inhibit glucose and sodium reabsorption, which increases the flow of Na⁺ to the macula densa, thereby inhibiting tubuloglomerular feedback (TGF) and subsequently decreasing renin production. GLP-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) can directly inhibit angiotensin II (Ang II) or indirectly suppress it by modulating TGF. These agents also affect Ang II type 1 receptors (AT1R) and Ang II type 2 receptors (AT2R) to mitigate Ang II and can indirectly interact with Ang II through Na⁺/H⁺ exchanger isotope 3 (NHE3). Thiazolidinediones (TZDs), as PPAR-γ agonists, can enhance the expression of the renin gene, inhibit the production of angiotensin-converting enzyme (ACE), regulate the levels of AT1R and AT2R, and decrease aldosterone production. Metformin also inhibits the production of renin and aldosterone in patients with polycystic ovary syndrome (PCOS).

Conclusions: These oral agents, which exhibit diverse effects on the components of the RAAS, modulate the activity of these components to exert antihypertensive, anti-inflammatory, cardioprotective, and renoprotective effects, thereby offering several beneficial outcomes in the management of diabetes.

Background: Migraine is a major cause of population ill health, with an estimated global prevalence of approximately 14-15%. However, given the limited research on the associations between specific migraine medications and adverse cerebrovascular events, this study aimed to investigate these relationships and their impact on cerebrovascular risk.

Methods: This study utilized data from the global pharmacovigilance database, which covers 170 countries from 1968 to 2024. We examined the reporting frequency of adverse cerebrovascular events with 10 migraine medications, with analysis stratified by sex and age. The information component (IC) was calculated using a Bayesian method, while the reporting odds ratio (ROR) was calculated using a frequentist approach to compare reported versus non-reported outcomes.

Results: Among the more than 140 million adverse drug events, 6,080 cases were identified as adverse cerebrovascular events associated with migraine-specific medications. Significant associations with cerebrovascular diseases were observed in both males (ROR, 1.24 [95% CI, 1.19-1.30]; IC 0.31 [IC_0.25, 0.24]) and females (1.73 [1.67-1.79]; 0.78 [0.72]), with most age groups showing significance, except for those 75 years and older. Among the 10 medication categories, 6 categories were associated with adverse cerebrovascular diseases: CGRP antagonists (ROR, 1.22 [95% CI, 1.12-1.33]; IC, 0.28 [IC_0.25,0.14]), ergot alkaloids (3.66 [2.97-4.51]; 1.84 [1.49]), 5-HT₁ receptor agonists (3.33 [2.97-4.51]; 1.72 [1.59]), beta-blockers (2.03 [1.94-2.13]; 1.02 [0.94]), calcium channel blockers (1.46 [1.30-1.64]; 0.54 [0.34]), and clonidine (2.18 [2.04-2.33]; 1.11 [1.00]).

Conclusion: This study found that commonly used migraine medications are significantly associated with an increased risk of cerebrovascular diseases, highlighting the need for careful patient evaluation and selection.