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15 recordsLinked to original sources
PubMed2026

Association between SGLT2 inhibitors and reporting of phimosis/paraphimosis: a comparative pharmacovigilance analysis of the WHO database.

PURPOSE: Recent data have discussed occurrence of phimosis with Sodium-glucose co-transporter-2 (SGLT2) inhibitors. However, the potential risk among the different SGLT2 inhibitors is unknown. METHODS: Using Individual Case Safety Reports (ICSRs) registered in the WHO pharmacovigilance database (01/01/2000-30/06/2025), comparisons between the different SGLT2 inhibitors and versus other drugs used in diabetes (DUD) were performed. Results are shown as Reporting Odds Ratios (ROR). RESULTS: Among 11 342 810 ICSRs, 227 were phimosis/paraphimosis with SGLT2 inhibitors, mainly between 45 and 64 years. The higher ROR value was found with empagliflozin followed by dapagliflozin and canagliflozin. ROR for SGLT2 inhibitors was higher that of all other DUD [34.72 (25.86-46.62)]. The reporting risk of phimosis/paraphimosis with SGLT2 inhibitors was also higher than that of each pharmacological class of DUD. CONCLUSION: The results suggest an association between SGLT2 inhibitors use and phimosis ICSRs. Empagliflozin had the higher reporting risk.

Humans↗
PubMed2025

Demographics, Overlap, and Latency of Severe Cutaneous Adverse Reactions in an FDA Database.

IMPORTANCE: Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS-TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and generalized bullous fixed drug eruption (GBFDE), are rare but life-threatening drug hypersensitivity syndromes. Due to their low incidence and diagnostic complexity, large-scale characterization of SCAR is challenging. OBJECTIVE: To characterize the demographics, causative agents, trends, latency, and phenotypic overlap of SCAR using a large-scale, sanitized pharmacovigilance dataset from FAERS (FDA Adverse Event Reporting System). DESIGN: Cross-sectional study of spontaneous adverse event reports. Cases were drawn from the U.S. Food and Drug Administration Adverse Event Reporting System (FDA FAERS) from January 2004 to December 2023 and subjected to sanitization and deduplication. Disproportionality analysis was used to characterize causative agents. Machine learning (random forest classifiers) was used to analyze predictors of drug latency and mortality. SETTING: Global pharmacovigilance reports submitted to FAERS. PARTICIPANTS: A total of 56,683 deduplicated SCAR reports were identified, representing 0.33% of reports during the study period. EXPOSURES: Suspected causative drugs, including both small molecules and biologics. MAIN OUTCOMES AND MEASURES: Main outcomes included the frequency and distribution of SCAR syndromes, reporting trends over time, latency from drug start to reaction onset, drug-specific disproportionality (PRR, ROR, IC), and co-reporting between SCAR types and related conditions. RESULTS: A total of 56,683 unique SCAR reports were identified, including SJS-TEN (28,871), DRESS (22,444), AGEP (6,183), and GBFDE (150). We identified 237 drugs with significant disproportionality for SCAR overall. Co-reporting between SCARs was significantly enriched (p < 1e-200), suggesting overlapping phenotypes. Latency varied by drug and syndrome (median: GBFDE 3 days, AGEP 4 days, SJS-TEN 12 days, DRESS 20 days). CONCLUSIONS AND RELEVANCE: SCAR syndromes display distinct but overlapping phenotypes, with variable latency and diverse causative agents. These findings, based on the largest SCAR dataset to date, highlight the need for improved classification frameworks and molecular validation. Large-scale pharmacovigilance, integrated with genomic and histopathologic data, will be critical to improving diagnosis, mechanistic understanding, and clinical management of SCAR.

Acute Generalized Exanthematous Pustulosis↗
PubMed2026

Morbidity and mortality from local anesthetics: localized and systemic toxicity.

PURPOSE OF THE REVIEW: Local anesthetics remain vital to modern medicine, yet their narrow therapeutic window continues to result in complications. This review synthesizes recent literature to define the current landscape of local anesthetic-associated adverse events. RECENT FINDINGS: Perioperative mortality attributable to local anesthetics persists despite sustained safety initiatives and professional society recommendations. Pharmacovigilance and case data identify lidocaine (oropharyngeal, topical, and via local infiltration) as the predominant contributor to adverse outcomes, including death. Local anesthetic systemic toxicity remains an issue, with a recent shift in epidemiology: an increasing proportion of toxic events originates from surgeon- and proceduralist-administered analgesia. Anesthesiologist-controlled methods also cause toxicity via catheter-based delivery and nerve blocks in highly vascular regions. Localized toxicity in the form of high neuraxial contributes to morbidity, with recent reviews reinforcing known risk factors; whereas localized neurotoxicity appears less troublesome when managed appropriately. SUMMARY: The cumulative evidence identifies shifts in the patterns of systemic and localized toxicities. Bupivacaine-based peripheral nerve blocks no longer represent the principal cause of complications because of the advent of ultrasound guidance and lipid emulsion therapy. In contrast, high neuraxial techniques persist as a cause of morbidity, accompanied by intravenous/oropharyngeal lidocaine, proceduralist-administered local infiltration analgesia, and catheter-based delivery.

Humans↗
PubMed2026

Maternal disease control and pregnancy outcomes with anti-CD20 therapy versus natalizumab in multiple sclerosis: a systematic review.

BACKGROUND: Management of multiple sclerosis (MS) during pregnancy requires balancing maternal disease control with fetal safety. Among high-efficacy disease-modifying therapies, anti-CD20 monoclonal antibodies and natalizumab are commonly used in women with active disease, yet their comparative effectiveness and safety during pregnancy remain incompletely defined. This systematic review evaluated maternal disease activity and pregnancy-related outcomes associated with anti-CD20 exposure compared with natalizumab in pregnant women with MS. METHODS: PubMed/MEDLINE, Web of Science, Scopus, and the Cochrane Library were searched from inception through February 2026. Eligible studies included pregnant women with MS exposed to anti-CD20 before or during pregnancy and reporting maternal disease activity compared to natalizumab. RESULTS: Seven studies were included, comprising six observational cohort studies and one pharmacovigilance disproportionality analysis. Across studies, anti-CD20 exposure was consistently associated with lower relapse activity than natalizumab, particularly in the postpartum period. Anti-CD20 strategies were also associated with markedly lower postpartum MRI activity and more favorable disability-related outcomes where reported. Meta-analysis of three studies demonstrated a significant reduction in postpartum MRI activity with anti-CD20 therapy compared with natalizumab (RR 0.06, 95% CI 0.02-0.24; I&#xb2; = 0%). No clear increase in major congenital anomalies was identified, although some data suggested higher odds of small for gestational age and maternal antibiotic use with anti-CD20 exposure. CONCLUSIONS: Anti-CD20 therapy was associated with lower maternal disease activity than natalizumab during pregnancy, especially for relapse prevention and postpartum MRI suppression. However, evidence regarding fetal and neonatal safety remains limited, warranting cautious individualized treatment decisions and further comparative research.

Humans↗
PubMed2026

GLP-1 Receptor Agonists and Musculoskeletal Outcomes: A Systematic Literature Review and Meta-Analysis.

INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for the treatment of type 2 diabetes and obesity, but their effects on musculoskeletal health remain completely misunderstood. OBJECTIVE: This systematic review/meta-analysis aims to synthesise clinical data on the effects of GLP-1 RAs on key relevant bone, muscle, and joint outcomes. METHODS: MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) (both via Ovid&#xae; platform) and Embase were searched from inception to March 2025 to identify relevant randomised controlled trials (RCTs) or real-world evidence (RWE) studies to be included. This bibliographic search was completed manually. A random-effect model meta-analysis was performed for any outcome reported in at least 2 studies. Subgroup analyses were performed on the type of GLP-1 RAs, type of comparator used and study design. Sensitivity analyses (i.e., leave-out sensitivity analyses and analyses restricted to the most adjusted effect estimate) were performed to test the robustness of the data. The strength of evidence was assessed using GRADE. This work has been performed in adherence with PRISMA statement. (PROSPERO Record ID: CRD420251024082). RESULTS: From 1148 potentially relevant references, 60 articles (46 RCTs, 13 RWE studies and 1 pharmacovigilance study, comprising 1,250,717 individuals) met our inclusion criteria. Different GLP-1 RAs were represented across the panel of studies, i.e., semaglutide, liraglutide, exenatide, dulaglutide, tirzepatide (dual agonist gastric inhibitory polypeptide [GIP]/GLP-1) and others. No effect on bone outcomes (i.e., bone mineral density [all sites] and fractures [all sites]) were observed when the meta-analytical models included the most adjusted effect size. Regarding muscle outcomes, a significant decrease of lean body mass/fat-free mass was consistently observed with GLP-1 RAs in the global model (k = 28, standardised mean difference [SMD] 0.52, 95% confidence interval [CI] -0.8; -0.23, I2 88%, p-value for heterogeneity <0.0001), which remained robust in all sensitivity analyses. Subgroup analyses showed that the effect was mainly driven by liraglutide and semaglutide, with a decrease in lean body mass/fat-free mass observed when GLP-1 RAs were compared with placebo. No publication bias was found. Regarding joint outcome, models revealed no significant change in The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, physical function and stiffness. CONCLUSIONS: This meta-analysis is the first to investigate the effects of GLP-1 RAs on a large panel of musculoskeletal health outcomes. While no significant effects were observed on bone- or joint-related outcomes, GLP-1 RAs were associated with reductions in lean body mass/fat-free mass, although the certainty of evidence was low and these changes appeared largely related to weight loss. Whether these changes translate into clinically meaningful impairments in muscle function or physical performance remains uncertain. Further studies in this field, including those looking at muscle function, strength or performance and using multivariate models considering confounding are needed to better reinforce the models and final findings.

Journal Article↗
PubMed2025

Association of genetically proxied cancer-targeted drugs with cardiovascular diseases through Mendelian randomization analysis.

BACKGROUND: Cancer-targeted therapies are progressively pivotal in oncological care. Observational studies underscore the emergence of cancer therapy-related cardiovascular toxicity (CTR-CVT), impacting patient outcomes. We aimed to investigate the causal relationship between different types of cancer-targeted therapies and cardiovascular disease (CVD) outcomes through a two-sample Mendelian randomization (MR) study. METHODS: This genome-wide association study was conducted using a two-sample Mendelian randomization framework. Genetic instruments for drug target gene expression were extracted from the eQTLGen consortium (31684 individuals, 37 cohorts). Genome-wide association study (GWAS) summary statistics for 19 cardiovascular diseases were derived from the FinnGen database. Primary analysis was carried out using the summary-data-based MR (SMR) method, with sensitivity analysis for validation. Colocalization analysis identifies shared causal variants between exposure eQTLs and CVD-associated single-nucleotide polymorphisms (SNPs). RESULTS: Among the 39 drug target genes, 8 were identified with detectable cis-eQTLs and were subsequently validated through positive control analysis for further investigation. In the SMR and sensitivity analyses, genetically proxied VEGFA inhibition showed significantly strong association with stroke (odds ratio [OR]&#x2009;=&#x2009;1.17, 95% confidence interval [CI]&#x2009;=&#x2009;1.09-1.26, p&#x2009;=&#x2009;1.33&#x2009;&#xd7;&#x2009;10-&#x2009;5). Additionally, the inhibition of FGFR1, FLT1, and MAP2K2 exhibited suggestive association with corresponding cardiovascular disease outcomes. Nevertheless, only VEGFA expression and stroke shared a causal variant (93.6%), whereas FGFR1, MAP2K2, and FLT1 did not share causal variants with corresponding cardiovascular diseases in the colocalization analysis. CONCLUSIONS: This genetic association study revealed evidence supporting the genetic association between the use of VEGFA inhibitors and increased stroke risk, highlighting the need for enhanced pharmacovigilance. These findings underscore the delicate balance between cardiovascular toxicity risk and the benefits of cancer-targeted therapy.

Humans↗
PubMed1979

[Systemic arterial spasms. Ergotamine tartrate].

The problem of the toxic effects of ergotism is raised by two cases of acute lower limb ischaemia observed in young patients. Although commonly encountered up to the 20th century, the problem is now reappearing sporadically from iatrogenic causes. The clinical features and treatment of ergotism are discussed. Prophylaxis is based on two main principles: the respect of contraindications, the most important being hypertension, coronary insufficiency, arteriopathies, acrocyanosis and thrombophlebitis, and less importantly, the association of tetracycline type antimicrobials, triacetyloleandomycin and phenothiazine; on the other hand, attention must also be paid to the instructions on its use, particularly with respect to the maximum dosage, 4 mg/day per os, 10 mg/week per os. The treatment should be given intermittently and not continuously. Full knowledge of the composition of composite drugs is required as many drugs are commercialised with their ergotamine content masked. This justifies, if there is still need, constant pharmacovigilance.

Adult↗
PubMed1979

[Direct determination of clonazepam (Rivotril) and 7-amino clonazepam in plasma by gas-chromatography (author's transl)].

A method is developed for direct gas-chromatographic determination of clonazepam (Rivotril) and its main metabolite, 7-amino clonazepam, in plasma, using desmethylflunitrazepam as internal standard. Following selective extraction, the benzodiazepines are analyzed by gas-chromatography, with a glass column filled with 3% OV17 on Gas Chrom Q and 63Ni electron capture detector. The procedure, which requires neither hydrolysis nor derivatisation, has a good selectivity. The sensitivity is 5 ng/ml of plasma for a valid quantitative determination. We have to improve this limit for fine pharmacokinetic studies, but the method is already available for therapeutic and pharmacovigilance controls. It is also suitable for diagnostic of eventual overdosing or poisoning, based on plasma or urine analysis.

Benzodiazepinones↗
PubMedDate not supplied

Determination of clonazepam ("Rivotril" or "Ro 5-4023") in plasma by gas chromatography using an internal standard.

A method has been developed for gas-chromatographic determination of clonazepam ("Rivotril" or "Ro 5-4023") in plasma, using methyl-clonazepam ("Ro 4082") as an internal standard. Following extraction of the benzodiazepines and hydrolysis, the benzophenones are analyzed by gas-chromatography, using a glass column filled with 3% OV 225 on Gas Chrom Q and a 63Ni electron-capture detector. The technique has good selectivity. The limit of sensitivity is less than 1 ng/ml of plasma. Using this method the plasma kinetics of clonazepam may be studied in man and the correlations between plasma levels and therapeutic activity investigated. It is also available for toxicological analysis, as well as pharmacovigilance purpose. The same internal standard and a similar method can also be used for the determination of flunitrazpem ("Rohypnol" or "Ro 5-4200") and its major metabolite (N-desmethyl-flunitrazepam) in plasma.

Administration, Oral↗
PubMed2026

Risk of venous thromboembolism after SARS-CoV-2 vaccination-Evidence from genome-wide association study and population-based observational study.

AIM: We aimed to investigate whether genetic variation is associated with venous thromboembolism after immunization with SARS-CoV-2 vaccines. METHODS: We conducted a genome-wide association study (GWAS) on cases of venous thromboembolism within 42&#x2009;days after SARS-CoV-2 vaccination, recruited from reports of adverse drug reactions sent to the Swedish Medical Products Agency. Two hundred one cases (43% women, 91% Swedish) were compared with 4891 Swedish population controls. Analyses were performed on two candidate variants in coagulation factor II (rs1799963) and coagulation factor V (rs6025), on 14 prespecified candidate genes and across the whole genome. To support the findings, we conducted an observational register study of the Swedish general population with/without a diagnosis of thrombophilia and the risks of venous thromboembolism after SARS-CoV-2 vaccination. RESULTS: In the GWAS, the main findings were that the candidate variants of coagulation factors II rs1799963 and V rs6025 were significantly associated with venous thromboembolism (odds ratio [OR] 2.4 [95% confidence interval (CI) 1.2-4.8], p&#x2009;=&#x2009;.015 and OR 1.8 [95% CI 1.3-2.6], p&#x2009;=&#x2009;.0022). No genetic marker passed the significance threshold in the candidate gene analysis or the full genome-wide analysis. In the register study, people with a thrombophilia diagnosis had a five-fold elevated risk of venous thromboembolism within 42&#x2009;days after vaccination, adjusted for potential confounders, OR 5.06 [95% CI 3.98-6.44]. CONCLUSION: Well-characterized genetic variants in the genes of coagulation factors II and V were associated with thromboembolism after SARS-CoV-2 immunization. Further research is recommended to elucidate their potential role in vaccine-related thromboembolic events.

Adult↗
PubMed2025

Comparative Safety of Janus Kinase Inhibitors vs Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: We conducted a retrospective cohort study comparing the safety of Janus kinase (JAK) inhibitors vs tumor necrosis factor-a (TNF) antagonists in patients with inflammatory bowel diseases (IBDs). METHODS: Using an administrative claims database, we identified patients with IBD who were new users of either JAK inhibitors or TNF antagonists between 2016 and 2023 and had insurance coverage for at least 1 year before and after treatment initiation. We compared the risk of infections (overall and serious infections requiring hospitalization), venous thromboembolism (VTE), and major adverse cardiovascular events (MACE) through stabilized inverse probability of treatment weighted Cox proportional hazards model accounting for disease characteristics, health care utilization, comorbidities, prior and concomitant medications, and competing risk of mortality. RESULTS: We included 856 patients treated with JAK inhibitors (age, 47 &#xb1; 17 years; 82% with ulcerative colitis [UC]) and 9422 patients treated with TNF antagonists (age, 45 &#xb1; 18 years; 44% with UC). JAK inhibitors were associated with higher risk of overall infections (incidence rate, 62.4 per 100 person-years [PY] vs 37.4 per 100 PY; hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.33-1.93), but not serious infections (4.9 vs 5.4; HR, 0.97; 95% CI, 0.66-1.44) compared with TNF antagonists. There was no difference in the risk of VTE (1.3 vs 1.2; HR, 0.66; 95% CI, 0.28-1.57) and MACE (0.4 vs 0.7; HR, 0.50; 95% CI, 0.19-1.30). Findings were largely stable on subgroup analyses based on type of IBD, type of JAK inhibitors, age, prior biologic exposure, concomitant use of corticosteroids, and baseline risk of adverse events. CONCLUSIONS: In an observational study of patients with IBD, JAK inhibitors were not associated with an increased risk of serious infections, VTE, or MACE compared with TNF antagonists, although the overall risk of infections was higher.

Humans↗
PubMed2026

HLA and non-HLA genetic analyses reveal suggestive variants associated with statin-induced liver injury.

BACKGROUND: Statins are widely prescribed for cardiovascular risk reduction and are generally well tolerated. However, they can cause drug-induced liver injury (DILI), and the genetic factors contributing to statin-DILI remain poorly understood. METHODS: HLA association and genome-wide association (GWAS) studies were conducted to identify genetic variants associated with statin-DILI. High-confidence cases (n=71) were identified from the Drug-Induced Liver Injury Network (DILIN) and compared with statin-exposed controls without liver injury (n=551) from the Indiana Biobank. Association testing was performed across ancestries and within ancestry, adjusting for age, sex, and three principal components of genotypes. Top variants were further evaluated in non-statin DILI cases and unexposed controls. In addition, we investigated the frequency of candidate variants among a comprehensive list of pharmacogenetic variants related to statins. RESULTS: HLA-DQA1*03:01 was significantly associated with increased risk of statin-DILI (OR=3.49, 95% CI 2.21-5.51, p-value=1.27&#xd7;10-7), with enrichment observed across multiple ancestry groups, particularly non-Hispanic Black and Hispanic individuals. From the GWAS, three loci showed suggestive associations (p-value <5&#xd7;10-06) with statin-DILI, including rs35197737 in RGS1 (OR=5.03, 95% CI 1.11-3.66, p=1.14&#xd7;10-7), rs75629598 in FRMD4A (OR=4.4, 95% CI=2.33-8.12, p=3.97&#xd7;10-6), and rs7658630 in the intergenic region on chromosome 4 (OR=4.86, 95% CI 2.66-8.85, p=2.68&#xd7;10-7). No pharmacogenetic variants revealed statistical significance. CONCLUSION: We identified HLA and non-HLA genetic variants associated with statin DILI. Future studies with larger sample sizes should confirm these observations.

Humans↗