BMC Pharmacol Toxicol. 2025 Feb 7;26(1):27. doi: 10.1186/s40360-025-00867-6.

ABSTRACT

OBJECTIVE: By using the FAERS database, we aim to identify and assess risk signals of adverse drug events (ADEs) potentially causing pericardial effusion, to inform clinical drug management and promote rational drug use.

METHODS: We obtained reports of pericardial effusion events from the FAERS database spanning from the first quarter of 2004 to the second quarter of 2024, and identified the top 50 drugs ranked by report frequency or signal strength. Four algorithms, namely the reported odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS), were employed for signal detection of these drugs. Furthermore, for drugs with positive signals, we conducted sensitivity analyses and employed the Weibull shape parameter test to perform a time to onset (TTO) analysis.

RESULTS: We identified 20,057 ADEs related to pericardial effusion, involving 19,693 patients for analysis. The patient population comprised 10,187 males (51.7%) and 7,939 females (40.3%). Adults aged 18-65 years were the largest group (7,798 cases, 39.6%). Regarding clinical outcomes, 9,924 patients (50.4%) experienced hospitalization, and 2,770 cases (14.1%) resulted in death. Ranked by the ROR risk signal strength, the top 3 drugs were hydralazine [ROR (95% CI): 27.11 (22.28-33)], dasatinib [ROR (95% CI): 15.62 (14.07-17.33)], and mesalazine [ROR (95% CI): 8.99 (6.84-11.8)]. We conducted a TTO analysis for the 26 drugs with positive signals. The median TTO and interquartile range (IQR) for the top 3 drugs causing the earliest pericardial effusion were: cytarabine 14 (7.5,38), selexipag 14.5 (4.25, 157.75), dabigatran etexilate 29 (9, 229). Most drugs exhibited an early failure type.

CONCLUSION: This study systematically compiled a list of drugs with potential risks of causing pericardial effusion. There is a significant association between pericardial effusion and the use of hydralazine, dasatinib, and mesalazine. Moreover, pericardial effusion is more common in patient groups receiving treatments with antineoplastic and immunomodulating agents.

PMID:39920868 | DOI:10.1186/s40360-025-00867-6

BMC Med. 2025 Feb 7;23(1):76. doi: 10.1186/s12916-025-03919-0.

ABSTRACT

BACKGROUND: Fluoroquinolone antibiotics have a high potential for serious adverse drug reactions, but real-world evidence in European patient cohorts is lacking. Therefore, we aim to examine the association between fluoroquinolone exposure and potentially life-threatening adverse events stratified by age and gender in Germany.

METHODS: We conducted an administrative cohort study using the active comparator new user design with a risk window up to 365 days between January 2013 and December 2019. Population-based longitudinal data from one of the largest German statutory health insurances were used. Episodes of newly dispensed fluoroquinolones (ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, norfloxacin, and enoxacin) were compared to other antibiotics (amoxicillin, amoxicillin clavulanic acid, azithromycin, cefuroxime, cephalexin, clindamycin, sulfamethoxazole-trimethoprim, and doxycycline). Endpoints were defined by incident diagnoses of aortic aneurysm/dissection, cardiac arrhythmia, hepatotoxicity, and all-cause mortality. Adjusted hazard ratios were estimated from piece-wise exponential additive mixed models with smooth non-linear effects for person-time and age and adjusted for comorbidities, year and quarter at index.

RESULTS: The cohorts comprised 15,139,840; 11,760,159; 11,027,175; and 15,305,757 antibiotic episodes. Patients during fluoroquinolone episodes were older (59 versus 51 years) and more often female (58% versus 54%). We counted 46,502; 446,727; 19,125; and 474,411 incident endpoints. Relative risk for all-cause mortality and hepatotoxicity was high for < 40-year- and 40-69-year-old females (aHR = 1.77, 95% CI 1.55-2.03 and aHR = 1.42, 95% CI 1.32-1.53), respectively. For aortic aneurysm/dissection a nominally increased relative risk for < 40-year-old females was found (aHR = 1.42, 95% CI 0.96-2.11), although 95% CI indicates that a small relative risk reduction is also supported by the data. Relative risk for cardiac arrhythmia was increased for men aged < 40 years (aHR = 1.14, 95% CI 1.08-1.20). High relative risks for each endpoint were also identified depending on choice of active comparator, and risks increased with higher defined daily doses and shorter follow-up.

CONCLUSIONS: This study contributes real-world evidence to endpoint-specific differences of risks in patient subgroups which need to be considered to improve fluoroquinolone drug safety.

PMID:39920723 | DOI:10.1186/s12916-025-03919-0

BMC Cancer. 2025 Feb 7;25(1):216. doi: 10.1186/s12885-025-13614-1.

ABSTRACT

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy is increasingly used to treat non-small cell lung cancer (NSCLC). However, little attention has been given to the comparative analysis of adverse events (AEs) associated with different ICIs.

METHODS: Disproportionality analysis and Bayesian confidence propagation neural network (BCPNN) were utilized to identify pharmacovigilance signals from the FDA Adverse Event Reporting System (FAERS). We compared the sex distribution of patients, risk of suffering more severe adverse reactions, and risk of hospitalization associated with different ICIs, using pairwise matrices that displayed odds ratio (OR) and their 95% confidence interval (CI). And we also compared the outcomes of reactions by using ordinal logistic regression.

RESULTS: We analyzed 13,580 reports of AEs associated with five ICIs, namely, durvalumab, pembrolizumab, ipilimumab, atezolizumab, and nivolumab from January 2013 to October 2022. Significant differences were observed in sex distribution of patients, risk of suffering more severe adverse reactions, risk of hospitalization, and the outcomes of reactions. In terms of respiratory AEs, pembrolizumab exhibited a higher risk compared to durvalumab (OR = 2.48, 95% CI: 1.72-3.59), atezolizumab (OR = 1.84, 95% CI: 1.07-3.16), and nivolumab (OR = 4.21, 95% CI: 1.72-10.28), while ipilimumab exhibited a higher risk compared to durvalumab (OR = 2.76, 95% CI: 1.14-6.65) and nivolumab (OR = 4.67, 95% CI: 1.14-15.51). In terms of endocrine and metabolic AEs, durvalumab (OR = 7.80, 95% CI: 1.33-45.90) and nivolumab (OR = 5.20, 95% CI: 1.17-23.03) exhibited a higher risk compared to ipilimumab.

CONCLUSION: Each ICI has distinctive features of pharmacovigilance signals. It is essential to acknowledge the AEs associated with the relevant system when clinicians administer ICIs.

PMID:39920614 | DOI:10.1186/s12885-025-13614-1

PLOS Glob Public Health. 2025 Feb 7;5(2):e0004110. doi: 10.1371/journal.pgph.0004110. eCollection 2025.

ABSTRACT

Drug-resistant tuberculosis remains a persistent public health threat. Maximizing successful treatment completion is a global health priority and a focus of the End TB strategy. Despite the implementation of programmatic management for drug-resistant tuberculosis in Ethiopia, there is limited understanding of the barriers related to successful treatment completion among Ethiopian patients. A qualitative study that is explorative, descriptive and contextual in nature was conducted to explore and describe the views and lived experiences of previously treated drug-resistant tuberculosis patients to gain an in-depth understanding of barriers to the successful completion of drug-resistant tuberculosis treatment. Six focus group discussion sessions with 42 purposively selected drug-resistant tuberculosis patients with previous treatment history and on retreatment regimens were conducted. The seven prominent themes revealed were: drug-related challenges encompassing adverse events and the lengthy treatment duration; clinical hurdles such as delayed consultation following prolonged illness, diagnostic delays, and suboptimal dosages; psycho-emotional difficulties including emotional trauma and facing stigma from both the community and healthcare professionals; socio-economic constraints; service-related issues such as interruptions in monitoring tests, inadequate follow-up, and accessibility barriers; patient-related factors such as a false sense of recovery and reverting to previously quit habits; and provider-related issues such as lack of responsiveness and ineffective communication. Addressing these factors demands policy-level decisions and programmatic guidance at the national level based on best practices, as well as good programmatic implementation from actors through regional and health facility-level structures.

PMID:39919126 | DOI:10.1371/journal.pgph.0004110

Drug Saf. 2025 Feb 7. doi: 10.1007/s40264-025-01515-y. Online ahead of print.

ABSTRACT

BACKGROUND: Safety signals for potential drug-induced adverse events (AEs) typically emerge from multiple data sources, primarily spontaneous reporting systems, despite known limitations. Increasingly, real-world data from sources such as electronic health records (EHRs) and administrative databases are leveraged for signal detection. Although network analysis has shown promise in mapping relationships between clinical attributes for signal detection in spontaneous reporting system databases, its application in real-world data from EHRs and administrative databases remains limited.

OBJECTIVE: This study aimed to evaluate the performance of network analysis in detecting safety signals within Italian administrative databases, using drug-induced acute myocardial infarction (AMI) as a proof of concept.

METHODS: We employed a case-crossover design to explore the association between drug exposure and AMI using the Healthcare Administrative Database of Mantova, Italy, from 2014 to 2018. Patients with their first AMI hospitalization were identified after a 365-day washout period to exclude prior hospitalizations. We constructed a network to analyse the relationships between prescribed drugs and diagnoses, represented as nodes, with undirected edges illustrating their interactions. For each patient with AMI, we identified all diagnoses and drugs recorded or redeemed within 365 days of the first AMI episode and generated various drug-diagnosis, drug-drug, and diagnosis-diagnosis pairs. We calculated the frequency of these pairs, and three types of edge weights quantified the strength of connections. We identified outlier drug-AMI pairs using a predictive score (F) based on frequency (C) and full edge weights (WF), with validation for known AMI associations. We prioritized signals using the F score, C of AMI, and WF, analysed through k-means clustering to identify patterns in the data.

RESULTS: From 2014 to 2018, a total of 3918 patients had an AMI, with 4686 AMI diagnoses. Of those, 2866 had prescriptions in the previous year, totalling 498,591 prescriptions. A network analysis identified 2968 unique nodes, revealing 529,935 diagnosis-diagnosis connections, 235,380 drug-diagnosis connections, and 102,831 drug-drug connections. The median number of connections (C) was 404 (Q1-Q3: 194-671) for drug nodes and 380 (Q1-Q3: 216-664) for diagnosis nodes. The median WF was 11.8 (Q1-Q3: 9-14), and the median F score across pairs was 0.1 (Q1-Q3: 0.1-0.3). A total of 249 potential safety signals were detected, with 63.4% aligning with known AEs. Among the remaining signals, 80 were prioritized, and five emerged as the highest priority: terazosin, tamsulosin, allopurinol, esomeprazole, and omeprazole.

CONCLUSIONS: Overall, our novel method demonstrates that network analysis is a valuable tool for signal detection and prioritization in drug-induced AEs based on EHRs and administrative databases.

PMID:39918677 | DOI:10.1007/s40264-025-01515-y

Front Pharmacol. 2025 Jan 23;16:1545300. doi: 10.3389/fphar.2025.1545300. eCollection 2025.

ABSTRACT

BACKGROUND: Breast cancer remains a leading cause of mortality among women worldwide, with existing therapeutic options often accompanied by significant side effects and a persistent risk of disease recurrence. This highlights the need for novel drug candidates with new mechanisms of action by targeting alternative signaling pathways. While hERG channel is notoriously regarded as an off-target due to drug-induced cardiotoxicity, its therapeutic potential as a drug target remains largely unexplored.

METHODS: This study investigated the role of hERG in breast cancer progression and its impact on patient survival. The anti-proliferative, anti-migratory, anti-invasive and pro-apoptotic effects of hERG activators were evaluated using the Cell Counting Kit-8, wound healing assay, transwell assay and cell apoptosis assay, respectively. Western blotting, Ca2+ imaging and immunofluorescence assays were employed to study their antitumor mechanisms of actions.

RESULTS: We identified two novel hERG activators, SDUY429 and SDUY436, which effectively inhibited the proliferation and migration of MDA-MB-231 and MCF-7 cells. In addition, SDUY436 demonstrated significant anti-invasive and pro-apoptotic effects in MDA-MB-231 cells. Mechanistically, the anti-proliferative activity of hERG activators were mediated through calcineurin activation via enhanced calcium ion influx, which facilitated the nuclear translocation of nuclear factor of activated T cells (NFAT) and upregulated p21Waf/Cip expression. Furthermore, both SDUY429 and SDUY436 remarkably suppressed the migration and invasion of MDA-MB-231 cells by downregulating the protein kinase B (AKT)/glycogen synthase kinase-3 beta (GSK3β)/β-catenin signaling pathway. The observed reduction in phospho-AKT-Ser473 (pAKTS473) expression resulted in the decreased levels of phospho-GSK3β-Ser9 (pGSK3βS9), thereby limiting the nuclear localization of β-catenin, which led to the inhibition of cell migration and invasion. Notably, combining SDUY429 or SDUY436 with the AKT inhibitor MK-2206 produced synergistic anti-proliferative effects.

CONCLUSION: These findings suggest that hERG activators hold promise as new potential therapeutic agents for the treatment of breast cancer, paving the way for future investigations into their clinical applications.

PMID:39917621 | PMC:PMC11799564 | DOI:10.3389/fphar.2025.1545300

Front Immunol. 2025 Jan 23;16:1515730. doi: 10.3389/fimmu.2025.1515730. eCollection 2025.

ABSTRACT

BACKGROUND: Ofatumumab is a humanized monoclonal antibody that targets CD20-positive B cells. It was approved by the FDA in 2020 for the treatment of relapsing multiple sclerosis (RMS) in adult patients, and in 2009 for the treatment of Chronic Lymphocytic Leukemia (CLL). With the escalating clinical application of Ofatumumab, comprehending its safety profile within actual healthcare environments is of considerable importance.

METHODS: This study compiled a dataset derived from the FAERS database, which included real-world safety data on Ofatumumab from Q4 2009 to Q2 2024. We applied four distinct methodologies, including ROR, PRR, MGPS, and BCPNN, to perform a disproportionality analysis of adverse events (AEs) associated with Ofatumumab. Furthermore, we utilized the Weibull distribution model to estimate the temporal risk pattern of AEs.

RESULTS: The investigation incorporated a total of 24,468 case reports pertaining to AEs associated with Ofatumumab. The commonly observed AEs encompass Fatigue, Headache, Chills, Pyrexia, Pain, Nausea, Nasopharyngitis, Vomiting, Urinary tract infection, and Pneumonia. Additionally, we identified potential AEs not specified on the drug label, such as Asthenia, Hypoesthesia, Dizziness, Malaise, Injection site pain, Paresthesia, and Diarrhea.

CONCLUSIONS: This investigation has identified several AEs associated with Ofatumumab and revealed previously unacknowledged potential adverse reaction signals. Healthcare providers can refer to these adverse reaction signals to more comprehensively consider the possible conditions that patients may present with during actual clinical practice.

PMID:39917308 | PMC:PMC11798770 | DOI:10.3389/fimmu.2025.1515730

Cureus. 2025 Jan 7;17(1):e77078. doi: 10.7759/cureus.77078. eCollection 2025 Jan.

ABSTRACT

Tuberculosis (TB) is a highly infectious disease and a global health challenge caused by Mycobacterium tuberculosis. The disease presents as drug-sensitive TB or drug-resistant TB (DR-TB). DR-TB could be of various types like isoniazid mono-resistant, multidrug-resistant (MDR)-rifampicin mono-resistant (MDR-RR), MDR-TB, extensively DR-TB (XDR-TB), or pre-XDR-TB. Management of DR-TB is challenging due to the longer treatment duration and adverse drug reactions (ADRs) to the second-line anti-TB drugs. Some of these could be life-threatening and require urgent care. Neuropsychiatric ADRs associated with cycloserine require greater attention due to their potential to cause treatment failure. The objective of this case report is to emphasize the importance of awareness about psychiatric ADRs caused by antitubercular agents. It also highlights the reversible nature of these adverse events upon drug withdrawal. To ensure methodological rigor in the assessment of psychosis, the Brief Psychiatric Rating Scale (BPRS) and Naranjo ADR Probability Scale were employed as diagnostic tools to evaluate the severity of psychiatric symptoms and establish the likelihood of an ADR, respectively. It is emphasized here that proper vigilance with immediate management is essential to avoid fatal outcomes. Herein, a case of ADR caused by cycloserine in a pulmonary MDR-TB case as a part of a new modified longer regimen in the Department of Respiratory Medicine at Shri B M Patil Medical College, Hospital and Research Centre, Vijayapura, Karnataka, is presented.

PMID:39917143 | PMC:PMC11802170 | DOI:10.7759/cureus.77078

Pharmacogenomics. 2025 Feb 7:1-12. doi: 10.1080/14622416.2025.2456449. Online ahead of print.

ABSTRACT

AIM: This study is designed to address the connection between antidepressant and antipsychotic-induced hepatotoxicity with pharmacogenetic and epigenetic indicators, using a novel combined approach of CYP450 polymorphism determination and early liver injury detection via microRNA testing.

METHODS: The multi-centric retrospective case-control study in Slovakia involves 151 cases with signs of hepatotoxicity and 604 controls without. Participants will be tested for selected CYP450, UGT1A1 polymorphisms, and microRNAs.

RESULTS: Anticipated findings will test if patients with specific CYP450 and UGT1A1 polymorphisms are at higher risk for drug-induced hepatotoxicity and if plasma microRNAs hsa-miR-122-5p and hsa-miR-192-5p, alone or combined, can differentiate patients with abnormal liver function.

CONCLUSION: The findings could contribute to personalized treatment approach by combining genetic and epigenetic biomarkers.

PMID:39916529 | DOI:10.1080/14622416.2025.2456449

Farm Hosp. 2025 Feb 5:S1130-6343(24)00169-7. doi: 10.1016/j.farma.2024.10.009. Online ahead of print.

ABSTRACT

INTRODUCTION: Older patients are more susceptible to medication use, and physiological changes resulting from aging and organic dysfunctions presented by critically-ill patients may alter the pharmacokinetic or pharmacodynamic behavior. Thus, critically-ill older people present greater vulnerability to the occurrence of pharmacotherapeutic problems.

OBJECTIVE: To evaluate pharmacotherapy and the development of potential adverse drug reactions (ADRs) in older patients admitted to an intensive care unit (ICU).

METHOD: A cohort study was conducted in an ICU for adults of a Brazilian University Hospital during a 12-month period. The patients' pharmacotherapy was evaluated daily, considering the occurrence of ADRs and drug-drug interactions (DDIs), the use of potentially inappropriate medications (PIMs) for older people, and the pharmacotherapy anticholinergic burden (ACB). A trigger tool was used for active search of ADRs, with subsequent causality evaluation. PIM use was evaluated by means of the Beers criteria and the STOPP/START criteria. The ABC scale was employed to estimate ACB. The Micromedex® and Drugs.com® medication databases were employed to evaluate the DDIs.

RESULTS: The sample of this study consisted of 41 patients, with a mean age of 66.8 years old (±5.2). The 22 triggers used assisted in identifying 15 potential ADRs, and 26.8% of the patients developed them. The mean estimated ACB score was 3.0 (±1.8), and the patients used 3.1 (±1.4) and 3.3 (±1.6) PIMs according to the Beers and the STOPP criteria, respectively. A total of 672 DDIs were identified, with a mean of 16.8 (±9.5) DDIs/patient during ICU hospitalization. Our findings show an association between occurrence of ADRs in the ICU and polypharmacy (p = 0.03) and DDIs (p = 0.007), corroborating efforts for rational medication use as a preventive strategy.

CONCLUSIONS: Using tools to evaluate the pharmacotherapy for older people in intensive care can assist in the recognition and prevention of pharmacotherapeutic problems, with emphasis on the identification of ADRs through the observation of triggers and subsequent causality analysis.

PMID:39915129 | DOI:10.1016/j.farma.2024.10.009

J Nucl Med. 2025 Feb 6:jnumed.124.268318. doi: 10.2967/jnumed.124.268318. Online ahead of print.

ABSTRACT

Prostate-specific membrane antigen (PSMA) is highly expressed in most prostate cancers (PCs). PET and CT imaging studies using 68Ga-labeled PSMA ligands demonstrated the specific localization of 68Ga in PC lesions and distant metastatic lesions. [68Ga]Ga-PSMA-R2 (68Ga-PSMA-R2) is a PSMA-targeted PET/CT radiotracer with potential diagnostic applications. Methods: PROfind (NCT03490032) was a phase 1/2, open-label, multicenter study of administration of 3 MBq/kg of 68Ga-PSMA-R2 (from >150 to ≤250 MBq) in patients with biochemical recurrence (BCR) or metastatic PC (mPC). Participants underwent baseline conventional imaging (CT/MRI or bone scan) and PET/CT. Whole-body PET/CT imaging sequences were obtained between 20 min and 4 h after injection. Primary endpoints were safety and tolerability; secondary endpoints included biodistribution, potential lesion identification, pharmacokinetics, and dosimetry. Potential lesions were identified by 2 masked expert panels; a third panel evaluated the identified lesions. Results: Six patients with BCR were enrolled into phase 1, and 24 patients with BCR or mPC (n = 12 each) into phase 2. Thirteen treatment-emergent adverse events were reported, including 1 serious adverse event (ileus), unrelated to drug administration. All adverse events were mild or moderate and deemed not related to 68Ga-PSMA-R2. Peak blood concentration of 68Ga-PSMA-R2 was typically observed approximately 5 min after injection, steadily decreasing over 6 h. Mean absorbed radiation dose was highest in the urinary bladder wall (0.120 mGy/MBq) and kidney (0.061 mGy/MBq). No other organ mean absorbed radiation dose exceeded 0.020 mGy/MBq. Mean absorbed radiation doses in the salivary and lacrimal glands were 0.016 and 0.008 mGy/MBq, respectively. Mean total body absorbed radiation dose was 0.014 mGy/MBq. Mean effective total body dose was 0.015 mSv/MBq (range, 0.012-0.018 mSv/MBq). 68Ga-PSMA-R2 PET/CT detected 85 lesions in 22 participants at 1 h after injection and 103 lesions in 22 participants at 2 h after injection. Conventional imaging detected 49 lesions in 8 participants with mPC but none in participants with BCR. Conclusion: 68Ga-PSMA-R2 was well tolerated, with no drug-related treatment-emergent adverse events. Safety and preliminary imaging performance data support further development of 68Ga-PSMA-R2 as a diagnostic agent in patients with PC.

PMID:39915126 | DOI:10.2967/jnumed.124.268318

Eur J Hosp Pharm. 2025 Feb 6:ejhpharm-2024-004445. doi: 10.1136/ejhpharm-2024-004445. Online ahead of print.

ABSTRACT

Cytomegalovirus (CMV) is a common herpesvirus that can cause severe infections in immunocompromised patients. Standard treatments, such as ganciclovir and valganciclovir, are usually effective, but refractory CMV requires alternatives like foscarnet, cidofovir, or immunotherapies. New treatments, such as maribavir, have shown promise for refractory cases. This report discusses a woman in her 50s with sarcoidosis, previously treated with infliximab, leflunomide, and hydroxychloroquine, who developed refractory CMV. Initial treatment with ganciclovir and intravenous immunoglobulin (IVIG) was discontinued due to severe pancytopenia, leading to the initiation of foscarnet. Despite this, CMV viremia persisted, leading to off-label use of maribavir, which reduced the viral load with mild gastrointestinal side effects. The patient also developed haemophagocytic syndrome, complicating her condition.Unfortunately, she succumbed to an opportunistic infection, leaving the complete efficacy of maribavir unconfirmed. This case highlights the potential of novel antiviral agents and underscores the need for further research on refractory CMV management.

PMID:39915049 | DOI:10.1136/ejhpharm-2024-004445

PLoS One. 2025 Feb 6;20(2):e0317680. doi: 10.1371/journal.pone.0317680. eCollection 2025.

ABSTRACT

BACKGROUND: Drug-induced autoimmune-like hepatitis (DI-ALH) is a potentially life-threatening condition that can lead to acute liver failure and necessitate liver transplantation. While the association between certain drugs and DI-ALH has been documented, a comprehensive analysis of drug-related signals in a large, real-world pharmacovigilance database is lacking. This study aimed to systematically identify drugs linked to DI-ALH by analyzing adverse event reports from the U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) database.

METHODS: We searched the FAERS database for the term "autoimmune hepatitis" and extracted DI-ALH reports from the first quarter of 2004 to the first quarter of 2024. Positive signal drugs were identified using Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM). To confirm a significant drug-adverse event association, each method had to meet predefined thresholds: for PRR and ROR, values were considered significant if the lower 95% confidence interval (CI) was greater than 1 and at least three reports were identified; for BCPNN, an Information Component (IC025) greater than 0 indicated a signal; for EBGM, a value greater than 2 for the lower 95% confidence interval (EBGM05) was used to denote a positive signal.

RESULTS: A total of 5,723 DI-ALH reports were extracted from the FAERS database. Disproportionality analysis identified 50 drugs with strong associations to DI-ALH, with biologics, statins, antibiotics, and antiviral drugs representing the most common categories. Among these, nitrofurantoin (ROR 94.79, CI 78.53-114.41), minocycline (ROR 77.82, CI 65.09-93.05), and nivolumab (ROR 47.12, CI 15.06-147.39) exhibited the strongest signals. Additionally, several previously unreported drugs, including mesalazine, aldesleukin, onasemnogene abeparvovec-xioi, and nefazodone, were identified as having strong associations with DI-ALH. These findings were consistent across all four signal detection methods, further validating the robustness of the associations.

CONCLUSION: This study provides a comprehensive assessment of drugs associated with DI-ALH through a rigorous analysis of the FAERS database using multiple signal detection methods. By identifying both well-known and previously underreported drugs, this study contributes to a more complete understanding of drug-induced liver injury. The findings have important implications for pharmacovigilance strategies and clinical risk assessment. However, limitations inherent in the FAERS database, such as underreporting and the potential for reporting bias, should be considered. Further clinical validation is warranted to confirm these associations.

PMID:39913410 | DOI:10.1371/journal.pone.0317680

Future Oncol. 2025 Feb 6:1-8. doi: 10.1080/14796694.2025.2461446. Online ahead of print.

ABSTRACT

PURPOSE: A phase I study of FOLFIRINOX3-bevacizumab (bFOLFIRINOX3)defined the RP2D for irinotecan at 70 mg/m² and showed promising activity. This phase II trial aimed to evaluate the efficacy of bFOLFIRINOX-3 in chemorefractory metastatic colorectal cancer (mCRC).

METHODS: In phase II, chemorefractory mCRC were enrolled. The regimen tested consisted of bevacizumab (5 mg/kg), folinic acid(400 mg/m²), 5-fluorouracil (2400 mg/m² for 46 h), oxaliplatin (85 mg/m²) and irinotecan (70 mg/m² administered before and after infusion of 5-fluorouracil). The primary endpoint was efficacy defined by 2-month progression-free survival(PFS). Secondary endpoints included objective response, median PFS, overall survival (OS) and toxicity.

RESULTS: 32 patients were enrolled (October 2018 to December 2022); median age 62.5 years (range 32-78). The majority had been treated with several previous lines of chemotherapy (median 3, range [1-8]). Median follow up was 12 months (range [1.5-12]). Two-month PFS was 96.9%. Best objective response rate (ORR) was 28.1%. Median PFS was 9.4 months (95%CI [6.9;11.5]) and median OS was not reached (95% [11.6; NR]). Grade 3 adverse events occurred in 81.2%; mostly diarrhea (37.5%) and neutropenia (12.5%). Grade 3 diarrhea consistently resolved after irinotecan dose reduction. The most common drug-related adverse events (all grades) were diarrhea (96.9%), fatigue (68.8%), nausea (68.7%), anemia (56.3%), peripheral neuropathy (53.4%) and thrombopenia (40.6%).

CONCLUSION: The combination of bFOLFIRINOX-3 yielded 2-month PFS of 96.9% and best ORR of 28.1%, and was well tolerated. These results are promising in chemotherapy refractory mCRC and provide a rationale for future randomized phase III trials.

CLINICAL TRIAL REGISTRATION: NCT03795311 (clinicaltrials.gov).

PMID:39913183 | DOI:10.1080/14796694.2025.2461446

Eur J Dermatol. 2024 Dec 1;34(6):643-650. doi: 10.1684/ejd.2024.4785.

ABSTRACT

Generalized pustular psoriasis (GPP) is a potentially life-threatening orphan disease. Interleukin (IL)-36 is a known pathogenetic key driver of GPP. The IL-36 receptor inhibitor spesolimab has shown efficacy and safety in clinical trials. However, evidence for spesolimab outside of clinical trials is limited. To provide additional evidence for the use of spesolimab beyond clinical trials, we evaluated individual patient data as part of the spesolimab Compassionate Use Program (CUP) for GPP patients in Germany. Adult patients with an acute GPP flare received 900 mg spesolimab intravenously at baseline and received a second dose on day 8. Data on demographics, efficacy and adverse events were collected from participating sites at baseline, on day 8 and at four weeks. The database included datasets from 12 GPP patients. At baseline, 72% of patients with complete data regarding efficacy (n=7) had a GPPGA (Generalized Pustular Psoriasis Physician Global Assessment) of ≥3, and all patients a PS (pustulation subscore) of ≥3. On day 8, 43% of patients had a GPPGA ≤1 and 72% a PS ≤1. After four weeks, all patients had a GPPGA ≤1 and 86% a PS ≤1. No drug-related adverse events were reported. These findings confirm the results of international, randomized clinical trials in a real-world setting. As spesolimab is no longer available in Germany, this study provides important information that cannot be replicated in this country.

PMID:39912471 | DOI:10.1684/ejd.2024.4785

Skin Appendage Disord. 2025 Feb;11(1):63-69. doi: 10.1159/000540104. Epub 2024 Jul 29.

ABSTRACT

INTRODUCTION: Drug-induced hair loss is one of several causes of hair loss commonly seen in clinical practice, and it is often a daunting task to determine a potential culprit drug when a patient is taking numerous medications. Our objective was to identify drugs responsible for hair loss, using the Food and Drug Administration's Adverse Events Reporting System (FAERS) database, a compilation of drug-related adverse events (AEs).

METHODS: Using the FAERS database, we queried all domestic reports with the reaction term "alopecia" listed as an AE in patients ≥18 years old from April 1, 1968, to September 29, 2023. Using descriptive statistics, individual agents were grouped by drug class.

RESULTS: We analyzed a total of 39,346 hair loss AE reports related to a single agent. Immunomodulatory agents and monoclonal antibodies represented the highest proportion of AE reports for alopecia, followed by hair loss drugs, contraceptives, and antitumor necrosis factor (anti-TNF) biologics.

CONCLUSION: In sum, we showed that immunomodulatory agents and monoclonal antibodies, hair loss drugs, including minoxidil and finasteride, contraceptives, kinase inhibitors, and anti-TNF drugs are most frequently associated with hair loss AEs in the FAERS database. Because many of these drugs are not prescribed primarily for dermatologic indications, our study provides guidance for dermatologists in identifying common medications associated with alopecia.

PMID:39911975 | PMC:PMC11793883 | DOI:10.1159/000540104

Eur Rev Med Pharmacol Sci. 2025 Jan;29(1):30-38. doi: 10.26355/eurrev_202501_37057.

ABSTRACT

OBJECTIVE: Antithrombin (AT) has anti-inflammatory and anti-coagulant properties, but its role in COVID-19 and the rate of deficiency is unknown. We hypothesize that AT3 deficiency is common in COVID-19, and supplementing AT3 will impact COVID-19 coagulopathy.

PATIENTS AND METHODS: This is a prospective randomized control trial. Patients with plasma AT3<100% were randomized to either standard of care (SOC) or SOC+AT3 q48hr weight-based for a goal of 120% for up to 5 doses. An additional reference group with AT3>100% received SOC.

RESULTS: 531 subjects were assessed for eligibility; 324 did not meet inclusion criteria, 151 did not consent, 6 withdrew consent, and 50 subjects completed the study. Enrollment AT3 (M±SD) was 91±13%. AT3 levels were <100% in 38 (76%) and <80% in 11 (22%) patients. SOC+AT3, SOC only, and AT3>100% had a disseminated intravascular coagulation (DIC) score change (M±SD) of 0.4±1.5, -0.13±1.85 and 0±1.54, respectively, (p=0.63). Hospital length of stay was 11.7 [6-14], 6 [4.5-10], 8.5 [6-21] respectively, (p=0.176). Mortality occurred in 2 (11%), 3 (15%), and 3 (25%) patients, respectively (p=0.56). There was one bleeding event in a subject with AT3>100%, and no bleeding events were observed with exogenous AT3. There were no observed drug-related adverse events. Subjects received a median dose of 1,825.5 IU (IQR 794).

CONCLUSIONS: COVID-19 is associated with relative AT3 deficiency (22% of this cohort). No bleeding complications or drug-related adverse events with exogenous AT3 were observed. There were no significant differences in length of stay or mortality. Further studies should evaluate higher doses of exogenous AT3 and focus on higher-risk groups.

CLINICALTRIALS: gov: NCT04899232.

PMID:39911044 | DOI:10.26355/eurrev_202501_37057

J Med Internet Res. 2025 Feb 5;27:e65546. doi: 10.2196/65546.

ABSTRACT

BACKGROUND: Medication-related harm, including adverse drug events (ADEs) and medication errors, represents a significant iatrogenic burden in clinical care. Digital health technology (DHT) interventions can significantly enhance medication safety outcomes. Although the clinical effectiveness of DHT for medication safety has been relatively well studied, much less is known about the cost-effectiveness of these interventions.

OBJECTIVE: This study aimed to systematically review the economic impact of DHT interventions on medication safety and examine methodological challenges to inform future research directions.

METHODS: A systematic search was conducted across 3 major electronic databases (ie, PubMed, Scopus, and EBSCOhost). The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed for this systematic review. Two independent investigators conducted a full-text review after screening preliminary titles and abstracts. We adopted recommendations from the Panel on Cost-Effectiveness in Health and Medicine for data extraction. A narrative analysis was conducted to synthesize clinical and economic outcomes. The quality of reporting for the included studies was assessed using the CHEERS (Consolidated Health Economic Evaluation Reporting Standards) guidelines.

RESULTS: We included 13 studies that assessed the cost-effectiveness (n=9, 69.2%), cost-benefit (n=3, 23.1%), and cost-utility (n=1, 7.7%) of DHT for medication safety. Of the included studies, more than half (n=7, 53.9%) evaluated a clinical decision support system (CDSS)/computerized provider order entry (CPOE), 4 (30.8%) examined automated medication-dispensing systems, and 2 (15.4%) focused on pharmacist-led outreach programs targeting health care professionals. In 12 (92.3% ) studies, DHT was either cost-effective or cost beneficial compared to standard care. On average, DHT interventions reduced ADEs by 37.12% (range 8.2%-66.5%) and medication errors by 54.38% (range 24%-83%). The key drivers of cost-effectiveness included reductions in outcomes, the proportion of errors resulting in ADEs, and implementation costs. Despite a significant upfront cost, DHT showed a return on investment within 3-4.25 years due to lower cost related with ADE treatment and improved workflow efficiency. In terms of reporting quality, the studies were classified as good (n=10, 76.9%) and moderate (n=3, 23.1%). Key methodological challenges included short follow-up periods, the absence of alert compliance tracking, the lack of ADE and error severity categorization, and omission of indirect costs.

CONCLUSIONS: DHT interventions are economically viable to improve medication safety, with a substantial reduction in ADEs and medication errors. Future studies should prioritize incorporating alert compliance tracking, ADE and error severity classification, and evaluation of indirect costs, thereby increasing clinical benefits and economic viability.

PMID:39909404 | DOI:10.2196/65546

Front Immunol. 2025 Jan 21;15:1508129. doi: 10.3389/fimmu.2024.1508129. eCollection 2024.

ABSTRACT

QUESTION: Can previously reported, largely anecdotal associations between exposure to any of a comprehensive list of putative trigger drugs and the development of pemphigus be reproduced using population level data?

FINDINGS: In this series of observational, retrospective, case-control, pharmacovigilance analyses of the FDA Adverse Event Reporting System, the odds of reporting the adverse event pemphigus were significantly elevated among individuals exposed to 11/36 previously reported trigger drugs namely, gold sodium thiomalate, penicillamine, piroxicam, rifampin, hydroxychloroquine, imiquimod, hydrochlorothiazide, irbesartan, lisinopril, nivolumab, and nifedipine.

MEANING: Environmental exposures such as drugs are relevant players in the pathogenesis of autoimmune diseases and clinicians who treat patients with autoimmune blistering diseases such as pemphigus should consider performing a detailed medication history leveraging this information regarding deleterious drug-disease interactions at initial evaluation as well as longitudinal monitoring of patients to better inform clinical care decisions.

IMPORTANCE: Pemphigus vulgaris (PV) is a rare, potentially fatal autoimmune disease with pathogenic contributions from both genetic as well as environmental factors, notably drug exposures. Despite anecdotal reports linking multiple drugs to PV, corroborating evidence from large datasets is missing.

OBJECTIVE: To examine the extent to which previously reported associations between a comprehensive list of 36 drugs implicated in PV pathogenesis could be replicated using population-level pharmacovigilance data.

DESIGN: Series of observational, retrospective, case-control, pharmacovigilance analyses (one analysis/drug, 36 total).

SETTING: Population based.

PARTICIPANTS: Individuals who submitted a report of a drug-related adverse event to the FDA from Q4 of 2003 to Q2 of 2023.

EXPOSURE: Cases were identified by the presence of adverse events described by the MedDRA preferred term "pemphigus" (10034280) and then sorted based on exposure to each of the drugs of interest.

MAIN OUTCOMES AND MEASURES: Reporting Odds Ratios (RORs) quantifying the association between a given drug exposure and reports of pemphigus adverse events.

RESULTS: The analyses revealed statistically significant associations between reports of pemphigus and exposure to 11/36 previously reported drugs, two of which had particularly high RORs (>200) [gold sodium thiomalate (ROR, 266.0; 95% CI, 202.6-349.3) and hydroxychloroquine (ROR, 282.6; 95% CI, 261.0-306.1)], three had very strong RORs (14-45) [penicillamine (ROR, 30.5; 95% CI, 11.4-81.7), piroxicam (ROR, 14.8; 95% CI, 8.2-26.7), and imiquimod (ROR, 42.3; 95% CI, 26.2-68.3)], and six had modestly strong RORs (2-5) [rifampin (ROR, 2.8; 95% CI, 1.4-5.6), hydrochlorothiazide (ROR, 1.6; 95% CI, 1.2-2.1), irbesartan (ROR, 2.7; 95% CI, 1.6-4.4), lisinopril (ROR, 5.3; 95% CI, 4.5-6.2), nivolumab (ROR, 2.7; 95% CI, 1.8-4.1), and nifedipine (ROR, 3.0; 95% CI, 1.9-5.0)]. Associations for other previously reported drugs (25/36) were not detected.

CONCLUSIONS AND RELEVANCE: This study represents a comprehensive evaluation of suspected drug triggers of pemphigus using real-world data. The significant associations reported here provide empirical support for the hypothesis that certain drugs act as triggers for PV. Moreover, all of the drugs found to be associated with PV in this study harbor immunomodulatory capacity, suggesting that the ability to induce such perturbations, directly or indirectly, may be a critical factor connecting drug exposure to pemphigus pathogenesis. However, the absence of signals for other previously reported putative trigger drugs does not preclude their potential role in PV pathogenesis. Our findings reinforce the need for larger, more definitive studies to confirm these associations and to explore the mechanisms by which these drugs may contribute to PV development. Finally, these findings underscore the importance of considering environmental factors in the development and course of PV in genetically susceptible individuals.

PMID:39906745 | PMC:PMC11790476 | DOI:10.3389/fimmu.2024.1508129

Clin Transl Sci. 2025 Feb;18(2):e70133. doi: 10.1111/cts.70133.

ABSTRACT

Piperaquine tetraphosphate (PQP), a long-acting antimalarial, is being considered in a combination for chemoprevention. Dihydroartemisinin-piperaquine tablets (hard and dispersible) approved for the treatment of acute uncomplicated malaria should be administered in a fasted state, as PQP bioavailability increases with food. A new taste-masked dispersible granules PQP formulation aims to minimize the impact of food on drug exposure. This randomized, open label, parallel group, Phase I pilot study was conducted between 24th July 2023, and 3rd January 2024, at the Ifakara Health Institute, Bagamoyo, Tanzania in 60 healthy African adults (five cohorts of 12). Single-dose pharmacokinetics and relative systemic exposure of the oral PQP dispersible granules formulation prototype (320 mg) was compared to the hard tablet when fasted and PQP granules in three different fed conditions. In the fasted state, the relative exposure of PQP granules versus the tablet was 73.9% (90% CI 48.3, 113.0) for Cmax and 86.5% (68.2, 109.6) for AUC0-t. Following a typical East African low-fat meal, a standard high-fat meal, or 250 mL whole milk, the relative exposure of PQP granules versus the fasted state was 202% (90% CI 132, 311), 275% (193, 391), and 294% (203, 425) for Cmax and 164% (124, 217), 184% (148, 228), and 195% (147, 259) for AUC0-t, respectively. Both formulations were well tolerated with one drug-related adverse event (moderate migraine). No severe or serious adverse events or clinically relevant laboratory or electrocardiograph changes were observed. PQP dispersible granules had lower systemic exposures versus the tablet when fasted, whereas various meals increased drug exposure.

PMID:39905737 | DOI:10.1111/cts.70133