J Res Pharm Pract. 2025 Apr 24;13(4):111-118. doi: 10.4103/jrpp.jrpp_2_25. eCollection 2024 Oct-Dec.

ABSTRACT

OBJECTIVE: In severe cases, COVID-19 can lead to a hyperinflammatory state, resulting in devastating outcomes. Immune modulation using steroids or other immune modulators can regulate the intensity of the inflammatory response; however, this theory has not been adequately assessed in practice. The current study aims to investigate the use of corticosteroids alone or in combination with tocilizumab to treat patients with severe COVID-19.

METHODS: This cross-sectional study was conducted on 166 Iranian patients with severe COVID-19 infection at Al-Zahra Hospital, who were treated with the standard treatment for severe COVID-19 infection, as per the 11th version of the Iranian guideline for COVID-19 treatment. Patients were categorized into three treatment groups based on the dose of corticosteroid treatment and tocilizumab therapy: (a) high-dose methylprednisolone (>1 mg/kg) alone, (b) low-dose methylprednisolone (<1 mg/kg) followed by one dose of tocilizumab (8 mg/kg); and (c) high-dose methylprednisolone (>1 mg/kg) followed by one dose of tocilizumab (8 mg/kg). Mortality of patients as our primary outcome, laboratory parameters, length of hospitalization, intensive care unit (ICU) admission requirement, and drug-related adverse events were compared between groups.

FINDINGS: The second group showed significantly better outcomes, including shorter ICU stays, lower C-reactive protein and lactate dehydrogenase levels, and higher oxygen saturation and platelet counts than the other groups. Logistic regression revealed increased risks of mortality, nosocomial infection, and adverse effects, including hepatic and renal dysfunction and gastrointestinal bleeding, in Groups B and C compared with Group A.

CONCLUSION: In all evaluated parameters, a low-dose steroid followed by tocilizumab was superior to a high-dose steroid alone or combined with tocilizumab. Although this combination treatment has been assessed worldwide, few studies have focused on its application in Iranian patients with severe COVID-19.

PMID:40432839 | PMC:PMC12105767 | DOI:10.4103/jrpp.jrpp_2_25

Medicina (Kaunas). 2025 May 17;61(5):911. doi: 10.3390/medicina61050911.

ABSTRACT

Tuberculosis remains a significant public health challenge globally. The emergence of multidrug-resistant Mycobacterium tuberculosis strains presents one of the biggest hurdles in tuberculosis management. Both first- and second-line tuberculosis drugs are associated with common adverse reactions, which can lead to treatment interruptions and decreased adherence. In this article, we review the most commonly used drugs for the treatment of tuberculosis, focusing on the adverse reactions they may cause. We will examine the frequency and timeline of adverse drug reactions involving gastrointestinal, cardiac, neurological, nephrological, and cutaneous systems. Identifying patients at risk of developing those reactions is crucial for healthcare providers to implement monitoring strategies and manage complications effectively. In the review, we present the data about risk factors, management recommendations, and drug discontinuation rates as a result of side effects.

PMID:40428869 | DOI:10.3390/medicina61050911

Bioinformatics. 2025 Jun 2;41(6):btaf319. doi: 10.1093/bioinformatics/btaf319.

ABSTRACT

MOTIVATION: Drug side effects refer to harmful or adverse reactions that occur during drug use, unrelated to the therapeutic purpose. A core issue in drug side effect prediction is determining the frequency of these drug side effects in the population, which can guide patient medication use and drug development. Many computational methods have been developed to predict the frequency of drug side effects as an alternative to clinical trials. However, existing methods typically build regression models on five frequency classes of drug side effects and tend to overfit the training set, leading to boundary handling issues and the risk of overfitting.

RESULTS: To address this problem, we develop a multi-source similarity fusion-based model, named multi-source similarity fusion (MSSF), for predicting five frequency classes of drug side effects. Compared to existing methods, our model utilizes the multi-source feature fusion module and the self-attention mechanism to explore the relationships between drugs and side effects deeply and employs Bayesian variational inference to more accurately predict the frequency classes of drug side effects. The experimental results indicate that MSSF consistently achieves superior performance compared to existing models across multiple evaluation settings, including cross-validation, cold-start experiments, and independent testing. The visual analysis and case studies further demonstrate MSSF's reliable feature extraction capability and promise in predicting the frequency classes of drug side effects.

AVAILABILITY AND IMPLEMENTATION: The source code of MSSF is available on GitHub (https://github.com/dingxlcse/MSSF.git) and archived on Zenodo (DOI: 10.5281/zenodo.15462041).

PMID:40424358 | DOI:10.1093/bioinformatics/btaf319

BMC Med Res Methodol. 2025 May 27;25(1):146. doi: 10.1186/s12874-025-02597-z.

ABSTRACT

BACKGROUND: The widespread use of long-term pharmacological treatments for chronic conditions has led to polypharmacy, raising concerns about adverse effects and interactions. Deprescribing, the discontinuation of drugs with unfavorable benefit-risk ratios, is gaining attention. Studies evaluating the discontinuation of drugs have a broad methodological spectrum. The selection of outcomes poses a particular challenge. This scoping review addresses the methodological challenges of outcome selection in RCTs investigating drug discontinuation.

METHODS: The scoping review includes RCTs that investigated the discontinuation of drugs whose efficacy and/or safety was in doubt. Data on study characteristics, the motivation for evaluating drug discontinuation, the number and type of primary endpoints, and the stated hypotheses were extracted and analyzed.

RESULTS: We included 103 RCTs. Most studies were from Europe and the USA and mainly investigated antipsychotics/antidepressants, immunosuppressants, steroids and antiepileptics. The discontinuation studies were often conducted due to side effects of the treatment and doubts about the benefits of the drug. The primary endpoints reflected either the course of the disease ("justification of treatment") or the disadvantages of the drug ("justification of withdrawal"). Non-inferiority hypotheses were generally prevalent in justification of treatment studies, while superiority hypotheses were more commonly used in justification of withdrawal studies. However, due to methodological and practical challenges this was not always the case.

CONCLUSION: We present a framework to choose outcomes and specify hypotheses for discontinuation studies. With regard to this, both key challenges (justification of treatment and justification of withdrawal) must be met.

PMID:40426033 | DOI:10.1186/s12874-025-02597-z

Sci Rep. 2025 May 27;15(1):18582. doi: 10.1038/s41598-025-03428-3.

ABSTRACT

A serious adverse reaction (SADR) may follow a vaccination against SARS-CoV-2 infection. We aimed to explore symptoms and reporting trends of SADRs to anti-SARS-CoV-2 vaccines based on the EudraVigilance database. This retrospective observational study analysed 250,966 suspected SADRs (with 62.8% reported in females), following the administration of 733,837,251 vaccine doses against SARS-CoV-2. Pfizer BioNTech (Comirnaty-Tozinameran), Moderna (Spikevax-Elastomeran), Janssen (Jcovden) and AstraZeneca (Vaxzevria) vaccines were analysed. The assessment included 897 types of SADRs across 12 categories. The most common clinical manifestations of SADRs to anti-SARS-CoV-2 vaccines vaccines encompassed neuropsychiatric (n = 121,877), cardiovascular (n = 78,167), as well as musculoskeletal and connective tissue disorders (n = 63,994). After summarising all SADRs, vaccination with Comirnaty was associated with the lowest risk of experiencing SADRs (754/million administered doses), followed by Spikevax (785/million doses), Jcovden (1,248/million doses) and Vaxzevria (2,301/million doses; p < 0.001). Regarding the vaccine administration timelines, the reporting of SADRs tends to be delayed and occurs over a longer time (p < 0.001). SADRs associated with anti-SARS-CoV-2 vaccines seem to be relatively rare. Compared to adenovirus-based vector vaccines (Jcovden, Vaxzevria), mRNA vaccines appear to offer improved safety profiles (Comirnaty, Spikevax). The risk of SADR to any SARS-CoV-2 vaccine seems to be outweighed by the benefits of active immunization against the virus.

PMID:40425703 | DOI:10.1038/s41598-025-03428-3

JAMA Netw Open. 2025 May 1;8(5):e2512455. doi: 10.1001/jamanetworkopen.2025.12455.

ABSTRACT

IMPORTANCE: Accurately quantifying adverse event (AE) costs is essential for cost-effectiveness analyses (CEAs) of anticancer drugs. Misestimates in AE costs may significantly affect cost-effectiveness conclusions.

OBJECTIVE: To assess whether AE cost quantification in anticancer drug CEAs accurately reflects the true cost of AEs and to evaluate whether replacing AE costs with actual values affects cost-effectiveness conclusions.

EVIDENCE REVIEW: A systematic search of PubMed, Web of Science, and Tufts CEA databases was conducted from October 24 to December 1, 2023, with an additional search from November 4 to 10, 2024, for English-language CEAs and claims-based studies examining AE costs for anticancer drugs published between January 2003 and December 2023. Claims-based AE costs were considered to represent actual values. AE costs were compared in absolute terms and as a proportion of total medical costs. Impact of replacing CEA AE cost estimates with actual values for incremental cost-effectiveness ratios (ICERs) was examined at thresholds of $100 000 and $150 000 per quality-adjusted life year (QALY). AE cost differences between CEA estimates and actual values and their impact on ICERs were the main outcomes.

FINDINGS: The sample included 11 claims-based US studies with 34 022 patients and 102 US payer-perspective CEAs. AE cost estimates in CEAs were consistently lower than actual values, with a median difference of 9.73% (IQR, 5.15%-27.22%; P = .002) in proportion of total medical costs and of $17 201 (IQR, $13 365-$48 970; P = .03) in absolute costs. Adjusting AE costs led to an ICER change of $42 656 per QALY, altering cost-effectiveness conclusions in 8 of 17 cases (47.1%). Among the 102 CEAs, 41 (40.2%) did not report AE types; of the remaining 61 (59.8%), 48 (78.7%) focused on treatment-related AEs instead of all-cause AEs. Of all CEAs, 79 (77.5%) considered grade 3 or higher AEs, ignoring grades 1 and 2. Only 13 studies (12.7%) accounted for AE-related dose reductions or interruptions, 87 (85.3%) did not consider postprogression AE costs, and 77 (82.8%) assumed AEs occurred only in the first treatment cycle. Substantial variability was observed in both drug AE and unit AE costs across studies.

CONCLUSIONS AND RELEVANCE: In this systematic review of AE costs in oncology CEAs, AE costs were frequently underestimated, potentially altering cost-effectiveness conclusions. Key problems included incomplete AE inclusion, inaccurate AE cost estimates, overlooked long-term AEs, and unaccounted dose modifications. Best practices and standardized guidelines should be established to improve AE cost quantification in oncology CEAs.

PMID:40423968 | DOI:10.1001/jamanetworkopen.2025.12455

J Biochem Mol Toxicol. 2025 Jun;39(6):e70316. doi: 10.1002/jbt.70316.

ABSTRACT

Valproic acid (VPA) is a frequently prescribed treatment for many psychiatric disorders, particularly for epilepsy. However, it has been associated with possible side effects including hepatotoxicity and neurotoxicity. The present study investigated the protective effect of vinpocetine (Vinpo) against VPA-induced hepatotoxicity and hippocampal neurotoxicity in rats. Vinpo (5 and 10 mg/kg/day; p.o) was given for 14 days, with/without VPA (500 mg/kg/day; p.o) in adult male Wistar rats. VPA showed marked increase in hepatic and hippocampal MDA levels with increased liver function enzymes as well as a marked decline in serum total antioxidant capacity (TAC). Simultaneously, VPA administration resulted in a significant reduction in cAMP, cAMP response element binding protein (CREB), and PI3K/AKT protein levels in liver tissue and hippocampus. These results were confirmed by histological degenerative changes in both tissues. VPA also associated with increased hepatic and dentate gyrus nuclear factor kappa (NF-κB) immunoexpression with increased Glial fibrillary acidic protein (GFAP) expression in the dentate gyrus. Administration of Vinpo markedly attenuated VPA-induced toxicity in rats by its anti-oxidant effect on MDA and TAC levels. Vinpo resulted in a significant increase in the levels of cAMP/CREB and PI3K/AKT in liver and hippocampus tissues, together with significant decrease in NF-κB nuclear expression. Vinpo ameliorated astrogliosis as indicated by reduction in the expression of GFAP. Vinpo exerted a hepatoprotective and neuroprotective role against VPA-induced toxicity by cAMP and PI3K/AKT dependent activation of CREB and this hold a promise as a safe and effective adjuvant while treating psychiatric patients with VPA.

PMID:40421768 | DOI:10.1002/jbt.70316

Sci Rep. 2025 May 25;15(1):18175. doi: 10.1038/s41598-025-03192-4.

ABSTRACT

The aim of this study is to evaluate the real-world safety of brodalumab by analyzing adverse events (AEs) associated with the drug. The AE reports related to brodalumab from the FAERS database from 2017 Q1 to 2023 Q4 were collected. Subsequently, we employed four disproportionality analysis methods to identify positive signals among AEs associated with brodalumab, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS). In 1480 AE reports with brodalumab as the primary suspected drug, 168 preferred terms (PTs) exhibiting positive signals were identified. This study confirmed several known positive AEs, such as injection site vesicles and injection site hemorrhage. In addition, the study identified several positive AEs not listed in the drug product information, including palmoplantar pustulosis and extranodal marginal zone b-cell lymphoma (malt type). This study evaluated the real-world safety profile of brodalumab and identified several unexpected AEs, such as palmoplantar pustulosis and extranodal marginal zone b-cell lymphoma (malt type). These findings provide new safety insights for clinicians and may contribute to the safer and more rational use of brodalumab in clinical practice.

PMID:40414978 | DOI:10.1038/s41598-025-03192-4

Can J Ophthalmol. 2025 May 22:S0008-4182(25)00243-1. doi: 10.1016/j.jcjo.2025.05.005. Online ahead of print.

ABSTRACT

OBJECTIVE: To identify potential teratogenic medication associated with optic nerve hypoplasia (ONH) and/or septo-optic dysplasia (SOD), by screening the Food and Drug Administration Adverse Events Reporting System (FAERS) database.

DESIGN: Retrospective pharmacovigilance study using disproportionality signal detection methods.

PARTICIPANTS: Adverse event reports submitted to FAERS between Q1 2004 and Q3 2024. Reports were included if ONH or SOD was listed as an adverse event and drug exposure occurred in utero.

METHODS: A qualitative assessment evaluated patient demographics, and a disproportionality analysis covered pharmacovigilance signal detection and drug-event reporting frequencies. Pharmacovigilance algorithms that were applied to determine the statistical significance of signals included the proportional reporting ratio (PRR), chi-squared with Yates' correction (χ2), reporting odds ratio (ROR), empirical Bayes geometric mean (EBGM), and information component (IC).

RESULTS: A total of 103 adverse event reports for ONH and/or SOD were identified. The 75 cases reporting prenatal medication exposure were included. Twenty-three reports were of male patients, 13 reports of female patients, and 39 of unspecified gender. Thirty drugs were implicated as primary suspect drugs. Diazepam was the most reported primary suspect medication (n = 15; 20%) followed by methadone and citalopram (n = 8; 11%). The disproportionality analysis showed a positive signal with one medication: diazepam (n = 15; PRR = 82.24; χ2 = 1008.66, ROR 95% CI: 102.55 [56.75-185.33], EBGM [EBGM05]: 48.45 [28.16], IC [IC05]: 4.46 [3.67]).

CONCLUSIONS: A possible association was found between prenatal diazepam exposure and ONH/SOD. Further investigation is required to confirm this relationship and drug safety profiles.

PMID:40414255 | DOI:10.1016/j.jcjo.2025.05.005

Sci Rep. 2025 May 24;15(1):18102. doi: 10.1038/s41598-025-03114-4.

ABSTRACT

The purpose of this study is to analyze FAERS data to identify cases of drug-induced photosensitivity (DIP), examine demographic patterns, determine the drug classes involved, and highlight emerging trends in these reactions. Additionally, we explore potential signal drugs by mining the relevant reported data, aiming to provide insights for safer clinical use of medications. We reviewed the publicly available FAERS database from 2004 to 2023. Using DIP-related search terms such as "photosensitivity reaction," "polymorphic light eruption," or et al., we identified reports of DIP. The frequency and trends of these reports were then analyzed. Between 2004 and 2023, the FDA received 17,384,824 reports of adverse reactions, with 20,236 of these linked to DIP. After excluding cases with incomplete data on age, gender, or country of origin, the median patient age was 52 years (IQR = 66). Females comprised 55.71% of the cases (11,274), and 66.96% (12,459) of the reports originated from the United States. The top 45 drugs were responsible for 9,810 cases (48.48%). The three drug classes most commonly associated with DIP in the FAERS database were immunosuppressants, monoclonal antibodies, and antineoplastic agents. A disproportionality analysis of the top drugs revealed several newly identified drugs with signals for photosensitivity, including adalimumab, adapalene, secukinumab, and fingolimod. By analyzing publicly available FAERS data, we identified key themes and trends in DIP reactions. Immunosuppressants and monoclonal antibodies show mild trends in DIP occurrence. Additionally, adalimumab, adapalene, secukinumab, and fingolimod are novel drug signals of DIP.

PMID:40413262 | DOI:10.1038/s41598-025-03114-4

J Biomed Semantics. 2025 May 23;16(1):10. doi: 10.1186/s13326-025-00331-8.

ABSTRACT

BACKGROUND: Vaccines are crucial for preventing infectious diseases; however, they may also be associated with adverse events (AEs). Conventional analysis of vaccine AEs relies on manual review and assignment of AEs to terms in terminology or ontology, which is a time-consuming process and constrained in scope. This study explores the potential of using Large Language Models (LLMs) and LLM text embeddings for efficient and comprehensive vaccine AE analysis.

RESULTS: We used Llama-3 LLM to extract AE information from FDA-approved vaccine package inserts for 111 licensed vaccines, including 15 influenza vaccines. Text embeddings were then generated for each vaccine's AEs using the nomic-embed-text and mxbai-embed-large models. Llama-3 achieved over 80% accuracy in extracting AE text from vaccine package inserts. To further evaluate the performance of text embedding, the vaccines were clustered using two clustering methods: (1) LLM text embedding-based clustering and (2) ontology-based semantic similarity analysis. The ontology-based method mapped AEs to the Human Phenotype Ontology (HPO) and Ontology of Adverse Events (OAE), with semantic similarity analyzed using Lin's method. Text embeddings were generated for each vaccine's AE description using the LLM nomic-embed-text and mxbai-embed-large models. Compared to the semantic similarity analysis, the LLM approach was able to capture more differential AE profiles. Furthermore, LLM-derived text embeddings were used to develop a Lasso logistic regression model to predict whether a vaccine is "Live" or "Non-Live". The term "Non-Live" refers to all vaccines that do not contain live organisms, including inactivated and mRNA vaccines. A comparative analysis showed that, despite similar clustering patterns, the nomic-embed-text model outperformed the other. It achieved 80.00% sensitivity, 83.06% specificity, and 81.89% accuracy in a 10-fold cross-validation. Many AE patterns, with examples demonstrated, were identified from our analysis with AE LLM embeddings.

CONCLUSION: This study demonstrates the effectiveness of LLMs for automated AE extraction and analysis, and LLM text embeddings capture latent information about AEs, enabling more comprehensive knowledge discovery. Our findings suggest that LLMs demonstrate substantial potential for improving vaccine safety and public health research.

PMID:40410898 | DOI:10.1186/s13326-025-00331-8

Clin Infect Dis. 2025 May 24:ciaf265. doi: 10.1093/cid/ciaf265. Online ahead of print.

ABSTRACT

BACKGROUND: We report an interim analysis of safety and efficacy of pemivibart in individuals with (cohort A) or without (cohort B) significant immunocompromise in the phase 3 CANOPY trial.

METHODS: Eligible participants (≥18 years; negative for current SARS-CoV-2 infection) received 2 intravenous 4500-mg pemivibart infusions (cohort A) or were randomized 2:1 to receive blinded pemivibart or placebo (cohort B) 90 days apart. Safety was a primary endpoint for both cohorts. The primary immunobridging endpoint for cohort A has previously been reported. Composite incidence of reverse transcription-polymerase chain reaction-confirmed symptomatic COVID-19, COVID-19 hospitalization, and all-cause mortality was an exploratory endpoint.

RESULTS: In September-November 2023, 306 participants received pemivibart (cohort A); 317 received pemivibart and 162 placebo (cohort B). The most common study drug-related adverse events were infusion-related reactions (cohort A: 11/306 [3.6%]; cohort B: 7/317 [2.2%, pemivibart] and 0/162 [placebo]). Four of 623 (0.6%) participants who received pemivibart experienced anaphylactic reactions (2 serious). In cohort A, the composite COVID-19 incidence through month 6 was 11/298 (3.7%; 2 deaths). In cohort B, 6/317 (1.9%; no deaths) and 19/160 (11.9%; no deaths) pemivibart and placebo participants, respectively, met the endpoint through month 6 (84.1% standardized relative risk reduction [RRR; 95% CI, 60.9-93.5; nominal P<.0001]), and 15/317 (4.7%; 1 death) and 29/160 (18.1%; no deaths) pemivibart and placebo participants, respectively, met the endpoint through month 12 (73.9% standardized RRR [95% CI, 52.8-85.6; nominal P<.0001]). Twelve month protection was conferred with no additional dosing.

CONCLUSIONS: Pemivibart provided prophylactic efficacy against COVID-19 and was well-tolerated by most participants. Anaphylaxis was an important safety risk.

CLINICAL TRIALS REGISTRATION: NCT06039449.

PMID:40410927 | DOI:10.1093/cid/ciaf265

Sci Rep. 2025 May 23;15(1):17993. doi: 10.1038/s41598-025-02333-z.

ABSTRACT

Over the years, toxicity prediction has been a challenging task. Artificial intelligence and machine learning provide a platform to study toxicity prediction more accurately with a reduced time span. An optimized ensembled model is used to contrast the results of seven machine learning algorithms and three deep learning models with regard to state-of-the-art parameters. In the paper, optimized model is developed that combined eager random forest and sluggish k star techniques. State-of-the-art parameters have been evaluated and compared for three scenarios. In first scenario with original features, in the second scenario using feature selection and resampling technique with the percentage split method, and in the third scenario using feature selection and resampling technique with 10-fold cross-validation. The principal component analysis is performed for feature selection. An optimized ensembled model performs well in comparison to other models in all three scenarios. It achieved an accuracy of 77% in the first scenario, 89% in the second scenario, and 93% in the third scenario. The proposed model shows the performance increase in accuracy by 8% as compared to the top performer Kstar machine learning model and 21% as compared to deep learning model AIPs-DeepEnC-GA which is remarkable. Also there is significant improvement in other important evaluation parameters in comparison to top performing models. Further concept of W-saw score and L-saw is presented for all the scenarios. An optimized ensembled model using feature selection and resampling technique with tenfold cross-validation performs best among all machine learning models in all the scenarios.

PMID:40410277 | DOI:10.1038/s41598-025-02333-z

BMC Cancer. 2025 May 22;25(1):917. doi: 10.1186/s12885-025-14342-2.

ABSTRACT

OBJECTIVE: This study aimed to analyze the characteristics of adverse reactions in cancer patients treated with Pembrolizumab based on the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) database, and to assess the characteristics and risk factors of fatality reports.

METHODS: The study data was sourced from the FAERS database, collecting adverse event reports related to Pembrolizumab from 2013 to June 2024. The main analysis variables included gender, age, cancer type, country, reporter type, and adverse reaction outcomes. Descriptive statistics, univariate analysis, and multivariate Logistic regression models were used to assess the relationship between each variable and fatal outcome.

RESULTS: A total of 46,883 adverse reactions were collected, including 5,483 reports with fatal outcomes. The number of events has been increasing since 2013, especially peaking in 2022 and 2023. The United States and Japan had the highest number of adverse reaction reports. The number of serious events reported increased significantly with age, especially in the 51-65 and 66-80 age groups. The age of patients who died was concentrated in the elderly group (≥ 65 years old), and the median treatment duration time of pembrolizumab was 17 days. Analysis showed that gender (OR = 0.75; 95%CI: 0.71-0.80, p < 0.01), age (OR = 0.89; 95%CI: 0.84-0.96, p < 0.01), and ingredients count (OR = 1.92; 95%CI: 1.84-2.01, p < 0.01) were significantly associated with the treatment duration of pembrolizumab.

CONCLUSION: The serious adverse reactions in cancer patients treated with Pembrolizumab are closely related to patient individual characteristics and cancer types. It is necessary to strengthen the monitoring of high-risk groups such as the elderly in clinical treatment to reduce the risk of fatal outcomes.

PMID:40405105 | DOI:10.1186/s12885-025-14342-2

Stat Med. 2025 May;44(10-12):e70059. doi: 10.1002/sim.70059.

ABSTRACT

Intra-patient dose escalation (IPDE) provides a strategy for more efficient Phase I clinical trials. However, IPDE poses additional challenges due to the need to account for carryover toxicity from previous dosings a patient has received. To that end, we propose two CRM-based approaches to IPDE that incorporate potential carryover toxicity. We compare these methods to the CRM without IPDE and the AIDE-CRM, an existing Bayesian adaptive approach to IPDE. In simulations across a range of scenarios, we show that our approaches have similar operating characteristics to the CRM without IPDE, but with a 20% reduction in time and participants needed to complete the trial; these results hold even in the presence of strong carryover toxicity that hinders the performance of the AIDE-CRM.

PMID:40405047 | DOI:10.1002/sim.70059

Ther Drug Monit. 2025 May 22. doi: 10.1097/FTD.0000000000001343. Online ahead of print.

ABSTRACT

BACKGROUND: Neuropsychiatric toxicity is a common adverse effect of antibiotics. Advanced age, renal insufficiency, high drug doses, and prolonged therapy are relevant risk factors, suggesting that this event might be caused due to the accumulation of antibiotics in the central nervous system. In this review, the authors aimed to evaluate the potential role of therapeutic drug monitoring in identifying patients at risk of antibiotic-induced neuropsychiatric toxicity.

METHODS: A MEDLINE PubMed search was conducted for articles published between January 1990 and December 2024, matching the terms "pharmacokinetics" or "therapeutic drug monitoring" with "antibiotics" (including individual drug classes) and "neurotoxicity" (including synonyms). Additional studies were identified from the reference lists of retrieved articles.

RESULTS: Significant associations have been reported between plasma concentrations of some beta-lactam antibiotics (ceftazidime, cefepime, piperacillin, and meropenem) or linezolid and drug-induced central nervous system adverse events (such as seizures, encephalopathy, peripheral neuropathy, and optic neuropathy). Safety thresholds of plasma concentrations have been proposed for these drugs.

CONCLUSIONS: Consistent data on the associations between plasma drug concentrations and neuropsychiatric disorders are available only for some antibiotics, whereas for others, there are few and often inconsistent data, hindering the establishment of therapeutic drug monitoring-based safety thresholds for these antibiotics.

PMID:40403142 | DOI:10.1097/FTD.0000000000001343

Expert Opin Investig Drugs. 2025 May 22. doi: 10.1080/13543784.2025.2510664. Online ahead of print.

ABSTRACT

BACKGROUND: BI 764,198 is a selective, oral transient receptor potential cation channel, subfamily C, member 6 inhibitor under investigation for focal segmental glomerulosclerosis.

RESEARCH DESIGN AND METHODS: Phase I study in 44 Japanese male volunteers. Single dose part: BI 764,198 20 mg (n = 6) vs. placebo (n = 2); multiple dose part: BI 764,198 40, 80, or 160 mg (n = 9 each) or placebo (n = 9) as a single dose then multiple daily dosing for 2 weeks. Primary endpoint: participants with drug-related adverse events (DRAEs); secondary endpoints: pharmacokinetic.

RESULTS: DRAEs were reported in 20.5% (9/44) of participants (total BI 764,198 21.2% [7/33]; placebo 18.2% [2/11]), mostly diarrhea (total BI 764,198 15.2% [5/33]; placebo 18.2% [2/11]) and headache (BI 764,198 80 mg 11.1% [1/9]; BI 764,198 160 mg 33.3% [3/9]). BI 764198 exposure increased near dose proportionally to 80 mg and was slightly higher than anticipated with 160 mg. Pharmacokinetics were similar in Asians and non-Asians after accounting for body weight. Limitations include small sample size per dose and short trial duration.

CONCLUSIONS: BI 764,198 was well tolerated; exposure increased near dose proportionally to 80 mg, as previously observed in predominantly White volunteers.

CLINICAL TRIAL REGISTRATION: This study was registered on Clinical Trials.gov, identifier NCT04665700.

PMID:40402558 | DOI:10.1080/13543784.2025.2510664

J Nurs Manag. 2025 May 14;2025:9921349. doi: 10.1155/jonm/9921349. eCollection 2025.

ABSTRACT

Background: Adverse drug reactions (ADRs), particularly in the context of polypharmacy, remain a persistent, unresolved problem for patients and healthcare professionals. The ADRe Profile identifies medicine-related harms, and supports their resolution, thereby improving care quality and preventing future problems. Objective: The objective of this study was to assess the validity and reliability of the ADRe Profile (https://www.swansea.ac.uk/adre/) in U.K. primary care general practices, building on assessments in other settings. Methods: The ADRe Profile's validity and reliability were investigated using complementary mixed methods: content validity index, contrast group construct validity, cognitive interviewing, and inter-rater reliability. Results: Cognitive interviews (n = 5) confirmed that the ADRe Profile needed only minor adjustments. The scale-level content validity index was 0.67 (n = 14), items ranging from 0.08 to 1. Significant differences in signs and symptoms associated with ADRs between service users taking different numbers of regular prescribed medicines confirmed construct validity (n = 68, U = 870.50, p < 0.001). Inter-rater reliability testing showed substantial agreement between service users and research nurse: 10 items had 100% agreement. Overall kappa mean was 0.71 (range: 0.31-1), (n = 42). Conclusions and Relevance: The ADRe Profile is suitable for use with older service users in primary care who live at home. Users understood the questions and provided meaningful answers. ADRe Profile responses were sufficiently reliable to be used as a basis for further investigations, prescriber referral and clinical actions. However, clinician judgement of content validity may depend on knowledge and experience, highlighting the importance of training. Clinicians acknowledged that the ADRe Profile was comprehensive but identified practical difficulties. Instruments to reduce ADRs should be validated before testing in feasibility studies and randomised controlled trials. Implications for Nursing Management: Managers need to optimise patient safety by introducing patient-centred symptom monitoring, with decision support. Before instruments are adopted, managers should check the reliability and validity data. Trial Registration: ClinicalTrials.gov identifier: NCT04663360.

PMID:40401039 | PMC:PMC12094870 | DOI:10.1155/jonm/9921349

Hosp Pharm. 2025 May 19:00185787251337621. doi: 10.1177/00185787251337621. Online ahead of print.

ABSTRACT

Background: Tendinopathies and ligament disorders are significant musculoskeletal adverse events associated with various drugs, leading to restricted mobility and reduced quality of life. Although certain drug classes such as fluoroquinolones and corticosteroids have established links to these conditions, there is limited research on other potential drug associations. This study aimed to comprehensively evaluate drugs associated with tendinopathies and ligament disorders using data from the USFDA Adverse Event Reporting System (AERS). Methods: A retrospective pharmacovigilance study utilizing spontaneous reports from the USFDA AERS database between March 2004 and June 2024 was conducted. The Standardized Medical Dictionary for Regulatory Activities (MedDRA) query "Tendinopathies and ligament disorders" and relevant Preferred Terms were used to identify cases. Disproportionality analysis was performed using both frequentist and Bayesian methods. Subgroup analyses were conducted by age, gender, and clinical outcomes. Results: Out of 29 153 222 reports, 40 485 unique reports were included, with 6641 related to tendon rupture and 2121 to ligament rupture. Fluoroquinolones, corticosteroids, lipid-modifying agents, immunosuppressants, and bisphosphonates were confirmed to have strong associations with tendon and ligament disorders. Emergent signals were identified for anti-inflammatory drugs, and various other drugs, including vaccines. Hospitalization rates were significantly higher in cases of tendon rupture compared to ligament rupture (P < .0001). Conclusion: This study confirms established drug associations and identifies new signals for tendinopathies and ligament disorders. Continued pharmacovigilance is necessary to validate these findings and enhance our understanding of drug-induced musculoskeletal disorders.

PMID:40400906 | PMC:PMC12089119 | DOI:10.1177/00185787251337621

Front Med (Lausanne). 2025 May 7;12:1467001. doi: 10.3389/fmed.2025.1467001. eCollection 2025.

ABSTRACT

Drug-induced pneumonia is a rare and potentially life-threatening adverse drug reaction. Moxifloxacin is a fluoroquinolone antibiotic with broad-spectrum antimicrobial activity. Despite reports of moxifloxacin-related side effects such as interstitial nephritis, recurrent tendinitis, and pseudoallergic reactions, moxifloxacin-induced pneumonia is exceedingly rare. We report the case of a 45-year-old male who developed fever and cough, and progressed to hypersensitivity syndrome related to drug-induced pneumonia following moxifloxacin therapy. Discontinuation of moxifloxacin led to resolution of fever with significant resolution of pulmonary lesions. Comprehensive laboratory investigations ruled out other causes, confirming drug-induced pneumonia due to moxifloxacin. This case report provides typical clinical manifestations and pulmonary imaging changes, as well as an analysis of differential diagnosis of pulmonary lesions and key management strategies. The case and related literature review contribute to enhancing our understanding of moxifloxacin-related pneumonia, with important clinical significance in promptly correcting adverse reactions and improving patient outcomes.

PMID:40400635 | PMC:PMC12092464 | DOI:10.3389/fmed.2025.1467001