Open Forum Infect Dis. 2025 Jul 16;12(7):ofaf356. doi: 10.1093/ofid/ofaf356. eCollection 2025 Jul.

ABSTRACT

BACKGROUND: Females and persons of Black race are often underrepresented in clinical trials. This post hoc analysis of data from three phase 3 studies evaluated the efficacy and safety of doravirine (DOR) by sex and race in adults living with HIV-1.

METHODS: DRIVE-FORWARD and DRIVE-AHEAD open-label extensions were pooled; participants randomized to first-line DOR-based regimen continued from week (W) 96 to W192 (DOR-continued group) and participants randomized to comparators switched to DOR from W96 to W192 (DOR-switch group). In DRIVE-SHIFT, virologically suppressed adults were randomized to switch to a DOR-based regimen on day 1 (immediate-switch group) or W24 (delayed-switch group) and continued through W144. Results are reported by sex assigned at birth (male vs female) and race (Black vs non-Black).

RESULTS: Across trials, female and Black participants each represented <20% of study populations. After continuing or switching to DOR, percentages of participants with HIV-1 RNA <50 copies/mL were comparable between sex and race subgroups. Mean changes in CD4+ T-cell counts and proportions of participants with drug-related adverse events or serious adverse events were generally similar between subgroups. In DRIVE-SHIFT, higher rates of nontreatment-related discontinuations were observed within Black versus non-Black subgroups. Differences in median weight change were generally larger between race subgroups than sex subgroups, although interquartile ranges were wide for all.

CONCLUSIONS: Participants who continued or switched to DOR generally had comparable efficacy and safety outcomes across sex and race subgroups. However, the sample size was limited. Future studies should ensure greater diversity when investigating factors leading to outcome disparities. ClinicalTrials.gov: NCT02275780, NCT02403674, NCT02397096.

PMID:40672760 | PMC:PMC12264332 | DOI:10.1093/ofid/ofaf356

Nat Med. 2025 Jul 16. doi: 10.1038/s41591-025-03781-w. Online ahead of print.

ABSTRACT

Claudin-18 isoform 2 (CLDN18.2), a tight junction protein expressed in non-malignant gastric epithelium and exposed on tumor cell surface during malignant transformation, is a promising therapeutic target for gastric and gastroesophageal junction (G/GEJ) cancers. SHR-A1904 is an antibody-drug conjugate comprising CLDN18.2-targeting monoclonal antibody, a DNA topoisomerase I inhibitor payload and a cleavable peptide-based linker. We conducted a first-in-human, three-stage, phase 1 study to evaluate SHR-A1904 in 95 previously treated patients with CLDN18.2-positive advanced G/GEJ cancer. In the dose-escalation stage (0.6-8.0 mg kg-1), dose-limiting toxicities were observed in two patients at 4.8 mg kg-1 (grade 3 febrile neutropenia and grade 3 increased blood bilirubin) and in one patient at 6.0 mg kg-1 (grade 3 gastric mucosal lesion). The maximum tolerated dose was not reached, and 6.0 mg kg-1 and 8.0 mg kg-1 were selected for pharmacokinetic and efficacy expansion. Treatment-emergent adverse events occurred in all 95 patients, most commonly anemia (72 (75.8%)), nausea (64 (67.4%)), hypoalbuminemia (61 (64.2%)) and decreased white blood cell count (56 (58.9%)). Additionally, 59 patients (62.1%) experienced drug-related grade 3 or higher adverse events. No treatment-related deaths were reported. Among response-evaluable patients, the confirmed objective response rate was 24.2% (95% confidence interval (CI), 11.1-42.3) at 6.0 mg kg-1 and 25.0% (95% CI, 12.1-42.2) at 8.0 mg kg-1. The median progression-free survival was 5.6 months (95% CI, 3.0-6.9) at 6.0 mg kg-1 and 5.8 months (95% CI, 3.0-8.6) at 8.0 mg kg-1. In conclusion, SHR-A1904 demonstrated a manageable safety profile and encouraging anti-tumor activity in patients with CLDN18.2-positive G/GEJ cancer, warranting further investigation. ClinicalTrials.gov identifier: NCT04877717 .

PMID:40670772 | DOI:10.1038/s41591-025-03781-w

Future Sci OA. 2025 Dec;11(1):2528490. doi: 10.1080/20565623.2025.2528490. Epub 2025 Jul 16.

ABSTRACT

Epilepsy, a prevalent neurological disorder, is characterized by recurring seizures due to atypical neural activity, impacting millions globally. Epileptic seizures are the sudden, involuntary jerking or trembling movements caused by abnormal neural activity and may lead to damage in the brain or other parts of the body. Although epilepsy is usually manageable with anti-seizure medications (ASMs), a considerable subset of patients experiences drug resistance or suboptimal treatment responses, highlighting the need for a more elaborate approach to therapy. Studies show that genetic factors significantly influence not only the susceptibility to epilepsy but also the variability in individual responses to ASMs. This signifies the importance of personalized medicine in optimizing treatment guidelines based on genetic profiles. This review examines the pharmacogenetic factors influencing the efficacy and safety of anti-ASMs in Arab populations. In populations across Saudi Arabia, Jordan, Egypt, Tunisia, and Iraq, genetic testing for variants in genes like MTHFR, MDR1, ABCB1, miR-146a, GABARG2, IL-1β, EPHX1, and CYP3A422 can predict drug resistance, and response, improve drug dosing, and minimize ADRs. Clinicians can personalize therapy by employing specific genetic markers associated with drug metabolism and efficacy, leading to better treatment outcomes and reduced risk of drug-induced complications.

PMID:40667778 | DOI:10.1080/20565623.2025.2528490

J Int Assoc Provid AIDS Care. 2025 Jan-Dec;24:23259582251358929. doi: 10.1177/23259582251358929. Epub 2025 Jul 15.

ABSTRACT

ObjectiveAdverse drug reactions (ADRs) induce iatrogenic harm in antiretroviral therapy (ART) care continuum. However, there is a dearth of concrete evidence in a resource-limited setting. Thus, this study was designed to consolidate existing knowledge, thereby informing policy and clinical care to improve patient safety.DesignSystematic review and meta-analysis.Data sourcesPubMed, CINAHL, Web of Science, and EMBASE databases were searched.Eligibility criteriaEmploying the condition, context, and population framework, observational primary studies were included.Data extraction and synthesisIndependent reviewers undertook data extraction and synthesis. This meta-analysis employed the random-effects restricted maximum likelihood (REML) method, with its protocol preregistered on the International Register of Systematic Reviews (CRD42024546390).ResultsThe pooled prevalence of ADRs was 36.7% [95% CI: 26.6-46.9, I2 = 99.64%].ConclusionAltogether, this study revealed that ART-related ADRs in Ethiopia was 36.7%, underscoring rigorous monitoring. Giving special emphasis to patients with female gender, advanced disease, comorbidities, malnutrition, TB treatment, and poor adherence is a prudent decision.

PMID:40665675 | DOI:10.1177/23259582251358929

BMC Med Inform Decis Mak. 2025 Jul 15;25(1):265. doi: 10.1186/s12911-025-03107-3.

ABSTRACT

BACKGROUND: Drug-induced immune thrombocytopenia (DITP) is a rare but potentially life-threatening adverse drug reaction, often underrecognized due to its nonspecific presentation and the lack of real-time diagnostic tools. Early identification of at-risk patients is critical to improving medication safety and preventing severe complications.

OBJECTIVE: To develop and externally validate a machine learning model for predicting the risk of DITP using routinely collected hospital data, and to optimize its clinical applicability through threshold adjustment.

METHODS: We conducted a retrospective cohort study using electronic medical records from Hai Phong International Hospital (2018-2024) for model development and internal validation. An independent cohort from Hai Phong International Hospital - Vinh Bao (2024) served as external validation. Eligible patients received at least one drug previously implicated in DITP and had serial platelet counts. A Light Gradient Boosting Machine (LightGBM) model was trained on demographic, clinical, laboratory, and pharmacological features. Model performance was assessed using area under the ROC curve (AUC), accuracy, recall, and F1-score. Shapley Additive explanations (SHAP) were used to interpret feature contributions. Threshold tuning and decision curve analysis (DCA) supported clinical applicability.

RESULTS: Among 17,546 patients in the training cohort and 1,403 in the external cohort, DITP occurred in 432 (2.46%) and 70 (4.99%) patients, respectively. In internal validation, LightGBM achieved an AUC of 0.860, recall of 0.392, and F1-score of 0.310. External validation confirmed model robustness with an AUC of 0.813 and an F1-score of 0.341 at the optimized threshold (0.09). SHAP analysis identified AST, baseline platelet count, and renal function as key contributors. DCA and clinical impact curves demonstrated potential benefit in supporting real-time risk stratification. Clopidogrel and vancomycin were frequently associated with suspected DITP cases.

CONCLUSION: This externally validated machine learning model enables early identification of hospitalized patients at risk of DITP using data available in routine care. Its integration into electronic medical records may support clinical decision-making, reduce diagnostic delays, and improve pharmacovigilance practices in hospital settings.

PMID:40665302 | DOI:10.1186/s12911-025-03107-3

Sci Rep. 2025 Jul 15;15(1):25572. doi: 10.1038/s41598-025-09472-3.

ABSTRACT

Clozapine is an atypical antipsychotic used for patients with treatment-resistant schizophrenia. This drug has serious adverse drug reactions (ADRs), including the risk of severe neutropenia (agranulocytosis). Patients who could benefit from clozapine may not be administered it due to concerns about monitoring ADRs. In addition, traditional toxicological assessments cannot predict clozapine-induced agranulocytosis. Predicting agranulocytosis could improve patient safety. Our study aimed to develop and validate machine learning (ML) models for predicting agranulocytosis in clozapine-prescribed patients using the Canada Vigilance Adverse Reaction Online Database (n = 9395 reports). We addressed the class imbalance (337 agranulocytosis-positive cases vs. 9058 agranulocytosis-negative cases) through systematically evaluating resampling techniques and selecting appropriate performance metrics for rare event prediction. Five ML algorithms were evaluated on a hold-out test set. The best-performing model was the Gradient Boosting with Synthetic Minority Over-sampling technique (GB-SMOTE), achieving recall (sensitivity) of 0.85, AUC-PR (area under the precision-recall (PR) curve) of 0.77, PPV (Positive Predictive Value) of 0.40 and a Matthews Correlation Coefficient of 0.56. SHAP feature analysis identified blood and lymphatic system disorders, leukocytosis, and neutropenia as the strongest predictors. Our results demonstrate the potential of ML for predicting clozapine-induced agranulocytosis and provide a framework for developing pharmacovigilance prediction models. This is clinically important and relevant to the management of schizophrenia, which remains a chronic disease with high morbidity and mortality.

PMID:40665079 | DOI:10.1038/s41598-025-09472-3

PLoS One. 2025 Jul 15;20(7):e0328371. doi: 10.1371/journal.pone.0328371. eCollection 2025.

ABSTRACT

BACKGROUND: Bile acid sequestrants (BASs), including cholestyramine, colestipol, and colesevelam, are widely used in endocrine and gastrointestinal disorders. However, their long-term safety remains under-characterized. This study leveraged real-world pharmacovigilance data to evaluate underreported and subclass-specific adverse events (AEs) associated with BASs.

METHODS: We analyzed 5,286 AE reports related to BASs from the FDA Adverse Event Reporting System (2004-2024) using four disproportionality methods: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS). AE signals were assessed at both the System Organ Class (SOC) and Preferred Term (PT) levels. Time-to-onset (TTO) analysis was also performed.

RESULTS: All three BASs showed prominent gastrointestinal AEs. Cholestyramine was notably associated with oropharyngeal irritation (e.g., throat irritation, ROR = 21.89; oropharyngeal discomfort, ROR = 36.53), while colestipol presented mechanical risks such as dysphagia (ROR = 21.51) and choking (ROR = 67.44). Colesevelam exhibited musculoskeletal toxicity, including myalgia (ROR = 4.74) and muscle spasms (ROR = 3.43). Consensus signals across all methods further revealed novel AEs such as dysgeusia, dental abnormalities, gastroesophageal reflux disease, and fecaloma. TTO analysis showed that most AEs occurred within the first month of therapy, with 15-16% persisting beyond 6 months.

CONCLUSION: This large-scale FAERS study updates the safety profiles of BASs, highlighting distinct risk patterns and delayed complications. The findings support personalized monitoring strategies that consider both drug-specific characteristics and temporal AE patterns.

PMID:40663524 | DOI:10.1371/journal.pone.0328371

Hum Vaccin Immunother. 2025 Dec;21(1):2530831. doi: 10.1080/21645515.2025.2530831. Epub 2025 Jul 15.

ABSTRACT

GARDASIL 9, a 9-valent HPV vaccine approved in 2014, is widely administered for the prevention of HPV-related malignancies. Although clinical trials demonstrated a favorable safety profile, rare or delayed-onset adverse events may not be captured pre-licensure. Post-marketing surveillance using VAERS offers a complementary approach for signal detection and safety monitoring. We conducted a retrospective pharmacovigilance analysis of VAERS reports following GARDASIL 9 administration from January 1, 2015 to December 31, 2024. Adverse events were encoded using MedDRA v26.0 and categorized by System Organ Class. Disproportionality analyses using four independent algorithms (ROR, PRR, IC, EBGM) were applied to identify positive safety signals. Subgroup assessments included serious reports, death reports, and reports in pregnant individuals. Among reported events, most were non-serious and consistent with known reactogenicity patterns, including syncope, headache, and injection site reactions. However, signals were also detected for certain events not listed in product labeling, including postural orthostatic tachycardia syndrome, eye movement disorder, autoimmune thyroiditis, and posture abnormality. In 57 death reports, neurological terms showed signal elevation but lacked consistent etiologic patterns. No positive signals were detected in the 18 pregnancy-associated reports. This VAERS-based analysis supports the established safety of GARDASIL 9 while highlighting rare signals that warrant further investigation. Given the limitations of passive surveillance, integration with active monitoring systems is essential to refine safety profiles and support ongoing public health vaccination efforts.

PMID:40662677 | DOI:10.1080/21645515.2025.2530831

Int Clin Psychopharmacol. 2025 Jul 16. doi: 10.1097/YIC.0000000000000596. Online ahead of print.

ABSTRACT

This 6-month open-label extension (OLE) period of a Phase 3 placebo-controlled study (NCT02600494) examined the safety of lumateperone in patients with bipolar I or bipolar II depression. Eligible patients completing the placebo-controlled period received lumateperone 42 mg once daily up to 175 days. The primary endpoint was safety and tolerability, assessed by adverse events (AEs) and clinical laboratory evaluations analyzed by imputing missing data using a last observation carried forward approach. The secondary endpoint was efficacy measured by Montgomery-Åsberg Depression Rating Scale (MADRS) total and Clinical Global Impression Scale-Bipolar Version-Severity (CGI-BP-S) scores. Of 127 patients in the OLE, 58.3% completed treatment, and 42.5% experienced a drug-related treatment-emergent AE (TEAE); the most common TEAEs were headache (20.5%), dry mouth (11.8%), dizziness (10.2%), and nausea (10.2%). The majority (92%) of TEAEs were of mild or moderate severity. There were no notable changes in extrapyramidal symptom scores, cardiometabolic parameters, or body morphology. MADRS total score (mean change, -8.9, nominal P < 0.0001), CGI-BP-S total score (-2.3, nominal P < 0.0001), and CGI-BP-S depression subscore (-1.3, nominal P < 0.0001) improved over time, from baseline to Day 175. Overall, 6-month lumateperone 42 mg was generally well tolerated, and depressive symptoms based on MADRS total score and CGI-BP-S improved over time.

PMID:40662488 | DOI:10.1097/YIC.0000000000000596

Dis Esophagus. 2025 Jul 3;38(4):doaf055. doi: 10.1093/dote/doaf055.

ABSTRACT

Dupilumab, the first biologic approved for eosinophilic esophagitis treatment (EoE-tx) in 2022, demonstrated favorable safety in phase-III clinical trials. However, real-world dupilumab-associated adverse reactions (DARs) for EoE-tx are unknown. This study aims to evaluate DAR for EoE-tx using the FDA Adverse Event Reporting System. FDA Adverse Event Reporting System was queried for DAR between 2022Q1 and 2023Q4. Individual DARs (iDARs) were categorized and compared between treatment groups: EoE, asthma, atopic dermatitis, and chronic rhinosinusitis with nasal polyps. Logistic regression was used to predict serious DAR and outcomes, and zero-truncated negative binomial regression was used to predict the number of iDAR. There were 51,000 DAR observations; 1459 for EoE-tx with 103 (7.1%) serious reactions and 44 (3.0%) serious outcomes including 3 deaths. For EoE-tx, the mean iDAR was 3.68 [3.51, 3.85], and the iDAR incidence rate ratio among men receiving EoE-tx was 0.73 [0.65, 0.83]. EoE-tx average iDAR primarily included general (0.75 [0.70, 0.80]), injection-site (0.69 [0.63, 0.74]), dermatologic (0.51 [0.46, 0.55]), and gastrointestinal (0.24 [0.21, 0.27]) reactions. Adults ≥50 years had 1.97 [1.28, 2.99] higher odds for serious DAR compared to younger adults in EoE-tx. Overall, dupilumab demonstrated a favorable safety profile across all indications, with low rates of serious adverse events. For EoE-tx specifically, higher total iDAR rates were observed, driven largely by increased injection-site and gastrointestinal reactions compared to other indications. Additionally, women exhibited higher iDAR rates than men across all indications.

PMID:40662440 | DOI:10.1093/dote/doaf055

Invest Radiol. 2025 Jul 15. doi: 10.1097/RLI.0000000000001224. Online ahead of print.

ABSTRACT

OBJECTIVE: To comprehensively analyze worldwide safety data of gadoxetate disodium after 20 years of use and to review its reclassification from group III to group II on the American College of Radiology (ACR) nephrogenic systemic fibrosis (NSF)-risk classification scheme.

MATERIALS AND METHODS: Two safety data sets were analyzed: 23 clinical phase I to IV studies and Bayer pharmacovigilance database (PV) from 2004 to 2024. In addition, a literature review on NSF reports with special focus on patients with different degrees of renal impairment was performed. Patients' exposure was based on the assumption that one vial or prefilled syringe was given to each patient for each procedure, with an estimated total of over 12 million administrations. The primary target variable was the number, frequency and characteristics of unrelated/related adverse events (AEs) in clinical studies and adverse drug reactions (ADRs) reported to PV. Incidence and reporting rates were analyzed by descriptive statistical methods.

RESULTS: A total of 10,282 patients were included in clinical phase I to IV studies. Drug-related AEs were reported in 6% and 1.7% in phase III and IV studies, respectively. Nine (0.11%) related serious adverse events (SAEs) were recorded in phase IV, none in phase III. The most frequently recorded AEs (related or unrelated to drug) in phases I to III were nausea (1.4%) and headache (1.2%). All other AEs were reported ≤ 1.0%. In phase IV, dyspnea (0.34%) and nausea (0.28%) (related or unrelated) were most frequently reported. More than 12 million doses of gadoxetate were administered according to sales data. Most frequently reported ADRs from the PV were hypersensitivity reactions (reporting rate 0.0147%), nausea (0.0029%) and pain (0.0019%). Exposure increased steadily from 16,578 administrations in 2006 to 1,289,979 per year by December 31, 2024. Conversely, the ADR rate decreased from 0.21% in 2006 to ≤0.05% in 2011 through 2024. No report diagnostic of or consistent with NSF was documented, even in patients with renal impairment.

CONCLUSION: Liver-specific gadoxetate disodium demonstrated a favorable safety profile in patients independent of their renal function. No report diagnostic of or consistent with NSF has been reported with over 20 years of use. The well-established benefit/risk profile of gadoxetate disodium prompted the ACR to reclassify it from group III to group II as of April 2024.

PMID:40662395 | DOI:10.1097/RLI.0000000000001224

Ann Behav Med. 2025 Jan 4;59(1):kaaf048. doi: 10.1093/abm/kaaf048.

ABSTRACT

BACKGROUND: Receiving negative instructions and observing another's adverse treatment-related experience can lead to worsened health outcomes via the nocebo effect. However, it is unknown whether the observation of a positive treatment-related experience can mitigate these effects.

PURPOSE: To investigate whether a positive social modeling intervention can reduce nocebo side effects induced by instruction and social modeling.

METHODS: Participants (N = 160) were told the study assessed a new cognitive enhancer (actually a placebo). Participants received side effect warnings and viewed an informational video describing the medication. Placebo-treated groups were randomized to either watch an additional clip where a peer reported a positive experience with no side effects or not. These groups were further randomized to either encounter a live model exhibiting side effects or not. A Natural History group did not view any modeling nor receive the placebo. The primary outcome was the severity of side effects.

RESULTS: A significant nocebo effect was observed, with increased symptom severity in placebo-treated groups compared to the Natural History group. The positive social modeling intervention (i.e., viewing a peer experience no side effects) significantly reduced symptom severity. No significant difference in symptom severity was found between instruction alone and instruction with side effect modeling, nor was there an interaction between the induction method and the positive social modeling intervention.

CONCLUSIONS: Positive social modeling reduces nocebo side effects induced by instruction alone and instruction with side effect modeling. Positive social modeling may be an effective method to mitigate the burden of nocebo side effects in clinical settings.

PMID:40662257 | DOI:10.1093/abm/kaaf048

MedComm (2020). 2025 Jul 13;6(7):e70288. doi: 10.1002/mco2.70288. eCollection 2025 Jul.

ABSTRACT

HER2 expression is correlated with diminished efficacy of Bacillus Calmette-Guérin (BCG) instillation in high-risk non-muscle-invasive bladder cancer (HR-NMIBC). The development of effective intravesical treatments for HER2-expressing HR-NMIBC is of great urgency. In this single-arm phase I trial (ChiCTR2300073975), HER2-expressing HR-NMIBC patients received an induction course of weekly intravesical Disitamab vedotin (RC48) following a 3+3 design (60, 120, or 180 mg) for 6 weeks, followed by optional maintenance dose monthly for 11 sessions. The primary objective was to assess the safety and tolerability of intravesical RC48. The secondary objective was to determine the oncological outcomes. Between August 2023 and March 2024, nine patients were enrolled, and all completed the induction course without dose-limiting toxicities (DLTs) or grade ≥3 drug-related adverse events (AEs). The reported drug-related AEs included urinary tract infection (55.6%, 5/9), urinary frequency (11.1%, 1/9), and hematuria (11.1%, 1/9). The 6-month and 12-month recurrence-free survival (RFS) rates were 100% (8/8) and 87.5% (7/8), respectively, whereas the progression-free survival (PFS) rates were 100% (8/8) and 100% (8/8). Taken together, these findings indicate that intravesical RC48 was well tolerated and showed preliminary efficacy in HER2-expressing HR-NMIBC. The maximum tolerated dose was not reached, and further dose exploration is ongoing (NCT06378242).

PMID:40661136 | PMC:PMC12256569 | DOI:10.1002/mco2.70288

Drug Ther Bull. 2025 Jul 14:dtb-2025-000029. doi: 10.1136/dtb.2025.000029. Online ahead of print.

NO ABSTRACT

PMID:40659495 | DOI:10.1136/dtb.2025.000029

Drug Ther Bull. 2025 Jul 14:dtb-2025-000030. doi: 10.1136/dtb.2025.000030. Online ahead of print.

NO ABSTRACT

PMID:40659494 | DOI:10.1136/dtb.2025.000030

Naunyn Schmiedebergs Arch Pharmacol. 2025 Jul 14. doi: 10.1007/s00210-025-04406-2. Online ahead of print.

ABSTRACT

BACKGROUND: Hypertriglyceridemia and hypercholesterolemia are well-known risk factors for atherosclerotic cardiovascular disease (ASCVD), especially in patients already at elevated cardiovascular risk. Despite current treatment approaches, including lifestyle changes and medication, many individuals do not reach ideal lipid levels, emphasizing the need for new therapeutic options. Olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III (ApoC-III) synthesis, has emerged as a promising candidate to reduce residual cardiovascular risk in these patients.

AIM: This systematic review and meta-analysis aimed to assess the effectiveness and safety of different dosages of Olezarsen in patients with high-risk hypertriglyceridemia. Additionally, it explored whether varying dosage regimens impacted lipid outcomes and adverse events.

METHODS: Following PRISMA guidelines, a comprehensive search was conducted in PubMed, Scopus, Web of Science, and Cochrane Library for randomized controlled trials (RCTs) published in English. The studies included compared different doses of Olezarsen with placebo in high-risk hypertriglyceridemia patients. Primary outcomes were changes in triglycerides (TG), very-low-density lipoprotein cholesterol (VLDL-C), apolipoprotein B (ApoB), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and treatment-emergent adverse events (TEAE). Secondary outcomes included changes in non-HDL-C and total cholesterol (TC). The data were analyzed as mean differences (MD) or odds ratios (OR) using a random-effects model.

RESULTS: Four RCTs (309 participants) were included. The pooled analysis demonstrated significant reductions in TG (MD = -76.11), VLDL-C (MD = -54.95 mg/dL), ApoB (MD = -12.40 mg/dL), non-HDL-C (MD = -18.03 mg/dL), and LDL-C (MD = -10.09 mg/dL) with Olezarsen treatment compared to placebo. Olezarsen also significantly increased HDL-C levels (MD = + 22.60 mg/dL), while total cholesterol remained unchanged. No significant differences in overall adverse events or drug-related adverse events were observed compared to placebo. Subgroup analysis revealed a dose-dependent effect on several lipid parameters without an increase in adverse events with higher doses.

CONCLUSION: Olezarsen effectively improves key lipid parameters, including TG, VLDL-C, ApoB, non-HDL-C, and LDL-C, while also safely raising HDL-C in patients with high-risk hypertriglyceridemia. Total cholesterol remained stable, and no increase in adverse events was noted. Further studies are needed to determine optimal dosing and long-term cardiovascular benefits.

PMID:40658236 | DOI:10.1007/s00210-025-04406-2

Cureus. 2025 Jun 12;17(6):e85873. doi: 10.7759/cureus.85873. eCollection 2025 Jun.

ABSTRACT

Chronic myeloid leukemia (CML) is a myeloproliferative disorder treated with tyrosine kinase inhibitors (TKIs). While TKIs are effective in treating CML, their adverse effects can impact patient management. We present a case of an 83-year-old female diagnosed with CML in August 2024, initially treated with dasatinib but discontinued due to gastrointestinal toxicity. She was later started on imatinib in October 2024. One month later, she presented with progressive weakness and dyspnea, ultimately found to have a large pleural effusion requiring intervention. This case highlights the challenges in managing TKI-related adverse effects, particularly in elderly patients.

PMID:40656327 | PMC:PMC12255514 | DOI:10.7759/cureus.85873

Ophthalmol Sci. 2025 Mar 28;5(5):100781. doi: 10.1016/j.xops.2025.100781. eCollection 2025 Sep-Oct.

ABSTRACT

OBJECTIVE: To report safety and early pharmacodynamic results from a first-in-human trial of intravitreal (IVT) anti-semaphorin 3A antibody in participants with diabetic macular ischemia (DMI).

DESIGN: HORNBILL, a phase I/IIa study of BI 764524, comprised a nonrandomized, open-label, uncontrolled, single-rising-dose (SRD) and masked, randomized, sham-controlled, multiple-dose (MD) parts.

PARTICIPANTS: Adults with DMI and stable diabetic retinopathy (DR) treated with pan-retinal photocoagulation and without center-involving diabetic macular edema.

METHODS: Twelve participants received single IVT doses of BI 764524 0.5 mg (n = 3), 1.0 mg (n = 3), or 2.5 mg (n = 6) in the SRD part. Thirty-one participants received 3 IVT doses of BI 764524 2.5 mg (n = 21) or sham procedures (n = 10) at 4-week intervals and were followed to week 22 in the MD part.

MAIN OUTCOME MEASURES: The primary SRD end point was the number of participants with dose-limiting events; secondary end points assessed drug-related and ocular adverse events (AEs). The primary MD end point was the number of participants with drug-related AEs; secondary end points included changes from baseline in foveal avascular zone (FAZ) area, best-corrected visual acuity (BCVA), and central subfield thickness (CST).

RESULTS: No dose-limiting events or drug-related AEs were reported with SRD; the highest tested dose (2.5 mg) was selected for the MD part. In the MD part, 2 investigator-assessed drug-related AEs (vitreous floaters and increased gamma-glutamyl transferase) were reported. No intraocular inflammation or occlusive retinal vasculitis cases occurred. At week 12 (4 weeks after the final injection), the adjusted mean FAZ area change was -0.004 mm2 in the BI 764524 group and +0.019 mm2 with sham. At week 22 (14 weeks after the final injection), the adjusted mean FAZ area change was -0.001 mm2 in the BI 764524 group and +0.010 mm2 with sham. No relevant BCVA and CST changes occurred.

CONCLUSIONS: HORNBILL met the primary safety end points; all evaluated BI 764524 doses were well tolerated. These findings support further investigation of BI 764524 in participants with DR and retinal nonperfusion.

FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

PMID:40655321 | PMC:PMC12246932 | DOI:10.1016/j.xops.2025.100781

Helicobacter. 2025 Jul-Aug;30(4):e70056. doi: 10.1111/hel.70056.

ABSTRACT

BACKGROUND: Rescue treatment for non-naive patients with persistent Helicobacter pylori (H. pylori) infection is lacking, especially in areas where tetracycline is unavailable. This trial aimed to evaluate the efficacy and safety of replacing proton pump inhibitor (PPI) with potassium-competitive acid blocker (P-CAB) in bismuth quadruple therapy (BQT) containing amoxicillin and furazolidone as rescue therapy.

MATERIALS AND METHODS: We conducted a prospective, open-label, noninferiority randomized controlled trial at six institutions in eastern China. A total of 444 patients with a history of H. pylori treatment failure were enrolled and randomly assigned in a 1:1 ratio to either the 14-day P-CAB-BQT group (vonoprazan 20 mg, colloidal bismuth 200 mg, amoxicillin 1000 mg and furazolidone 100 mg, all given twice daily) or the 14-day PPI-BQT group (rabeprazole 10 mg given twice daily, and the same dose of three other drugs as the 14-day P-CAB-BQT group). The primary endpoint was the eradication rate assessed by 13C urea breath test. The secondary endpoints were adverse events and compliance.

RESULTS: H. pylori eradication rates of PPI-BQT versus P-CAB-BQT group were 83.8% versus 91.9% in the intention-to-treat (ITT) analysis (treatment difference: 8.1%; 95% CI: 2.1%-14.1%; non-inferiority p < 0.001, p-value for difference = 0.008); 86.1% versus 95.8% in the modified ITT (MITT) analysis (treatment difference: 9.7%; 95% CI: 4.4%-15.0%; non-inferiority p < 0.001, p-value for difference < 0.001); and 86.3% versus 95.6% in the per-protocol (PP) analysis (treatment difference: 9.3%; 95% CI: 3.8%-14.8%; non-inferiority p < 0.001, p-value for difference < 0.001). The P-CAB-BQT regimen was shown to be non-inferior to the PPI-BQT regimen and yielded higher eradication rates across all analysis populations (ITT, MITT, and PP). The overall frequency of adverse events (27.9% and 34.2%, p = 0.151) and compliance (93.7% and 94.6%, p = 0.686) were similar between PPI and P-CAB groups. Among the patients suspected of drug-induced fever (8.6% and 7.2%, p = 0.597), 82.9% experienced fever after administration of furazolidone for > 10 days. The eradication rates were not affected by prior choice of antibiotics and the number of treatment attempts.

CONCLUSIONS: The 14-day P-CAB-BQT therapy containing amoxicillin and furazolidone provided a satisfactory eradication rate and a good safety profile as rescue treatment for H. pylori eradication, regardless of prior choice of antibiotics and the number of treatment attempts. Shortening the treatment course to 10-11 days could prevent the majority of drug-induced fevers.

PMID:40653634 | DOI:10.1111/hel.70056

BMC Infect Dis. 2025 Jul 12;25(1):915. doi: 10.1186/s12879-025-11294-7.

ABSTRACT

BACKGROUND: Adverse drug reactions (ADRs) represent a significant global public health concern, contributing substantially to patient morbidity and mortality. While viral load dynamics are known to influence ADRs incidence, this relationship has been insufficiently explored in clinical research. Current evidence is limited by methodological constraints, as most prior studies have analyzed these factors separately rather than employing integrated approaches that account for the endogenous nature of time-varying biomarkers like viral load. Joint modelling techniques offer a robust solution by simultaneously analyzing longitudinal and time-to-event data, providing more efficient and precise estimates of this critical association. This study aimed to determine the incidence and predictors of ADRs and its association with changes in viral load among adult patients on antiretroviral therapy (ART) at Nigist Eleni Mohammed Memorial Comprehensive Specialized Hospital (NEMMCSH) of central Ethiopia.

METHODS: A retrospective follow-up study at NEMMCSH from March 1, 2018 to April 30, 2022 among 376 randomly selected age above 15 years patients who initiated first-line ART and had two or more viral load measurements during follow-up. Data were extracted from medical records and analyzed using joint modeling techniques combining Cox proportional hazards regression with linear mixed effects models. Results are presented as adjusted hazard ratios (aHR) with 95% confidence intervals. Model adequacy was assessed through residual diagnostics, and statistical significance was determined at α = 0.05.

RESULT: A total of 376 adult patients on ART were followed for a combined 45,752 person-months of observation (median follow-up = 23 months; range: 1-50 months), accounting for variability in enrollment dates and censoring events. Overall, 93 patients (26.70%) developed ADRs with an incidence rate of 14.2 per 1000 person-months observation (95% CI: 13.20-15.40). The ART regimen (AZT/3TC/NVP) (AHR = 2.15: 95% CI: 1.01-4.57), TB co-infection (AHR = 0.79: 95% CI: 0.68-0.87) and ART duration (AHR = 0.96: 95% CI: 0.95-0.97) were significant predictors of ADRs. The time-dependent true value of the viral load log was significantly associated with the risk of adverse drug reaction (α = 1.67: AHR = 5.31: 95% CI: 1.64-7.23).

CONCLUSION: ADRs among HIV patients continue to be a public health concern. Viral load changes were significant associations with the risk of adverse reactions. To reduce ART adverse reactions, we recommend health professionals closely monitor and follow those patients on ART regimens (AZT/3TC/NVP).

PMID:40652201 | DOI:10.1186/s12879-025-11294-7