BMC Complement Med Ther. 2025 Apr 2;25(1):124. doi: 10.1186/s12906-025-04837-7.

ABSTRACT

INTRODUCTION: Cancer is currently the second most common cause of death worldwide and is often treated with chemotherapy. Music therapy is a widely used adjunct therapy offered in oncology settings to attenuate negative impacts of treatment on patient's physical and mental health; however, music therapy research during chemotherapy is relatively scarce. The aim of this study is to evaluate the impact of group music therapy sessions with patients and caregivers on their perceived anxiety, stress, and wellbeing levels and the perception of chemotherapy-induced side effects for patients.

MATERIALS AND METHODS: This is a retrospective cohort study following the STROBE guidelines. From April to October 2022, 41 group music therapy sessions including 141 patients and 51 caregivers were conducted. Participants filled out pre- and post-intervention Visual Analogue Scales (VAS) assessing their anxiety, stress, and wellbeing levels, and for patients the intensity of chemotherapy-induced side effects.

RESULTS: The results show a statistically significant decrease of anxiety and stress levels (p < .001), an increase in well-being of patients and caregivers (p < .001, p = .009), and a decrease in patients' perceived intensity of chemotherapy-induced side effects (p = .003). Calculated effect sizes were moderate for anxiety, stress, and well-being levels, and small for chemotherapy-induced side effects.

DISCUSSION: This is the first study regarding group music therapy sessions for cancer patients and their caregivers during chemotherapy in Colombia. Music therapy has been found to be a valuable strategy to reduce psychological distress in this population and to provide opportunities for fostering self-care and social interaction.

CONCLUSIONS: Music therapy should be considered as a valuable complementary therapy during chemotherapy. However, it is crucial to conduct prospective studies with parallel group designs to confirm these preliminary findings.

PMID:40176020 | DOI:10.1186/s12906-025-04837-7

Adv Pharmacol. 2025;103:65-80. doi: 10.1016/bs.apha.2025.01.004. Epub 2025 Feb 12.

ABSTRACT

The high rate of medication failures poses a significant challenge for the pharmaceutical sector. Selecting appropriate data from experiments for ADMET (absorption, distribution, metabolism, excretion, and toxicity) prediction and applying it effectively in the context of physiological characteristics is difficult. Currently, ADMET prediction is conducted early in the drug design process to filter out molecules with weak pharmacokinetic properties. Numerous ADMET models for prediction have been designed using computational methods. Verified ADMET datasets have been determined through experiments, utilizing key classifying factors and descriptors to develop in silico approaches. This chapter discusses the relevance of ADMET evaluation in drug design, methodologies for model creation, available ADMET predictive tools, and the limitations of these predicted models.

PMID:40175055 | DOI:10.1016/bs.apha.2025.01.004

Ir J Med Sci. 2025 Apr 1. doi: 10.1007/s11845-025-03948-x. Online ahead of print.

ABSTRACT

BACKGROUND: This study aims to conduct a systematic review and meta-analysis of the currently present literature analyzing the effectiveness and safety profile of prusogliptin, a novel dipeptidyl peptidase-IV (DPP-4) inhibitor, as compared to placebo in type 2 diabetes mellitus (T2DM) patients.

METHODS: This systemic review and meta-analysis complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search strategy based on various MeSH terms was run on: PubMed/Medline, SCOPUS, and Cochrane Central, which were then systematically searched from inception till March 2024 to select all relevant Randomized Control Trials (RCT).

RESULTS: The analysis of the findings from three RCTs with 957 patients revealed that prusogliptin reduced Hemoglobin A1c (HbA1c)% levels in T2DM patients significantly [Mean Difference (MD): -0.62, 95% Confidence Interval (CI): -0.74 to -0.50, I2 = 0%, p < 0.001] and led to more patients with a HbA1c% ≤ 7% [Odds Ratio (OR): 2.65, 95%CI: 1.94 to 3.61, I2 = 0%, p < 0.00001]. However, prusogliptin led to a non-significant increase in weight when compared with placebo (MD: 0.22, 95% CI: -0.50 to 0.93, I2 = 60%, p = 0.551). The safety profile of prusogliptin revealed a non-significant decrease in treatment-emergent adverse events (OR: 0.90, 95% CI: 0.59 to 1.38, I2 = 43%, p = 0.64) and a non-significant increase in treatment-emergent serious adverse events (OR: 1.02, 95% CI: 0.43 to 2.44, I2 = 0%, p = 0.96) and drug-related adverse events (OR: 1.07, 95%CI: 0.68 to 1.69, I2 = 0%, p = 0.76).

CONCLUSION: Prusogliptin has a favorable efficacy in attaining glycemic control in patients with T2DM. However, its safety profile yields uncertain outcomes. More literature is required for a definitive result.

PMID:40172782 | DOI:10.1007/s11845-025-03948-x

Afr J Prim Health Care Fam Med. 2025 Mar 31;17(1):e1-e4. doi: 10.4102/phcfm.v17i1.4929.

ABSTRACT

Prescribing cascades contribute to the increasing prevalence of polypharmacy and its associated risks, where a drug-induced adverse event is misinterpreted as a new condition and treated with additional medications. Notable cascades include the use of anticholinergics leading to cognitive impairment, dyspepsia or constipation, which then prompt prescriptions for dementia medications, proton pump inhibitors or laxatives, respectively. Similarly, calcium channel blockers and gabapentinoids often induce oedema, resulting in unnecessary diuretic use. Strategies for prevention include careful review of adverse effects, deprescribing where appropriate and clinician education to improve symptom interpretation and prescribing practices. Recognising these cascades can mitigate unnecessary interventions and improve patient outcomes.

PMID:40171689 | DOI:10.4102/phcfm.v17i1.4929

Nat Commun. 2025 Apr 1;16(1):3137. doi: 10.1038/s41467-025-58321-4.

ABSTRACT

In sickle cell disease (SCD), the β6Glu→Val substitution in the β-globin leads to red blood cell sickling. The transplantation of autologous, genetically modified hematopoietic stem and progenitor cells (HSPCs) is a promising treatment option for patients with SCD. We completed a Phase I/II open-label clinical trial (NCT03964792) for patients with SCD using a lentiviral vector (DREPAGLOBE) expressing a potent anti-sickling β-globin. The primary endpoint was to evaluate the short-term safety and secondary endpoints included the efficacy and the long-term safety. We report on the results after 18 to 36 months of follow-up. No drug-related adverse events or signs of clonal hematopoiesis were observed. Despite similar vector copy numbers in the drug product, gene-marking in peripheral blood mononuclear cells and correction of the clinical phenotype varied from one patient to another. Single-cell transcriptome analyses show that in the patients with poor engraftment, the most immature HSCs display an exacerbated inflammatory signature (via IL-1 or TNF-α and interferon signaling pathways). This signature is accompanied by a lineage bias in the HSCs. Our clinical data indicates that the DREPAGLOBE-based gene therapy (GT) is safe. However, its efficacy is variable and probably depends on the number of infused HSCs and intrinsic, engraftment-impairing inflammatory alterations in HSCs. Trial: NCT03964792.

PMID:40169559 | DOI:10.1038/s41467-025-58321-4

Clin Exp Dermatol. 2025 Apr 1:llaf147. doi: 10.1093/ced/llaf147. Online ahead of print.

ABSTRACT

This is a secondary analysis of a multicentre randomised controlled trial of ciclosporin and methotrexate in children and young people (CYP) with severe atopic dermatitis (AD). Longitudinal trough ciclosporin and erythrocyte methotrexate polyglutamates (MTX-PG) concentrations were measured to evaluate their associations with treatment response and adverse events. Both ciclosporin (4 mg/kg/day) and methotrexate (0.4 mg/kg/week) led to a significant reduction in disease severity scores over the 36-week treatment period. Higher trough ciclosporin concentrations were associated with lower disease severity scores and may serve as a useful tool for therapeutic drug monitoring of ciclosporin in CYP with AD. However, in contrast to a previously published study, steady-state erythrocyte-MTX-PG concentrations showed no significant association with treatment response. Drug concentrations were comparable between patients with and without drug-related adverse events.

PMID:40168525 | DOI:10.1093/ced/llaf147

BMC Pharmacol Toxicol. 2025 Mar 31;26(1):73. doi: 10.1186/s40360-025-00912-4.

ABSTRACT

BACKGROUND: Melasma is a common hyperpigmentation disorder that causes significant distress to patients. In the real world, it is closely associated with various medications, making the timely identification and discontinuation of causative drugs an important aspect of clinical management. This study investigates the relationship between melasma and drug exposure based on data from the FDA Adverse Event Reporting System (FAERS) database.

METHODS: This study includes reports from the first quarter of 2004 to the second quarter of 2024, focusing on cases related to melasma. We employed four statistical methods to analyze the association between suspected drugs and adverse events related to melasma.

RESULTS: Within a specific timeframe, we extracted a total of 408 adverse reaction reports related to melasma. The result shows that a higher number of cases in female patients compared to male patients. The United States had the highest number of reported cases. We identified 22 drugs that were notably associated with melasma. Among these, the contraceptive "Ethinylestradiol and norethindrone" demonstrated the strongest signal of association.

CONCLUSIONS: Melasma is associated with exposure to various medications, with a notable proportion of cases coincided with contraceptive use. The mechanisms involved include hormonal disturbances and oxidative stress.

PMID:40165336 | DOI:10.1186/s40360-025-00912-4

PLoS Genet. 2025 Mar 31;21(3):e1011638. doi: 10.1371/journal.pgen.1011638. eCollection 2025 Mar.

ABSTRACT

Safety failures are an important factor in low drug development success rates. Human genetic evidence can select drug targets causal in disease and enrich for successful programs. Here, we sought to determine whether human genetic evidence can also enrich for labeled side effects (SEs) of approved drugs. We combined the SIDER database of SEs with human genetic evidence from genome-wide association studies, Mendelian disease, and somatic mutations. SEs were 2.0 times more likely to occur for drugs whose target possessed human genetic evidence for a trait similar to the SE. Enrichment was highest when the trait and SE were most similar to each other, and was robust to removing drugs where the approved indication was also similar to the SE. The enrichment of genetic evidence was greatest for SEs that were more drug specific, affected more people, and were more severe. There was significant heterogeneity among disease areas the SEs mapped to, with the highest positive predictive value for cardiovascular SEs. This supports the integration of human genetic evidence early in the drug discovery process to identify potential SE risks to be monitored or mitigated in the course of drug development.

PMID:40163513 | PMC:PMC11977994 | DOI:10.1371/journal.pgen.1011638

Drug Des Devel Ther. 2025 Mar 26;19:2243-2252. doi: 10.2147/DDDT.S486562. eCollection 2025.

ABSTRACT

PURPOSE: To evaluate pharmacokinetics (PK) and safety of fezolinetant after single-dose and multiple-dose administration of 15, 30, and 60 mg in healthy Chinese women.

PATIENTS AND METHODS: This was a fixed-sequence crossover study in 16 healthy Chinese female subjects, 18-45 years old. All received single doses of fezolinetant 15 mg, 30 mg or 60 mg with a 3-day washout. From Day 10, subjects received multiple doses of 30 mg fezolinetant once-daily for 7 days. PK parameters were obtained during the single- and multiple-dose periods. Safety assessments were based on adverse events, vital signs, and laboratory tests.

RESULTS: Fezolinetant exhibited rapid absorption, with median time of the maximum concentration (tmax) 1.50 to 1.75 hours after single-dose administration of fezolinetant tablets in the fasted state, followed by a decline in plasma levels, with a mean t1/2 of 6.12-7.69 hours at dose levels of 15, 30 and 60 mg. There was a dose-proportional increase in maximum concentration and total exposure for fezolinetant across the doses studied. Mean peak concentration (Cmax) values were 221, 439 and 834 ng/mL, for the 15, 30, and 60 mg doses, respectively. The drug exposure parameters had a low-to-moderate variability (21.1-39.7%). Minimum accumulation was observed after multiple doses. Metabolite ES259564 showed rapid formation following a single dose of fezolinetant, with a median tmax of 1.50-2.00 hours. Plasma levels then declined, with mean t1/2 ranging from 5.72-6.31 hours. Dose-proportional increases in Cmax and AUCinf were observed following single-doses of fezolinetant. Steady state was achieved on the second day after starting multiple-dose administration. In total, 3 (18.8%) subjects experienced 4 drug-related treatment-emergent adverse events; all mild in severity.

CONCLUSION: Linear PK was confirmed within the dose range of 15 to 60 mg in healthy Chinese women.

PMID:40160966 | PMC:PMC11955179 | DOI:10.2147/DDDT.S486562

Int Cancer Conf J. 2024 Dec 28;14(2):91-96. doi: 10.1007/s13691-024-00742-x. eCollection 2025 Apr.

ABSTRACT

A 70-year-old woman with the breast cancer exhibited interstitial lung disease 20 months after the administration with anastrozole, which was performed as the post-operative adjuvant therapy. The drug-induced lymphocyte stimulation test revealed that anastrozole was responsible for the development of interstitial lung disease in this patient. The interstitial lung disease was effectively treated by prednisolone. Then, tamoxifen was used as an alternative therapy, resulting in the occurrence of agranulocytosis 24 days after the administration with tamoxifen. Both anastrozole and tamoxifen are widely used and are highly effective drugs for the treatment of breast cancer. However, the current patient shows that both drugs could cause, albeit very rare, serious side effects in some patients.

PMID:40160876 | PMC:PMC11950607 | DOI:10.1007/s13691-024-00742-x

J Hazard Mater. 2025 Mar 28;492:138044. doi: 10.1016/j.jhazmat.2025.138044. Online ahead of print.

ABSTRACT

Drug-induced osteotoxicity refers to the harmful effects certain pharmaceuticals have on the skeletal system, posing significant safety risks. These toxic effects are critical concerns in clinical practice, drug development, and environmental management. However, current toxicity assessment models lack specialized datasets and algorithms specifically designed to predict osteotoxicity In this study, we compiled a dataset of osteotoxic molecules and used clustering analysis to classify them into four distinct groups Furthermore, target prediction identified key genes (IL6, TNF, ESR1, and MAPK3), while GO and KEGG analyses were employed to explore the complex underlying mechanisms Additionally, we developed prediction models based on molecular fingerprints and descriptors. We further advanced our approach by incorporating models such as Transformer, SVM, XGBoost, and molecular graphs integrated with Weave GNN, ViT, and a pre-trained KPGT model. Specifically, the descriptor-based model achieved an accuracy of 0.82 and an AUC of 0.89; the molecular graph model reached an accuracy of 0.84 and an AUC of 0.86; and the KPGT model attained both an accuracy and an AUC of 0.86. These findings led to the creation of Bonetox, the first online platform specifically designed for predicting osteotoxicity. This tool aids in assessing the impact of hazardous substances on bone health during drug development, thereby improving safety protocols, mitigating skeletal side effects, and ultimately enhancing therapeutic outcomes and public safety.

PMID:40158503 | DOI:10.1016/j.jhazmat.2025.138044

J Dermatol. 2025 Mar 29. doi: 10.1111/1346-8138.17706. Online ahead of print.

ABSTRACT

The concept of immune reconstitution inflammatory syndrome (IRIS) has recently been applied to patients with non-HIV infection with immune fluctuations. However, quantitative criteria to diagnose non-HIV IRIS have not been established. Similarly, immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) are also caused by immune fluctuations. No study has directly compared the immunological indicators of non-HIV IRIS and irAEs. Thus, we investigated whether irAEs can be included in non-HIV IRIS. We aimed to search for diagnostic biomarkers for non-HIV IRIS and to compare the immunopathogenesis of non-HIV IRIS and irAEs based on immunological indicators. We selected drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) and dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid (DPP4i-BP) as underlying diseases of non-HIV IRIS. Blood cell counts, cytokines or chemokines, and herpesvirus-derived DNA in saliva were quantified and compared between IRIS/irAE-positive and -negative as well as non-HIV IRIS and irAEs groups. The DPP4i-BP group had a shorter incubation time to IRIS onset than the DIHS/DRESS group; the irAE group had a longer incubation time than the DIHS/DRESS group. A higher neutrophil-to-lymphocyte ratio and serum interferon gamma inducible protein 10 levels could be potential biomarkers of IRIS and irAEs onset; however, no useful cut-off values for diagnosis were indicated. Meanwhile, the transition of regulatory T cells (Tregs) from the baseline to the onset of IRIS or irAEs differed between IRIS in DIHS/DRESS and irAEs. Only the DIHS/DRESS group showed an increase of Epstein-Bar virus (EBV) (p < 0.0001) and human herpesvirus 6 (p < 0.05) positivity in saliva at the onset of IRIS compared to that at baseline. Although non-HIV IRIS and irAEs have a small number of common immunological indicators, the dynamics of Tregs, cytokines, or chemokines and positivity of herpesvirus-derived DNA in saliva differ, suggesting that non-HIV IRIS and irAEs should remain as separate entities.

PMID:40156255 | DOI:10.1111/1346-8138.17706

BMC Med. 2025 Mar 28;23(1):188. doi: 10.1186/s12916-025-04021-1.

ABSTRACT

BACKGROUND: Acute Type A Aortic Dissection (aTAAD) is a severe and life-threatening condition. While animal studies have suggested that ketorolac could slow the progression of aortic aneurysms and dissections, clinical data on its efficacy in aTAAD patients remain limited. This study seeks to evaluate the safety and effectiveness of ketorolac in this patient group.

METHODS: Patients were randomly assigned to receive either ketorolac or a placebo (0.9% saline). Treatment began at least 2 h prior to surgery (60 mg ketorolac or 2 ml saline administered once intramuscularly) and continued for 48 h post-surgery (30 mg ketorolac or 1 ml saline administered intramuscularly twice daily). The primary endpoints included assessing the safety and efficacy of ketorolac in improving the prognosis of aTAAD, focusing on mortality and organ malperfusion syndrome. Secondary endpoints included drug-related adverse events, blood test results, and other postoperative outcomes.

RESULTS: Of 179 patients who underwent aTAAD repair, 110 met the inclusion criteria and were randomized into two groups of 55. One patient discontinued the intervention due to erythroderma on the first postoperative day, leaving 54 patients in the ketorolac group and 55 in the placebo group for analysis. No significant differences were found in the primary endpoints. However, the ketorolac group showed lower intraoperative bleeding (median: 1.8 L vs. 2.0 L, P = 0.03), shorter intensive care unit (ICU) stays (median: 6.5 days vs. 8 days, P = 0.04), and lower total hospital costs (median: ¥170,430 vs. ¥187,730, P = 0.03).

CONCLUSIONS: Short-term ketorolac therapy did not alter the primary outcome but was associated with reduced intraoperative bleeding, shorter ICU stays, and potentially lower hospitalization costs. It demonstrates safety and a certain degree of effectiveness during the perioperative period. These findings suggest that ketorolac could be a viable option for perioperative management in patients with aTAAD.

TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Register ( www.chictr.org.cn , No: ChiCTR2300074394).

PMID:40156036 | DOI:10.1186/s12916-025-04021-1

BMC Geriatr. 2025 Mar 28;25(1):205. doi: 10.1186/s12877-025-05851-7.

ABSTRACT

BACKGROUND: Globally, falls are considered a serious healthcare problem for aged care residents. Fall-risk-increasing drugs (FRIDs) are medications that can increase the risk of falling, given their adverse effects. Medication reviews are advocated to identify potentially inappropriate use of FRIDs. However, their impact on clinical and resident-centered outcomes is unclear. This study explored aged care residents' use of FRIDs and the content of medication review reports concerning these.

METHODS: A retrospective cross-sectional study of medication review reports completed between 1st July 2021 and 30th June 2022 was conducted. Statistical descriptive analysis was used to examine the use of FRIDs (defined as medications listed in the Screening Tool of Older Persons Prescriptions in older adults with high fall risk (STOPPFall)). The resident's medicine experience, identified drug-related problems (DRPs), and related recommendations concerning FRIDs were explored via content analysis. For recommendations to deprescribe FRIDs, clinical situations detailed in the reports were compared to those presented in STOPPFall.

RESULTS: Medication review reports relating to 966 residents were analysed. Of these residents, 83.2% (n = 804) used FRIDs, with 31.2% (n = 301) taking three or more FRIDs. In total, pharmacists made recommendations concerning 2635 identified DRPs, of which 19.7% (n = 520) were the potentially inappropriate use of FRIDs and deprescribing was recommended. The clinical situation for which deprescribing was most frequently recommended was the use of a FRID for an indication of limited clinical benefit 37.9% (n = 197). The clinical situation was not detailed for 130 (25.0%) recommendations to deprescribe FRIDs, and only three reports included the resident's viewpoint on deprescribing.

CONCLUSIONS: FRID use was found to be highly prevalent among aged care residents. Pharmacists frequently identified opportunities to deprescribe FRIDs. However, reports often omitted resident viewpoints and the clinical grounds for deprescribing. Using resident-centered communication in medication review reports could improve their impact on FRID use and resident outcomes.

PMID:40155803 | DOI:10.1186/s12877-025-05851-7

J Immunother Cancer. 2025 Mar 28;13(3):e011273. doi: 10.1136/jitc-2024-011273.

ABSTRACT

INTRODUCTION: Immune checkpoint inhibitors (ICIs) can yield remarkable clinical responses in subsets of patients with solid tumors, but they also commonly cause immune-related adverse events (irAEs). The predictive features of clinically severe irAEs leading to cessation of ICIs have yet to be established. Given the similarities between irAEs and autoimmune diseases, we sought to investigate the association of a germline polygenic risk score for autoimmune disease and discontinuation of ICIs due to irAEs.

METHODS: The Genetics of immune-related adverse events and Response to Immunotherapy (GeRI) cohort comprises 1302 patients with non-small cell lung cancer (NSCLC) who received ICI therapy between 2009 and 2022 at four academic medical centers. We used a published polygenic risk score for autoimmune diseases (PRSAD) in the general population and validated it in the All of Us. We then assessed the association between PRSAD and cessation of ICI therapy due to irAEs in the GeRI cohort, using cause-specific and Fine-Gray subdistribution hazard models. To further understand the differential effects of type of therapy on the association between PRSAD and cessation of ICI due to irAEs, we conducted a stratified analysis by type of ICI therapy.

RESULTS: Using a competing risk model, we found an association between PRSAD and ICI cessation due to irAEs (HR per SD=1.24, p=0.004). This association was particularly strong in patients who had ICI cessation due to irAEs within 3 months of therapy initiation (HR per SD=1.40, p=0.005). Individuals in the top quintile of PRSAD had 4.8% ICI discontinuation for irAEs by 3 months, compared with 2% discontinuation by 3 months among patients in the bottom quintile (log-rank p=0.03). In addition, among patients who received combination programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte associated protein 4 (CTLA4) inhibitors, ICI discontinuation for irAEs by 3 months occurred in 4 of the 13 patients (30.8%) with high PRSAD genetic risk (top quintile) versus 3 of 21 patients (14.3%) with low PRSAD genetic risk (bottom quintile).

CONCLUSIONS: We demonstrate an association between a polygenic risk score for autoimmune disease and early ICI discontinuation for irAEs. Our results suggest that germline genetics may be used as an adjunctive tool for risk stratification around ICI clinical decision-making in solid tumor oncology.

PMID:40154961 | DOI:10.1136/jitc-2024-011273

Cardiovasc Toxicol. 2025 Mar 28. doi: 10.1007/s12012-025-09987-1. Online ahead of print.

ABSTRACT

The pharmaceutical industry is evolving with the use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) for in vitro cardiac safety screening. Traditional reliance on QT-interval prolongation as a main arrhythmogenicity marker is being challenged. In addition, the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative recommends using computer modeling and in silico platforms as a more comprehensive approach for arrhythmogenicity testing in conjunction with hiPSC-CM in vitro screening. Our study presents an innovative platform that integrates in vitro hiPSC-CM propagation test with in silico models to assess the potential arrhythmogenic effect of drug-induced impact on ionic currents and electrophysiological intercellular coupling. Utilizing the electrophysiological and morphological characteristics of hiPSC-CM, we offer a thorough evaluation of potential drug-induced cardiac risks by computer modeling. We show, using the examples of lidocaine (100-300 μM) and Cyclophosphamide (639, 852 μM), that with the use of an integrative experimental and computer platform, it is possible to correctly display the clinical manifestations of side effects in advance.

PMID:40153244 | DOI:10.1007/s12012-025-09987-1

Genes (Basel). 2025 Feb 24;16(3):265. doi: 10.3390/genes16030265.

ABSTRACT

Background/Objectives: The accurate prediction of adverse drug reactions (ADRs) to oncological treatments still poses a clinical challenge. Chemotherapy is usually selected based on clinical trials that do not consider patient variability in ADR risk. Consequently, many patients undergo multiple treatments to find the appropriate medication or dosage, enhancing ADR risks and increasing the chance of discontinuing therapy. We first aimed to develop a pharmacogenetic model for predicting chemotherapy-induced ADRs in cancer patients (the ANTIBLASTIC DRUG MULTIPANEL PLATFORM) and then to assess its feasibility and validate this model in patients with non-small-cell lung cancer (NSCLC) undergoing oncological treatments. Methods: Seventy NSCLC patients of all stages that needed oncological treatment at our facility were enrolled, reflecting the typical population served by our institution, based on geographic and demographic characteristics. Treatments followed existing guidelines, and patients were continuously monitored for adverse reactions. We developed and used a multipanel platform based on 326 SNPs that we identified as strongly associated with response to cancer treatments. Subsequently, a network-based algorithm to link these SNPs to molecular and biological functions, as well as efficacy and adverse reactions to oncological treatments, was used. Results: Data and blood samples were collected from 70 NSCLC patients. A bioinformatic analysis of all identified SNPs highlighted five clusters of patients based on variant aggregations and the associated genes, suggesting potential susceptibility to treatment-related toxicity. We assessed the feasibility of the platform and technically validated it by comparing NSCLC patients undergoing the same course of treatment with or without ADRs against the cluster combination. An odds ratio analysis confirmed the correlation between cluster allocation and increased ADR risk, indicating specific treatment susceptibilities. Conclusions: The ANTIBLASTIC DRUG MULTIPANEL PLATFORM was easily applicable and able to predict ADRs in NSCLC patients undergoing oncological treatments. The application of this novel predictive model could significantly reduce adverse drug reactions and improve the rate of chemotherapy completion, enhancing patient outcomes and quality of life. Its potential for broader prescription management suggests significant treatment improvements in cancer patients.

PMID:40149417 | DOI:10.3390/genes16030265

Pediatr Neurol. 2025 May;166:96-102. doi: 10.1016/j.pediatrneurol.2025.03.001. Epub 2025 Mar 8.

ABSTRACT

BACKGROUND: A postmarketing analysis of the adverse events (AEs) associated with fenfluramine (FFA) was conducted using the US Food and Drug Administration's Open Public Data Program (openFDA).

METHODS: The openFDA database was queried to retrieve FFA AE reports. Two algorithms, namely, the reporting odds ratio (ROR) and proportional reporting ratio, were employed for the purpose of detecting potential safety signals.

RESULTS: From the openFDA data platform, a total of 6,269,521 AE reports were collected during the study period; the number of AE reports with FFA as the primary suspect was 2386. Of these, 1526 (63.96%) were reported by consumers or non-health professionals, 2009 (84.20%) were reported by the United States, 1053 (44.13%) were unknown indications, and serious AEs were reported in 1315 cases (55.11%). A total of 62 signals were generated. The top 10 signals included atonic seizures (ROR of 918.52, 95% confidence interval [CI]: 670.65-1257.99), seizure clusters (ROR of 787.02, 95% CI: 595.26-1040.56), mitral valve thickening (ROR of 773.94, 95% CI: 463.47-1292.38), pulmonary valve incompetence (ROR of 600.71, 95% CI: 432.09-835.13), echocardiogram abnormal (ROR of 417.13, 95% CI: 307.87-565.16), change in seizure presentation (ROR of 287.55, 95% CI: 214.81-384.91), tricuspid valve incompetence (ROR of 221.42, 95% CI: 179.68-272.84), aortic valve incompetence (ROR of 176.59, 95% CI: 131.89-236.45), tonic convulsion (ROR of 173.68, 95% CI: 110.28-273.54), and myoclonic epilepsy (ROR of 158.05, 95% CI: 102.60-243.46).

CONCLUSIONS: This study employed the openFDA database to identify safety signals associated with FFA, thereby offering significant insights for clinical monitoring and risk identification in patients undergoing FFA therapy.

PMID:40147090 | DOI:10.1016/j.pediatrneurol.2025.03.001

PLoS Med. 2025 Mar 27;22(3):e1004565. doi: 10.1371/journal.pmed.1004565. eCollection 2025 Mar.

ABSTRACT

BACKGROUND: Adverse drug reactions (ADRs) harm patients and are costly for healthcare systems. Genetic variation contributes to variability in medication response and prospective knowledge of these variants can decrease risk of ADRs, as shown in the PREPARE trial. Reduction in ADRs would affect only those reactions to drugs contained in well-validated pharmacogene-drug pairs. The scope of ADRs represented by these drugs on a population scale is unclear. The objective of this study was to characterize the pharmacogene-drug-associated ADR reporting landscape from a national regulatory pharmacovigilance dataset to elucidate the scale of potential ADR mitigation by pharmacogenomics (PGx) implementation.

METHODS AND FINDINGS: All publicly available Yellow Card ADR reports to the United Kingdom Medicines and Healthcare Products Regulatory Agency, from 1963 to 2024, were compiled using programmatic data extraction. The ADRs were analysed with descriptive statistics, stratified by PGx status and by associated genes. Prescribing prevalence from the literature was compared with age range matched ADR reports for PGx-associated drugs. There were 1,345,712 ADR reports, attributed to 2,499 different substances. 115,789 adverse drug reports (9%) were associated with drugs for which ADR risk can be modified based on pharmacogenomic prescribing guidance. Seventy-five percent of these (n = 87,339) were due to medicines which interact with only three pharmacokinetic pharmacogenes (CYP2C19, CYP2D6, SLCO1B1). Forty-seven percent of all the PGx mitigatable ADRs identified were attributed to psychiatric medications (n = 54,846), followed by 24% attributed to cardiovascular medications (n = 28,279). Those experiencing PGx mitigatable ADRs, as compared with non-PGx mitigatable ADRs, were older and the ADRs more often consisted of severe non-fatal reactions. Many PGx-associated psychiatric drug ADRs were overrepresented as compared with prescribing prevalence, but fatal cardiac arrhythmias were uncommon consequences, comprising only 0.4% of these ADRs (n = 172 of n = 48,315 total ADRs). Limitations of this data source include under reporting of ADRs and reporting bias. These findings are based on analysis of the Yellow Card dataset described and may not represent all ADRs from a generalised patient population.

CONCLUSIONS: Nine percent of all reported ADRs are associated with drugs where a genetic variant can cause heightened risk of an ADR and inform prescribing. A panel of only three pharmacogenes could potentially mitigate three in every four PGx modifiable ADRs. Based on our findings, Psychiatry may be the single highest impact specialty to pilot PGx to reduce ADRs and associated morbidity, mortality and costs.

PMID:40146782 | DOI:10.1371/journal.pmed.1004565

JAMA Netw Open. 2025 Mar 3;8(3):e252668. doi: 10.1001/jamanetworkopen.2025.2668.

ABSTRACT

IMPORTANCE: The use of immune checkpoint inhibitors (ICIs) is increasing. Little is known about the frequency of late-onset immune-related adverse events (irAEs) and the patient-specific risk factors associated with their development.

OBJECTIVES: To assess the incidence of persistent or de novo late-onset irAEs requiring hospitalization and identify patient factors associated with risk of late-onset irAEs.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective observational cohort study conducted from January 2011 to October 2022 included patients who received ICIs and were hospitalized with irAEs at an academic medical center. Exclusion criteria included ICI therapy outside of the hospital system and no irAE diagnosis during admission. Data were analyzed from November 15, 2022, to January 8, 2025.

EXPOSURE: Late-onset irAEs.

MAIN OUTCOMES AND MEASURES: The main study outcomes were (1) incidence of irAE hospitalization at 0 to 6 months (early), more than 6 to 12 months (intermediate), and more than 12 months (late) after ICI initiation and (2) patient factors associated with risk of late-onset irAEs.

RESULTS: Among the 795 patients hospitalized with irAEs, the median age was 67.3 years (IQR, 58.3-74.8 years); 476 (59.9%) were male. Most patients (n = 517 [65.0%]) received anti-programmed death ligand 1 (PD-L1) and anti-programmed cell death 1 monotherapy, with the most common indications being melanoma (n = 335 [42.1%]) and lung cancer (n = 167 [21.0%]). The median time from start of ICI therapy to hospital admission was 2.7 months (IQR, 1.2-6.1 months), with 14.7% of patients (n = 117 of 795) presenting 6 to 12 months after initial ICI exposure and 10.8% of patients (86 of 795) presenting more than 12 months after initial exposure. The irAEs most likely to present late included those involving the kidney (10 of 32 [31.3%]) and hematologic (5 of 23 [21.7%]) organ systems. In univariate analysis, ICI type was significantly associated with the timing of hospital admission for irAEs; of the 517 patients receiving anti-PD-L1-based therapy, 13.5% (n = 70) presented late compared with 5.4% (9 of 167) receiving dual therapy with anti-cytotoxic T-lymphocyte-associated protein 4 (P < .001). Patients receiving perioperative ICI therapy were significantly more likely to be admitted at the intermediate interval (16 of 68 [23.5%]) compared with those with metastatic disease (87 of 678 [12.8%]) (P = .03). Timing of irAE was also significantly associated with active ICI exposure; among the patients presenting late, 7.4% (48 of 651) had received ICI therapy within the last 60 days compared with 26.4% (38 of 144) who had not had recent ICI exposure (P < .001).

CONCLUSIONS AND RELEVANCE: The findings of this retrospective observational cohort study suggest that late irAEs are possible, with a subset of patients presenting years after the start of ICI therapy. Clinicians must remain vigilant for irAEs regardless of elapsed time from ICI therapy, especially as patients live longer and ICIs become more widely used. Future investigations are needed to better understand the risk factors for late-onset irAEs and the distinct immunologic pathways that underlie such events.

PMID:40146104 | DOI:10.1001/jamanetworkopen.2025.2668