Front Pharmacol. 2025 Mar 13;16:1542269. doi: 10.3389/fphar.2025.1542269. eCollection 2025.

ABSTRACT

INTRODUCTION: Drug-related problems (DRPs) are a significant concern in many patient populations, including breastfeeding women. This study aimed to identify and characterize those problems in a group of breastfeeding women seeking specialized pharmaceutical care.

MATERIALS AND METHODS: A prospective observational study was conducted among women who registered for a pharmacist's online consultation regarding medication safety in lactation. 200 patients were enrolled. Patient medical history, medication use, breastfeeding practices, and DRPs were assessed. DRPs were classified using the Pharmaceutical Care Network Europe Association (PCNE) classification system. Causality assessment for adverse events was performed using the Naranjo algorithm and the Liverpool Causality Assessment Tool (LCAT).

RESULTS: This study found a high prevalence of DRPs among 190 out of 200 breastfeeding women. Of these, 27 experienced potential DRPs, and 163 manifested actual DRPs. A total of 218 DRPs were identified, with ineffective therapy being the most frequent (63.3%, n = 138). Among all identified causes (n = 265), the most common were patient-related factors (47.5%, n = 126) and dispensing-related issues, particularly regarding the information provided to patients about medication safety during lactation. Pharmacist interventions were accepted by 79.5% (n = 151) of patients, with 70% (n = 133) of DRPs successfully resolved.

CONCLUSION: This study highlights the significant burden of DRPs among breastfeeding women and the potential for medical professionals to improve patient outcomes through evidence-based interventions. Future research should focus on developing evidence-based guidelines for medication use during lactation and improving healthcare provider education to optimize maternal and infant health.

PMID:40183105 | PMC:PMC11965936 | DOI:10.3389/fphar.2025.1542269

Cancer Pathog Ther. 2024 May 31;3(2):129-134. doi: 10.1016/j.cpt.2024.05.003. eCollection 2025 Mar.

ABSTRACT

BACKGROUND: Whole-tissue autologous therapeutic vaccines (WATVs) are a form of cancer immunotherapy that use a patient's own pathological tissue. Concerns exist regarding the potential of WATVs to induce autoimmunity or the spread of cancer; however, their adverse events (AEs) have not been adequately studied. This literature review primarily aimed to evaluate the risks of autoimmunity and cancer seeding associated with using WATVs in human clinical trials. Its secondary objectives included assessing the incidence of AEs graded 1-5 using the Common Terminology Criteria for Adverse Events v5.0.

METHODS: The inclusion criteria were any clinical trial using human subjects in which at least part of the cancer vaccine was derived from the patient's own tumor tissue, which likely preserved the unique tumor-associated antigens (TAAs) present in the patient's tumor (i.e., whole-tissue). Tumor vaccine trials that used limited TAAs or highly processed tumor antigens were excluded. Published clinical trials were searched using Google Scholar until March 2024. The authors elaborated on the risk of bias in such cases, as indicated. All reviewed publications were searched for evidence of autoimmunity, cancer seeding, and other AEs. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement guided the review.

RESULTS: Data from 55 human clinical trials, abstracts, case reports, and unpublished data were analyzed, including 3323 patients treated with WATVs for various cancers. The primary outcomes were: (1) no documented cases of WATV-induced autoimmunity, (2) no documented cases of WATV-induced spreading or seeding of noninfectious cancers, and (3) the observed 0.24% (2/838) risk of spreading or seeding infectious cancers was attributed to inadequate sterilization. The secondary outcomes were: (1) no deaths were attributed to WATV therapy, (2) 0.18% (6/3323) incidence of grade 4 AEs, (3) 0.42% (14/3323) incidence of grade 3 AEs, (4) the incidence of grades 1-2 AEs was 52.21% (478/916).

CONCLUSIONS: WATVs carry no risk of inducing autoimmunity and essentially no risk of cancer seeding if properly sterilized. WATVs also exhibit a side effect profile comparable to that of routine vaccinations, with common, mild, and transient adverse effects. The combined risk of grade 3 and 4 AEs was 0.60% (20/3323). No deaths were causally associated with WATV treatment.

PMID:40182122 | PMC:PMC11963168 | DOI:10.1016/j.cpt.2024.05.003

BMC Pharmacol Toxicol. 2025 Apr 3;26(1):74. doi: 10.1186/s40360-025-00915-1.

ABSTRACT

BACKGROUND: Sickle cell disease (SCD) is a severe genetic disorder causing anemia, pain, and organ damage, affecting millions globally. Voxelotor, approved in the United States in 2019, targeted sickle cell disease pathophysiology. Despite its therapeutic benefits, concerns remain regarding its long-term safety and potential side effects, including headaches and gastrointestinal disturbances. This study used the FDA Adverse Event Reporting System (FAERS) to assess voxelotor's safety, aiming to enhance treatment strategies and clinical decision-making in SCD management.

METHODS: In this study, we utilized the FAERS to extract voxelotor-related adverse event reports from 2019 to 2024. We conducted descriptive and disproportionality analyses using four algorithms: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinkage (MGPS) to identify significant adverse event signals. The reliability of voxelotor adverse drug reactions (ADRs) was further improved by comparing with hydroxyurea ADRSs. Finally, adverse reactions were divided into acute ADRS, delayed ADRs and efficacy related reports to analyze the adverse event onset time.

RESULTS: A total of 16,677,340 case reports were collected in the FAERS database, of which 20,902 reports related to voxelotor were identified. Voxelotor induced adverse events occurred in 27 system organ categories (SOC). Key system organ classes affected were the blood and gastrointestinal systems. Notably, some adverse events, such as priapism and osteonecrosis, were not listed on the drug's label. The median adverse event onset time of acute ADRs, delayed ADRs and efficacy related reports were 1, 189.5 and 271 days, respectively.

CONCLUSION: This study systematically analyzed ADRs of voxelotor, highlighting the need for ongoing monitoring and further research on voxelotor's long-term safety and efficacy in treating sickle cell disease.

PMID:40181444 | DOI:10.1186/s40360-025-00915-1

J Transl Med. 2025 Apr 3;23(1):393. doi: 10.1186/s12967-024-06057-y.

ABSTRACT

BACKGROUND: Non-small cell lung cancer (NSCLC) is highly heterogeneous, leading to varied treatment responses and immune-related adverse reactions (irAEs) among patients. Habitat radiomics allows non-invasive quantitative assessment of intratumor heterogeneity (ITH). Therefore, our objective is to employ habitat radiomics techniques to develop a robust approach for predicting the efficacy of Immune checkpoint inhibitors (ICIs) and the likelihood of irAEs in advanced NSCLC patients.

METHODS: In this retrospective two center study, two independent cohorts of patients with NSCLC were used to develop (n = 248) and validate signatures (n = 95). After applying four kinds of machine learning algorithms to select the key preoperative CT radiomic features, we used clinical, radiomics and habitat radiomic features to develop the clinical signature, radiomics signature and habitat radiomic signature for ICIs prognostics and irAEs prediction. By combining habitat radiomic features with corresponding clinicopathologic information, the nomogram signature was constructed in the training cohort. Next, the internal validation cohort (n = 75) of patients, and the external validation cohort (n = 20) of patients treated with ICIs were included to evaluate the predictive value of the four signatures, and their predictive performance was assessed by the area under operating characteristic curve (AUC).

RESULTS: Our study introduces a radiomic nomogram model that integrates clinical and habitat radiomic features to identify patients who may benefit from ICIs or experience irAEs. The Radiomics Nomogram model exhibited superior predictive performance in the training, validation, and external validation sets, with AUCs of 0.923, 0.817, and 0.899, respectively. This model outperformed both the Whole-tumor Radiomics Signature model (AUCs of 0.870, 0.736, and 0.626) and the Habitat Signature model (AUCs of 0.900, 0.804, and 0.808). The radiomics model focusing on tumor sub-regional habitat showed better predictive performance than the model derived from the entire tumor. Decision Curve Analysis (DCA) and calibration curves confirmed the nomogram's effectiveness.

CONCLUSION: By leveraging machine learning to predict the outcomes of ICIs, we can move closer to achieving tailored ICIs for lung cancer. This advancement will assist physicians in selecting and managing subsequent treatment strategies, thereby facilitating clinical decision-making.

PMID:40181378 | DOI:10.1186/s12967-024-06057-y

Korean J Anesthesiol. 2025 Apr 4. doi: 10.4097/kja.24815. Online ahead of print.

ABSTRACT

BACKGROUND: We hypothesized that intranasal combination of dexmedetomidine (2 μg/kg) and ketamine (3 mg/kg) (IN DEXKET) improves the success rate of sedation in pediatric patients compared with chloral hydrate (CH; 50 mg/kg).

METHODS: This prospective, two-center, single-blinded, randomized controlled trial involved 136 pediatric patients (aged < 7 years) requiring procedural sedation. The participants were randomized to receive CH or IN DEXKET via a mucosal atomizer device. The primary outcome was the success rate of sedation (Pediatric Sedation State Scale, scores 1-3) within 15 min. The secondary outcomes included sedation failure at 30 min and overall complications of first-attempt sedation.

RESULTS: After excluding eight patients, 128 were included (CH = 66, IN DEXKET = 62). IN DEXKET showed a similar sedation success rate (75.8% [47/62] vs. 66.7% [44/66]; P = 0.330) but a lower complication rate (3.2% [2/62] vs. 16.7% [11/66]; P = 0.017) than CH. In the subgroup analysis for patients aged < 1 year, IN DEXKET showed a reduced complication rate than CH (2.6% [1/38] vs. 22.9% [8/35]; P = 0.012). In the subgroup analysis of children aged 1-7 years, IN DEXKET showed a higher sedation success rate within 15 min (79.2% [19/24] vs. 51.6% [16/31]; P = 0.049) and a lower sedation failure after 30 min (0% vs. 29.0% [9/31]; P = 0.003) than CH.

CONCLUSIONS: The intranasal combination of dexmedetomidine (2 μg/kg) and ketamine (3 mg/kg) is a safe and effective alternative to CH (50 mg/kg) for sedation in pediatric patients aged < 7 years.

PMID:40180590 | DOI:10.4097/kja.24815

Lung Cancer. 2025 Mar 12;203:108478. doi: 10.1016/j.lungcan.2025.108478. Online ahead of print.

ABSTRACT

OBJECTIVES: To evaluate the safety and effectiveness of entrectinib, an orally-administered potent multi-kinase inhibitor, for the treatment of proto-oncogene tyrosine-protein kinase-1 (ROS1) gene fusion-positive, unresectable, advanced/recurrent non-small cell lung cancer (NSCLC) in Japan.

MATERIALS AND METHODS: Patients with ROS1 gene fusion-positive, unresectable, advanced/recurrent NSCLC who initiated entrectinib therapy were enrolled in this all-case post marketing surveillance between February 21, 2020 and November 30, 2021. Outcomes were to identify the: (1) type and onset of initial cognitive disorder and ataxia during entrectinib therapy; (2) status of treatment and outcome of drug-related cognitive disorder and ataxia events; (3) incidence of other adverse drug reactions (ADRs) of safety concern: cognitive disorder and/or ataxia, cardiac disorder (excluding QT interval prolongation), QT interval prolongation, syncope, and interstitial lung disease; (4) incidence of serious adverse events (AEs) and ADRs; and (5) effectiveness.

RESULTS: Of the 276 patients who initiated entrectinib, 269 and 260 were included in the safety and effectiveness analysis sets, respectively. Cognitive disorder/ataxia was the most common ADR of safety concern, occurring in 72 patients (26.8 %). The median time to onset of initial cognitive disorder/ataxia symptoms was 2.0 days. Overall, entrectinib dose reduction, interruption, or discontinuation occurred in 9.7 %, 28.3 %, and 15.2 % of patients, respectively. Most ADRs of safety concern were manageable; 86.9 % of patients with ADRs were recovered/recovering. Serious AEs were reported in 42.8 % of patients. The overall response rate (ORR) was 38.8 % and median time to treatment failure was 6.4 months. ORR was 70.8 % versus 26.8 % to 34.7 % with entrectinib as first-line versus second- or later-line treatment, and 65.3 % versus 28.2 % in patients without versus with a history of tyrosine kinase inhibitor treatment.

CONCLUSIONS: Consistent with clinical trials, entrectinib is tolerable and effective in Japanese patients with ROS1 gene fusion-positive, unresectable, advanced/recurrent NSCLC.

STUDY REGISTRATION: UMIN Clinical Trials Registry (UMIN000046619).

PMID:40179540 | DOI:10.1016/j.lungcan.2025.108478

Rev Med Suisse. 2025 Apr 2;21(912):660-663. doi: 10.53738/REVMED.2025.21.912.660.

ABSTRACT

In everyday practice, many patients experience reactions to substances from different drug families. Multiple Drug Hypersensitivity Syndrome (MDHS) and Multiple Drug Intolerance Syndrome (MDIS) both involve reactions to several unrelated drugs but differ in pathophysiology and clinical presentation. Rare and immune-mediated, MDHS involves T lymphocytes and presents with severe delayed exanthems, eosinophilia, and moderate hepatic cytolysis triggered by at least two chemically distinct drugs. In contrast, MDIS is a diagnosis of exclusion, characterized by adverse reactions-often pseudoallergic and immediate-to three or more unrelated drugs, occurring upon separate exposures with negative allergy tests.

PMID:40176614 | DOI:10.53738/REVMED.2025.21.912.660

Int J Clin Pharm. 2025 Apr 3. doi: 10.1007/s11096-025-01904-4. Online ahead of print.

ABSTRACT

BACKGROUND: Methotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) treatment. However, patients using MTX often experience drug-related problems (DRPs), negatively affecting adherence and persistence.

AIM: To identify the number and type of DRPs experienced by RA patients during the first 3 months of MTX treatment.

METHOD: A longitudinal observational study was conducted in the Sint Maartenskliniek, The Netherlands, between March and August 2023. Adult RA patients were interviewed at 2, 6 and 12 weeks after MTX initiation using the United Kingdom's New Medicines Service interview guide. DRPs were categorized using a classification system for patient-reported DRPs, and analyzed descriptively.

RESULTS: All fifty participants (median age 62 years (IQR 51-68), 66% female) reported a DRP, with a median of 6 (IQR 3-8) DRPs per patient and a total of 301 DRPs. The top 5 most frequently reported DRPs were concerns about (long-term) side-effects, nausea, fatigue, remembering intake and information needs regarding dose instructions. Of the DRPs reported at weeks 2 and 6, 33% were unresolved at week 12.

CONCLUSION: Patients with RA experience numerous DRPs in the first 3 months of MTX use. Resolving DRPs soon after occurrence may reduce the burden of drug treatment and improve adherence and/or persistence.

PMID:40178797 | DOI:10.1007/s11096-025-01904-4

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

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