Biomedicines. 2025 Mar 29;13(4):822. doi: 10.3390/biomedicines13040822.

ABSTRACT

Background: Optimizing sedative techniques for drug-induced sleep endoscopy (DISE) enhances accuracy and reproducibility in tailoring treatment for obstructive sleep apnea (OSA). The Schnider and Eleveld pharmacokinetic-pharmacodynamic (PK-PD) models, which predict propofol concentration in effect-site compartment based on patient-specific parameters, were utilized to guide intravenous sedation in this study. We compared the effectiveness of propofol sedation guided by the novel general-purpose Eleveld model versus the Schnider model using target-controlled infusion (TCI) systems. Methods: We investigated twenty-five adult OSA patients, randomized into two groups: the Schnider model group (n = 12) and the Eleveld model group (n = 13). DISE was conducted following standardized protocols, targeting effect-site concentration TCI mode. Data concerning sedation levels, effect-site concentration of propofol, procedural timing, propofol dosages, respiratory and cardiovascular parameters, and any procedural incidents were collected. Results: DISE was performed successfully in all enrolled patients from both groups. A significant difference was observed in the effect-site concentration of propofol (CeP) at the moment of endoscopy between the Eleveld and Schnider groups (2.1 ± 0.4 µg/mL vs. 3.3 ± 0.7 µg/mL, respectively; p < 0.001). The E group also demonstrated a shorter time to attain the optimal sedation plane compared to the S group (6.1 ± 1.7 vs. 9.8 ± 2.2 min, respectively; p < 0.001) and a reduced total procedural time (11.2 ± 1.4 vs. 15.0 ± 2.1 min, respectively; p < 0.001). The incidence of adverse events was comparable between groups. Conclusions: The Eleveld model demonstrated a shorter time to achieve the optimal sedation plane, a shorter total procedural time, and a significant difference in effect-site concentration at the time of endoscopy compared to the Schnider model. The incidence of adverse events was comparable between the two groups, suggesting that the Eleveld model may offer improved efficiency without compromising safety during DISE.

PMID:40299425 | DOI:10.3390/biomedicines13040822

Front Pharmacol. 2025 Apr 14;16:1579633. doi: 10.3389/fphar.2025.1579633. eCollection 2025.

ABSTRACT

BACKGROUND: Postoperative pain following cesarean section can cause maternal anxiety, limited ambulation, and even postpartum depression. In this study, we aimed to investigate the effects of esketamine for postoperative patient-controlled intravenous analgesia in women following cesarean section.

METHODS: One hundred women were randomly assigned to two groups. The esketamine group received 1 mg⋅kg-1⋅d-1 of esketamine +1 µg⋅kg-1⋅d-1 of sufentanil for intravenous postoperative analgesia, and the control group received 1 µg⋅kg-1⋅d-1 of sufentanil for intravenous analgesia. The primary outcome was the pain intensity during the postoperative 24 h, and it was assessed using a visual analog scale (VAS). The secondary outcomes included hemodynamic parameters, total consumption of analgesics, blood loss, and drug-related side effects (hypotension, hypertension, bradycardia, nausea, and vomiting).

RESULTS: The VAS scores at rest were lower in the esketamine group than in the control group during the postoperative 6 h-24 h (p < 0.05), and the VAS scores at cough in the esketamine group were lower during the postoperative 4 h-24 h (p < 0.05). There were significant differences at blood loss during the postoperative 24 h (137.6 ± 33.0 vs 159.6 ± 41.3 mL, p = 0.004). Blood pressure and heart rate were greater in the esketamine group than in the control group during the postoperative 8 h-24 h (p < 0.05). The incidence of nausea and vomiting was significantly lower in the esketamine group than in the control group (4% vs 18%, p = 0.025).

CONCLUSION: This study indicated that esketamine not only improved postoperative pain but also reduced postpartum blood loss and the incidence of nausea and vomiting in women undergoing cesarean section (registration number: ChiCTR2400082094).

SYSTEMATIC REVIEW REGISTRATION: https://www.chictr.org.cn, Identifier ChiCTR2400082094.

PMID:40297147 | PMC:PMC12034930 | DOI:10.3389/fphar.2025.1579633

Cureus. 2025 Mar 28;17(3):e81392. doi: 10.7759/cureus.81392. eCollection 2025 Mar.

ABSTRACT

Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), is widely prescribed to treat depressive episodes but is rarely associated with hematological side effects such as thrombocytopenia. This report presents the case of a 26-year-old Omani man with bipolar disorder and chronic idiopathic thrombocytopenia who developed a significant decline in platelet count while being treated with fluoxetine during a depressive episode. Thrombocytopenia, defined as a platelet count below 150 × 10³/µL, can result from various factors, including immune dysregulation, infections, or drug-induced effects. Prior to initiating fluoxetine, the patient's platelet levels had been stable. However, it progressively declined during treatment, eventually reaching a critical level of 34 × 10³/µL. Extensive investigations ruled out other causes, implicating fluoxetine as the primary contributor. Discontinuing the medication led to a gradual improvement in the patient's platelet count. This case underscores the importance of promptly recognizing platelet decline and the need for healthcare providers to remain vigilant about SSRI-induced hematological side effects, especially in patients with pre-existing thrombocytopenia.

PMID:40296929 | PMC:PMC12035503 | DOI:10.7759/cureus.81392

Ther Adv Psychopharmacol. 2025 Apr 25;15:20451253251332275. doi: 10.1177/20451253251332275. eCollection 2025.

ABSTRACT

BACKGROUND: Despite the therapeutic benefits, non-adherence to lithium is common. One recent study showed that most patients discontinue lithium due to adverse effects. Little is known about individuals starting and discontinuing lithium repeatedly.

OBJECTIVES: We aimed to determine reasons for discontinuing and restarting lithium multiple times in patients with bipolar or schizoaffective disorder.

DESIGN: Retrospective cohort study based on psychiatric case records of the SLaM Biomedical Research Centre Case Register (SLaM BRC case register).

METHOD: Anonymised clinical data were extracted via the Clinical Record Interactive Search (CRIS) application. Patients with at least three events of lithium discontinuation between 2012 and 2022 were included.

RESULTS: Of 2888 eligible patients, 123 patients had discontinued lithium on at least three occasions. Psychiatric reasons, such as suspected lack of insight, feeling subjectively well or disagreeing with diagnosis, were the most common reasons for lithium discontinuations. They accounted for 77.2% of cases in the first event of discontinuation, 73.2% in the second and 72.3% in the third event. Adverse physical effects accounted for 19.5% of cases in the first event of discontinuation, 25.2% in the second and 26.0% in the third event. Relapse into the underlying affective disorder accounted for 83.7% each of reinstatements in the first and second events and 82.1% in the third event.

DISCUSSION: In our sample, lithium was discontinued due to adverse effects in only a minority of patients. In most cases, the reasons for lithium discontinuation were considered psychiatric. Lithium was mainly restarted due to relapse. This warrants a better understanding of the reasons for repeatedly discontinuing lithium and the best way to promote lithium adherence to prevent a perpetual cycle of remitting when on lithium and relapsing when off lithium.

PMID:40296869 | PMC:PMC12035018 | DOI:10.1177/20451253251332275

Clin Pharmacol Drug Dev. 2025 Apr 29. doi: 10.1002/cpdd.1538. Online ahead of print.

ABSTRACT

Long-acting (LA) cabotegravir 200-mg/mL (CAB200) injections are approved for HIV-1 prevention and as a complete LA HIV-1 treatment regimen with rilpivirine. A high-concentration suspension formulation, cabotegravir 400 mg/mL (CAB400-D), was developed to enable less frequent dosing and self-administration. This phase 1, double-blind, randomized study (NCT04484337) evaluated intramuscular (IM) gluteal, subcutaneous (SC) abdominal, and IM thigh CAB400-D injections (200-800 mg [0.5-2.0 mL]) in adults without HIV, using CAB200 injections as active control. Co-administration with recombinant human hyaluronidase (rHuPH20), topical nonsteroidal anti-inflammatory drug, or topical steroid was evaluated for some SC injections. Pharmacokinetics, adverse events (AEs), and participant-reported outcomes were assessed. Overall, 138 participants were enrolled. Absorption was faster with CAB400-D versus CAB200. Within 4 weeks, CAB400-D plasma exposures were similar across administration routes and higher than those of CAB200. Co-administration with rHuPH20 increased the spontaneous absorption rate of CAB400-D but not CAB200. No deaths or drug-related serious AEs were observed. Five (4%) participants discontinued treatment due to AEs (injection-site reactions [ISRs], n = 3 discontinuations). Most (99%) participants experienced ≥ 1 ISR. Participants reported good acceptability of injections. Although CAB400-D injections demonstrated acceptable safety/tolerability, faster absorption than CAB200 limited potential dosing intervals to monthly dosing. Alternative cabotegravir formulations with longer dosing intervals are under clinical evaluation.

PMID:40296638 | DOI:10.1002/cpdd.1538

BMC Cancer. 2025 Apr 28;25(1):799. doi: 10.1186/s12885-025-14218-5.

ABSTRACT

OBJECTIVE: While PD-L1 expression serves as a predictive biomarker for programmed cell death 1 and its ligand (PD-1/PD-L1) inhibitor efficacy in patients with non-small cell lung cancer (NSCLC), its association with treatment-related adverse events (TRAEs) has yet to be fully elucidated. This study systematically evaluated the correlation between PD-L1 expression status and TRAEs in patients with NSCLC.

METHODS: We systematically searched the Cochrane Library, Embase, and PubMed databases from inception to June 30, 2024, to identify prospective clinical trials examining PD-1/PD-L1 inhibitors among NSCLC patients that reported treatment-related toxicity data stratified by PD-L1 expression.

RESULTS: Twenty-six prospective trials (N = 5,453) were analyzed. At the 1%, 25%, and 50% PD-L1 cutoffs, PD-L1-negative patients presented significantly reduced risks of grade 3-4 TRAEs (OR = 0.37, 0.53, 0.41; 95% CI = 0.18-0.77, 0.31-0.90, 0.19-0.97; P < 0.01, 0.02, 0.04). Similarly, PD-L1-negative patients had significantly reduced risks of AEs leading to treatment discontinuation at the 1% and 25% PD-L1 cutoffs (OR = 0.25, 0.38; 95% CI = 0.08-0.76, 0.16-0.89; P = 0.01, 0.03) but not at the 50% PD-L1 cutoff (OR 0.28, 95% CI 0.07-1.12, P = 0.07). Subgroup analyses revealed elevated all-grade TRAEs with the 22C3 immunohistochemistry assay (P < 0.001), whereas first-line therapy recipients (P = 0.006) and open-label trial participants (P = 0.002) presented increased grade 3-4 TRAEs.

CONCLUSIONS: PD-L1 positivity may predict increased risks of grade 3-4 TRAEs and AEs leading to treatment discontinuation in NSCLC patients receiving PD-1/PD-L1 blockade. Furthermore, PD-L1 expression might be a useful biomarker for toxicity management in patients with NSCLC after PD-1/PD-L1 inhibitor treatment.

PMID:40295968 | DOI:10.1186/s12885-025-14218-5

In Vivo. 2025 May-Jun;39(3):1458-1469. doi: 10.21873/invivo.13947.

ABSTRACT

BACKGROUND/AIM: The concurrent use of vascular endothelial growth factor (VEGF) inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs) raises concerns regarding the increased risk of adverse drug reactions (ADRs) due to potential pharmacodynamic interactions. However, no studies have specifically addressed this issue. The objective of this study was to investigate whether the combination of these drugs increased the risk of ADRs.

PATIENTS AND METHODS: Disproportionality analysis was conducted on ADR reports from the Japanese Adverse Drug Event Report (JADER) and FDA Adverse Event Reporting System (FAERS) databases. The concomitant signal score and Ω shrinkage measure were used to identify safety signals associated with the drug combination. Additionally, logistic regression analysis focused on reports of ADRs related to cancer treatment and assessed the significance of the adjusted reporting odds ratio (aROR) for the interaction between these drugs.

RESULTS: Disproportionality analysis included ADR data from the JADER (n=1,509,399) and FAERS (n=38,610,433) databases. The concomitant signal score and Ω shrinkage measure identified a signal for gastrointestinal perforation in both databases. Logistic regression on cancer treatment-related ADRs (JADER: n=255,177; FAERS: n=1,167,941) showed a synergistic increase in gastrointestinal perforation risk with the drug combination [aROR for interaction term: JADER: 1.74 (95% confidence interval (CI)=1.45-2.07); FAERS: 1.49 (95% CI=1.29-1.72)].

CONCLUSION: The combination of VEGF inhibitors and NSAIDs is associated with an increased risk of gastrointestinal perforation, a serious and potentially fatal ADR. Therefore, caution is warranted when prescribing a combination of these drugs.

PMID:40294980 | DOI:10.21873/invivo.13947

N Engl J Med. 2025 Apr 28. doi: 10.1056/NEJMoa2503704. Online ahead of print.

ABSTRACT

BACKGROUND: Innovative oral targeted therapies are warranted for patients with human epidermal growth factor receptor 2 (HER2)-mutant non-small-cell lung cancer (NSCLC). Zongertinib is an oral, irreversible, HER2-selective tyrosine kinase inhibitor that has been shown to have efficacy in persons with advanced or metastatic solid tumors with HER2 alterations in a phase 1 study.

METHODS: We evaluated zongertinib in a multicohort, phase 1a-1b trial involving patients with advanced or metastatic HER2-mutant NSCLC. Here we report the primary analysis of zongertinib in previously treated patients: those with tumors harboring a mutation in the tyrosine kinase domain (cohort 1), those with tumors harboring a mutation in the tyrosine kinase domain previously treated with a HER2-directed antibody-drug conjugate (cohort 5), and those with tumors harboring a non-tyrosine kinase domain mutation (cohort 3). In cohort 1, patients were initially randomly assigned to receive zongertinib at a dose of 120 mg or 240 mg once daily. Patients in cohorts 5 and 3 initially received 240 mg daily. After an interim analysis of data from cohort 1, subsequently recruited patients across all cohorts received zongertinib at a dose of 120 mg. The primary end point was an objective response assessed by blinded independent central review (cohorts 1 and 5) or by investigator review (cohort 3). Secondary end points included the duration of response and progression-free survival.

RESULTS: In cohort 1, a total of 75 patients received zongertinib at a dose of 120 mg. At the data cutoff (November 29, 2024), 71% of these patients (95% confidence interval [CI], 60 to 80; P<0.001 against a ≤30% benchmark) had a confirmed objective response; the median duration of response was 14.1 months (95% CI, 6.9 to not evaluable), and the median progression-free survival was 12.4 months (95% CI, 8.2 to not evaluable). Grade 3 or higher drug-related adverse events occurred in 13 patients (17%). In cohort 5 (31 patients), 48% of the patients (95% CI, 32 to 65) had a confirmed objective response. Grade 3 or higher drug-related adverse events occurred in 1 patient (3%). In cohort 3 (20 patients), 30% of the patients (95% CI, 15 to 52) had a confirmed objective response. Grade 3 or higher drug-related adverse events occurred in 5 patients (25%). Across all three cohorts, no cases of drug-related interstitial lung disease occurred.

CONCLUSIONS: Zongertinib showed clinical benefit with mainly low-grade adverse events in patients with previously treated HER2-mutant NSCLC. (Funded by Boehringer Ingelheim; Beamion LUNG-1 ClinicalTrials.gov number, NCT04886804.).

PMID:40293180 | DOI:10.1056/NEJMoa2503704

Cureus. 2025 Mar 27;17(3):e81305. doi: 10.7759/cureus.81305. eCollection 2025 Mar.

ABSTRACT

Attention-deficit hyperactivity disorder (ADHD) is generally treated with stimulant medications without significant complications. Delusional parasitosis (Ekbom syndrome) can occur secondary to ADHD treatment. It is a rare condition defined as having a fixed, false belief that one is infected with insects, parasites, or organisms and that one experiences cutaneous sensations without any clinical evidence of infestation. Although stimulant treatment with methylphenidate or mixed amphetamine salts has been associated with delusional parasitosis, there is yet a case in the literature illustrating delusional infestation secondary to lisdexamfetamine. The following case is unique in that lisdexamfetamine caused delusional parasitosis in a 53-year-old man with ADHD who previously tolerated mixed amphetamine salts and armodafinil without side effects. The discontinuation of lisdexamfetamine, coupled with a second-generation antipsychotic, quickly resolved the delusion. For those who may prescribe lisdexamfetamine or treat patients with ADHD, it is crucial to carefully assess medication use, as discontinuation or dose adjustment of the suspected causative drug can have a positive impact on the course of delusional parasitosis.

PMID:40291316 | PMC:PMC12034334 | DOI:10.7759/cureus.81305

Cureus. 2025 Mar 28;17(3):e81364. doi: 10.7759/cureus.81364. eCollection 2025 Mar.

ABSTRACT

Drug-induced thrombocytopenia (DITP) is a rare but serious immune-mediated reaction characterized by drug-dependent antibodies that bind platelet surface glycoproteins, leading to severe thrombocytopenia. Biologic therapies, including IL-23 inhibitors like risankizumab, have been implicated in such adverse events. We present the case of a 47-year-old male with a history of psoriasis and prior deep vein thrombosis, who developed severe bleeding manifestations shortly after initiating risankizumab therapy for psoriatic arthritis. Clinical evaluation included mucocutaneous bleeding, petechiae, and a precipitous drop in platelet count to 3 x 10^3/uL. Management strategies involved platelet transfusions, high-dose steroids, intravenous immunoglobulin (IVIG), and thrombopoietin receptor agonists due to inadequate initial response. Despite aggressive treatment, the patient's thrombocytopenia persisted, necessitating prolonged hospitalization and consideration of alternative therapies. This case underscores the critical importance of recognizing and managing rare hematologic complications associated with biologic therapies. Vigilance in monitoring platelet counts during IL-23 inhibitor therapy is essential to mitigate severe adverse outcomes.

PMID:40291297 | PMC:PMC12034315 | DOI:10.7759/cureus.81364

Front Public Health. 2025 Apr 11;13:1572611. doi: 10.3389/fpubh.2025.1572611. eCollection 2025.

ABSTRACT

INTRODUCTION: Pharmacovigilance plays a vital role in ensuring drug safety and protecting public health. Oropharyngeal adverse drug reactions (O-ADRs) are found to be under-reported, especially by oral health professionals, limiting the identification and management of these events.

AIMS: This study aimed to evaluate the knowledge, attitudes, and practices (KAP) of healthcare professionals and students regarding O-ADRs and to assess their specific expertise by a self-e-learning test.

MATERIALS AND METHODS: A cross-sectional survey was conducted using a KAP questionnaire between April 2023 and April 2024, involving 943 participants, including physicians, dentists, dental hygienists, and students. Additionally, three sets of self-e-learning tests on O-ADRs were administered. The study employed descriptive statistics, Kruskal-Wallis tests, and logistic regression to analyze factors affecting KAP and reporting behaviors.

RESULTS: Significant gaps in KAP were identified. Only 26.5% of participants demonstrated frequent best practices for reporting O-ADRs, with dentists and dental hygienists showing lower reporting rates (13.8% and 9.3%, respectively) compared to physicians (18.8%). The results of logistic regression analyses showed that practical knowledge was significantly associated with work experience (OR = 2.15, p = 0.026). Students exhibited the lowest levels of practical knowledge and reporting proficiency, with only 17.6% demonstrating competence. The self-e-learning test highlighted knowledge deficits: only 22.9% of participants correctly identified O-ADR associated with antiseptic mouth rinses, additional 30.2% recognized those linked to antimicrobial drugs.

CONCLUSIONS: This study highlights the need for targeted educational interventions to address gaps in O-ADR knowledge and practice. Tailored training, user-friendly digital tools, and a strong pharmacovigilance culture are crucial for improving reporting rates and ensuring patient safety.

PMID:40290502 | PMC:PMC12021887 | DOI:10.3389/fpubh.2025.1572611

J Antimicrob Chemother. 2025 Apr 28:dkaf128. doi: 10.1093/jac/dkaf128. Online ahead of print.

ABSTRACT

OBJECTIVES: Isavuconazole is efficacious in the treatment of aspergillosis, mucormycosis, and other invasive fungal infections. Therapeutic drug monitoring is generally not assessed during treatment with isavuconazole due to its high oral bioavailability, modest drug-drug interactions, and linear pharmacokinetics. This study aimed to determine whether an exposure-toxicity relationship exists for isavuconazole in those experiencing potential adverse drug events.

METHODS: This retrospective study analysed adult outpatients receiving isavuconazole and the occurrence of adverse events. Patients with and without adverse events were compared to identify serum drug concentrations predictive of potential drug-related toxicity.

RESULTS: Ninety-five patients, corresponding to 219 serum levels total, were analysed. Thirty-seven (38.9%) developed adverse events, most commonly transaminitis (29.7%), diarrhoea (24.3%), and nausea (18.9%). Using Youden's index, a serum level of 5.86 µg/mL corresponded to a threshold balancing sensitivity (41.0%) and specificity (87.1%) in the determination of toxicity risk. All 24 patients undergoing isavuconazole dose reduction demonstrated resolution of symptoms.

CONCLUSIONS: Our findings identified an exposure-toxicity relationship for isavuconazole. Therapeutic drug monitoring may be beneficial for those on isavuconazole therapy who develop signs or symptoms of potential toxicity. Additionally, in patients with adverse events attributed to isavuconazole, dose reduction often led to resolution.

PMID:40289250 | DOI:10.1093/jac/dkaf128

Invest New Drugs. 2025 Apr 28. doi: 10.1007/s10637-025-01533-8. Online ahead of print.

ABSTRACT

HP518 is an oral PROteolysis TArgeting Chimera (PROTAC) protein degrader targeting the wild-type androgen receptor (WT-AR) and mutant AR ligand-binding domain (AR-LBD). A multicenter, first-in-human, open-label Phase 1 dose escalation study was conducted in patients with metastatic castration-resistant prostate cancer (mCRPC) to evaluate the safety, pharmacokinetics, and anti-tumor activity of HP518. Twenty-two patients with mCRPC with disease progression on at least 1 novel androgen receptor pathway inhibitor (ARPI) and ≤ 1 line of chemotherapy received HP518 once daily orally in sequential cohorts. Patients were not selected for AR-LBD mutations. Objectives were to assess safety, tolerability, maximum tolerated dose, pharmacokinetics (PK), as well as efficacy by PSA50 response and radiographic response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and Prostate Cancer Working Group 3 (PCWG3) criteria. Exploratory objectives included genomic profiling using cell-free DNA. The majority of treatment-emergent adverse events (TEAEs) were Grade 1 or 2. The most common AEs were nausea and vomiting, fatigue, constipation, diarrhea, and decreased appetite. Only one (vomiting) out of 10 serious adverse events (SAE) was considered drug-related. No patient experienced a dose-limiting toxicity (DLT), and no AEs led to dose reduction or study discontinuation. Following multiple dosing of HP518, the PK appeared to plateau showing a less than dose-proportional relationship between exposure and dosage. Two patients demonstrated a partial response, and three patients showed a PSA50 response. In this initial Phase 1 study, HP518 demonstrated an acceptable safety profile and responses in a limited subset of mCRPC patients with progression after ARPI warranting further investigation. ClinicalTrials.gov Identifier: NCT05252364.

PMID:40289067 | DOI:10.1007/s10637-025-01533-8

Int J Infect Dis. 2025 Apr 25:107914. doi: 10.1016/j.ijid.2025.107914. Online ahead of print.

ABSTRACT

OBJECTIVES: This study assessed adverse event with tuberculosis preventive therapy (TPT) regimens among individuals with latent tuberculosis infection (LTBI).

METHODS: Using national health insurance data, we analyzed individuals newly diagnosed with LTBI between 2015 and 2020. The TPT group, prescribed 3 months of isoniazid and rifampicin (3HR), 4 months of rifampicin (4R), or 9 months of isoniazid (9H), was matched with a control group through 1:1 propensity score matching. Drug-related adverse events were reported.

RESULTS: Of 220,483 diagnosed with LTBI, 49.0% received TPT, primarily 3HR (74.6%). The incidence of any adverse events with TPT was 11.90%, with 8.94% of these events being severe events requiring hospitalization. Hepatotoxicity risk was 6.48-, 4.79-, and 3.50-fold with 3HR, 9H, and 4R, respectively, compared to controls. Severe cutaneous adverse reaction risk was 4.27-, 1.83-, and 1.93-fold with 3HR, 9H, and 4R. 4R had the lowest risk of any adverse events, while 3HR had the highest. Permanent discontinuation occurred in 2.3%, 3.1%, and 3.3% with 4R, 9H, and 3HR, respectively. Unlike 9H, rifampicin-based regimens showed no age-related trend in adverse event risk.

CONCLUSIONS: 4R is a better option considering safety across a broad age range, suggesting it could be encouraged in the LTBI population.

PMID:40288747 | DOI:10.1016/j.ijid.2025.107914

Molecules. 2025 Mar 31;30(7):1548. doi: 10.3390/molecules30071548.

ABSTRACT

Predicting the toxicity of drug molecules using in silico quantitative structure-activity relationship (QSAR) approaches is very helpful for guiding safe drug development and accelerating the drug development procedure. The ongoing development of machine learning techniques has made this task easier and more accurate, but it still suffers negative effects from both the severely skewed distribution of active/inactive chemicals and relatively high-dimensional feature distribution. To simultaneously address both of these issues, a binary ant colony optimization feature selection algorithm, called BACO, is proposed in this study. Specifically, it divides the labeled drug molecules into a training set and a validation set multiple times; with each division, the ant colony seeks an optimal feature group that aims to maximize the weighted combination of three specific class imbalance performance metrics (F-measure, G-mean, and MCC) on the validation set. Then, after running all divisions, the frequency of each feature (descriptor) that emerges in the optimal feature groups is calculated and ranked in descending order. Only those high-frequency features are used to train a support vector machine (SVM) and construct the structure-activity relationship (SAR) prediction model. The experimental results for the 12 datasets in the Tox21 challenge, represented by the Modred descriptor calculator, show that the proposed BACO method significantly outperforms several traditional feature selection approaches that have been widely used in QSAR analysis. It only requires a few to a few dozen descriptors for most datasets to exhibit its best performance, which shows its effectiveness and potential application value in cheminformatics.

PMID:40286190 | PMC:PMC11990530 | DOI:10.3390/molecules30071548

Immunol Allergy Clin North Am. 2025 May;45(2):223-249. doi: 10.1016/j.iac.2025.01.010.

ABSTRACT

With their groundbreaking clinical responses, immune checkpoint inhibitors (ICIs) have ushered in a new chapter in cancer therapeutics. However, they are often associated with life-threatening or organ-threatening autoimmune/autoinflammatory phenomena, collectively termed immune-related adverse events (irAEs). In this review, we will first describe the mechanisms of action of ICIs as well as irAEs. Next, we will review biomarkers for predicting the development of irAEs or stratifying risks.

PMID:40287170 | DOI:10.1016/j.iac.2025.01.010

Pharmaceuticals (Basel). 2025 Apr 13;18(4):565. doi: 10.3390/ph18040565.

ABSTRACT

Objectives: The multidisciplinary city-hospital Oncoral follow-up of cancer outpatients has been set up to ensure the safety of oral anticancer drugs (OADs). The aim of this study was to assess Oncoral by Relative Dose Intensity (RDI) in patients with hematological malignancies treated with ibrutinib as a model. Methods: The study included all outpatients treated with ibrutinib and followed in Oncoral between January 2016 and June 2020. Patients benefited from interviews leading to pharmacist and nurse interventions (PNI) on drug-related problems as adverse events (AE), drug-drug interactions (DDI), and drug intake. Results: In total, 83 patients were enrolled. At least one PNI was performed for 86.7%, focusing on drug intake and DDIs (54.5%), the management of AEs (27.0%), and community-hospital coordination (18.5%). Major DDIs with ibrutinib were found in 10 patients, with at least one moderate interaction in 28%. Grade 3-4 AEs mainly concerned cytopenia and infection. Adherence tended to decrease after the first 6 months. At 6 months, the mean RDI was 93.7 ± 11.3%; RDI reductions occurred in 43% patients. RDI was lower in patients who discontinued treatment before day 90 and worsened over time in patients still being treated at month 6 (Friedman's test, p < 0.01). Age and gender were predictors of early treatment termination (OR 1.10 [1.03; 1.19] and 6.44 [1.65; 37.21]). The estimates of 30-month OS and PFS were 73.8% (95% CI [64.7%; 84.2%]) and 61.8% (95% CI [51.8%; 73.7%]). Conclusions: The Oncoral follow-up is a secure, coordinated pathway assessed by RDI. Multidisciplinary follow-up should be the gold-standard for outpatients receiving OADs.

PMID:40284000 | DOI:10.3390/ph18040565

Pharmaceuticals (Basel). 2025 Apr 8;18(4):543. doi: 10.3390/ph18040543.

ABSTRACT

Background: Hypereosinophilic syndrome (HES) is a heterogeneous group of rare disorders defined by the presence of marked eosinophilia resulting in end organ damage. The diagnostic approach is multidisciplinary and treatment goals include reductions in flares and eosinophils with minimal drug-related side effects. Results: Eleven patients (n = 11) with a diagnosis of idiopathic HES were included in the study [M/F: 6/5, median age: 54 (95% CI: 38.2 to 68.5), smokers/never smokers: 5/6]. Asthma was present in the majority of them (n = 8, 72.7%); four patients (n = 4, 36.4%) presented with eosinophilic pleural effusions, two patients (n = 2, 18.2%) with cardiac arrhythmias, and one with bilateral eyelid angioedema. Eight patients (72.7%) were treated with mepolizumab (300 mg/month) and three (27.3%) with benralizumab (30 mg/4 weeks). The median values of eosinophils at baseline and 12 months after initiation of biologic agent were 3000 (95% CI: 2172 to 11,365) K/μL and 50 (95% CI: 3 to 190) K/μL, respectively, p = 0.0002. All patients with concomitant asthma (n = 8) experienced elimination of asthma flares, asthma control (ACQ < 0.75), functional improvement (mean ΔFEV1: 857 ± 594 mL), and an 82% reduction in oral corticosteroids, p = 0.0001. Materials and Methods: Patients with highly characterized idiopathic HES treated with anti-eosinophilic agents between 1 October 2019 and 1 October 2023 were retrospectively included in the study. The aim of this study was to present clinical, laboratory, and functional features and outcomes in patients with thoroughly investigated idiopathic HES treated with biologic agents targeting eosinophils. Conclusions: Biologic agents in patients with idiopathic HES-following thorough diagnostic investigation-are both safe and effective, sparing the toxicity of immunosuppressive agents. Real-life data from larger registries are greatly anticipated.

PMID:40283978 | DOI:10.3390/ph18040543

Genes (Basel). 2025 Apr 15;16(4):453. doi: 10.3390/genes16040453.

ABSTRACT

BACKGROUND/OBJECTIVES: Lung cancer has a high mortality rate worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent. Carboplatin and paclitaxel are key treatments for NSCLC; however, adverse drug reactions (ADRs) pose significant challenges. This study examined the impact of genetic variations in ABCB1 and ABCC2 genes on the incidence of ADRs and survival in NSCLC patients treated with carboplatin and paclitaxel.

METHODS: Variants were identified using RT-PCR, and ADRs classified according to the Common Toxicity Criteria for Adverse Events, Version 4.03.

RESULTS: The ABCB1 rs1128503 (c.1236C>T) CC genotype was associated with a higher chance of nausea (OR: 3.5, 95% CI 1.367-9.250, p = 0.0093), vomiting (OR: 13.553, 95% CI 1.705-107.723, p = 0.0137), and a higher risk of death in CT or TT genotypes (HR: 1.725, 95% CI 1.036-2.871, p = 0.0361). The ABCC2 rs717620 (c.-24C>T) TT genotype was associated with increased ALP levels (OR: 14.6, 95% CI 1.234-174.236, p = 0.0335). The ABCB1 rs2032582 non-CC genotypes (TT+AA+TA+CA+CT) were associated with an increased risk of death (HR: 1.922, 95% CI 1.093-3.377, p = 0.0232). Patients with hypocalcemia (HR: 2.317, 95% IC 1.353-3.967, p = 0.022), vomiting (HR: 3.047, 95% IC 1.548-5.997, p = 0.0013), and diarrhea (HR: 2.974, 95% IC 1.590-5.562, p = 0.0006) were associated with lower overall survival.

CONCLUSIONS: The data suggest that ABCB1 variants may influence gastrointestinal ADRs and patient survival, highlighting the importance of pharmacogenomics in predicting ADRs and drug resistance. This approach offers more precise pharmacotherapy, reduces ADRs, and enhances the patients' quality of life and survival.

PMID:40282412 | DOI:10.3390/genes16040453

Hum Genomics. 2025 Apr 25;19(1):44. doi: 10.1186/s40246-025-00753-6.

ABSTRACT

BACKGROUND: Statins are essential for managing cardiovascular disease (CVD), but adverse effects often lead to treatment discontinuation and non-adherence, underscoring the need for personalized approaches. This study aimed to evaluate the influence of pharmacogenomic (PGx) variants and demographic factors on statin-associated adverse effects in a multiethnic cohort from the United Arab Emirates (UAE).

METHODS: This sub-analysis of the EmHeart Study included 675 patients using rosuvastatin or atorvastatin. Patients were genotyped for SLCO1B1 and ABCG2 actionable variants using real-time PCR. Data on demographics, comorbidities, and statin use were extracted from electronic health records. Adverse events, including statin-associated muscle symptoms (SAMS) and liver enzyme elevation, were tracked over 12 months. Associations were analyzed using chi-square tests and logistic regression.

RESULTS: Rosuvastatin users carrying the ABCG2 rs2231142 variant had a threefold increased risk of liver enzyme elevation, particularly among East Asian patients (P < 0.005). Atorvastatin users with the SLCO1B1 rs4149056 variant exhibited a twofold increased risk of SAMS, with higher rates observed in females and Arabs (P < 0.05). The combination of rosuvastatin with ezetimibe further exacerbated risks of SAMS and liver enzyme elevation.

CONCLUSION: This study highlights the importance of genetic testing and demographic factors, such as ethnicity and gender, in tailoring statin therapy to minimize adverse effects. Despite extensive research on PGx-guided statin prescribing, clinical implementation remains limited. Integrating PGx testing into routine practice and enhancing physician awareness of genetic and demographic risk factors can improve the safety, efficacy, and adherence of lipid-lowering therapies in diverse populations.

PMID:40281622 | DOI:10.1186/s40246-025-00753-6