Cephalalgia. 2025 Apr;45(4):3331024251335927. doi: 10.1177/03331024251335927. Epub 2025 Apr 23.

ABSTRACT

BackgroundFocusing on calcitonin gene-related peptide (CGRP) as a specific target has changed and improved migraine management. After the positive results of monoclonal antibodies directed to the CGRP pathway (anti-CGRP mAbs), randomized controlled trials also demonstrated the efficacy of gepants in migraine prevention. The present study aimed to assess the effectiveness of atogepant in preventing migraine after a 12-week treatment in clinical practice.MethodsAdult patients with a clinical indication for atogepant 60 mg daily were screened for participation in this multicentric prospective observational cohort study. At baseline (T0) and after 12 weeks (T3) since the first atogepant administration, monthly migraine days (MMDs), monthly headache days (MHDs) and monthly acute medications (MAMs) were assessed. The co-primary endpoints were the changes in MMDs from T0 to T3 and the percentage of T3 Responders (those with a reduction of MMDs ≥50%, i.e. 50% response rate (RR)). At T0 and T3, we also collected the Headache Impact Test (HIT-6), the Migraine Disability Assessment (MIDAS) questionnaire, the Migraine Treatment Optimization Questionnaire-6 (mTOQ-6), the Migraine-Specific Quality-of-Life Questionnaire (MSQ), the 12-item Allodynia Symptom Checklist (ASC-12) and the Migraine Interictal Burden Scale (MIBS-4).ResultsOne hundred and six patients (56/106 (52.8%) with chronic migraine (CM), 93/106 (87.7%) female, aged 50.6 ± 13.2 years) from 10 Italian centers completed the 12-week observation since the first atogepant tablet intake. From baseline to T3, a reduction of 6.9 MMDs (SD 9.7; p < 0.001) was achieved in the whole group and, specifically, of -4.9 (SD 6.6; p < 0.001) in episodic migraine (EM) and of -8.6 (SD 11.7; p < 0.001) in CM patients. Overall, 60/106 (56.6%) of patients were Responders (60.0% in the EM and 46.4% in the CM group). Non-Responders previously experienced more ineffective treatments than Responders with anti-CGRP mAbs (65.2% vs. 43.3%, respectively, p = 0.031) and with onabotulinumtoxinA (56.5% vs. 28.3%, p = 0.005), and presented more medication overuse at baseline (55.7% vs. 44.3%, p = 0.003). However, no baseline characteristics were significantly associated with the Responder status in the multiple regression analysis. For T0 to T3, MAMs, MIDAS, ASC-12 and mTOQ-6 reduced (p ≤ 0.001 consistently), and MSQ role-function restriction increased (p = 0.026), whereas HIT-6 and MIBS-4 did not change. Only seven subjects (7/106, 6.6%) dropped out of atogepant treatment: four for lack of effectiveness and three for adverse events or poor tolerability.ConclusionsThe STAR study demonstrates the effectiveness and tolerability of atogepant 60 mg at 12 weeks in a real-world setting. Previous ineffective anti-CGRP mAbs were not a relevant prognostic factor.Trial RegistrationThe study was preregistered on clinicaltrial.gov, NCT06414044.

PMID:40267275 | DOI:10.1177/03331024251335927

J Endocrinol Invest. 2025 Apr 23. doi: 10.1007/s40618-025-02586-5. Online ahead of print.

ABSTRACT

Diabetes and cancer are two of the most common public health concerns worldwide. The complex interplay of these two conditions is a growing area of research, as patients with diabetes are at increased risk for developing cancer, and vice versa. Furthermore, both patient populations show increased risk of many communicable infectious diseases and their adverse consequences, while vaccination can play a crucial role in their prevention, improving patient outcomes. Vaccination should represent a standard part of care for patients with cancer, diabetes, and both the diseases simultaneously, including people undergoing cancer treatment or in remission. Several international guidelines provide recommendations for vaccinating people with cancer or diabetes, but the two conditions have not been specifically evaluated together. Here we present a multidisciplinary consensus position paper on vaccination in patients with cancer and diabetes. The position paper is the result of a collaborative effort between experts from the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF). The paper provides a comprehensive overview of the current state-of-the-art knowledge on vaccination in patients with cancer and diabetes. It discusses the importance of vaccination in preventing infections, focuses attention on the need to consider the unique challenges faced by patients with cancer and diabetes when it comes to vaccine administration, and highlights the need for coordinated care to optimize treatment outcomes. Overall, the consensus position paper provides healthcare professionals caring for patients with cancer and diabetes recommendations on the use of various vaccines, including influenza, COVID-19, HZV, and HPV vaccines, as well as guidance on how to address common concerns and challenges related to vaccine administration.

PMID:40266540 | DOI:10.1007/s40618-025-02586-5

Cardiol Rev. 2025 Apr 23. doi: 10.1097/CRD.0000000000000937. Online ahead of print.

ABSTRACT

Obesity-related hypertension (HTN) is a growing global health concern, being a significant contributor to cardiovascular morbidity and mortality. The article reviews the complex pathophysiological mechanisms involved in the link between obesity and HTN, including neurohormonal activation, inflammation, insulin resistance, and endothelial dysfunction. The role of adipokines, specifically leptin and adiponectin, in blood pressure regulation is highlighted, along with the impact of advanced glycation end-products on vascular function. We discuss the effectiveness of lifestyle therapies, including weight loss, and diet for the management of obesity HTN. We also discuss the utilization of pharmacologic agents, including GLP-1 receptor agonists, and the impact of bariatric surgery on long-term blood pressure control. Despite enhanced treatment, significant barriers to treatment exist, including obesity stigma, limited access to health care, and adherence problems. Future research must focus on personalized approaches, like pharmacogenomics, to optimize hypertension treatment in the obese.

PMID:40265912 | DOI:10.1097/CRD.0000000000000937

RSC Adv. 2025 Apr 22;15(16):12866-12875. doi: 10.1039/d5ra00709g. eCollection 2025 Apr 16.

ABSTRACT

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, with amyloid-beta (Aβ) plaques and acetylcholine deficits being central pathological features. Inhibition of dual targets including acetylcholinesterase (AChE) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) represents a promising strategy to address cholinergic deficits and amyloid pathology. In this study, we used computational approaches to evaluate 8000 tripeptides as potential dual inhibitors of AChE and BACE-1. Machine learning models revealed the four top-lead tripeptides including WHM, HMW, WMH, and HWM. Molecular docking simulations indicated that WHM possessed the most favorable interactions through hydrogen bonds, π-π stacking, and salt bridges with key catalytic residues in both enzymes. Molecular dynamics simulations confirmed the stability of the protein-ligand complexes, with WHM exhibiting the most consistent conformations and significant disruption of catalytic residue geometries. Free energy perturbation analysis further supported WHM's superior stability across both targets. ADMET predictions suggested moderate oral absorption and limited brain penetration, consistent with the typical behavior of peptide-based compounds. Overall, WHM demonstrated the strongest potential as a dual inhibitor of AChE and BACE-1, offering a promising lead for future therapeutic development in AD.

PMID:40264872 | PMC:PMC12013280 | DOI:10.1039/d5ra00709g

Front Psychiatry. 2025 Apr 8;16:1584673. doi: 10.3389/fpsyt.2025.1584673. eCollection 2025.

ABSTRACT

INTRODUCTION: Treatment-resistant depression (TRD) affects approximately 30% of patients with major depressive disorder (MDD), for whom effective treatment options are limited. Repetitive transcranial magnetic stimulation (rTMS) has shown efficacy in alleviating depressive symptoms in TRD. However, it remains unclear if these improvements are driven or mediated by changes in cognitive function or biological markers, such as brain-derived neurotrophic factor (BDNF).

METHODS: This study examines the effects of rTMS on depressive symptoms, cognition, and BDNF levels, as well as the potential moderating role of lifetime suicidal attempts (LSA) on cognition and the predictive value of baseline BDNF for clinical outcomes. Twenty-five TRD patients were included, with 13 in the rTMS treatment group (receiving 20 sessions of rTMS over four weeks) and 12 as control group. Depression severity, cognitive function (Mini-Mental State Examination, Verbal Fluency, Digit Span), and serum BDNF levels were measured pre- and post-treatment. Mixed-effects linear regression models assessed clinical and biological associations.

RESULTS: rTMS significantly reduced HAM-D (p < 0.001) and CGI (p < 0.001) scores compared to controls. Cognitive performance improved significantly in MMSE (p = 0.049) and Digit Span (p = 0.04), with no significant changes in BDNF levels (p = 0.39). LSA did not moderate cognitive outcomes, and baseline BDNF did not predict clinical improvement (p = 0.68).

DISCUSSION: rTMS reduced depressive symptoms in TRD patients, with modest cognitive benefits. Baseline BDNF did not predict outcomes, though the lack of significant change suggests complex neuroplastic responses. Future studies should include larger samples and refined biomarker assessments.

PMID:40264519 | PMC:PMC12011827 | DOI:10.3389/fpsyt.2025.1584673

Clin Exp Allergy. 2025 Apr 22. doi: 10.1111/cea.70065. Online ahead of print.

NO ABSTRACT

PMID:40263895 | DOI:10.1111/cea.70065

Pharmacogenomics J. 2025 Apr 23;25(3):10. doi: 10.1038/s41397-025-00373-2.

ABSTRACT

We examined the association of selected candidate pharmacodynamic (PD) genes in MDD with treatment outcomes, defined according to remission thresholds for Hamilton Depression Rating Scale (HDRS) with 6- and 17- items. To this end, we recruited 158 individuals living with MDD followed in an academic community mental health center. We reconstructed their clinical history and tested the association of a selected panel of pharmacodynamic genes with clinical remission. Our multivariate models were corrected for illness duration, substance use, lifetime stressful events, and sex. We found partially concordant associations for candidate biomarkers and clinical remission defined with HDRS-6 and HDRS-17. In the logistic regression model, two polymorphisms were statistically significantly associated with HDRS-17 remission: namely rs10975641 and rs11628713. Our results suggest that polymorphisms in PD genes might influence clinical response in MDD. Interestingly, we showed some degree of concordance of the association depending on the definition of the response.

PMID:40263270 | DOI:10.1038/s41397-025-00373-2

Heart Lung Circ. 2025 Apr 21:S1443-9506(24)01910-3. doi: 10.1016/j.hlc.2024.11.011. Online ahead of print.

ABSTRACT

BACKGROUND: The incidence of sudden cardiac death (SCD) in patients with schizophrenia is three to four times higher than in the general population. While the majority of SCD in patients with schizophrenia are due to ischaemic or structural heart disease, about 10% of deaths remain unexplained. In recent reviews of premature deaths in patients with schizophrenia, these deaths were postulated to be secondary to malignant cardiac arrhythmias.

METHODS: A retrospective study conducted jointly by the Victorian Institute of Forensic Medicine and the Department of Genomic Medicine, The Royal Melbourne Hospital, Australia, was designed to identify novel genomic loci that link schizophrenia and sudden unexplained death. Cases included deceased patients over a 5-year period (2016-2021) with an in-life diagnosis of schizophrenia and an unascertained cause of death after comprehensive post-mortem histopathological and toxicological assessment. Individuals also required a source of DNA to be available.

RESULTS: Thirty-six individuals, 26 males and 10 females, age range 18-65 years, met the study inclusion criteria. Autopsy revealed 10 individuals had cardiomegaly, six had cardiac hypertrophy, six had a body mass index (BMI) >40, and four had mild myocardial fibrosis. Thirteen next of kin (NOK) (36%) consented to involvement in the study and 12 individuals (92%) underwent whole exome sequencing (WES) via a research platform. Two clinically actionable results were detected-a pathogenic Desmoplakin (DES) variant and a dihydropyrimidine dehydrogenase (DPYD) pharmacogenomic variant.

CONCLUSION: Our study, with comprehensive autopsy examination adds to the literature on SCD in schizophrenia. Genes that are currently associated with inherited arrhythmias or schizophrenia such as Neuregulin 1 were not found in this study group. The pathogenic DES variant would likely have been found had the family accepted referral to a Cardiac Genetics service, at the time of death.

PMID:40263070 | DOI:10.1016/j.hlc.2024.11.011

Psychiatry Res. 2025 Apr 19;348:116506. doi: 10.1016/j.psychres.2025.116506. Online ahead of print.

ABSTRACT

Non-specific response to treatment (NSRT) is the primary contributor to the failure of randomized clinical trials in major depressive disorder (MDD). The objective of this study is to develop artificial neural network (ANN) models to predict the individual probability for NSRT. Pre-randomization data from a failed antidepressant trial were considered as potential predictors of the NSRT probability (prob-NSRT) using the response endpoint in subjects randomized to placebo. The inverse of the individual prob-NSRT (NSRT propensity score) was used as a weight in the mixed-effects model applied to assess treatment effect (TE). The comparison of the results obtained with and without the NSRT propensity score indicated that the weighted analyses provided an estimate of TE significantly larger than the conventional analyses. The propensity score weighted (PSW) analysis, adjusting for inter-individual variability in prob-NSRT, enhanced signal detection of TE. These findings support the potential role of PSW methodology for analyzing RCTs and determining TE. However, external validation of these ANN models in at least one independent trial is needed before advocating regulatory or broader clinical use.

PMID:40262198 | DOI:10.1016/j.psychres.2025.116506

Clin Pharmacol Ther. 2025 Apr 22. doi: 10.1002/cpt.3680. Online ahead of print.

ABSTRACT

The polymorphic CYP2D6 enzyme plays a pivotal role in the metabolism of approximately 25% of clinically prescribed drugs. However, the impact of specific genetic variants on the interindividual variability in CYP2D6-mediated drug metabolism remains insufficiently quantified. This translational study sought to address this gap by analyzing the genotypes and phenotypes of patients in two large clinical cohorts, focusing on the metabolism of the CYP2D6 substrates risperidone and desmethyltamoxifen. The analysis incorporated novel polymorphic haplotypes and substrate-specific differences among the CYP2D6.1, CYP2D6.2, and CYP2D6.35 enzyme variants. The study revealed that CYP2D6.2 and CYP2D6.35 exhibit reduced metabolic capacity for these substrates, both in vivo and in an in vitro expression model. This was evidenced by decreased catalytic turnover (Kcat), decreased substrate affinity, and altered substrate docking. Furthermore, novel polymorphic haplotypes on the CYP2D6*1, CYP2D6*2, and CYP2D6*35 backgrounds were identified, each associated with a 30-40% increase in CYP2D6 activity. Incorporating these findings into prediction equations significantly improved the genetic prediction accuracy (R2) for CYP2D6-mediated metabolism of desmethyltamoxifen from 59% to 71% and risperidone, also metabolized by CYP3A4, from 42% to 46%. These results highlight the importance of accounting for drug-specific interactions with enzyme variants and integrating distinct polymorphic haplotypes into CYP pharmacogenomic models and guidelines for better translation into clinical practice.

PMID:40261922 | DOI:10.1002/cpt.3680

Appl Microbiol Biotechnol. 2025 Apr 22;109(1):97. doi: 10.1007/s00253-025-13481-7.

ABSTRACT

Previous studies have established a correlation between the microbiome-derived metabolite trimethylamine N-oxide (TMAO) and decreased renal function, but with great heterogeneity. Moreover, population-based evidence remains scarce, particularly in Chinese populations. We designed a meta-analysis and a population-based cross-sectional study in China to examine the associations between TMAO and chronic kidney disease (CKD). In meta-analysis, among 2125 pooled subjects with 1240 controls and 885 CKD patients, a significant association was observed between TMAO and CKD, with a standardized mean difference of - 0.93 (95% confidence interval: - 1.11, - 0.75). Meta-regression analysis identified gender, age, and body mass index (BMI) as significant heterogeneity factors. In our population-based study of 5584 subjects with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 from Sijing community, 100 developed CKD in 2 years. We matched 195 controls by age and gender from the 5484 non-CKD subjects. Male subjects and alcohol consumers exhibited a lower risk of CKD with adjusted odds ratio (OR) of 0.471 (P < 0.05) and 0.320 (P < 0.05), respectively. When comparing subjects in the lowest tertile of TMAO, adjusted OR reached to 1.243 (P > 0.05) for those in the middle and 2.123 (P < 0.05) in the highest tertile (P for trend < 0.05). TMAO demonstrated a moderate capacity to distinguish CKD from non-CKD subjects (AUC = 0.614, P < 0.01). Our findings indicate TMAO is significantly associated with the risk of CKD, and suggest age, gender, and BMI may confound the relationship between TMAO and CKD. KEY POINTS: • Subjects with elevated TMAO levels have an increased risk of CKD. • TMAO demonstrates a moderate capacity to distinguish CKD from non-CKD cases. • Age, gender and BMI may confound the relationship between TMAO and CKD.

PMID:40261397 | DOI:10.1007/s00253-025-13481-7

Clin Transl Sci. 2025 Apr;18(4):e70193. doi: 10.1111/cts.70193.

ABSTRACT

Medication prescribing is imperfect, and unintended side effects complicate patient care. Pharmacogenomics (PGx) is an emerging solution that associates genotypes with personalized drug-related outcomes, but it has not been widely adopted. We hypothesize that patient and provider attributes may predict and promote PGx utilization. We studied PGx using data from the ACCOuNT study, a multi-institutional prospective trial that implemented broad preemptive PGx result delivery for African American inpatients [Clinicaltrials.gov NCT03225820]. Patients were genotyped, and their PGx information was made available within an integrated informatics portal. Utilization of PGx data (defined as the active choice to review PGx information) was left to the enrolled provider's discretion. Our primary endpoint was to identify patient and care team attributes associated with PGx use. We identified statistically significant univariate predictors and utilized logistic regression to compare relative predictiveness. This study included 187 patients (60.4% female, median age 55, 75.4% treated at the University of Chicago, 17.6% at Northwestern University, and 7.0% at the University of Illinois Chicago) and 188 providers (63.8% MD, 22.3% PharmD, 6.4% PA, and 7.4% APN). In multivariate analysis, we found that the use of PGx information in a prior admission significantly predicted the use in subsequent admissions (OR 7.62, p < 0.05). Similarly, pharmacist participation on care teams significantly predicted PGx use (OR 4.52, p < 0.05). In the first systematic analysis of the impact of patient and care team factors on inpatient PGx clinical decision support (CDS) adoption, we found that actionable care team attributes, such as pharmacist participation or successful initial adoption measures, predict PGx CDS use.

PMID:40259529 | DOI:10.1111/cts.70193

Clin Transl Sci. 2025 Apr;18(4):e70209. doi: 10.1111/cts.70209.

ABSTRACT

Phenoconversion is the discrepancy between genotype-predicted phenotype and clinical phenotype, due to nongenetic factors. In oncology patients, the impact of phenoconversion on drug selection, efficacy, toxicity, and treatment outcomes is unknown. This study will assess acceptability and feasibility of investigating phenoconversion using probe medications in a pediatric and adolescent and young adult (AYA) oncology population. This prospective, single-arm, single-blind, nonrandomized feasibility study, will enroll individuals aged 6-25 years with a new diagnosis of Hodgkin Lymphoma or Non-Hodgkin Lymphoma. Genotyping will be performed at baseline using whole genome sequencing or targeted panel testing. Longitudinal phenotyping will be conducted throughout the cancer treatment using exogenous oral enzyme-specific probes, specifically subtherapeutic dextromethorphan (CYP2D6) and omeprazole (CYP2C19, CYP3A4) for enzyme activity assessment. The primary outcome measure will be the proportion of patients who consent to the study and successfully complete baseline and at least two longitudinal time points with valid probe drug metabolic ratio measurements. Secondary outcomes include classification of clinical phenotypes based on probe drug metabolic ratios, probe drug safety, barriers to consent, acceptability of pharmacogenomic and phenoconversion testing, longitudinal genotype/phenotype concordance, inflammatory profiles, and patient and disease factors influencing phenoconversion. The trial has received ethics approval (2023/ETH1954) and is registered at ClinicalTrials.gov (NCT06383338). Findings will be disseminated through peer-reviewed publications and professional conferences, providing critical insights to advance the understanding of phenoconversion in oncology from pediatrics to adults. These results will help shape future research and drive the implementation of more personalized precision medicine strategies for all people with cancer.

PMID:40259519 | DOI:10.1111/cts.70209

Drug Metab Dispos. 2025 Mar 12;53(5):100063. doi: 10.1016/j.dmd.2025.100063. Online ahead of print.

ABSTRACT

Fluoroquinolone tissue distribution and cellular accumulation are hindered by efflux transporters, including ATP-binding cassette subfamily B member 1 (ABCB1), ATP-binding cassette subfamily G member 2 (ABCG2), and ATP-binding cassette subfamily C member 4 (ABCC4). Genetic polymorphisms (single-nucleotide polymorphisms) can impact transporter activity, leading to interindividual variability in the systemic and cellular pharmacokinetics of their substrates. This study assesses the impact of these transporters on moxifloxacin and ciprofloxacin (CIP) cellular accumulation in vitro, and the effect of common single-nucleotide polymorphisms in ABCB1 [c.1199G>A (rs2229109); common haplotype c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), and c.3435C>T (rs1045642)] and ABCG2 [c.421C>A (rs2231142)]. Recombinant human embryonic kidney (HEK) cell lines overexpressing wild-type or variant transporters were generated via stable plasmid transfection. The impact of transporter overexpression on fluoroquinolone cell disposition was assessed through accumulation experiments in the presence of specific inhibitors to establish the link between transporter expression and differential accumulation. Results indicated that ABCB1 overexpression reduced moxifloxacin cellular concentration by 30% but inconsistently with that of CIP and that zosuquidar or elacridar reversed these effects. ABCG2 had no impact. ABCC4 markedly reduced CIP accumulation by 25%, even at the basal level, an effect reversed by MK517. Contrarily to the wild-type and the c.1199A carriers, ABCB1 CGT and TTT variants did not reduce antibiotic accumulation. In conclusion, moxifloxacin and CIP are substrates of the wild-type and 1199G>A ABCB1, while CGT and TTT haplotypes had a marginal impact on fluoroquinolone transport by ABCB1. CIP is a preferential ABCC4 substrate. Because of the large body distribution of these transporters, our findings may help rationalize their role and the impact of their polymorphisms in fluoroquinolone disposition in tissues and cells. SIGNIFICANCE STATEMENT: This study demonstrates that moxifloxacin and ciprofloxacin are substrates of ABCB1, with ciprofloxacin also transported by ABCC4. Specific ABCB1 polymorphisms (CGT and TTT haplotypes) reduce the ABCB1 transport capacity toward fluoroquinolones. These findings highlight the importance of considering ABCB1 and ABCC4 inducers or inhibitors, which may affect fluoroquinolone disposition in tissues and cells, as well as ABCB1 polymorphisms that could explain interindividual variability in pharmacokinetic profiles.

PMID:40253817 | DOI:10.1016/j.dmd.2025.100063

J Mol Biol. 2025 Apr 17:169160. doi: 10.1016/j.jmb.2025.169160. Online ahead of print.

ABSTRACT

There is growing research on the allosteric behaviour of proteins, including studies on allosteric mutations that contribute to human diseases and the development of allosteric drugs. Allostery also plays a key role in drug metabolism, an essential factor in drug development. However, population specific variations, particularly in 3D protein structures, remain understudied. This study focuses on CYP3A4, a key enzyme responsible for metabolizing over 50% of FDA-approved drugs and often linked to adverse drug reactions. Given the vast genetic diversity of Africa, we investigated 13 CYP3A4 alleles from African populations using post-molecular dynamics analyses, with 12 being single variations and one containing a double variation. Except for one, all allele variations were located away from the active site, suggesting allosteric effects. Our comparative analyses of reference and variant structures, through hydrogen bond interactions, dynamic residue network analysis and substrate channel dynamics, revealed notable differences at both global and residue levels. The *32-I335T variant showed the largest changes compared to the reference structure, while *3-M445T (near normal metabolizer) exhibited the least change, with other variants falling in between. The *32-I335T variant showed a distorted conformation in the radius of gyration, a distinct kink in the I helix with specific hydrogen bonds and altered channel patterns. The *12-L373F variant, associated with reduced metabolism of midazolam and quinine, showed increased rigidity in its vicinity, potentially interfering with catalytic activity. Our findings align with clinical and wet lab data, suggesting that our approaches could be applied to analyse variants without clinical evidence.

PMID:40252954 | DOI:10.1016/j.jmb.2025.169160

Epilepsy Behav. 2025 Apr 18;168:110434. doi: 10.1016/j.yebeh.2025.110434. Online ahead of print.

ABSTRACT

BACKGROUND: Drug-resistant epilepsy (DRE) presents a significant clinical challenge since many patients fail to respond adequately to pharmacological treatments, resulting in persistent seizures and a great decline in quality of life. This highlights the urgent need for alternative or adjunctive therapeutic strategies. Carbohydrate-restricted diets have emerged as promising adjunctive treatments for epilepsy. However, while the efficacy of these diets has been well-established in pediatric populations, their effectiveness on adult DRE patients remains underexplored. This study aims to evaluate and compare the efficacy of various carbohydrate-restricted diets in treating DRE among all age groups, providing valuable insights into their potential clinical applications.

METHODS: PRISMA guidelines for network meta-analysis were followed. Randomized controlled trials (RCTs) comparing the efficacy of different carbohydrate-restricted diets in DRE patients, and published in PubMed, Embase, Cochrane, and Web of Science up to 22 December 2023 were screened. The primary outcomes were >50 %, >90 % seizure frequency reduction from the baseline and seizure freedom. Secondary outcomes included compliance and adverse events. Random-effects models with a Bayesian-based approach were employed to estimate between-group comparisons, with results presented as odds ratios (OR) and 95 % credible intervals (CrI).

RESULTS: A total of 17 RCTs involving 1468 DRE patients were included. The diets evaluated were the ketogenic diet (KD), modified Atkins diet (MAD), and low glycemic index treatment (LGIT). For >50 % and >90 % seizure reduction from baseline, all three diets resulted in significant efficacy compared to the normal diet. Notably, MAD was the only diet that demonstrated a statistically significant association with seizure freedom (OR 7.36, 95 % CrI 2.21-60.36), compared to the normal diet, while its lower compliance (OR 0.39, 95 % CrI 0.18-0.76) was likely influenced by the inclusion of adult subjects. Adverse effects were reported across all three diets with similar profiles, highlighting the need for individualized monitoring.

CONCLUSIONS: This meta-analysis indicated that in RCTs, the included diet therapies were overall equivalent in efficacy and side effects, with the MAD showing a higher chance of seizure freedom. Compliance was lower with the MAD, but this was likely due to a preponderance of adult studies using this therapy.

PMID:40252525 | DOI:10.1016/j.yebeh.2025.110434

JCO Precis Oncol. 2025 Apr;9:e2400858. doi: 10.1200/PO-24-00858. Epub 2025 Apr 18.

ABSTRACT

PURPOSE: Contemporary prophylactic antiemetic regimens have improved the control of chemotherapy-induced nausea and vomiting (CINV). However, over 50% of patients still suffer from nausea. This study aimed to correlate the genetic determinants of individual patients with the efficacy of three prophylactic antiemetic regimens.

METHODS: Patients with breast cancer in two previously reported prospective antiemetic studies consented for the present pharmacogenetic study. Before high-emetogenic doxorubicin and cyclophosphamide (AC) (neo)adjuvant chemotherapy, they received a combination of antiemetic prophylaxis: regimen A and regimen B were, respectively, aprepitant/ondansetron/dexamethasone with or without olanzapine; regimen C was netupitant/palonosetron/dexamethasone. The effectiveness of antiemetic regimens was mainly assessed by complete protection (CP) rates. Patients' genotypes in three genes, HTR3A, HTR3B and TACR1, were analyzed.

RESULTS: Patients who were homozygous TT (p.129Tyr) of a non-nonsynonymous variant in HTR3B rs1176744 and homozygous GG of TACR1 rs3821313 had better outcome with regimen B. Digenic interaction analysis further reveals interaction between rs1176744 and rs3821313. Homozygotes TT of rs1176744 and homozygotes GG of rs3821313 achieved the highest CP rate with regimen B (10/12 patients; 83%), in contrast to only 29% (7/24) with regimen A (P = .0027). Homozygotes GG in both HTR3A rs1176722 and TACR1 rs3821313 showed the poorest response to regimen A with a CP rate of 17% (2/12), whereas patients given regimen B had the highest CP rate (70%; 7/10; P = .0159). The findings were confirmed upon logistic regression adjusted for clinical factors.

CONCLUSION: The present study confirmed our hypothesis that among Chinese patients with breast cancer who received AC, the selection of optimal antiemetic prophylaxis may be aided by assessing an individual's pharmacogenetic profile. It also highlights a novel digenic interaction that has not been known before for pharmacogenetic analysis.

PMID:40249884 | DOI:10.1200/PO-24-00858

Curr Pharm Biotechnol. 2025 Apr 16. doi: 10.2174/0113892010353450250408114725. Online ahead of print.

ABSTRACT

BACKGROUND: Overdose involving opioids is the black heart of the addiction crisis. "Pre-addiction," as an encouraging concept by NIDA and NIAAA, seems best captured with the construct of dopamine dysregulation. Referring to the abundant publications on "Reward Deficiency Syndrome" (RDS), Genetic Addiction Risk Score (GARS) test, RDSQ29, and KB220, Pre-addiction can be referred to as "reward dysregulation" as a suitable suggestion. The hypothesis is that the true phenotype is RDS, and other behavioral disorders are endophenotypes where the genetic variants play important roles, specifically in the Brain Reward Cascade (BRC).

METHODS: This study tested the pharmacogenomics of the GARS panel by a multi-model in silico investigation in four layers: 1) Protein-Protein Interactions (PPIs); 2) Gene Regulatory Networks (GRNs); 3) Disease, drugs and chemicals (DDCs); and 4) Gene Coexpression Networks (GCNs).

RESULTS: All in silico findings were combined in an Enrichment Analysis for 59 refined genes, which represented highly significant associations of dopamine pathways in the BRC and supported our hypothesis.

CONCLUSION: This paper provides scientific evidence for the importance of incorporating GARS as a predictive test to identify Pre-addiction, introduce unique therapeutic targets assisting in the treatment of pain, drug dosing of prescription pharmaceuticals, and identify the risk for subsequent addiction early in -life.

PMID:40247807 | DOI:10.2174/0113892010353450250408114725

J Chemother. 2025 Apr 17:1-7. doi: 10.1080/1120009X.2025.2489837. Online ahead of print.

ABSTRACT

Fluoropyrimidines (FPs) are antineoplastic agents used for the treatment of various solid tumors, especially gastrointestinal cancers. Patients with variations in dihydropyrimidine dehydrogenase gene (DPYD), which can determine the partial or complete deficiency of the dihydropyrimidine dehydrogenase enzyme (DPD), are at an increased risk of developing severe and potentially life-threatening toxicity. Worldwide the introduction of pharmacogenetic testing into clinical practice has been a slow process and in our center the analysis of the DPYD gene has been adopted since April 2020. We evaluated the clinical application of routine DPYD screening and its ability to prevent early-onset of fluoropyrimidine-related toxicity in patients treated at the Oncology Reference Center of Basilicata (IRCCS-CROB), a recognized cancer centre in Southern Italy. From April 2020 to November 2022, 300 patients (male 137; female 163) diagnosed with various types of cancer were subjected to DPYD genotyping, before starting treatment with FPs. In accordance with the current European Medicines Agency (EMA) and the Italian Association of Medical Oncology (AIOM) guidelines patients were tested for four DPYD variants that are associated with reduced DPD activity. FPs dose adjustments in DPYD variant carriers were made following the previously mentioned guidelines. Three hundred patients underwent DPYD testing and thirteen (4.3%) patients were found to be heterozygous variant carriers; ten out of thirteen patients received FP dose reduction as indicated by the guidelines, one out of thirteen patients received alternative treatment, two of the thirteen patients received no treatment at all. The main toxicities observed in patients who received a DPYD genotype-based dose reduction were anemia, neutropenia, nausea and mucositis but events were primarily grade 1 or 2. Our experience confirms the technical feasibility and the usefulness of DPYD genotyping to reduce the risk of severe FPs toxicities.

PMID:40247645 | DOI:10.1080/1120009X.2025.2489837

Clin Pharmacol Ther. 2025 Apr 17. doi: 10.1002/cpt.3681. Online ahead of print.

ABSTRACT

The ESR1 gene is relevant in breast cancer treatments in the pharmacogenetics context. However, Native, African, and mixed populations are known to be underrepresented in genomic studies. This is particularly important given that the difference in variants' frequencies among different populations can lead to population-specific clinical implications. Therefore, this study aims to infer the genomic subcontinental ancestry and allele frequencies of the ESR1 gene variants in 2,427 individuals from 26 populations worldwide from the 1000 Genomes Project and 125 Natives from Peru, whose genomes have not yet been analyzed in the literature regarding this gene. Linear regression with Bonferroni correction analyses was conducted based on ancestry inference and frequencies. Our findings demonstrate subcontinental differentiation of African, Asian, European, and Native populations. Overall, 102 associations (P < 0.01) were found for 68 clinically relevant variants. Particularly, subcontinental associations were observed for variants associated with the Native, Asian, European, and African components. We highlight the findings for the rs9349799 and rs2234693 variants, previously associated with altered responses to breast cancer treatments. rs9349799 was positively associated with the South-Asian component, while rs2234693 was negatively associated with the Coast/Amazonian Native and positively associated with the East-African component. Nearly half of the variants are intronic, highlighting the importance of studying whole genomes rather than just exomes. These results emphasize subcontinental differences' relevance for designing pharmacogenetic panels. Including neglected populations in genomic and pharmacogenomic studies is essential for democratic access to scientific advances and for more egalitarian and effective pharmacogenetic implementation, tailored to each population's specificities.

PMID:40247433 | DOI:10.1002/cpt.3681