Arch Clin Biomed Res. 2025;9(3):183-195. Epub 2025 May 5.

ABSTRACT

Antidepressants are widely prescribed for major depressive disorder and anxiety, yet their long-term use is associated with weight gain, affecting up to 55-65% of patients. This adverse effect contributes to treatment discontinuation, relapse, and worsened metabolic health outcomes, including increased risk for obesity and type 2 diabetes. This artic le presents a critical evaluation of the published reports on the mechanisms underlying antidepressant-induced weight gain, comparative effects across drug classes, and mitigation strategies. Weight gain varies significantly by antidepressant class. Tricyclic antidepressants, monoamine oxidase inhibitors, and a tetracyclic antidepressant, mirtazapine, are associated with the most substantial weight increases, while selective serotonin reuptake inhibitors typically induce weight gain after prolonged use. Mechanisms involve serotonergic and dopaminergic signaling, receptor desensitization, insulin resistance, and altered leptin and ghrelin levels. Genetic factors, including CYP2C19 metabolizer status, and lifestyle factors such as baseline body mass index and diet, further influence risk. Bupropion, a norepinephrine-dopamine reuptake inhibitor, is the only commonly prescribed antidepressant consistently associated with weight loss or neutrality. Mitigation strategies include switching medications, adding agents like metformin or GLP-1 receptor agonists, and incorporating behavioral interventions. Antidepressant-induced weight gain is a multifactorial issue requiring individualized management. Understanding pharmacologic mechanisms and patient-specific risk factors is essential for optimizing treatment efficacy while minimizing metabolic burden.

PMID:40444017 | PMC:PMC12121960

Expert Opin Drug Metab Toxicol. 2025 May 29. doi: 10.1080/17425255.2025.2510302. Online ahead of print.

ABSTRACT

INTRODUCTION: Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare, severe epileptic encephalopathies requiring complex, individualized treatment due to drug-resistant seizures, non-seizure outcomes, and comorbidities. Polytherapy is an inevitable aspect of managing these conditions, making the management of drug-drug interactions (DDIs) crucial for optimizing efficacy, minimizing toxicity, and addressing broader patient needs.

AREAS COVERED: This review discusses current and emerging pharmacological therapies for seizures in DS and LGS. We explore documented and theoretical DDIs between these drugs and other antiseizure medications (ASMs), focusing on pharmacokinetic and pharmacodynamic characteristics. The clinical significance of these DDIs is emphasized, with practical recommendations for their management.

EXPERT OPINION: Advances in understanding DDIs are key to optimizing treatment, particularly through the combination of ASMs with distinct mechanisms of action. A rational therapeutic approach should consider not only seizure control but also comorbidities. Understanding metabolic pathways involved in pharmacokinetic interactions is essential for predicting and avoiding adverse effects. Digital tools and decision-support apps can assist clinicians in quickly assessing DDIs and selecting the most effective drug combinations. Ongoing research in pharmacogenetics and personalized medicine holds promise for improving the management of complex conditions like DS and LGS, offering potential for better, individualized therapeutic strategies.

PMID:40443019 | DOI:10.1080/17425255.2025.2510302

Clin Transl Sci. 2025 Jun;18(6):e70220. doi: 10.1111/cts.70220.

ABSTRACT

Leukopenia is a common dose-dependent side effect of azathioprine, often leading to drug discontinuation. Variants in TPMT and NUDT15 are associated with azathioprine-induced leukopenia but only explain 25% of cases. Thus, we aimed to identify novel genetic risk factors among TPMT and NUDT15 normal metabolizers through a genome-wide association study (GWAS). Using BioVU, Vanderbilt's electronic health record linked to genetic data, we assembled a discovery cohort of new users of azathioprine. The analysis was conducted in 1184 new users of azathioprine who had no history of prior thiopurine use or an organ transplant. A replication cohort of 521 patients was derived from All of Us, an NIH-funded project that links healthcare data and genetics. The GWAS was adjusted for sex, age, indication (inflammatory bowel disease, systemic lupus erythematosus, other autoimmune condition, or unknown), concurrent use of xanthine oxidase inhibitors (allopurinol or febuxostat) or immunosuppressants, prior TPMT or NUDT15 testing, and 10 principal components of ancestry. In BioVU, 65% of patients were female with a median age of 44 [IQR: 30, 57] and 125 patients developed leukopenia. In All of Us, 69% were female with a median age of 51 [36, 61], and 44 patients developed leukopenia. An intronic variant in PTPN2, rs11664064, reached genome-wide significance in BioVU (OR = 3.61; p = 1.96E-8) and replicated in All of Us (OR = 2.42, p = 0.039). Our finding suggests an association between rs11664064 in PTPN2 and azathioprine-induced leukopenia. PTPN2 plays a role in immune cell development and differentiation, providing a plausible mechanism for this association.

PMID:40442974 | DOI:10.1111/cts.70220

Br J Clin Pharmacol. 2025 Jun;91(6):1842-1852. doi: 10.1111/bcp.70004.

ABSTRACT

AIMS: Phenoconversion, a genotype-phenotype mismatch, challenges a successful implementation of personalized medicine. The aim of this study was to detect and determine phenoconversion using the solanidine metabolites 3,4-seco-solanidine-3,4-dioic acid (SSDA) and 4-OH-solanidine as diet-derived cytochrome P450 2D6 (CYP2D6) biomarkers in a geriatric, multimorbid cohort with high levels of polypharmacy.

METHODS: Blood samples and data of geriatric, multimedicated patients were collected during physician counsel (CT: NCT05247814). Solanidine and its metabolites were determined via liquid chromatography/tandem mass spectrometry and used for CYP2D6 phenotyping. CYP2D6 genotyping was performed and activity scores (AS) were assigned. Complete medication intake was assessed. A shift of the AS predicted via genotyping as measured by phenotyping was calculated.

RESULTS: Solanidine and its metabolites were measured in 88 patients with complete documentation of drug use. Patients had a median age of 83 years (interquartile range [IQR] 77-87) and the majority (70.5%, n = 62) were female. Patients took a median of 15 (IQR 12-17) medications. The SSDA/solanidine metabolic ratio correlated significantly with the genotyping-derived AS (P < .001) and clearly detected poor metabolizers. In the model adjusted for age, sex, Charlson Comorbidity Index and estimated glomerular filtration rate each additional CYP2D6 substrate/inhibitor significantly lowered the expected AS by 0.53 (95% confidence interval 0.85-0.21) points in patients encoding functional CYP2D6 variants (R2 = 0.242).

CONCLUSIONS: Phenotyping of CYP2D6 activity by measurement of diet-derived biomarkers elucidates phenoconversion in geriatric patients. These results might serve as a prerequisite for the validation and establishment of a bedside method to measure CYP2D6 activity in multimorbid patients for successful application of personalized drug prescribing.

PMID:40441673 | DOI:10.1111/bcp.70004

Mol Biol Rep. 2025 May 29;52(1):513. doi: 10.1007/s11033-025-10625-w.

ABSTRACT

Several hereditary and environmental variables contribute to an individual's susceptibility to developing asthma. The pathophysiologic underpinnings of asthma are becoming better understood by ongoing genetic investigations. Most risk factors are differences in one or two base pairs or single-nucleotide polymorphisms (SNPs). Moreover, pharmacogenetics is a significant area of study in asthma genetics; this branch of the field examines the interplay between genes and environmental factors, with pharmacologic medication exposure serving as the environmental factor and phenotypic change as the result of interest. Asthma is an obvious candidate for gene therapy (GT) because of the disease's accessibility and the shortcomings of existing treatments. The functional effect of polymorphisms linked with asthma and their translation into disease-relevant pathways have been obfuscated since almost all of these variations are located in non-coding genomic areas. Repurposing current asthma medications and developing novel therapies may be possible with the help of genomics-guided identification of potential therapeutic targets for the condition. Further research using genomics data and tools to map and identify the relevant gene(s) and phenotype-specific SNPs is needed to understand better the processes involved in asthma's etiology and use pharmacogenomics to develop better medications for tailored treatment plans. This study uses fresh research to investigate the link between heredity and asthma. This research aimed to examine the impact of pharmacogenetic variables and gene therapies on the responsiveness to asthma therapy.

PMID:40439783 | DOI:10.1007/s11033-025-10625-w

Mikrochim Acta. 2025 May 29;192(6):386. doi: 10.1007/s00604-025-07158-1.

ABSTRACT

MnO2 nanozyme-based strategy is for the first time exploited for dual-mode colorimetric and fluorescence determination of antioxidant activity and HPLC - UV - MS/MS profiling of antioxidants. MnO2 nanosheets (MnO2 NS) with outstanding oxidase-like property can trigger rhodamine B (RhB) chromogenic reaction, leading to design an accurate, selective, and sensitive dual-mode colorimetric and fluorescence method for total antioxidant capacity (TAC) determination. Additionally, antioxidants in complex extract can react with MnO2 NS catalytic reactive oxygen species (ROS) intermediates (•O2‒ and 1O2), which deduced the HPLC peaks decreased or disappeared. And screened antioxidants can be identified by MS/MS analysis. As proof of concept, antioxidant levels of four flavonoids (quercetin, rutin, hesperidin, and nobiletin) with different substituent groups and six samples (peels, pulps, and juices for two citrus cultivars ChunJian tangerine and Debao navel orange) were successfully measured. Nineteen flavonoids with ROS scavenging activity from citrus samples have been screened out and characterized. Especially, polymethoxyflavones, nonactive in DPPH•/ABTS•+-based assays, presented certain ROS scavenging activity. Together, this study provided a novel and efficient platform to accurately and selectively measure and screen physiological antioxidants in real complex samples, revealing its great promise and convenient applications in future.

PMID:40439768 | DOI:10.1007/s00604-025-07158-1

J Invest Dermatol. 2025 May 29:S0022-202X(25)00468-3. doi: 10.1016/j.jid.2025.05.001. Online ahead of print.

NO ABSTRACT

PMID:40439658 | DOI:10.1016/j.jid.2025.05.001

Children (Basel). 2025 Apr 28;12(5):567. doi: 10.3390/children12050567.

ABSTRACT

INTRODUCTION: Methadone is an opioid-sparing opioid and it is increasingly used in children undergoing surgery due to its beneficial effects on postoperative pain scores, decreased opioid requirements, and fewer adverse effects compared to other opioids. Intraoperative methadone is not well studied in pediatric cardiac surgery. We hypothesized that intraoperative methadone-based analgesia would provide comparable effectiveness in pain management to non-methadone-based analgesia, including caudal morphine, following pediatric cardiac surgery.

METHODS: We conducted a retrospective cohort study of 287 children undergoing cardiac surgery using single institutional electronic health records with Society of Thoracic Surgeons database outcomes. Patients were administered intravenous opioids plus caudal morphine (≤6 years) or intravenous opioids in the non-methadone group versus intravenous methadone (two 0.1 mg/kg doses given intraoperatively) with or without additional intraoperative opioids. The primary outcome was postoperative opioid use in morphine milligram equivalents (MME)/kg.

RESULTS: This study included 287 pediatric cardiac surgical patients with a mean age of 3.8 years, 59% male, and 72% White. Among 287 patients, 67 (23%) received intraoperative methadone. Unadjusted analysis showed the methadone group had lower postoperative opioid use on the day of surgery (median = 0.3 vs. 0.5 MME/kg, p = 0.005). Adjusted analyses showed there were no significant differences in postoperative opioid use, average pain, maximum pain, antiemetic use, reintubation, and use of naloxone between methadone and non-methadone groups. Hospital length of stay was 2.62 times longer (95% CI: [1.55, 4.41] p < 0.001) in the methadone group vs non-methadone group, but this was only shown in the younger children (≤6 years), who also had higher max pain scores in the methadone group. All outcomes were similar between analgesia groups in older children (>6 years).

CONCLUSIONS: Intraoperative methadone-based analgesia had comparable effectiveness in postoperative opioid use, pain, and antiemetic use compared to non-methadone-based intraoperative pain management for pediatric cardiac surgery. Large prospective studies of perioperative methadone are needed to examine methadone's analgesic benefits in children undergoing cardiac surgery.

PMID:40426746 | PMC:PMC12109820 | DOI:10.3390/children12050567

Hum Genomics. 2025 May 28;19(1):62. doi: 10.1186/s40246-025-00765-2.

ABSTRACT

BACKGROUND: Variations in pharmacogenes that regulate drug absorption, distribution, metabolism, and excretion (ADME) contribute to approximately 20-30% of interindividual differences in drug response. While many common variants are successfully utilized in clinical settings to predict individual drug responses, a significant portion of the genetic basis underlying this variability remains unidentified. This includes rare variants, which are estimated to account for 4-6% of drug response variability.

RESULTS: To comprehensively elucidate the functional consequences and molecular mechanisms of rare variants, we conducted in vitro enzyme expression studies combined with in silico structure-function analyses. We selected 11 rare variants in the CYP2C19 and CYP2D6 genes identified among participants within the Estonian Biobank. Variant cDNAs were heterologously expressed in HEK-293 cells, and detailed enzyme activity analyses were performed. The experimental results were further validated against average scores from five optimized in silico prediction models: LRT, Mutation Assessor, PROVEAN, VEST3, and CADD. To explore structure-activity relationships, we performed in silico docking of substrates into available 3D enzyme structures. Our findings reveal that most of the rare genetic variants caused significant functional alterations, including: (i) Likely impairments in substrate transport to the active site due to narrowing of access channels; (ii) Changes in catalytic rates; and (iii) Potential effects on substrate extrusion rates from the active site. The in silico prediction tools accurately anticipated the functional impact of 6 out of the 11 variants (54%).

CONCLUSIONS: Evaluating the functionality of rare variants will become increasingly essential as rapid and cost-effective whole-genome sequencing technologies continue to advance. Our results highlight the need for further refinement of in silico prediction models, particularly those leveraging 3D crystal enzyme structures, to enhance the accuracy of functional predictions for rare genetic variants.

PMID:40437642 | DOI:10.1186/s40246-025-00765-2

Sci Adv. 2025 May 30;11(22):eadt5833. doi: 10.1126/sciadv.adt5833. Epub 2025 May 28.

ABSTRACT

Linezolid, an oxazolidinone antibiotic, is widely used to treat multidrug-resistant tuberculosis and drug-resistant Gram-positive infections. However, prolonged use is associated with severe hematologic toxicity, the underlying mechanisms of which remain incompletely understood, particularly regarding the role of linezolid metabolites. Our clinical study indicates that elevated exposure to PNU142586, a primary metabolite of linezolid, is associated with an increased risk of linezolid-induced toxicity, even in the absence of renal impairment. To elucidate its mechanism, we identify DNA topoisomerase 2-α (TOP2A) and DNA topoisomerase 2-β (TOP2B) as primary targets of PNU142586 at molecular, cellular, and in vivo levels. PNU142586 disrupts replication and transcription by impeding DNA binding to TOP2A and TOP2B with a favorable conformation for cleavage and by inhibiting adenosine 5'-triphosphate hydrolysis, ultimately leading to antiproliferative and cytotoxic effects, including mitochondrial dysfunction. The present study thus provides mechanistic insight into linezolid-induced hematologic toxicity and offers a foundation for safer antibiotic development and improved clinical monitoring through biomarker identification.

PMID:40435237 | DOI:10.1126/sciadv.adt5833

ACS Appl Mater Interfaces. 2025 May 28. doi: 10.1021/acsami.5c08389. Online ahead of print.

ABSTRACT

Cellulose and its derivatives are increasingly explored in biomedical applications due to their biocompatibility, biodegradability, and mechanical performance. In regenerative medicine, aerogel scaffolds with tunable morphology and composition are highly valued for their ability to support tissue regeneration. Three-dimensional (3D) printing offers an effective method to fabricate aerogels with hierarchical pore structures, comprising interconnected macropores and mesopores, that are crucial for tissue engineering. For clinical use, 3D printing should ensure the structural integrity of printed structures and achieve a printing resolution that allows for customization. In this work, the X-aerogel technology, implemented via polyurea cross-linking, was applied to 3D-printed cellulose structures, thereby expanding the potential applications of both technologies. Specifically, 3D-printed methylcellulose (MC) and MC doped with bacterial cellulose nanofiber (MCBCf) gels were cross-linked with an aliphatic polyurea, yielding, after supercritical drying, the corresponding (X-MC and X-MCBCf) aerogels. Elaborate characterization with ATR-FTIR, XPS, ToF-SIMS, N2 porosimetry, He pycnometry, and SEM confirmed the formation of polyurea on the biopolymer framework, reinforcing the structure and improving the mechanical properties without altering the morphology or textural characteristics of the materials. A significant outcome of cross-linking with polyurea is the long-term stability of X-MC and X-MCBCf aerogels in water, in contrast to their native counterparts, and their capacity to absorb water up to 1800% w/w within only 2 h. Preliminary biological evaluation of the materials, including in vitro (cell compatibility, hemolytic activity), in ovo (HET-CAM), and in vivo (A. salina model) tests, showed good cell viability, blood compatibility, and safety for living organisms. From a fundamental materials perspective, the most important finding of this work is the disproportionally high stability of X-MC and X-MCBCf in physiological environments, achieved with only a minimal (almost undetectable) amount of cross-linking polyurea. From an application standpoint, the findings of this study, collectively, position these aerogels as sustainable and promising candidates for tissue engineering scaffolds.

PMID:40433903 | DOI:10.1021/acsami.5c08389

Pharmacogenomics. 2025 May 28:1-8. doi: 10.1080/14622416.2025.2510186. Online ahead of print.

ABSTRACT

BACKGROUND: Green tea extract was tested for the secondary prevention of colorectal adenoma in the placebo-controlled MIRACLE trial. Genome-wide screening on adenoma recurrence was performed in n = 550 participants 3 years after randomization to green tea or placebo intake.

METHODS: Single Marker Analysis followed by regression analyses was calculated for all 700.078 markers assuming an additive genetic model and including all covariates from the main MIRACLE trial analysis. The outcome was an adenoma rate at 3-year follow-up colonoscopy comparing participants carrying a genetic variant versus wildtype.

RESULTS: The gene showing the strongest association with the outcome in both, SMA as well as regression analysis, was the organic anion transporter SLCO1A2. In the variant carriers, the adenoma frequency was 41.4% in the green tea group and 35.7% in the placebo group (RR 1.16 [0.81; 1.65] p = 0.61), whereas in the nonvariant carriers, the frequency of reoccurrence was 54.5% in the green tea group and 66.5% in the placebo group (RR 0.82 [0.69; 0.97], p = 0.03).

CONCLUSION: Individuals with genetic variants in the transporter SLCO1A2 may be protected against colon adenoma irrespective of the green tea intake. In nonvariant carriers of SLCO1A2, green tea was associated with a clear benefit in outcome (18% risk reduction).

PMID:40433816 | DOI:10.1080/14622416.2025.2510186

Iran J Med Sci. 2025 May 1;50(5):351-358. doi: 10.30476/ijms.2024.102645.3570. eCollection 2025 May.

ABSTRACT

BACKGROUND: The cytochrome P450 (P450s or CYPs) enzyme family, particularly CYP2D6, significantly influences drug metabolism, handling approximately 20-25% of prescribed medications. Understanding genetic polymorphisms is crucial for personalized medicine and optimizing drug therapy in specific geographic and racial contexts. Given the complex nature of studying CYP2D6 genotypes, this study aimed to assess the prevalence of rare CYP2D6 star alleles, including rs267608319 (CYP2D6*31), rs1931013246 (CYP2D6*55), rs569439709 (CYP2D6*113), and rs747089665 (CYP2D6*135), within the Iranian population.

METHODS: Blood samples were obtained from 389 individuals across several ethnic groups in Tehran, Iran, from May to December 2022. PCR was used to amplify the region containing the desired variant. Genotyping was performed using the Sanger sequencing method.

RESULTS: Our analysis revealed a high frequency of normal alleles for all four studied variants, indicating the absence of the risk allele in the Iranian population. These findings suggest that the studied alleles have no apparent effect on various ethnic groups in Iran.

CONCLUSION: The Iranian population has a typical genetic makeup for CYP2D6 variations, impacting medication prescribing. Understanding genetic differences is crucial for personalized drug therapies. Further research into Iranian genetic variations is essential for advancing personalized medicine.

PMID:40433186 | PMC:PMC12104541 | DOI:10.30476/ijms.2024.102645.3570

Front Psychiatry. 2025 May 13;16:1570436. doi: 10.3389/fpsyt.2025.1570436. eCollection 2025.

ABSTRACT

BACKGROUND: Behavioral regressions in low verbal patients with severe autism constitute a dramatic challenge for clinicians. A physical comorbidity burden is often involved but difficult to evidence.

AIM: We present five cases of patients under 30 years old (three men and two women), recently hospitalized in a specialized multidisciplinary inpatient unit, settled in Lausanne University Hospital, and for which at some point, a urinary retention contributed to the constitution of a complex behavioral picture.

METHODS: For each patient, we report the individual risk factors, clinical presentation and the conditions for making the diagnosis.

RESULTS: As the usual guidelines for screening, management, and follow-up of urinary retentions are irrelevant in this population, we provide and discuss some recommendations: limitation of anticholinergic burden, strict application of the protocol for going to the toilet with training protocol, regularization of intestinal transit, daily bladder-scan control, and eventually use of Tamsulosin hydrochloride. These recommendations significantly improved the urinary status of our patients.

CONCLUSION: We conclude that chronic urinary retention is probably a recurrent and unrecognized feature in many young adults with autism and challenging behaviors, reflecting the long-term impact of iatrogenic medication and requiring a specific attention.

PMID:40433175 | PMC:PMC12106420 | DOI:10.3389/fpsyt.2025.1570436

Front Pharmacol. 2025 May 13;16:1592134. doi: 10.3389/fphar.2025.1592134. eCollection 2025.

ABSTRACT

Tacrolimus, a calcineurin inhibitor, is widely used to prevent allograft rejection in kidney transplant recipients. Its metabolism is predominantly mediated by the cytochrome P450 3A5 (CYP3A5) enzyme, and single nucleotide variants (SNVs) within intron 3 of the CYP3A5 gene are strongly associated with interindividual variability in enzyme expression and activity. These SNVs can generate a cryptic splice site, resulting in either preserved enzymatic function classified as expressers (CYP3A5 *1/*1 and *1/*3) or loss of function, classified as non-expressers (CYP3A5 *3/*3). Differential expression of CYP3A5 contributes to variability in tacrolimus pharmacokinetics and clinical outcomes, including graft rejection and therapeutic efficacy. In this study, we evaluated three pharmacokinetic parameters: trough concentration (TAC-C0), weight-adjusted daily dose (TAC-D, mg/kg), and dose-normalized trough concentration (TAC-C0/D). One-way ANOVA was used to assess differences in these parameters between CYP3A5 expressers and non-expressers. Additionally, Poisson regression was performed to examine associations between clinical/genetic variables and the incidence rate of acute rejection events. Genotyping was conducted in 45 pediatric kidney transplant recipients. The CYP3A5 *3/*3 genotype was most prevalent (66.7%), followed by *1/*3 (26.7%) and *1/*1 (6.7%). During the 6-month post-transplant period, CYP3A5 expressers required significantly higher tacrolimus doses to achieve target trough levels. Increased drug exposure was associated with a higher incidence of rejection events, whereas CYP3A5 expression correlated with a reduced rate of rejection. These findings underscore the clinical utility of CYP3A5 genotyping for optimizing tacrolimus dosing strategies. Carriers of functional CYP3A5 alleles (*1/*3 or *1/*1) benefit from individualized dose adjustments to achieve therapeutic concentrations and reduce the risk of graft rejection.

PMID:40432883 | PMC:PMC12107630 | DOI:10.3389/fphar.2025.1592134

Nutrients. 2025 May 16;17(10):1694. doi: 10.3390/nu17101694.

ABSTRACT

Background: Nutritional biomarkers are essential for assessing the impact of dietary interventions on health. Amino Acids (AA) serve as potential biomarkers due to their role in metabolic pathways, although the influence of combining macronutrients on AA metabolism remains unclear. Objective: This study aims to evaluate the effects of combining macronutrients (fat, protein, and fiber) on AA metabolism. Methods: A dietary intervention was conducted with 41 participants who were assigned to two groups: the Protein Fat (PF) group and the Protein Fat and Fiber (PFF) group. AA concentration was measured using LC-MS/MS. Results: Our findings indicated that combining macronutrients reduced plasma levels of AA with statistically significant differences between the two diets (p < 0.05 for EAA and BCAA; p < 0,01 for NEAA and AAA). Metabolic profile analysis showed differences between the groups, especially at 55 days (55 D) (R2X: 0.749; R2Y: 0.589; Q2: 0.582, p < 0.001) and 98 days (98 D) (R2X: 0.886; R2Y: 0.7; Q2: 0.605, p < 0.001). Five metabolites (leucine, asparagine, alanine, cysteine, and creatine) were the most influential factors in group differentiation (VIP score), with values ranging between 1.04 and 1.75. Conclusions: The combination of macronutrients led to a significant reduction in plasma amino acids and amines in the PFF group, with recovery post-intervention. These findings highlight the possibility that these metabolites are related to different health statuses.

PMID:40431435 | DOI:10.3390/nu17101694

Pharmaceutics. 2025 May 8;17(5):624. doi: 10.3390/pharmaceutics17050624.

ABSTRACT

Background/Objectives: Carbamazepine is widely used as a first-line treatment for pediatric patients with benign epilepsy. However, most commercial formulations have doses of 100 mg or higher, limiting their suitability for pediatric use. The aim of this study was to develop mini orally disintegrating tablets (ODTs) containing 50 mg of carbamazepine, utilizing direct compression technology, specifically tailored to meet the unique needs of pediatric patients. Methods: The development was carried out following a Quality by Design (QbD) approach, beginning with preformulation studies using the SeDeM expert system. Various co-processed excipients (PROSOLV® ODT and PARTECK® ODT) and non-co-processed excipients (L-HPC LH11 and L-HPC NBD-022) were evaluated. Additionally, modifications to the radius parameter of the SeDeM expert system were investigated to improve formulation design. Results: Optimized Formulations 13 and 14 achieved disintegration times below 1 min, hardness values between 25 and 60 N, and friability under 1%, fulfilling the predefined Critical Quality Attributes (CQAs). Tablets were successfully produced with a diameter of 5 mm and a weight below 100 mg. Moreover, reducing the SeDeM incidence radius from 5.0 to values between 4.0 and 3.5 proved viable, enabling the inclusion of excipients previously considered unsuitable and broadening formulation options without compromising quality. Conclusions: This study demonstrates the feasibility of producing small, fast-disintegrating, and mechanically robust 50 mg carbamazepine ODTs tailored for pediatric patients. It also validates the adjustment of SeDeM parameters as an effective strategy to expand excipient selection and enhance formulation flexibility in pediatric drug development.

PMID:40430915 | DOI:10.3390/pharmaceutics17050624

Pharmaceutics. 2025 Apr 29;17(5):585. doi: 10.3390/pharmaceutics17050585.

ABSTRACT

Background: Childhood cancers represent a heterogeneous group of malignancies and remain one of the leading causes of mortality among children under 14 years of age, ranking second only to accidental injuries, and fourth among individuals aged 15 to 19 years. Despite notable improvements in cure rates, a substantial proportion of patients experience acute or long-term toxicities associated with treatment. Methotrexate (MTX), a chemotherapeutic agent, has been employed effectively for over six decades in the management of pediatric malignancies. High-dose methotrexate constitutes a cornerstone of pediatric cancer therapy; however, its clinical utility is frequently constrained by dose-limiting toxicities. Objectives: This study investigates the impact of genetic polymorphisms in genes involved in nucleotide metabolism, as well as methotrexate and folate metabolic pathways, on treatment-related toxicity in childhood cancer. Methods: Using real-time polymerase chain reaction, 14 polymorphisms across 12 genes were analyzed in a cohort of 107 patients. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events v. 5.0. Results: Multivariate logistic regression analysis revealed that the male sex (p = 0.3) and the AA genotype of MTHFD1 rs2236225 were associated with grade III-IV gastrointestinal toxicity (p = 0.03), while the A allele of MTHFR rs1801133 and the AA genotype of GSTP1 rs1695 were associated with grade I-IV hematologic toxicity (p < 0.01 and p = 0.02, respectively). Conclusions: High-dose methotrexate (HDMTX) is a critical agent in the treatment of childhood cancers. Our findings suggest that genetic polymorphisms within methotrexate and folate metabolic pathways may serve as potential predictive biomarkers of treatment-related toxicity.

PMID:40430876 | DOI:10.3390/pharmaceutics17050585

Pharmaceutics. 2025 Apr 24;17(5):555. doi: 10.3390/pharmaceutics17050555.

ABSTRACT

Background: Advancements in pharmacogenomics, artificial intelligence (AI), and CRISPR gene-editing technology are revolutionizing precision medicine by enabling highly individualized therapeutic strategies. Artificial intelligence-driven computational techniques improve biomarker discovery and drug optimization while pharmacogenomics helps to identify genetic polymorphisms affecting medicine metabolism, efficacy, and toxicity. Genetically editing based on CRISPR presents a precise method for changing gene expression and repairing damaging mutations. This review explores the convergence of these three fields to enhance improved precision medicine. Method: A methodical study of the current literature was performed on the effects of pharmacogenomics on drug response variability, artificial intelligence, and CRISPR in predictive modeling and gene-editing applications. Results: Driven by artificial intelligence, pharmacogenomics allows clinicians to classify patients and select the appropriate medications depending on their DNA profiles. This reduces the side effect risk and increases the therapeutic efficacy. Precision genetic modifications made feasible by CRISPR technology improve therapy outcomes in oncology, metabolic illnesses, neurological diseases, and other fields. The integration of artificial intelligence streamlines genome-editing applications, lowers off-target effects, and increases CRISPR specificity. Notwithstanding these advances, issues including computational biases, moral dilemmas, and legal constraints still arise. Conclusions: The synergy of artificial intelligence, pharmacogenomics, and CRISPR alters precision medicine by letting customized therapeutic interventions. Clinically translating, however, hinges on resolving data privacy concerns, assuring equitable access, and strengthening legal systems. Future research should focus on refining CRISPR gene-editing technologies, enhancing AI-driven pharmacogenomics, and developing moral guidelines for applying these tools in individualized medicine going forward.

PMID:40430848 | DOI:10.3390/pharmaceutics17050555

Pharmaceutics. 2025 Apr 22;17(5):542. doi: 10.3390/pharmaceutics17050542.

ABSTRACT

Background/Objectives: Irinotecan is used in monotherapy or combined with other drugs for treating different cancer streams. SN-38, the active metabolite of irinotecan, is 70% inactivated by the uridine diphosphate (UDP) glucuronosyltransferase family 1 member A1 (UGT1A1) enzyme. The UGT1A1*6 (rs4148323) and *28 (rs3064744) alleles in the gene encoding the enzyme lead to decreased enzyme expression and increased severe irinotecan toxicity. Carrying one or two copies of these alleles results in a UGT1A1 intermediate or poor metabolizer status (IM, PM). The Food and Drug Administration (FDA)-approved drug labels and European Medicines Agency (EMA) European Public Assessment Report (EPAR) for irinotecan recommend dose adjustments based on UGT1A1 genotypes, but only for UGT1A1 PM patients. However, available pharmacogenetic (PGx) dosing guidelines for the UGT1A1-irinotecan interaction lack a consensus about considered genetic variants, genotype-translated phenotypes, and therapeutic recommendations. We aimed to describe evidence regarding the impact of the UGT1A1 genotype in irinotecan toxicity to inform irinotecan-dosing recommendations based on possible UGT1A1 genotypes. Methods: A systematic review was performed to find all the Phase I clinical trials looking for the maximum tolerated dose (MTD) or dose-limiting toxicities (DLTs) of irinotecan depending on the UGT1A1 genotype. Results: Toxicity-related events and the MTD of irinotecan differ among UGT1A1 normal metabolizers (NM), IM, and PM patients considering the UGT1A1*28 and/or *6 variants. Conclusions: Dose adjustments might also be recommended for UGT1A1 IM patients (*1/*28 or *1/*6 genotypes), with a 15% dose reduction considered.

PMID:40430836 | DOI:10.3390/pharmaceutics17050542