Pharmacogenomics. 2025 Apr 16:1-11. doi: 10.1080/14622416.2025.2490467. Online ahead of print.

ABSTRACT

AIM: The aim of this study is to find out the effect of SOD1 rs36232792 and SOD2 rs5746136 on the risk of opioid use disorder (OUD).

METHODS: Individuals with OUD (n = 101) and controls (n = 104) were included. SOD1 rs36232792 was genotyped by PCR. A novel PCR-RFLP method for SOD2 rs5746136 was optimized.

RESULTS: A significant difference was observed between individuals with OUD and controls in view of the frequency of 'Ins/Del+Del/Del' genotypes of the SOD1 rs36232792 (p = 0.049), but not for SOD2 rs5746136 (p = 0.254). The intensity of anxiety and depressive symptoms was significantly higher in individuals with OUD compared to controls (p = 0.001).

CONCLUSION: The SOD1 rs36232792 polymorphism could contribute to the risk of OUD in a Turkish population. A novel PCR-RFLP method for SOD2 rs5746136 confirmed by sequencing can be used in a research laboratory without advanced equipment.

PMID:40235344 | DOI:10.1080/14622416.2025.2490467

Pediatr Infect Dis J. 2025 May 1;44(5):428-430. doi: 10.1097/INF.0000000000004683. Epub 2025 Jan 10.

ABSTRACT

We investigated the steady-state pharmacokinetics of generic abacavir (ABC)/lamivudine (3TC) dispersible tablets (DTs) in young children living with HIV aged 3 months to <7 years, weighing 6 to <20 kg. Twenty-eight Thai children were enrolled and received ABC/3TC-DT plus pediatric dolutegravir-DT once daily. ABC/3TC was administered using WHO weight band (WB) doses: 180/90 mg, 240/120 mg and 300/150 mg for children weighing 6 to <10 kg (WB 1, n = 7), 10 to <14 kg (WB2, n = 9) and 14 to <20 kg (WB3, n = 12), respectively. ABC geometric mean (GM) AUC 0-24 h (CV%) was 14.2 (50.5%), 15.6 (32.6%) and 20.7 (28.3%) mg.h/L, respectively, and 3TC GM AUC 0-24 h was 14.8 (44.1%), 18.2 (28.0%) and 19.9 (26.2%) mg.h/L, respectively. ABC and 3TC exposures were within target ranges across WBs. These data supported current ABC/3TC-DT WHO-weight band dosing guidance for young children in Thailand.

PMID:40232882 | DOI:10.1097/INF.0000000000004683

Protein Pept Lett. 2025 Apr 14. doi: 10.2174/0109298665364226250328084245. Online ahead of print.

ABSTRACT

BACKGROUND: Since the Coronavirus Disease (COVID-19) became a pandemic in late 2019, vaccination remains the primary approach to combating the virus. Nevertheless, the emergence of new variants poses challenges to vaccine efficacy. This study aimed to identify targets within the SARS-CoV-2 spike (S) protein to detect T-cell responses to the five variants of concern from SARS-CoV-2: Alpha, Beta, Delta, Gamma, and Omicron.

METHODS: Here was employed immunoinformatics tools to develop a peptide-based vaccine targeting the spike protein of SARS-CoV-2 and its major variants, including Alpha, Beta, Delta, Gamma, and Omicron. The peptides were screened for antigenicity, toxicity, allergenicity, and physicochemical properties to ensure their safety and efficacy.

RESULTS: The potential T-cell epitopes with high immunogenicity and IFN-γ induction, are essential for a robust immune response by a comprehensive computational analysis. Population coverage analysis revealed significant coverage across diverse geographical regions, with significant efficacy in areas heavily impacted by the pandemic. Molecular docking simulations revealed strong interactions between the selected peptides and major histocompatibility complex class I (MHC-I) molecules, indicating their potential as vaccine candidates.

CONCLUSION: Our study provides a systematic approach to the rational design of a peptide-based vaccine against COVID-19, providing insights for further experimental validation and development of effective vaccines.

PMID:40231512 | DOI:10.2174/0109298665364226250328084245

Front Pharmacol. 2025 Mar 31;16:1588440. doi: 10.3389/fphar.2025.1588440. eCollection 2025.

ABSTRACT

[This corrects the article DOI: 10.3389/fphar.2020.00325.].

PMID:40230696 | PMC:PMC11994894 | DOI:10.3389/fphar.2025.1588440

Prog Neuropsychopharmacol Biol Psychiatry. 2025 Apr 12:111363. doi: 10.1016/j.pnpbp.2025.111363. Online ahead of print.

ABSTRACT

Pharmacogenetics in psychiatry may have benefits for medication treatment success. However, medication regimes leading to drug-drug interactions and potential phenoconversion of actionable pharmacogenetic phenotypes challenge the application of pharmacogenetics. Although polypharmacy is common, its impact in patients with psychosis is understudied, even though these patients might benefit from pharmacogenetics-guided medication adjustment. Here, we investigated the impact of two pharmacogenes relevant in psychiatric practice, CYP2C19 and CYP2D6, and the effect of sex and age. Medication use and predicted occurrence of phenoconversion was examined in a sample of patients with psychosis over a period of approximately six years. Bayesian statistics were applied to examine longitudinal effects. Our results show that women used more medications, including CYP2C19 and CYP2D6 inhibitors and (actionable) substrates. No significant sex or age differences were found for phenoconversion of either enzyme. A sex-effect on CYP2C19 inhibitor use was found but appeared to be driven by weakly inhibiting oral contraceptives, which were reported only in women. The phenoconversion rate for both enzymes appeared to change over time, suggesting that phenoconversion is a dynamic state that may affect patients differently over their lifetime. To further improve treatment in this patient population, long-term and regular updated medication monitoring in (pharmacogenetic) research as well as application in practice are recommended.

PMID:40228694 | DOI:10.1016/j.pnpbp.2025.111363

Bioorg Med Chem Lett. 2025 Apr 12:130240. doi: 10.1016/j.bmcl.2025.130240. Online ahead of print.

ABSTRACT

A series of hybrids (8a-h and 11a-h) containing 2,4-diphenylpyrimidine scaffold and coumarin moiety were designed and synthesized as novel focal adhesion kinase (FAK) inhibitors for the intervention of non-small-cell lung cancer (NSCLC). Most compounds effectively suppressed the proliferative of NSCLC cells, and compound 8a was identified as the most active compound with IC50 value of 0.28 μM in H1299 cells, superior to TAE226 (IC50 = 2.28 μM). In addition, 8a was also found to inhibit the invasion and migration of NSCLC cells. Furthermore, 8a exhibited potent kinase inhibitory activity of FAK (IC50 = 4.968 nM) with a considerable selectivity profile against various kinase families, subsequently resulting in cell cycle arrest, apoptosis- inducing as well as the decrease of MMP-2 and MMP-9 expression in H1299 cells dose-dependently. Moreover, 8a was relatively safe to mice and inhibited the growth of implanted NSCLC tumors more potently than TAE226 in mice. Therefore, 8a may be a promising candidate for the treatment of NSCLC.

PMID:40228675 | DOI:10.1016/j.bmcl.2025.130240

Depress Anxiety. 2024 Mar 25;2024:2057881. doi: 10.1155/2024/2057881. eCollection 2024.

ABSTRACT

AIM: To determine serum concentrations of leptin and ghrelin in patients with major depressive disorder (MDD) before and after vitamin D3 supplementation.

METHODS: A total of 72 participants were recruited in this study (40 MDD patients and 32 healthy controls). MDD was diagnosed by using Beck's Depression Inventory (BDI) scale. Blood samples were collected from all participants at the beginning of the study to determine baseline serum 25(OH)D3, leptin, and ghrelin concentrations. Patients were then treated weekly with vitamin D3 (50,000 IU) for 3 months, and blood samples were collected again by the end of the study.

RESULTS: At baseline, serum leptin concentrations were significantly higher in MDD patients than in healthy controls. In contrast, serum ghrelin concentrations were significantly lower compared to those in healthy controls. After supplementation with vitamin D3 for three months, MDD patients showed improvements characterized by a decrease in their BDI's scores and an increase in their serum vitamin D and ghrelin concentrations. No effects of vitamin D3 supplementation were seen on serum leptin concentration.

CONCLUSIONS: The antidepressant effects of vitamin D3 supplementation could be mediated by ghrelin but not leptin.

PMID:40226697 | PMC:PMC11918899 | DOI:10.1155/2024/2057881

Front Pharmacol. 2025 Mar 28;16:1523536. doi: 10.3389/fphar.2025.1523536. eCollection 2025.

ABSTRACT

INTRODUCTION: Since April 2020, pretherapeutic screening for accessing the deficiency of the DPD enzyme by genotyping the dihydropyrimidine dehydrogenase gene (DPYD) is required by the European Medicine Agency (EMA) prior to the administration of fluoropyrimidine-based chemotherapy. In May 2020, the Spanish Drug and Medical Devices Agency (AEMPS) published an informative note highlighting the importance of DPYD analysis prior fluoropyrimidines derivatives administration to prevent the development of severe adverse drug reactions (ADRs). The publication of these recommendations marked a turning point in the daily routine in many pharmacogenetics laboratories in Spain. This article aims to illustrate the current state of the DPYD testing in the reference genomic medicine center in Galicia, 4 years after the EMA's updated recommendations.

METHODS: The Pharmacogenetics Unit in the reference genomic medicine center conducted genotyping of the four DPYD variants recommended by regulatory agencies that oncologists can adjust fluoropyrimidine treatment based on DPYD genotype results.

RESULTS: Between 1 June 2020 to 1 May 2024, both included, a total of 2,798 DPYD requests were analyzed. DPYD genotyping results revealed a 3.15% prevalence of heterozygosity for at least one of the four DPYD variants, being rs56038477 the most prevalent variant (1.31%).

CONCLUSION: This study addresses the importance of the DPYD analysis implementation in clinical practice after the changes in EMA and AEMPs recommendations which has led to a significant increase in DPYD genotyping requests. This highlights the significance of preemptive genotyping for accurately adjusting fluoropyrimidines doses before initiating treatment.

PMID:40223928 | PMC:PMC11985815 | DOI:10.3389/fphar.2025.1523536

Acta Inform Med. 2025;33(1):54-57. doi: 10.5455/aim.2024.33.54-57.

ABSTRACT

BACKGROUND: Out of 25-30% of individuals do not respond to 5-Alpha Reductase Inhibitors (5-ARI) as a primary treatment of Benign Prostatic Hyperplasia (BPH), 7% experience disease progression despite treatment. Personalized medicine, which leverages human genomics, offers an approach to tailor treatments based on individual genetic profiles, facilitating early detection of drug resistance and optimizing therapeutic strategies.

OBJECTIVE: The aim of the study was to advance personalized medicine in BPH by identifying genetic factors that influence treatment outcomes, thus improving therapeutic efficacy.

METHODS: This cohort study involved patients responsive and resistant to treatment of BPH. After prostate resection, DNA was extracted and subjected to protein sequencing. The quality of the DNA was assessed, and next-generation sequencing (NGS) was performed. The sequencing data analyzed using FastQC, Samtools, MuTect2, ANNOVAR, and VEP. Whole-genome sequencing (WGS) data were compared to the Human GRCh38 reference genome. Single nucleotide polymorphisms (SNPs) and their positions were visualized through Integrated Genomics Viewer (IGV). Statistical analyses were conducted using R software.

RESULT: Two genetic variants associated with BPH, was a single nucleotide polymorphism (SNP) in the NOS3 gene at rs1799983 (T>A/G), and an SNP at rs61767072 in the SRD5A2 gene. All samples that exhibited resistance to combination drug therapy showed mutations in SNP rs61767072, specifically a deletion at base A in the SRD5A2 gene. Strong correlation reported between SNP rs61767072 and resistance to BPH combination therapy while mutations involving base A and base G in the NOS3 gene did not exhibit any significant correlation with resistance to BPH combination therapy.

CONCLUSION: Variations in genetic makeup significantly affect personalized medical care. Identification of specific SNPs such as rs61767072 may be the basis for the development of more personalized therapies. This study provides evidence that pharmacogenomic approaches are needed in urology practice to improve treatment outcomes.

PMID:40223852 | PMC:PMC11986343 | DOI:10.5455/aim.2024.33.54-57

Drug Test Anal. 2025 Apr 13. doi: 10.1002/dta.3887. Online ahead of print.

ABSTRACT

Pharmacological potential of Hypoxen, previously registered as Olifen is evaluated herein. Hypoxen is categorized as antihypoxic agent. The active substance is polydihydroxyphenylene thiosulfonate sodium. Human studies are limited and no clinical trials following international standards is available. There is however a developed body of knowledge emerging from original studies conducted by the Russian Military Medical Academy in 1980s and 1990s despite limited online access. Hypoxen is promoted to improve oxygen supply or reduce oxygen consumption under hypoxic conditions and physical load. It is thought to support faster recovery, and can be used in complex treatments of diseases accompanied by hypoxia like myocardial ischemia. From clinical perspective, it may enhance cellular respiration by improving coupling in the respiratory chain/accelerating oxidative phosphorylation, but also inhibit succinate dehydrogenase (SDH), and activate mitochondrial ATP-sensitive potassium channels (mitoKATP) in skeletal muscles and myocardium. In 2023, the World Anti-Doping Agency (WADA) added Hypoxen to the Monitoring Program as there had been documented evidence of its use by athletes. On in vitro experiments compared the influence of Hypoxen on oxidative phosphorylation with mitochondrial uncoupling agent 2,4-dinitrophenol (DNP) a unique metabolic modulator that strongly accelerates the metabolism rate, prohibited since 2024 by WADA. Most studies focus on exercise performance, and may provide some evidence that Hypoxen has the potential to enhance performance, the first criteria considered for addition of substance to the WADA Prohibited List. Pharmacodynamics and ergogenic effects of Hypoxen suggests potential as metabolic modulator.

PMID:40223246 | DOI:10.1002/dta.3887

Crit Rev Oncol Hematol. 2025 Apr 11:104720. doi: 10.1016/j.critrevonc.2025.104720. Online ahead of print.

ABSTRACT

Chemotherapy-induced toxicities remain challenging in pediatric oncology, affecting patient outcomes, hospital stays, and quality of life. Genetic variation can partly explain these toxicities, and pharmacogenomics could potentially optimize treatment. This review provides an overview of pharmacogenomic studies in relation to chemotherapy-induced toxicity in children with solid tumors. A systematic literature search was performed in PubMed, Embase, and Web of Science following PRISMA guidelines. Two independent reviewers assessed eligibility, risk of bias using ROBINS-I, and extracted data. Out of 9000 articles screened, 279 were deemed relevant, and 59 met the inclusion criteria by focusing on children with solid tumors and pharmacogenomics in relation to chemotherapy-induced toxicity. Following risk of bias assessment, 24 articles with low to moderate risk of bias were summarized. Identifying specific SNPs associated with toxicities proved challenging due to variability across studies. For methotrexate, the genes ABCC2, MTHFR, and SXR were associated with myelosuppression and hepatotoxicity. The genes ABCC3, COMT, ERCC2, GSTP1, GSTT1, LRP2, SLC22A2, and TPMT showed associations with ototoxicity due to platinum-based drugs. Anthracycline-induced cardiotoxicity was associated with CBR2, CELF4, GSTM1, HAS3, RARG, and SLC28A3, and further with HNMT and SLC22A2 in younger children, with ABCB4 in females, and with SULT2B1 in males. A dose-dependent effect of CELF4 on cardiotoxicity was noted with anthracycline doses over 300mg/m². This review highlights the complexity and variability of pharmacogenomic associations with chemotherapy-induced toxicities in pediatric oncology. While certain genetic variants show associations with specific toxicities, larger multinational/center studies are needed to strengthen the associations and improve clinical guidelines.

PMID:40222694 | DOI:10.1016/j.critrevonc.2025.104720

Brain Stimul. 2025 Apr 11:S1935-861X(25)00094-4. doi: 10.1016/j.brs.2025.04.013. Online ahead of print.

ABSTRACT

BACKGROUND: Reduced inhibitory control is associated with obesity and neuroimaging studies indicate that diminished prefrontal cortex activity influence eating behavior and metabolism. The hypothalamus regulates energy homeostasis and is functionally connected to cortical and subcortical regions especially the frontal areas.

OBJECTIVES: We tested network-targeted transcranial direct current stimulation (net-tDCS) to influence the excitability of brain regions involved in appetite control.

METHODS: In a randomized, double-blind parallel group design, 44 adults with overweight or obesity (BMI 30.6 kg/m2, 52.3 % female) received active (anodal or cathodal) or sham 12-channel net-tDCS on the hypothalamus appetite-control network for 25 minutes on three consecutive days while performing a Stop-Signal-Task to measure response inhibition. Before and after stimulation, state questionnaires assessed changes in desire to eat and food craving. Directly after stimulation, participants received a breakfast buffet to evaluate ad-libitum food intake. An oral glucose tolerance test was conducted at follow-up. Resting-state functional MRI was obtained at baseline and follow-up.

RESULTS: The Stop-Signal Reaction Time (SSRT) was shorter in both active groups versus sham, indicating improved response inhibition. Additionally, a stronger increase in hypothalamic functional connectivity was associated with shorter SSRT. Caloric intake of sweet food was lower in the anodal group versus sham, but no main effects between groups were observed on total and macronutrient intake, food craving ratings and desire to eat. At follow-up, no differences were observed between groups on peripheral metabolism.

CONCLUSION: Our study suggests that modulating hypothalamic functional network connectivity patterns via net-tDCS may improve food choice and inhibitory control.

PMID:40222666 | DOI:10.1016/j.brs.2025.04.013

Biochimie. 2025 Apr 11:S0300-9084(25)00067-7. doi: 10.1016/j.biochi.2025.04.003. Online ahead of print.

ABSTRACT

Prostanoids are lipid mediators of human body that involved in the inflammation and platelet aggregation. Prostacyclin is a vasodilator and inhibitor of platelet aggregation, and a product of the enzymatic reaction catalyzed by prostacyclin synthase (PTGIS). Thromboxane is a vasoconstrictor and synthesized by thromboxane synthase (TBXAS1). An imbalance of prostanoids can accompany cardio-/ cerebrovascular diseases and cancers. PTGIS and TBXAS1 are clinically relevant membrane-bound enzymes of the multigene family of cytochromes P450 (CYPs), also known as CYP8A1 and CYP5A1, respectively. Particular studies of these functional antagonists will contribute to elucidation of pathogenic mechanisms. The purpose of this work was to analyze the literature landscape over a period of 2020-2024 in the field of biological, pharmacogenomic, and pharmacological features of PTGIS and TBXAS1 as well as to explore the potential of their regulation at the post-transcriptional and post-translational levels using systems biological analysis. The review discusses recent findings on the novel features of both synthases established in gene knockout and overexpression experiments, aspects of current preclinical pharmacology, and potential ways of gene expression regulation. Identification of protein-protein interactions and post-translational modifications appear to be the main options for modulating of PTGIS and TBXAS1 activity. The microsomal CYPs used to form complexes with each other and direct interactions of CYP2E1 with both synthases can probably lead to modulation of their activity. A progress in the preclinical development of low molecular weight compounds as inhibitors of TBXAS1 is more prospective than PTGIS that is applied as a gene therapy biological for in vivo production of prostacyclin due to its noticeable anticancer and vasodilator effects.

PMID:40222477 | DOI:10.1016/j.biochi.2025.04.003

Hum Genomics. 2025 Apr 12;19(1):40. doi: 10.1186/s40246-025-00751-8.

ABSTRACT

Genomics of athletic performance is an emerging discipline with a high degree of controversy. With the existing level of evidence, it is both premature and highly risky to exploit current human genomics knowledge to predict exercise and sports performance or enhance existing training methodologies. Until more solid evidence on the influence of genomic variants in athletic performance becomes available, accompanied by regulatory approved genome-guided recommendations, all genetic associations should be restricted from general public access as commercial services, since genomic markers cannot per se predict athletic performance for talent identification, resistance to injuries or the ability to recover from them. Evidently, the complex interplay of genetics with other physical, physiological and even psychological and mental characteristics to produce a world-class athlete is still not understood.

PMID:40221803 | DOI:10.1186/s40246-025-00751-8

J Clin Med. 2025 Mar 21;14(7):2142. doi: 10.3390/jcm14072142.

ABSTRACT

Background/Objectives: Polymorbidity and polypharmacy are major challenges in geriatric care, resulting in a reduced quality of life and increased health care costs. Methods: We evaluated the proactive medication management of nursing home residents through personal visits and the use of a clinical decision support system (CDSS) with an integrated Beers Criteria list. Results: Among 56 nursing home residents, we observed a high prevalence of polypharmacy with an average of 7.9 regular and 5.1 on-demand prescriptions. Proactive medication management led to persistent medication changes in 87.5% of patients. Regular prescriptions were reduced in 21 residents and increased in 18 residents, resulting in a reduced use of cardiovascular drugs and antacids (p < 0.05), but no significant overall reduction in polypharmacy. CDSS alerts based on Beers Criteria made no clinically relevant contribution to medication reduction. Conclusions: Proactive geriatric medication management led to persistent medication changes and no reduction in overall polypharmacy but reduced the use of selected drug classes that are associated with an increased risk of adverse reactions and costs. The clinical relevance and implementability of Beers Criteria were low, revealing major limitations of algorithm-based alerts for older patients, who require additional personalized evaluations of their individual complex healthcare needs.

PMID:40217592 | DOI:10.3390/jcm14072142

Inflammopharmacology. 2025 Apr 12. doi: 10.1007/s10787-025-01725-x. Online ahead of print.

NO ABSTRACT

PMID:40216663 | DOI:10.1007/s10787-025-01725-x

OMICS. 2025 Apr 11. doi: 10.1089/omi.2024.0199. Online ahead of print.

ABSTRACT

Anophthalmia is the most severe ocular malformation inherited in an autosomal, X-linked, recessive, or dominant form. We report here the use of whole exome sequencing (WES) to help the clinical diagnosis of familial anophthalmia in Harare, Zimbabwe. A mother presented her two sons, who are half-brothers, at the Eye, Ear, Nose, and Throat Institute, Ophthalmology Unit in Harare, Zimbabwe. Upon clinical examination, half-brothers were diagnosed with clinical bilateral anophthalmia. The mother requested a genetic diagnosis for her two sons. To segregate the phenotype with genotype, whole blood was collected from two half-brothers, their mother, maternal aunt, and maternal uncle to the half-brothers, and an unrelated healthy control. Genetic characterization was done, first, through a candidate gene approach screening of putative genes SOX2, OTX2, VSX2, PAX6, and RAX. When no causative variants were identified, the next step employed WES. Variants in 80 genes associated with anophthalmia were prioritized and subjected to pathogenicity testing. One pathogenic variant, BCOR c.254C>T (rs121434618, p. Pro85Leu), segregated with the mother and her two sons. The present clinical genomics study of a family and a healthy control sample underscores WES as a valuable tool that can help clinical diagnosis of anophthalmia in the Zimbabwean clinical setting. In this article, we also offer a reasoned discussion and call from the field, to fund clinical genomics and omics research and development in planetary health, especially in the current era of uncertainties in international aid and funding of innovative technologies. The findings reported herein encourage further research on the clinical utility of WES as a diagnostic tool in Africa and around the world as well, given that the candidate gene approach might miss the important genes or variants of relevance to disease pathophysiology.

PMID:40216558 | DOI:10.1089/omi.2024.0199

BMJ Health Care Inform. 2025 Apr 10;32(1):e101163. doi: 10.1136/bmjhci-2024-101163.

ABSTRACT

STUDY OBJECTIVES: Describe the implementation of an interoperable solution to support pharmacogenomic-guided prescribing in primary care in the National Health Service, England.

METHODS: We used an iterative approach to software development going through clinical workflow mapping, architecture design and development, and pilot-testing.

RESULTS: We configured a commercial health data management platform to store pharmacogenomic results in a structured format and created a knowledge base of pharmacogenomic guidance. This solution was deployed 'as-a-service' using an open application programming interface (API) specification, allowing third parties to receive pharmacogenomic results and guidance by querying the service using a patient identifier and medicine code. This was integrated with existing clinical decision support tools and presented contextual information to prescribers within their native electronic health record (EHR).

DISCUSSION: Pharmacogenomic results and guidance will be used across care settings and have greatest utility at the point of prescribing. This requires a solution, which separates the data from the applications, allowing integration with different EHRs through APIs.

CONCLUSIONS: A vendor-agnostic standards-based solution can support the implementation of pharmacogenomic-guided prescribing across primary care.

PMID:40216452 | DOI:10.1136/bmjhci-2024-101163

Toxicol Appl Pharmacol. 2025 Apr 9:117341. doi: 10.1016/j.taap.2025.117341. Online ahead of print.

ABSTRACT

Amiodarone is an effective therapy for arrhythmias, its prolonged management may lead to significant adverse drug reactions. Amiodarone-induced hepatotoxicity is described by phospholipidosis, hepatic steatosis, cholestatic hepatitis, and cirrhosis. However, the systemic and hepatic lipidome disturbances and underlying toxicological mechanisms remain comprehensively elucidated. Untargeted lipidomics were utilized to analyze serum and liver samples from the rats orally administered a daily dose of amiodarone of either 100 or 300 mg/kg for one week. Changes in the expression of hepatic lipid-related genes were also examined utilizing transcriptomics. We found a higher magnitude of lipidome alterations in the 300 mg/kg than those in the 100 mg/kg groups. Treated animals showed elevated abundances of phosphatidylcholines, ether-linked phosphatidylcholines, sphingomyelins, and ceramides, and decreased levels of triacylglycerols, ether-linked triacylglycerols, and fatty acids. We also found 199 lipid-related differentially expressed hepatic genes between the 300 mg/kg group versus controls, implying lipid metabolism and signaling pathways disturbances. Specifically, elevation of serum phosphatidylcholines and ether-linked phosphatidylcholines, as well as hepatic bismonoacylglycerophosphates were associated with reduced expression of phospholipase genes and elevated expression of glycerophospholipid biosynthesis genes, possibly driving phospholipidosis. Perturbations of sphingolipid metabolism might also be the key events for amiodarone-induced toxicity. Alterations in gene expression levels related to lipid storage and metabolism, mitochondria functions, and energy homeostasis were also found. Collectively, our study characterized the sophisticated perturbations in the lipidome and transcriptome of amiodarone-treated rats and suggested potential mechanisms responsible for amiodarone-induced hepatotoxicity.

PMID:40216313 | DOI:10.1016/j.taap.2025.117341

Vet J. 2025 Apr 9:106347. doi: 10.1016/j.tvjl.2025.106347. Online ahead of print.

ABSTRACT

Multimodal analgesic administration is a promising strategy for mitigating side effects typically associated with analgesia; nevertheless, variation in analgesic effectiveness still poses a considerable safety concern for both horses and veterinarians. Pharmacogenomic studies have started delving into genetic influences on varying drug effectiveness and related side effects. However, current findings have narrow implications and are limited in their ability to individualize analgesic dosages in horses. Hydromorphone and detomidine were administered to a cohort of 48 horses at standardized time intervals, with dosage rates recorded. Analgesic effectiveness was scored (1-3) based on pain response to dura penetration during cerebrospinal fluid centesis. Genome-wide association (GWA) analyses identified two SNVs passing the nominal significance threshold (P<1×10-5) in association with analgesic effectiveness. One SNV identified on chromosome 27 (rs1142378599) is contained within the LOC100630731 disintegrin and metalloproteinase domain-containing protein 5 gene. The second identified SNV is an intergenic variant located on chromosome 29 (rs3430772468) These SNVs accounted for 26.11% and 31.72% of explained variation in analgesic effectiveness respectively, with all eight of the horses with the lowest analgesic effectiveness expressing the A/C genotype at rs3430772468, with six of which also expressing the C/T genotype at rs1142872965. Whilst highlighting the multifactorial nature of analgesic efficacy, this study serves as an important step in the application of genome-wide approaches to better understand genetic factors underpinning commonly observed variation in analgesic effectiveness in horses, with the goal of tailoring analgesic dosage to minimize commonly observed side effects and improve the outcomes of equine pain management.

PMID:40216012 | DOI:10.1016/j.tvjl.2025.106347