BMC Cardiovasc Disord. 2025 Mar 13;25(1):179. doi: 10.1186/s12872-025-04611-0.

ABSTRACT

BACKGROUND: To systematically evaluate the effect of ABCG2 c.421 C > A (rs2231142) single nucleotide polymorphism (SNP) on the lipid-modulating efficacy of rosuvastatin (RST).

METHODS: Searches were conducted using the Wan Fang database, Web of Science, Embase, PubMed, Cochrane Library, and China Journal Full Text Database. The time frame for the search was from the database's creation to September 1, 2024. The RevMan 5.4 software was used to conduct a meta-analysis after the literature was filtered based on the inclusion and exclusion criteria, and pertinent data was extracted following methodological quality evaluation.

RESULTS: A total of 7 studies, including 1347 patients, were included. Meta-analysis showed that in a dominant model of inheritance, RST had a significant effect on low-density lipoprotein cholesterol (LDL-C) [MD = -7.23, 95% CI (-8.71, -5.75), P < 0.05], total cholesterol (TC) [MD = -7.15, 95% CI (-8.71, -5.75), P < 0.05], and triglyceride (TG) [MD = -7.34, 95% CI (-10.88, -3.80), P < 0.05] in patients harboring an A allele decreased significantly more than CC, but there was no significant difference in the change of high-density lipoprotein cholesterol (HDL-C) [MD = -2.22, 95% CI (-19.87, 15.43), P = 0.81]. The results of the sensitivity analysis suggested that all outcome indicators were stable. However, this study's small sample size may be heterogeneous, and more large-sample, multi-center studies are needed for future validation.

CONCLUSIONS: The ABCG2 c.421 C > A (rs2231142) SNP significantly affected the lipid-modulating efficacy of RST, especially the down-regulation of LDL-C, TC, and TG.

PMID:40082758 | DOI:10.1186/s12872-025-04611-0

Nat Comput Sci. 2025 Mar 13. doi: 10.1038/s43588-025-00777-x. Online ahead of print.

ABSTRACT

The accelerating growth of make-on-demand chemical libraries provides unprecedented opportunities to identify starting points for drug discovery with virtual screening. However, these multi-billion-scale libraries are challenging to screen, even for the fastest structure-based docking methods. Here we explore a strategy that combines machine learning and molecular docking to enable rapid virtual screening of databases containing billions of compounds. In our workflow, a classification algorithm is trained to identify top-scoring compounds based on molecular docking of 1 million compounds to the target protein. The conformal prediction framework is then used to make selections from the multi-billion-scale library, reducing the number of compounds to be scored by docking. The CatBoost classifier showed an optimal balance between speed and accuracy and was used to adapt the workflow for screens of ultralarge libraries. Application to a library of 3.5 billion compounds demonstrated that our protocol can reduce the computational cost of structure-based virtual screening by more than 1,000-fold. Experimental testing of predictions identified ligands of G protein-coupled receptors and demonstrated that our approach enables discovery of compounds with multi-target activity tailored for therapeutic effect.

PMID:40082701 | DOI:10.1038/s43588-025-00777-x

J Cancer Res Clin Oncol. 2025 Mar 13;151(3):109. doi: 10.1007/s00432-025-06160-7.

ABSTRACT

INTRODUCTION: Telomerase reverse transcriptase (TERT) is a catalytic subunit of telomerase that maintains genome stability by maintaining telomere length (TL). The massive proliferation of donor cells in the recipient's body for engraftment results in accelerated telomere shortening. Genetic variability within the TERT gene affects telomerase activity, and was shown to influence of haematopoietic stem cell transplantation (HSCT) outcome. In the present study, we aimed to analyse the effect of recipient and donor TL and TERT single nucleotide polymorphism (SNP) on the occurrence of post-HSCT complications.

METHODS: Our study included 120 recipient-donor pairs. TERT promoter (TERTp) SNP (rs2853669) SNP variant was detected with the use of the LightSNiP typing assay employing real-time polymerase chain reaction (PCR) amplifications. Telomere length measurements were performed using qPCR test kits (ScienCell's Absolute Human Telomere Length Quantification qPCR Assay Kit [AHTLQ], Carlsbad, CA, USA).

RESULTS: The presence of TERTp rs2853669 T allele in the recipient was associated with a higher risk for acute graft-versus-host-disease (aGvHD) manifestation (p = 0.046) and a significantly shorter aGvHD-free survival (p = 0.041). The latter association was further confirmed in a Cox proportional hazards model (p = 0.043). However, no statistically significant association between telomere length and post-transplant complications was observed. Furthermore, we found that shorter TL characterized donors of patients with late complete chimerism at 180 day after HSCT (p = 0.011).

CONCLUSION: Our results suggest that recipient allele TERTp rs2853669 T is a marker of unfavourable outcome in the context of aGvHD. Shorter TL in donors could be associated with later achievement of complete chimerism.

PMID:40082305 | DOI:10.1007/s00432-025-06160-7

Gene. 2025 Mar 11:149386. doi: 10.1016/j.gene.2025.149386. Online ahead of print.

ABSTRACT

Vancomycin is a commonly administered antibiotic for various Gram-positive infections in critically ill patients. Vancomycin has a narrow therapeutic index and its main adverse drug reaction is acute kidney injury (AKI). In this regard, various pharmacokinetic parameters have been widely considered for therapeutic drug monitoring (TDM) purposes. Higher vancomycin trough concentration and area under the curve (AUC) values would be associated with higher rates of AKI. Therefore, dose adjustment based on targeted pharmacokinetic values would be essential to avoid toxicity and achieve optimal clinical response. However, there are numerous reports regarding the discrepancy between pharmacokinetic parameter values and AKI. In this regard, we examined the possible role of pharmacogenetics in vancomycin-induced AKI to distinguish patients who are genetically prone to AKI. In this cross-sectional study, polymorphisms of osteopontin (OPN) and Apolipoprotein E (APOE) along with pharmacokinetic parameters were assessed in 87 critically ill patients admitted to ICU wards and received vancomycin. The results indicated a significant difference in OPN and APOE genotype distribution between AKI and non-AKI patients (P = 0.001 and 0.02, respectively). Stepwise multivariate logistic regression analysis showed that patients with e2e3 genotype were 4.2-fold more prone to AKI (P = 0.029; OR = 4.2; 95 %CI = 1.2-15.7). Moreover, there was a significant correlation between pharmacokinetic parameters (calculated trough concentration, AUCτ, AUC24h, and t1/2) and vancomycin-induced AKI. Genotyping the patients for OPN and APOE polymorphisms before vancomycin initiation would be promising as a routine clinical practice to obtain an efficient clinical response and prevent vancomycin-induced AKI, especially in critically ill patients.

PMID:40081681 | DOI:10.1016/j.gene.2025.149386

Biochim Biophys Acta Mol Basis Dis. 2025 Mar 12;1871(5):167755. doi: 10.1016/j.bbadis.2025.167755. Online ahead of print.

ABSTRACT

The Arylamine-N-acetyltransferase-2 (NAT2) enzyme is involved in metabolism of commonly used drugs driving differences in efficacy and tolerability of treatments. To bridge the current knowledge gap on metabolism of cytotoxic drugs by NAT2, and identify anticancer agents whose effects depend on NAT2 activity, we assessed 147 clinically used drugs. Hit compounds were evaluated for metabolic conversion by acetylation in presence of recombinant NAT2. Among those 147 drugs we found doxorubicin, daunorubicin, epirubicin, valrubicin, teniposide, afatinib, carmustine, vincristine, panobinostat, and vorinostat to have increased toxicity to cancer cells expressing the rapid NAT2 allele. Additionally, we report NAT2-mediated acetylation of idarubicin, daunorubicin, doxorubicin, vorinostat, and CUDC-101. These findings have implications for pharmacogenomics and cancer precision medicine using conventional chemotherapeutic drugs, as improving their efficacy and safety may affect >4 million cancer patients worldwide that receive these drugs as standard of care.

PMID:40081304 | DOI:10.1016/j.bbadis.2025.167755

Forensic Sci Int. 2025 Mar 7;370:112445. doi: 10.1016/j.forsciint.2025.112445. Online ahead of print.

ABSTRACT

Methadone is a synthetic opioid that is often used for prevention of withdrawal symptoms and for management of chronic pain. In concentrations above the therapeutic level however, methadone can lead to detrimental side effects, such as respiratory depression. Several cytochrome P450 (CYP) enzymes are involved in methadone metabolism, foremost in building the main metabolite 2-ethylidene-1,5-dimethyl-3,3diphenylpyrrolidine (EDDP). It is well known that genetic polymorphisms within the CYPs can lead to an altered metabolism, affecting methadone elimination and peak concentrations. The metabolic ratio, in forensic toxicology suggested to assist in distinguishing between chronic and acute intake, can also be affected by genetic variations in CYP genes. The aim of the study was therefor to examine, whether the metabolizer type of CYP2D6, CYP2C19 and CYP2B6 can be associated with a certain type of intoxication, methadone concentration or metabolic ratio in postmortem blood samples of methadone intakers. The metabolic ratio of EDDP/methadone was determined in 37 blood samples from deceased methadone intakers in 2023. These cases were genotyped for CYP2D6, CYP2C19 and CYP2B6 via SNaPshot analysis. In case of CYP2D6 a copy number variations analysis was applied using qPCR. Metabolizer phenotypes were determined according to guidelines by the Dutch Pharmacogenetics Working Group (DPWG) and the Clinical Pharmacogenetics Implementation Consortium (CPIC). Our results show a significantly increased metabolic ratio of EDDP/methadone in the CYP2D6 intermediate metabolizer (IM) group, compared to the CYP2D6 normal metabolizer (NM) group. Further, when separating the methadone intakers by type of intoxication, CYP2D6 IM had a significantly higher metabolic ratio in the mix intoxication and the non-intoxication group compared to NM, poor and ultrarapid metabolizers (PM, UM).

PMID:40080971 | DOI:10.1016/j.forsciint.2025.112445

Mol Oncol. 2025 Mar 13. doi: 10.1002/1878-0261.70008. Online ahead of print.

ABSTRACT

Ewing sarcoma (EwS) is a rare and aggressive malignancy, which frequently affects children. One of the few recurrent genomic variants in EwS is genomic copy number deletion of CDKN2A; however, the clinical consequences of dysregulation of CDKN2A in EwS are unclear. In this study, we revisit CDKN2A to investigate its role as a potential prognostic biomarker in EwS using data from EwS pre-clinical models as well as clinical samples from patients with EwS. We demonstrate the potential essentiality of CDKN2A dysregulation and sustained downstream CDK4/CCND1 activity. Finally, we present evidence that high expression of CDKN2A is a negative prognostic biomarker at diagnosis in EwS in three independent datasets. Our data may suggest that the role of CDKN2A may change across the clinical context of EwS, however, further study is necessary to validate the function of CDKN2A expression in EwS.

PMID:40080912 | DOI:10.1002/1878-0261.70008

Clin Transl Sci. 2025 Mar;18(3):e70194. doi: 10.1111/cts.70194.

ABSTRACT

Pharmacogenomics research has predominantly focused on populations of European ancestry, limiting the application to diverse populations such as American Indian and Alaska Native (AIAN) communities. Our community-centric study aims to understand perspectives on utilizing pharmacogenomics to guide tobacco cessation in an AIAN community using a survey with qualitative and quantitative components. We assessed participant (n = 273) tobacco usage and cessation history, pharmacogenomics knowledge, and perceptions of utilizing pharmacogenomics in the context of tobacco cessation. We found that the majority of participants (92%) were aware of the risks associated with tobacco usage and believed it to be a problem within their community (76%). Our results showed that 29% of participants had some level of knowledge regarding pharmacogenomics and only 6% had previously participated in pharmacogenomics research, demonstrating the need for further education and awareness. Community involvement was a priority for participants, with 64% preferring Tribal inclusion in all research stages and 63% favoring partnerships with local health centers. We also found support for future research, with 68% viewing pharmacogenomics as a beneficial tool. Concerns were raised regarding the handling of genetic material and result dissemination, emphasizing the importance of ethical research practices, transparent communication, and community partnership. Our findings serve as a foundation for shaping future research efforts and developing a framework for implementing tobacco cessation interventions. Our community-centered approach addresses the specific needs of this AIAN community and offers insights applicable to research practices within other underserved and marginalized populations, particularly those with a historical distrust of research.

PMID:40078094 | DOI:10.1111/cts.70194

Int J Mol Sci. 2025 Feb 24;26(5):1960. doi: 10.3390/ijms26051960.

ABSTRACT

Kidney transplantation is currently the treatment of choice for patients with end-stage kidney diseases. Although significant advancements in kidney transplantation have been achieved over the past decades, the host's immune response remains the primary challenge, often leading to potential graft rejection. Effective management of the immune response is essential to ensure the long-term success of kidney transplantation. To address this issue, immunosuppressives have been developed and are now fully integrated into the clinical management of transplant recipients. However, the considerable inter- and intra-patient variability in pharmacokinetics (PK) and pharmacodynamics (PD) of these drugs represents the primary cause of graft rejection. This variability is primarily attributed to the polymorphic nature (genetic heterogeneity) of genes encoding xenobiotic-metabolizing enzymes, transport proteins, and, in some cases, drug targets. These genetic differences can influence drug metabolism and distribution, leading to either toxicity or reduced efficacy. The main objective of the present review is to report an historical overview of the pharmacogenetics of immunosuppressants, shedding light on the most recent findings and also suggesting how relevant is the research and investment in developing validated NGS-based commercial panels for pharmacogenetic profiling in kidney transplant recipients. These advancements will enable the implementation of precision medicine, optimizing immunosuppressive therapies to improve graft survival and kidney transplanted patient outcomes.

PMID:40076585 | DOI:10.3390/ijms26051960

Pharmacogenomics J. 2025 Mar 12;25(1-2):7. doi: 10.1038/s41397-025-00366-1.

ABSTRACT

In view of the limited data related to preemptive pharmacogenomics (PGx) testing in the primary care setting, we designed a study to assess the feasibility of implementing preemptive PGx services at outpatient clinics, with the aim to assess the practicality and challenges of implementing preemptive PGx testing within primary care, and its impact on clinical workflows and patient care. This prospective study was conducted between October 2022 and August 2023 at five outpatient clinics located in Singapore. Patients aged 21 to 65 with a reported history or risk of developing any of the target chronic conditions or any patients receiving one of the 29 PGx-associated medications were recruited. Patients' buccal samples were processed using a multi-gene qPCR-based panel of 21 allele variants of five pharmacogenes. Surveys were administered to study participants and clinicians to assess their perceptions and outcomes related to PGx testing. Among the 222 patients, 95% had at least one clinically actionable variant. Of these patients, 113 reported taking at least one of the 29 studied drugs, with 21.2% of them receiving at least one clinically actionable recommendation based on their PGx results. A total of 150 patients (67.6%) participated in the post-test follow-up survey. Among them, 70% expressed feeling relieved and happy upon receiving their test reports and reported increased confidence in taking their prescribed medication. Furthermore, clinicians identified the necessity for clearer legal regulations regarding PGx testing and insurance coverage to enhance future adoption of PGx testing. Given a high prevalence of clinically actionable variants in almost all tested patients, this study underscores the feasibility and clinical benefits of preemptive PGx testing in primary care clinics in Singapore.Clinical Trial Registration: This study is registered with ClinicalTrials.gov, identifier NCT05504135, with the registration date of August 17, 2022.

PMID:40074758 | DOI:10.1038/s41397-025-00366-1

J Genet Eng Biotechnol. 2025 Mar;23(1):100476. doi: 10.1016/j.jgeb.2025.100476. Epub 2025 Mar 5.

ABSTRACT

Hypertension is the foremost modifiable risk factor for cardiovascular and renal diseases, and overall mortality on a global scale. Genetic variants have the potential to alter an individual's drug responses. In the present study, we employed a comprehensive computational analysis to evaluate the structural and functional implications of deleterious missense variants to examine the influence of RAAS genes such as AT1R, AT2R, and MasR on susceptibility to hypertension. The objective of this research was to identify potentially deleterious missense variants within these target genes. A total of 13 in silico tools were used to identify deleterious missense SNPs. Protein stability, evolutionary conservation, and 3D structural modeling were assessed using tools like I-Mutant 3.0, MUpro, DynaMut2, ConSurf, and Project HOPE, while protein-protein interactions were analyzed via STRING. Our findings revealed three deleterious missense variants (rs397514687, rs886058071, rs368951368) in AT1R; two deleterious missense variants (rs3729979 and rs372930194) in AT2R; and three deleterious missense variants (rs768037685, rs149100513, and rs377679974) in MasR, all of which exhibited significant damaging effects as determined by the 13 Computational tools employed. All these deleterious missense variants adversely affected protein stability and were found to be highly conserved. Notably, these variants altered the charge, size, and hydrophobicity of the amino acids, with a predominant occurrence in alpha helix regions, with the exception of rs377679974 in MasR. The computational analysis and structural comparisons conducted in this study indicate that these deleterious missense variants have a discernible impact on the structure and function of the target proteins. However, it is essential to conduct experimental validation to verify the detrimental effects of the missense variants identified through this computational analysis. Therefore, we may conduct future experimental analyses to validate these findings. This research will aid in the identification of candidate deleterious markers that may serve as potential targets for therapeutic strategies and disease diagnosis.

PMID:40074423 | DOI:10.1016/j.jgeb.2025.100476

Cancer Chemother Pharmacol. 2025 Mar 12;95(1):40. doi: 10.1007/s00280-025-04756-x.

ABSTRACT

In recent years, assessing dihydropyrimidine dehydrogenase (DPD) activity has become crucial for cancer patients undergoing 5-fluorouracil (5FU)-based chemotherapy due to the life-threatening toxicity associated with reduced DPD function. The methods for evaluating DPD activity have evolved, with the analysis of DPYD polymorphisms in blood samples becoming the preferred approach. As the indications for liver transplantation are increasing-particularly due to a rise in cases of cholangiocarcinoma (CCA) and non-resectable colorectal liver metastasis-more cancer patients with a history of liver transplantation may experience disease relapse. Furthermore, 5-fluorouracil chemotherapy is a standard treatment for both cancers. This growing need to evaluate DPD activity in transplanted livers arises because standard tests conducted on blood samples reflect the activity of native liver tissue and may produce misleading results. This paper presents two clinical cases from 2022 to 2023 involving patients who underwent successful liver transplants but were later diagnosed with intrahepatic CCA in the explanted liver. Both patients were subsequently prescribed capecitabine as adjuvant chemotherapy, making it essential to assess DPD activity in donor liver tissue to ensure safe treatment protocols. However, there are currently no established guidelines for this specific patient group. If we follow standard clinical practice, this critical analysis will be insufficient, as it only describes the DPD activity of the native liver. It is imperative to determine the DPD activity of the transplanted liver. In summary, this case report highlights the importance of managing this complex situation effectively.

PMID:40072607 | DOI:10.1007/s00280-025-04756-x

Balkan J Med Genet. 2025 Mar 6;27(2):69-75. doi: 10.2478/bjmg-2024-0012. eCollection 2024 Dec.

ABSTRACT

Clopidogrel, a P2Y12 receptor antagonist, is widely used to prevent cardiovascular events, but significant variability in its efficacy persists among patients. AKR1D1, involved in bile acid synthesis and regulation of CYP enzymes, may contribute to this variability. This study aims to investigate whether clopidogrel and its inactive metabolite, 2-oxoclopidogrel, interact with AKR1D1 at the enzymatic or transcriptional level. Enzymatic activity assays demonstrated that neither clopidogrel nor 2-oxoclopidogrel acts as a substrate or inhibitor of AKR1D1. Expression studies in HepG2 cells further revealed no significant changes in AKR1D1 mRNA levels following treatment with these compounds. These findings indicate that clopidogrel does not directly influence AKR1D1's metabolic functions, including bile acid synthesis, steroid hormone clearance, or the production of 5β-reduced steroids, which regulate CYP enzyme expression. From a physiological perspective, the absence of interaction minimizes the risk of adverse effects on CYP-mediated drug metabolism, nutrient absorption, lipid digestion, and the absorption of lipophilic drugs. Future research should explore AKR1D1's broader substrate specificity, particularly focusing on non-steroidal compounds, and investigate the clinical implications of AKR1D1 polymorphisms in clopidogrel-treated patients to enhance personalized therapeutic strategies.

PMID:40070864 | PMC:PMC11892939 | DOI:10.2478/bjmg-2024-0012

Balkan J Med Genet. 2025 Mar 6;27(2):77-85. doi: 10.2478/bjmg-2024-0015. eCollection 2024 Dec.

ABSTRACT

The CYP2C19*2 c.681G>A (rs4244285) loss-of-function (LOF) allele has been associated with reduced clopidogrel efficacy and increased risk of major adverse cardiovascular events (MACE). PGx-guided treatment, despite the recommendations, is not fully implemented in routine clinical practice. The primary aim of this hybrid retrospective-prospective study was to determine whether identifying CYP2C19 LOF patients may benefit the antiplatelet drug prescribing decisions made in Kosovo. The study cohort consisted of clopidogrel treated patients presenting at the University Clinical Center in the period from December 2023 to May 2024. To evaluate the correlation between CYP2C19 LOF and the treatment outcome in a follow-up period of 2 years, we first assessed the CYP2C19*2 genotype using the Taq Man Real Time PCR method. Among 150 patients, 58 (19.33%) were identified as carriers CYP2C19*2 LOF allele. The observed allele distribution was significantly different when compared with the one reported for a healthy Kosovar population (13.03%). CYP2C19*2 LOF carriers exhibited a 1.6-fold higher probability of developing cardiovascular disease compared to non-carriers, based on allelic and codominant model of statistical analysis (OR=1.60; 95% CI=1.08-2.37; p=0.018 and OR=1.64; 95% CI=1.04-2.57; p=0.031, respectively). The median observation time of follow up was not reached until this analysis was conducted. Our data supports the potential association of the CYP2C19*2 LOF allele with an increased risk for CVD in the population of Kosovo. Our data add to the evidence advising careful consideration of CYP2C19 genetic diversity when recommending PGx-guided clopidogrel therapy, particularly in populations, such the Kosovar, where genetic determinants are not yet fully elucidated.

PMID:40070858 | PMC:PMC11892937 | DOI:10.2478/bjmg-2024-0015

Front Pharmacol. 2025 Feb 12;16:1523399. doi: 10.3389/fphar.2025.1523399. eCollection 2025.

ABSTRACT

Proton pump inhibitors (PPIs) are widely prescribed medications for the management of acid-related disorders, due to their effectiveness and favorable pharmacokinetics. However, the occurrence and severity of adverse drug reactions (ADRs) in patients using PPIs, particularly in relation to their association with CYP2C19 polymorphisms, are of great concern. This association has largely been investigated through observational studies, which have shown conflicting or weak findings. Therefore, this review aims to examine the current evidence regarding the long-term ADRs of PPIs and their link to CYP2C19 variants.

PMID:40070570 | PMC:PMC11894441 | DOI:10.3389/fphar.2025.1523399

Curr Drug Saf. 2025 Mar 11. doi: 10.2174/0115748863355987250223072145. Online ahead of print.

ABSTRACT

The growing popularity of personalized medicine presents new hazards and difficulties for pharmacovigilance. This implies that it needs to modify its current approach. This research examines how drug safety monitoring for certain medications evolves over time. We briefly discuss the connection between meticulous pharmacovigilance procedures and adaptable treatment approaches. We describe how pharmacogenetics may be used to make drugs safer and how genetic testing may be used to forecast a drug's potential side effects. With an emphasis on post-marketing monitoring in phase IV, we address shortcomings of research on pre-marketing and the need for a comprehensive strategy for medication safety. The significance of pharmacogenetics in reducing risk before exposure and the need to reconsider pharmacoepidemiological techniques for monitoring outcomes after exposure are discussed in the study. We emphasize the significance of including genetic patient-specific profiles in publications related to tailored therapy and the use of state-of-the-art computer techniques for data processing. We also discuss privacy, ethical, and data security issues that arise with precision medicine, emphasizing the consequences for patient consent and data management.

PMID:40070333 | DOI:10.2174/0115748863355987250223072145

Pharmacol Rep. 2025 Mar 12. doi: 10.1007/s43440-025-00707-8. Online ahead of print.

ABSTRACT

BACKGROUND: OSU6162, a monoamine stabilizer, has demonstrated efficacy in reducing alcohol and anxiety-related behaviors in preclinical settings. In a previous randomized, double-blind, placebo-controlled trial involving patients with alcohol dependence (AD), OSU6162 significantly reduced craving for alcohol but did not alter drinking behaviors. This retrospective secondary analysis explores whether genetic predispositions related to AD and associated traits might influence the response to OSU6162 treatment in original trial participants.

METHODS: Polygenic risk scores (PRSs) were calculated for 48 AD patients using PRSice-2 and genome-wide association study (GWAS) data for (i) alcohol use disorder and alcohol consumption, (ii) problematic alcohol use, (iii) drinks per week, (iv) major depression, and (v) anxiety (case-control comparisons and quantitative anxiety factor scores). Linear regression analyses, adjusted for population stratification, assessed interaction effects between PRSs and treatment type (OSU6162 or placebo) on various clinical outcomes.

RESULTS: Significant interactions were found between treatment type and anxiety factor score PRS at the genome-wide significance threshold. In the OSU6162-treated group, a higher anxiety PRS was associated with reductions in the number of drinks consumed (FDR = 0.0017), percentage of heavy drinking days (FDR = 0.0060), and percentage of drinking days (FDR = 0.0017), with a trend toward reduced blood phosphatidylethanol (PEth) levels (FDR = 0.068). These associations were absent in the placebo group.

CONCLUSIONS: These preliminary findings suggest that anxiety PRS may help predict response to OSU6162 treatment in AD. Further research with larger cohorts and more comprehensive genetic data is needed to confirm these results and advance personalized medicine approaches for alcohol use disorder.

PMID:40069537 | DOI:10.1007/s43440-025-00707-8

Drug Des Devel Ther. 2025 Mar 4;19:1527-1541. doi: 10.2147/DDDT.S495647. eCollection 2025.

ABSTRACT

BACKGROUND: Significant variability in the metabolism of midazolam (MDZ) exists among mechanically ventilated (MV) patients in the intensive care unit (ICU) due to complex clinical conditions and genetic factors. The NR1I2 gene (PXR), which encodes a nuclear receptor that regulates drug-metabolizing enzymes like CYP3A4, plays a critical role in MDZ metabolism. Polymorphisms in NR1I2, along with variations in genes such as CYP3A4, CYP3A5, and ABCB1, may influence enzyme activity and MDZ pharmacokinetics (PK). Understanding these factors is essential for optimizing MDZ dosing in high-risk patient populations.

METHODS: We studied 61 MV ICU patients receiving continuous MDZ infusion. A population pharmacokinetic (PopPK) model was used to assess MDZ PK, with genetic factors (NR1I2 rs2461817, CYP3A4, CYP3A5, ABCB1, and other PXR polymorphisms) and clinical covariates (body weight (BW), aspartate aminotransferase (AST) levels) evaluated for their impact on MDZ clearance (CL).

RESULTS: The PK of MDZ and its metabolite, 1-hydroxymidazolam (1-OH-MDZ), were accurately described using a one-compartment model. The estimated population means for MDZ and 1-OH-MDZ CL were 22.6 L/h (inter-individual variability [IIV] 59.4%) and 67.1 L/h (IIV 57.7%), respectively. MDZ CL was significantly associated with the NR1I2 rs2461817 polymorphism and AST levels, accounting for 11.3% of the variability. MDZ CL decreased by 32.7% as AST increased from 22 IU/L to 60 IU/L, and by 40.7% in patients homozygous for the NR1I2 rs2461817 variant. BW also influenced the CL of 1-OH-MDZ, demonstrating a 34.2% increase as weight increased from 54 kg to 65 kg. Simulations confirmed the significant impact of NR1I2 rs2461817 on MDZ CL.

CONCLUSION: The PopPK model highlights the significant impact of NR1I2 rs2461817 polymorphism on MDZ CL in Chinese MV patients, emphasizing the need to consider genetic and clinical factors for optimizing MDZ dosing in ICU settings.

PMID:40066084 | PMC:PMC11891766 | DOI:10.2147/DDDT.S495647

Pharmacogenomics J. 2025 Mar 10;25(1-2):6. doi: 10.1038/s41397-025-00365-2.

ABSTRACT

Tacrolimus (TAC) is one of the most widely prescribed maintenance immunosuppressant drugs in solid organ transplantation. Kidney transplantation is often the preferred treatment for patients with the kidney failure and is complemented with TAC treatment. TAC treatment is often associated with adverse drug events, which can be reduced by pharmacogenomic (PGx)-guided prescription. We conducted a cost-utility analysis to assess the cost-effectiveness of PGx-guided TAC treatment versus the conventional scheme in patients who recently underwent kidney transplantation in Slovenia. Clinical data were collected from the PREPARE study. The effectiveness of the treatment was determined by mean survival and utility values and Incremental Cost-Effectiveness Ratio was also calculated. Costs of PGx-guided treatment was comparable to conventional treatment but shared reduced risk for severe ADEs and 43% improved quality of life. PGx-guided arm showed a mean of 0.956 Quality-Adjusted Life Years (QALYs) (95% CI: 0.900-1.014) compared to 0.862 QALYs (95%CI: 0.801-0.918) in the other arm. Probabilistic sensitivity analyses confirmed the results' robustness. In conclusion, PGx-guided treatment represents a cost-effective option for the TAC treatment of kidney-transplanted patients in the Slovenian healthcare setting.

PMID:40064851 | DOI:10.1038/s41397-025-00365-2

Eur J Pharm Sci. 2025 Mar 8:107063. doi: 10.1016/j.ejps.2025.107063. Online ahead of print.

ABSTRACT

Future long-duration crewed space missions beyond Low Earth Orbit (LEO) will bring new healthcare challenges for astronauts for which pharmacological countermeasures (pharmacological countermeasures) are crucial. This paper highlights current pharmacological countermeasures challenges described in the ESA SciSpacE Roadmap, with a focus on the cardiovascular system as a model to demonstrate the potential implication of the challenges and recommendations. New pharmacological approaches and procedures need to be adapted to spaceflight (spaceflight) conditions, including ethical and reglementary considerations. Potential strategies include combining pharmacological biomarkers such as pharmacogenomics with therapeutic drug monitoring, advancing microsampling techniques, and implementing a pharmacovigilance system to gain deep insights into pharmacokinetics/pharmacodynamics (PK/PD) spaceflight alteration on drug exposure. Emerging therapeutic approaches (such as long-term regimens) or manufacturing drugs in the space environment, can address specific issues related to drug storage and stability. The integration of biobanks and innovative technologies like organoids and organ-on-a-chip, artificial intelligence (AI), including machine learning will further enhance PK modelling leading to personalized treatments. These innovative pharmaceutical tools will also enable reciprocal game-changing healthcare developments to be made on Earth as well as in space and are essential to ensure space explorers receive safe effective pharmaceutical care.

PMID:40064402 | DOI:10.1016/j.ejps.2025.107063