Int J Mol Sci. 2025 Jan 23;26(3):925. doi: 10.3390/ijms26030925.

ABSTRACT

Human immunodeficiency virus (HIV) and hepatitis B virus (HBV) continue to be global public health issues. Globally, about 39.9 million persons live with HIV in 2023, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS) 2024 Fact Sheet. Consequently, the World Health Organisation (WHO) reported that about 1.5 million new cases of HBV occur, with approximately 820 thousand mortalities yearly. Conversely, the lower percentage of HBV (30%) cases that receive a diagnosis is a setback in achieving the WHO 2030 target for zero HBV globally. This has necessitated a public health concern to repurpose antiretroviral (ARV) drugs for the treatment of HBV diseases. This review provides an introductory background, including the pros and cons of repurposing antiretrovirals (ARVs) for HBV treatment. We examine the similarities in replication mechanisms between HIV and HBV. We further investigate some clinical studies and trials of co-infected and mono-infected patients with HIV-HBV. The topical keywords including repurposing ARV drugs, repurposing antiretroviral therapy, Hepatitis B drugs, HBV therapy, title, and abstracts are searched in PubMed, Web of Science, and Google Scholar. The advanced search includes the search period 2014-2024, full text, clinical trials, randomized control trials, and review. The search results filtered from 361 to 51 relevant articles. The investigations revealed that HIV and HBV replicate via a common route known as 'reverse transcription'. Clinical trial results indicate that an early initiation of ARVs, particularly with tenofovir disoproxil fumarate (TDF) as part of a regimen, significantly reduced the HBV viral load in co-infected patients. In mono-infected HBV, timely and correct precise medication is essential for HBV viral load reduction. Therefore, genetic profiling is pivotal for successful ARV drug repurposing in HBV treatment. Pharmacogenetics enables the prediction of the right dosages, specific individual responses, and reactions. This study uniquely explores the intersection of pharmacogenetics and drug repurposing for optimized HBV therapy. Additional in vivo, clinical trials, and in silico research are important for validation of the potency, optimum dosage, and safety of repurposed antiretrovirals in HBV therapy. Furthermore, a prioritization of research collaborations comprising of regulators and funders to foster clinically adopting and incorporating repurposed ARVs for HBV therapy is recommended.

PMID:39940695 | DOI:10.3390/ijms26030925

Drug Metab Pers Ther. 2025 Feb 14. doi: 10.1515/dmpt-2024-0061. Online ahead of print.

ABSTRACT

OBJECTIVES: The clinical outcomes of tamsulosin therapy for LUTS/BPH patients vary, with up to one-third of patients reporting unsatisfactory results. Enhancing the effectiveness and safety of tamsulosin therapy for LUTS/BPH patients remains a significant challenge in current medical practice. Limited data exists regarding the impact of CYP2D6 genetic polymorphisms on the efficacy and safety of tamsulosin therapy. Given that tamsulosin is metabolized by CYP2D6, variations in this enzyme may influence the drug's pharmacodynamic response. The objective of this study was to evaluate the impact of CYP2D6 pharmacogenetic markers on tamsulosin efficacy and safety in patients with LUTS associated with BPH.

METHODS: The study included 142 male patients with LUTS and a confirmed diagnosis of BPH (N40 ICD-10). Patients were followed for a minimum of 8 weeks and underwent four examinations (at days 0, 14, 28, and 56). Treatment efficacy was assessed using the IPSS with quality of life assessment, transrectal ultrasound of the prostate with estimation of prostate volume and residual urine volume, and maximum urinary flow rate (Qmax). Allelic variants of CYP2D6 (*2, *3, *4, *6, *9, *10, and *41) were determined by polymerase chain reaction in all patients..

RESULTS: In the subgroup with moderate symptoms, individuals classified as poor and intermediate metabolizers exhibited significantly higher ΔQmax compared to normal metabolizers (4.25 [2.5; 6.1] vs. [0.6; 4.3], p=0.001826). Moreover, carriers of the CYP2D6*10 CT heterozygous genotype demonstrated lower IPSS scores at the last two visits compared to those with the CC genotype (visit 3: -7.45 ± 3.93 vs. -5.25 ± p=0.05; visit 4: -8.91 ± 3.88 vs. -6.31 ± 5.7), as well as reduced IPSS irritative symptoms at visit 2 (-3.87 ± 2.70 vs -2.47 ± 3.1, p=0.05), and a significant increase in ΔQmax ([2.5; 5.9] vs. [0.6; 4.7], p=0.01). In the subgroup with severe symptoms, individuals with CYP2D6*41 GA + AA genotypes exhibited less residual urine volume following therapy compared to those with the GG genotype ([15.0; 32.0] vs. [3.0; 19.0], p=0.007029). The CYP2D6 polymorphic variants did not impact the tamsulosin safety. The study did not reach the estimated power for CYP2D6*3, CYP2D6*6, and CYP2D6*9 polymorphisms due to their low frequency of occurrence in the study population. The multivariate logistic regression model indicated that potential predictors of tamsulosin therapy efficacy in LUTS/BPH patients may include BMI (p<0.001), prostate volume (p<0.002), as well as the carriage of CYP2D6*4 (p<0.001) and CYP2D6*10 (p=0.012) markers. The model explained 81.9 % of the variance in the predicted outcome and accurately forecasted tamsulosin therapy efficacy in BPH with a precision of 92.1 %.

CONCLUSIONS: The present study identified potential markers that could serve as predictors of the effectiveness of tamsulosin. Specifically, genetic markers such as CYP2D6*4, CYP2D6*10, CYP2D6*41, and non-genetic factors like BMI and prostate volume were associated with the clinical efficacy of tamsulosin therapy in LUTS/BPH patients..

PMID:39940086 | DOI:10.1515/dmpt-2024-0061

Nature. 2025 Feb;638(8050):351-359. doi: 10.1038/s41586-024-08243-w. Epub 2025 Feb 12.

ABSTRACT

Recent advances in functional genomics and human cellular models have substantially enhanced our understanding of the structure and regulation of the human genome. However, our grasp of the molecular functions of human genes remains incomplete and biased towards specific gene classes. The Molecular Phenotypes of Null Alleles in Cells (MorPhiC) Consortium aims to address this gap by creating a comprehensive catalogue of the molecular and cellular phenotypes associated with null alleles of all human genes using in vitro multicellular systems. In this Perspective, we present the strategic vision of the MorPhiC Consortium and discuss various strategies for generating null alleles, as well as the challenges involved. We describe the cellular models and scalable phenotypic readouts that will be used in the consortium's initial phase, focusing on 1,000 protein-coding genes. The resulting molecular and cellular data will be compiled into a catalogue of null-allele phenotypes. The methodologies developed in this phase will establish best practices for extending these approaches to all human protein-coding genes. The resources generated-including engineered cell lines, plasmids, phenotypic data, genomic information and computational tools-will be made available to the broader research community to facilitate deeper insights into human gene functions.

PMID:39939790 | DOI:10.1038/s41586-024-08243-w

J Pediatr Pharmacol Ther. 2025 Feb;30(1):146-148. doi: 10.5863/1551-6776-30.1.146. Epub 2025 Feb 10.

NO ABSTRACT

PMID:39935567 | PMC:PMC11809527 | DOI:10.5863/1551-6776-30.1.146

Eur Arch Psychiatry Clin Neurosci. 2025 Feb 12. doi: 10.1007/s00406-025-01970-9. Online ahead of print.

ABSTRACT

This study investigates treatment-resistant schizophrenia (TRS) by analysing genetic markers in dopamine and serotonin receptors. Conducted on a cohort of 221 patients with treatment-resistant mental disorders, the research focused on DRD2 and HTR2A gene variants-specifically, rs1801028, rs6314, rs7997012, and rs6311. The findings suggest specific associations between certain genetic variants and TRS. Notably, the HTR2A rs6314 A|G genotype and rs7997012 G|G genotype were significantly more prevalent in TRS patients compared to healthy controls (HCs). Haplotype analyses revealed associations between specific haplotypes-such as A|G (rs6314-rs7997012)-and TRS, indicating their potential predictive value for TRS versus HCs. The study underscores the involvement of the serotonergic system in TRS. These findings offer valuable insights into the genetic factors contributing to TRS, paving the way for future research and the development of personalised prevention and treatment strategies in psychiatry.

PMID:39934320 | DOI:10.1007/s00406-025-01970-9

Open Heart. 2025 Feb 11;12(1):e003088. doi: 10.1136/openhrt-2024-003088.

ABSTRACT

AIMS: Clopidogrel is the most commonly prescribed thienopyridine as part of dual anti-platelet therapy for the treatment of cardiovascular diseases. However, clopidogrel responsiveness shows variability based on CYP2C19 polymorphism. Therefore, we planned a study with an objective of evaluating safety, tolerability, pharmacodynamics and pharmacokinetics of a novel thienopyridine antiplatelet agent AT-10 in healthy Indian subjects compared with standard dosage regimen of clopidogrel based on their CYP2C19 genotyping.

METHODS: Two CYP2C19 genotype-based groups were identified, that is, poor metabolisers and extensive metabolisers, with 20 subjects in each group (n=40) for participating in a randomised, two-period, crossover study. Each study period lasted 6 days including administration of loading and maintenance doses of AT-10 (40 mg/10 mg) or clopidogrel (300 mg/75 mg). The pharmacokinetics and pharmacodynamics were assessed on day 1 and day 6 at several time intervals.

RESULTS: Overall result of pharmacodynamic parameters showed that mean %inhibition of platelet aggregation between AT-10 and clopidogrel in all subjects at 6 hours postdose (loading dose) (AT-10: clopidogrel; 73.30% vs 18.53%) and 6 hours postdose on day 6 (maintenance dose) (AT-10: clopidogrel; 83.41% vs 51.19 %) obtained from the AT-10 group was significantly higher than the clopidogrel group. Further, %inhibition of platelet aggregation from AT-10 treatment in poor metaboliser group was significantly higher than the clopidogrel treatments in extensive metaboliser group.Overall pharmacokinetic comparison in all subjects indicates that AT-10 gives greater exposure to active Metabolite H4 than clopidogrel.

CONCLUSION: AT-10 showed better inhibition of platelet aggregation in poor metabolizers as compared to Clopidogrel. AT-10 may emerge as a potential alternative to Clopidogrel as an anti-platelet drug. It can be further developed in clinical studies for the unmet medical needs in management of CVDs and overcome the pharmacogenomic limitations of Clopidogrel.

TRIAL REGISTRATION NUMBER: Clinical Trial Registry-India URL: http://ctri.nic.in.

REGISTRATION NUMBER: CTRI/2021/03/032206.

PMID:39933830 | DOI:10.1136/openhrt-2024-003088

J Int Med Res. 2025 Feb;53(2):3000605251315355. doi: 10.1177/03000605251315355.

ABSTRACT

Linezolid, a synthetic oxazolidinone antibiotic, is used to treat gram-positive bacterial infections, including methicillin-resistant Staphylococcus aureus. Despite its efficacy, linezolid can cause serotonin syndrome, a potentially fatal condition associated with excessive serotonin activity in the brain. This narrative review examined the pharmacological mechanisms of this interaction, particularly linezolid's mild monoamine oxidase-inhibitory activity, which can trigger serotonin syndrome in combination with serotonergic drugs. Serotonin syndrome causes cognitive, autonomic, and somatic symptoms ranging from mild (tremors, diarrhea) to severe (hyperthermia, seizures, multiorgan failure). The Hunter Serotonin Toxicity Criteria have superior sensitivity and specificity over the Sternbach Criteria for diagnosis. Clinical evidence indicates that although the incidence of linezolid-induced serotonin syndrome is low, the risk justifies careful monitoring and risk assessment. This review emphasizes enhanced pharmacovigilance and standardized reporting criteria to better capture and analyze data on linezolid-induced serotonin syndrome. Assessments of the pharmacological mechanisms, large-scale clinical trials, and cohort studies are essential to elucidate risk factors and outcomes. Developing comprehensive clinical guidelines and education programs for healthcare providers is crucial to improve linezolid's safety profile. Exploring pharmacogenomic approaches and alternative therapies with lower serotonin syndrome risks is recommended to enhance patient outcomes while maintaining linezolid's efficacy in treating severe bacterial infections.

PMID:39932284 | DOI:10.1177/03000605251315355

PLoS One. 2025 Feb 10;20(2):e0305511. doi: 10.1371/journal.pone.0305511. eCollection 2025.

ABSTRACT

Type 2 diabetes (T2D) is a chronic disorder affecting 462 million worldwide, often managed with metformin as first-line treatment. However, metformin's response varies among individuals, including up to 30% experiencing serious adverse drug reactions (ADRs) and 20-50% inefficacy. These differences may be due to various factors, including pharmacogenetic (PGx) variants. The PGx variants documented so far could affect both the safety and efficacy of metformin, but due to a lack of replication studies, none reached the clinical evidence-level needed to be used as a predictive marker for treatment response. Therefore, this study aims to evaluate the association between the presence of candidate PGx variants and metformin response in T2D subjects. We conducted an association study involving 108 T2D participants currently or previously treated with metformin. A characterization of their therapeutic response was carried out through questionnaires and pharmacological profile reviews. DNA samples were collected during their single visit to perform genotyping of 24 selected candidate PGx variants. Association analyses between candidate PGx variants and metformin response were performed. Among the subjects included in the analyses (n = 84), 25% were non-responders, and 58% experienced ADRs. At the time of study enrollment, 93.9% of non-responders continued to use metformin. The odds of being a non-responder to metformin are 5.6 times higher for homozygous carriers of the alternative allele of a variant within the PCK1 gene (rs4810083) compared to the other genotypes (95% interval confidence [1.9-16.6]). Two variants in perfect linkage disequilibrium within the SLC22A2 gene (rs316019 and rs316009) were associated with increase odds of having ADRs, where homozygous genotype carriers are 7.3 times more likely to have ADRs presentation (95% interval confidence [1.85-29.01]). This study identified associations between PCK1 and SLC22A2 candidate PGx variants and metformin response in T2D treatment. Additional genetic and functional studies are necessary to elucidate the variants' impact in metformin's pharmacological mechanisms.

PMID:39928707 | DOI:10.1371/journal.pone.0305511

Expert Opin Drug Saf. 2025 Feb 10. doi: 10.1080/14740338.2025.2465865. Online ahead of print.

ABSTRACT

BACKGROUND: During the 2019 coronavirus disease (COVID-19) pandemic, although patients were advised to continue using angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), it remains unclear whether the pandemic influenced the occurrence of adverse reactions to these drugs. This study aims to analyze and compare changes in ACEIs and ARBs adverse events before and during the COVID-19 pandemic, exploring its potential impact on the safety of these medications.

METHODS: We used real-world data to explore the impact of the COVID-19 pandemic on adverse events related to ACEIs and ARBs.

RESULTS: During the pandemic, ACEI-related adverse events (70 cases) and ARB-related adverse events (7 cases) showed increased reporting rates and RORs, with a notable rise in ACEI-related ear and labyrinth disorders. Additionally, 170 new adverse event signals were detected for ACEIs (8 with significantly increased risk) and 191 signals for ARBs (2 with significantly increased risk).

CONCLUSIONS: This study, based on real-world data, revealed significant signals indicating that ACEI use during the COVID-19 pandemic may have increased the risk of renal adverse events and ear labyrinth diseases. The study emphasized the need for increased caution when using ACEIs and ARBs during the pandemic.

PMID:39927493 | DOI:10.1080/14740338.2025.2465865

Pediatr Transplant. 2025 Mar;29(2):e70044. doi: 10.1111/petr.70044.

ABSTRACT

BACKGROUND: Pediatric solid organ transplantation is a complex process including a tightly orchestrated medication regimen, essential for prevention of infection, rejection, graft failure, and mortality. Pharmacogenomic (PGx) testing tailors medication therapy to the individual patient, focusing on safety, efficacy, and avoidance of adverse effects. Implementation of PGx panel results into clinical practice for pediatric transplant patients has not been evaluated.

METHODS: Pediatric patients evaluated for heart, kidney, or combined heart-kidney transplant at a tertiary children's hospital from October 2021 to October 2023 received PGx panel testing.

PRIMARY OUTCOME MEASURE: Report the prevalence of actionable PGx variants for key genes impacting pharmacotherapy in pre- and post-heart and kidney transplant populations.

RESULTS: A total of 73 patients were included, predominately white (84.9%) and male (64.4%), with a mean age of 8.8 ± 6.4 years. Indications for PGx testing included evaluation for heart transplant (38.4%), kidney transplant (38.4%), combined heart-kidney transplant (4.1%), or to inform posttransplant care (19.2%). All patients had at least one actionable phenotype identified. 37 of 73 patients (50.7%) had at least one actionable phenotype for the transplant-specific genes captured including CYP3A5, SLCO1B1, G6PD, TPMT, prothrombin (Factor 2), and Factor V Leiden. 16 of 73 patients (21.9%) had actionable CYP3A5 phenotypes. 15 of 73 (20.5%) had actionable SLCO1B1 phenotypes. 9 of 73 patients (12.3%) had actionable TPMT phenotypes. 5 of 73 (6.8%) had Prothrombin or Factor V Leiden variants.

CONCLUSIONS: Routine pretransplant PGx testing provided information that was actionable and could be utilized to optimize posttransplant medications for all patients.

PMID:39924350 | DOI:10.1111/petr.70044

CNS Neurosci Ther. 2025 Feb;31(2):e70258. doi: 10.1111/cns.70258.

ABSTRACT

BACKGROUND: Antiplatelet drugs are a cornerstone in managing atherosclerotic vascular disease (ASVD). However, their interactions with other medications present significant challenges to treatment efficacy and safety. Patients with ASVD often require multiple treatment regimens due to complex comorbidities, which increases the risk of drug-drug interactions (DDIs). These interactions can lead to drug resistance, reduced therapeutic outcomes, or adverse effects. A thorough understanding of DDIs is crucial for optimizing patient care.

AIMS: This review aims to explore the clinical significance. mechanisms, and implications of DDIs in antiplatelet therapy Additionally, it seeks to identify future research directions to advance personalized treatment strategies and improve therapeutic outcomes.

MATERIALS AND METHODS: A systematic literature review was conducted using key databases, focusing on clinical studies, mechanistic research, and guidelines related to antiplatelet therapy and DDIs. Findings were analyzed to identify common interaction patterns, associated risks, and management strategies.

RESULTS: The review identifies common DDIs involving antiplatelet drugs, particularly with anticoagulants, nonsteroidal anti-inflammatory drugs, and proton pump inhibitors. These interactions primarily occur through pharmacokinetic mechanisms, such as alterations in drug metabolism via cytochrome P450 enzymes, and pharmacodynamic mechanisms, including synergistic or antagonistic effects on platelet inhibition. Clinically, DDIs can increase bleeding risk, reduce antiplatelet efficacy, and contribute to adverse cardiovascular outcomes. Strategies to mitigate these risks include individualized drug selection, dose adjustments, genetic testing, and therapeutic drug monitoring.

DISCUSSION: Effective management of DDIs in antiplatelet therapy is essential to improve clinical outcomes. A patient-specific approach, considering comorbidities, genetic predispositions, and concurrent medications, is crucial. The review categorizes DDIs based on clinical settings and underscores the need for further research on predictive biomarkers, pharmacogenomics, and advanced monitoring techniques.

CONCLUSION: DDIs significantly impact the effectiveness and safety of antiplatelet therapy, necessitating a comprehensive understanding of their mechanisms and clinical implications. Future research should focus on developing personalized treatment approaches, integrating genetic testing, and optimizing pharmacological monitoring to minimize risks and improve therapeutic outcomes. This review provides a foundation for advancing clinical practice and enhancing the management of patients with ASVD.

PMID:39924343 | DOI:10.1111/cns.70258

BMC Med Ethics. 2025 Feb 8;26(1):23. doi: 10.1186/s12910-025-01181-w.

ABSTRACT

Little is known about how people living with HIV should be engaged in the decision-making process for returning individual pharmacogenomic research results. This study explored the role people living with HIV want to play in making decisions about whether and how individual results of pharmacogenomic research should be presented to them. A convergent parallel mixed methods study was conducted, comprising a survey of 221 research participants and five deliberative focus group discussions with 30 purposively selected research participants. Most participants (122, 55.2%) preferred the collaborative role, 67 (30.3%) preferred the active role and 32 (14.5%) preferred the passive role. Factors that significantly influenced preference for an active role compared with a collaborative role were marital status (OR: 0.282, p = 0.013), research experience (OR: 4.37, p = 0.028), and religion (OR: 2.346, p = 0.041). The reasons proffered for the active role included prior experience with antiretroviral treatment and increased exposure to research activities. The reasons given for preferring the passive role included limited level of awareness about the interaction between patients' genes and drugs, trust in researchers to make the right decision, and fear of making decisions with harmful implications. Overall, findings from our study show that participants want to be engaged in the decision-making process. Research teams ought to provide adequate and simple information about the pharmacogenomic research and implications of the results to support participants' informed decisions.

PMID:39923018 | DOI:10.1186/s12910-025-01181-w

BMJ Glob Health. 2025 Feb 8;10(2):e016026. doi: 10.1136/bmjgh-2024-016026.

ABSTRACT

International collaboration in genomic research is gaining momentum in African countries and is often supported by external funding. Over the last decade, there has been an increased interest in African genomic data. The contribution of this rich data resource in understanding diseases predominant in both African and global populations has been limited to date. There has been some non-governmental funding dedicated to the advancement of genomic research and innovation by African-based and African-led research groups, but the impact of these initiatives is hard to quantify. However, there is now an opportunity for the global research community to leverage decades of genomic data and biospecimens originating from African populations. The experience we describe in this paper is of an access governance framework established under the Human, Heredity, and Health in Africa (H3A) consortium, given the task of managing wider access to the data and biospecimen resources collected via its various projects. The function of the Data and Biospecimen Access Committee (DBAC) is to facilitate the advancement of medicine and health while fostering the development of bioinformatics capabilities at Africa-based institutions or regional hubs. Our collective experiences and lessons learnt as a committee provide examples of nuanced considerations when evaluating access to African data. The committee was semi-autonomous in its establishment and had independence in decision-making. The DBAC continually advocates for the responsible use of genomic data and biospecimens that were obtained from African research participants, under broad consent, by primary researchers who no longer have oversight over the future use of these resources.

PMID:39922566 | DOI:10.1136/bmjgh-2024-016026

Toxicol In Vitro. 2025 Feb 6:106018. doi: 10.1016/j.tiv.2025.106018. Online ahead of print.

ABSTRACT

We have explored a new approach using a similarity measure-based read-across derived hypothesis to address the precise risk assessment of vitiligo active chemicals. In this analysis, we initially developed a data set by combining vitiligo active compounds taken from the previous literature with non-vitiligo chemicals, which are non-skin sensitizers reported in another literature. Afterward, we performed the manual curation process to obtain a curated dataset. Furthermore, the optimum similarity measure was identified from a validation set using a pool of 47 descriptors from the analysis of the most discriminating features. The identified optimum similarity measure (i.e., Euclidean distance-based similarity along with seven close source compounds) has been utilized in the read-across derived similarity-based classification studies on close source congeners concerning target compounds. In this study, we identified the positive and negative contributing features toward the assessment of vitiligo potential as well, including the estimation of target chemicals with better accuracy. The applicability domain status of the reported compounds was also studied, and the outliers were identified. As there are no comparative studies in this regard to the best of our knowledge, we can further affirm that it is the first report on the in-silico identification of potential vitiligo-linked chemical exposomes (ViCE) based on the similarity measure of the read-across.

PMID:39922550 | DOI:10.1016/j.tiv.2025.106018

Clin Exp Med. 2025 Feb 8;25(1):51. doi: 10.1007/s10238-025-01576-4.

ABSTRACT

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Sorafenib is the first FDA-approved systemic therapy for advanced HCC. This study investigates the influence of IL-23R (rs7517847) and ATG-10 (rs10514231) genetic polymorphisms on Sorafenib response, survival outcomes, average tolerable dose, and adverse events. This prospective open-label cohort study included 100 HCC patients, assessing IL-23R and ATG-10 genotypes via real-time polymerase chain reaction (RT-PCR). Patient's responses were evaluated using modified RECIST criteria. Statistical analyses evaluated the association of genetic variants with response, progression-free survival (PFS), overall survival (OS), average tolerable Sorafenib dose, and adverse events. IL-23R TT carriers had the highest Sorafenib response rate (80%) compared to GT (13.3%) and GG (6.7%) (P = 0.021), while ATG-10 TT carriers had a 13.9-fold increased response likelihood (P = 0.001). The T allele in ATG-10 significantly predicted longer PFS (P = 0.025) and OS (P = 0.011), suggesting a potential prognostic role. IL-23R GG carriers received significantly higher Sorafenib doses than TT (P = 0.0174) and GT (P = 0.0227), whereas ATG-10 had no effect on dosage. However, its CT genotype was significantly associated with a higher risk of Hand-Foot Syndrome (P = 0.012), and independent of dose (P = 0.0018). IL-23R and ATG-10 polymorphisms influence Sorafenib response, survival, and tolerability in HCC patients. Genetic screening may improve personalized treatment strategies by optimizing Sorafenib efficacy and minimizing toxicity.This trial was registered on clinicaltrials.gov with registration number NCT06030895, registered on "September 11th, 2023," retrospectively.

PMID:39921803 | DOI:10.1007/s10238-025-01576-4

Clin Transl Sci. 2025 Feb;18(2):e70154. doi: 10.1111/cts.70154.

ABSTRACT

This trial aimed to identify the effects of providing pharmacogenomic (PGx) results and recommendations for patients with chronic pain treated in primary care practices compared to standard care. An open-label, prospective, largely virtual, type-2 hybrid effectiveness trial randomized participants to PGx or standard care arms. Adults with pain ≥ 3 months who were treated with tramadol, codeine, or hydrocodone enrolled. Alternative analgesics were recommended for CYP2D6 intermediate or poor metabolizers (IM/PMs). Prescribing decisions were at providers' discretion. The trial randomized 253 participants. A modified intent-to-treat primary analysis assessed change in pain intensity over 3 months among IM/PMs (PGx: 49; Standard care: 57). The PGx and standard care arms showed no difference in pain intensity change (-0.10 ± 0.63 vs. -0.21 ± 0.75 standard deviation; p = 0.74) or PGx-aligned care (69% vs. 63%; standardized difference [SD] = 0.13). In IM/PMs, secondary analyses of pain intensity change suggested improvements with PGx-aligned (n = 70; -0.21 ± 0.70) vs. unaligned care (n = 36; -0.06 ± 0.69) (SD = -0.22), with this difference increasing when examining IM/PMs with an analgesic change (aligned: n = 31, -0.28 ± 0.76; unaligned: n = 36, -0.06 ± 0.69; SD = -0.31). This approach to PGx implementation for chronic pain was not associated with different prescribing (i.e., similar proportions of PGx-aligned care) or clinical outcomes. Secondary analyses suggest that prescribing aligned with PGx recommendations showed a small improvement in pain intensity. However, the proportion of patients with a clinically meaningful improvement (≥ 30%) in pain intensity was similar. Future efforts should identify effective implementation methods.

PMID:39921243 | DOI:10.1111/cts.70154

Hum Genomics. 2025 Feb 7;19(1):11. doi: 10.1186/s40246-025-00720-1.

ABSTRACT

Pharmacogenomics (PGx) aims to delineate a patient's genetic profile with differences in drug efficacy and/or toxicity, particularly focusing on genes encoding for drug-metabolizing enzymes and transporters. Clinical implementation of PGx is a complex undertaking involving a multidisciplinary approach that includes, among others, a thorough understanding of a country's preparedness to adopt this modern discipline and a detailed knowledge of PGx biomarkers allelic spectrum at a population level. In several European populations, particularly in countries with lower income, clinical implementation of PGx is still in its infancy. We have previously performed a pilot study to determine the prevalence of PGx biomarkers in 18 European populations, as the first step towards population PGx at the European level. Here, we provide a comprehensive analysis of the current state of PGx in Greece, including a detailed allelic frequency spectrum of clinically actionable PGx biomarkers, the level of PGx education in academia, the provision of PGx testing services from public and private laboratories, and the aspects of the regulatory PGx environment, especially with respect to the discrepancies between the Greek National Organization of Medicines and the European Medicine Agency and health technology assessment. This study would not only provide the foundations for expediting the adoption of PGx in clinical reality in Greece but can also serve as a paradigm for replicating future studies in other European countries, to expand on previously available pilot studies.

PMID:39920803 | DOI:10.1186/s40246-025-00720-1

Pharmacol Res Perspect. 2025 Feb;13(1):e70075. doi: 10.1002/prp2.70075.

ABSTRACT

Aromatase inhibitors are used for patients with hormone-receptor positive breast cancer. Alzheimer's disease is the most prevalent cause of dementia. Several studies have suggested an association between the use of aromatase inhibitors and the development of Alzheimer's disease. The objective of this study was to identify potential pharmacovigilance signals associated with dementia and Alzheimer's disease and third-generation aromatase inhibitors in menopausal and postmenopausal women. VigiBase, the global database of individual case safety reports of the World Health Organization, was used to investigate this possible association. A disproportionality analysis was performed for women aged 45 years and older. The reporting odds ratio (ROR) and its 95% CI for reporting dementia are exemestane, 2.08 (1.35-3.19); anastrozole, 1.59 (1.09-2.32); and letrozole, 1.43 (1.05-1.95) and for Alzheimer's disease are exemestane, 0.94 (0.30-2.92); anastrozole: 2.63 (1.55-4.45); and letrozole, 1.33 (0.76-2.35). For senile dementia, only letrozole has cases, with an ROR of 6.77 (2.51-18.31). Signals of disproportionate reporting have been observed between the occurrence of dementia, dementia Alzheimer's type, and senile dementia with aromatase inhibitors, which is in line with estrogen functions and aromatase activity, as well as the findings from preclinical studies. Additional research is required to elucidate this intricate matter.

PMID:39917951 | DOI:10.1002/prp2.70075

Pharmacogenomics. 2025 Feb 7:1-12. doi: 10.1080/14622416.2025.2456449. Online ahead of print.

ABSTRACT

AIM: This study is designed to address the connection between antidepressant and antipsychotic-induced hepatotoxicity with pharmacogenetic and epigenetic indicators, using a novel combined approach of CYP450 polymorphism determination and early liver injury detection via microRNA testing.

METHODS: The multi-centric retrospective case-control study in Slovakia involves 151 cases with signs of hepatotoxicity and 604 controls without. Participants will be tested for selected CYP450, UGT1A1 polymorphisms, and microRNAs.

RESULTS: Anticipated findings will test if patients with specific CYP450 and UGT1A1 polymorphisms are at higher risk for drug-induced hepatotoxicity and if plasma microRNAs hsa-miR-122-5p and hsa-miR-192-5p, alone or combined, can differentiate patients with abnormal liver function.

CONCLUSION: The findings could contribute to personalized treatment approach by combining genetic and epigenetic biomarkers.

PMID:39916529 | DOI:10.1080/14622416.2025.2456449

CNS Neurosci Ther. 2025 Feb;31(2):e70253. doi: 10.1111/cns.70253.

ABSTRACT

BACKGROUND: Berberine (BBR) has been reported to mitigate epileptic seizures. However, the potential mechanism of its anti-seizure effect remains uncharacterized.

AIMS: This study aimed to investigate the protective effect of BBR on acute epileptic seizures induced by kainic acid (KA) in mice and further explore its mechanism of action in the aspect of analysis of gut microbiota.

MATERIALS AND METHODS: The protective effect of BBR against acute epileptic seizures was assessed via Racine score and Nissl training. Alterations of gut microbiota and metabolites in seizure mice after BBR treatment were analyzed through 16S sequencing and lipidomics, respectively.

RESULTS: Our results showed that the BBR remarkably alleviated acute epileptic seizures and hippocampal neuron damage in KA-induced mice. The analysis of gut microbiota indicated that BBR reduced the acute epileptic seizures in KA-induced mice by increasing the abundance of Bacteroidetes and Alloprevotella, regulating short-chain fatty acids (SCFAs). Results of lipidomics also identified 21 candidate metabolites in the colon and hippocampus possibly involved in the protective effect of BBR against acute seizures.

CONCLUSION: These findings suggest that BBR exerts neuroprotection against KA-induced epileptic seizures through remodeling gut microbiota-associated lipid metabolism in the colon and hippocampus. BBR may serve as a valuable candidate drug for curing patients with epilepsy.

PMID:39915895 | DOI:10.1111/cns.70253