Naunyn Schmiedebergs Arch Pharmacol. 2024 Nov 4. doi: 10.1007/s00210-024-03569-8. Online ahead of print.

ABSTRACT

Azathioprine (AZA) has been extensively used for immunomodulatory effects in autoimmune disorders and transplantation. This article is proposed to review the contemporary and prospective use of AZA in viral, rheumatic, and dermatological disorders. The primary objective is to draw attention to possible developments in regards to AZA application in recent years, with an emphasis on the use of pharmacogenomics and nanotechnology to improve its efficacy in practice. This study reveals that AZA, having the active metabolites 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), may be useful in the treatment of systemic lupus erythematosus (SLE), pemphigus vulgaris, and psoriasis. Pharmacogenomic testing of thiopurine methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) genotypes minimizes the occurrence of myelosuppression. Furthermore, new formulations of AZA using biocompatible polymers and nanoparticles for drug delivery were reported to improve its efficacy and lower systemic toxicity. This paper aims to establish the multifunctional nature of AZA in modern medicine, thus emphasizing its potential for other applications. Through the combination of pharmacogenomic analysis along with nanotechnology application, AZA makes the promise of enhancing patients' treatment efficacy and extending the stock of medical information available. These advancements offer new possibilities for application of precision medicine and improvements in the use of AZA therapy.

PMID:39495265 | DOI:10.1007/s00210-024-03569-8

Pharmgenomics Pers Med. 2024 Oct 29;17:473-486. doi: 10.2147/PGPM.S481068. eCollection 2024.

ABSTRACT

INTRODUCTION: Despite the availability of various antihypertensive medications, the response to these medications varies among individuals. Understanding how individual genetic variations affect drugs treatment outcomes is a key area of focus in precision medicine. This study investigated the correlation between single nucleotide polymorphisms (SNPs) in selected genes (CACNA1C, CACNA1D, ABCB1, ACE, ADBR2, and NOS1AP) and the blood pressure (BP) control by amlodipine.

METHODS: Four hundred individuals of Pashtun ethnicity undergoing amlodipine treatment for hypertension were included in the present study and divided into the controlled (BP less than 140/90 mmHg) and uncontrolled (BP greater than 140/90 mmHg) hypertension groups. Blood samples (3 mL) were collected from each participant, and DNA was extracted using the Kit method. Ten SNPs in amlodipine pharmacogenes were selected and genotyped using real-time PCR with the TaqMan® system. Logistic regression model was used to determine the association between SNPs and the amlodipine BP response.

RESULTS: Notable association were observed between SNP rs2239050/CACNA1C and amlodipine blood pressure response, with GG genotype carriers demonstrating a better response (P=0.004) than individuals carrying CC or CG genotypes. SNP rs312481/CACNA1D also exhibited a positive pharmacogenetic association, Individuals with the GG genotype showing a considerable reduction in BP (P=0.021) compared to participants with AA or GA genotypes. In case of SNP rs429/ACE individuals carrying TA genotype were less likely to achieve BP control (P=0.002) than AA genotype carriers.

CONCLUSION: Our finding suggests that the SNPs rs2239050/CACNA1C, rs312481/CACNA1D and rs429/ACE influence amlodipine blood pressure response in patients with hypertension. It is recommended that prior knowledge of amlodipine associated pharmacogenetic variants is important that could improve its treatment outcomes in hypertensive patients.

PMID:39492848 | PMC:PMC11531276 | DOI:10.2147/PGPM.S481068

World J Gastroenterol. 2024 Oct 21;30(39):4305-4307. doi: 10.3748/wjg.v30.i39.4305.

ABSTRACT

The current letter to the editor pertains to the manuscript entitled 'Uridine diphosphate glucuronosyltransferase 1A1 prevents the progression of liver injury'. Increased levels of uridine diphosphate glucuronosyltransferase 1A1 during liver injury could mitigate damage by reducing endoplasmic reticulum stress, oxidative stress, and dysregulated lipid metabolism, impeding hepatocyte apoptosis and necroptosis.

PMID:39492821 | PMC:PMC11525851 | DOI:10.3748/wjg.v30.i39.4305

Cytokine. 2023 Oct 28;172:156402. doi: 10.1016/j.cyto.2023.156402. Online ahead of print.

ABSTRACT

BACKGROUND: Rattus rattus are the main carriers of various zoonotic diseases including leptospirosis. Regrettably, information underlying the cytokine response of wild R. rattus upon leptospirosis infection is lacking. This study aims to understand the immune response presented by specifically the kidney and liver of R. rattus during leptospirosis infection.

METHODOLOGY: High-throughput RNA-Sequencing technology was employed to discover the transcriptome alterations in the kidney and liver of R. rattus during natural infection. Both kidney and liver tissues from the healthy and infected rats were sequenced using the BGISEQ-500 sequencing platform. The GO and KEGG databases were utilized to functionally annotate the differentially expressed transcripts of the selected cytokines; TNF-α, IL-1β, IL-6, IL-10, MIP-1α, and IFN-γ.

RESULTS: A higher number of upregulated genes were signified in the kidney as compared to the liver during infection. Among the six selected cytokines, Interleukin-6 was found to be expressed during the early stage in the liver of R. rattus, while all the other six genes were upregulated during the late stage of leptospirosis in the kidney of R. rattus. The GO of the annotated genes was classified under inflammatory response and cellular response to lipopolysaccharide, while the KEGG pathway indicated cytokine-cytokine receptor interaction and the Toll-like receptor (TLR) signalling pathway. The upshots of this study correlated the different phases of cytokine response in different organs of R. rattus during leptospirosis infection.

CONCLUSION: Overall, these studies formulate a conceptual framework based on host and pathogen relationships of leptospirosis transmission patterns and the discovery of biomarkers in tracking the early stages of leptospires colonization.

PMID:39492111 | DOI:10.1016/j.cyto.2023.156402

Am J Pharm Educ. 2024 Nov 2:101319. doi: 10.1016/j.ajpe.2024.101319. Online ahead of print.

ABSTRACT

OBJECTIVE: To assess the feasibility of a pilot pharmacogenomics concierge service that incorporates student practice-based learning opportunities and a survey to determine patients' interest and willingness to pay.

METHODS: Participants in the pilot study (n=34) completed a survey to determine their willingness to pay for concierge services. Six participants indicating the highest level of interest were selected to participate in the program free of charge. Students conducted preliminary genetic testing to assess the potential value of a pharmacogenomics service. For the subset of participants (n=6) invited to the concierge service, confirmatory genetic testing was completed by a third-party lab. A layered learning model allowed senior students to mentor and train junior students in the area of pharmacogenomics.

RESULTS: Six invited participants completed the concierge program and third party pharmacogenomic testing, and the majority (83%) received pharmacogenomic consultation with the pharmacist. Completed surveys from participants in the pilot program (n=34) indicated a willingness to pay $25-50 a month to have continued access to a pharmacist. Surveyed individuals rated their likelihood of utilizing the concierge service at a mean rating of 8.6 (SD=1.88) on a scale of 1 to 10 although this rating dropped significantly if insurance did not cover the cost. The pilot program offered opportunities for practice-based learning through a layered learning model.

CONCLUSION: This pilot concierge program presented several successes and challenges which may help others avoid common pitfalls and spur discussion on optimal ways to develop new pharmacy services and experiential opportunities for students.

PMID:39491725 | DOI:10.1016/j.ajpe.2024.101319

Autoimmun Rev. 2024 Oct 26:103673. doi: 10.1016/j.autrev.2024.103673. Online ahead of print.

ABSTRACT

Primary Sjögren's syndrome (pSS) is a chronic, systemic autoimmune disease characterized by a wide spectrum of glandular and extra-glandular features. Genetic and epigenetic factors play an important role in the disease susceptibility and phenotype. There are a multitude of genes that have been identified as implicated in the pathogenesis of pSS, both in HLA and extra-HLA regions with a strong contribution given by genes in interferon signalling pathways. Among the HLA alleles, the most consistent associations have been found with DR2 and DR3 alleles at the DRB1 locus. Moreover, several gene variants outside the MHC locus are in genes involved in NF-κB signalling, B- and T-cell function and methylation processes possibly responsible for lymphomagenesis. There is still a lack of knowledge on precise genetic patterns and prediction models of diseases, and data on pharmacogenetics is scarce. A comprehensive summary of the common genetic factors and an extensive analysis of novel epigenetic aspects is provided, together with a view on the relationships between novel therapeutic agents for pSS and genetic targets in signalling pathways, aiming at improving tailored treatment strategies in the view of a more personalized medicine.

PMID:39490751 | DOI:10.1016/j.autrev.2024.103673

J Affect Disord. 2024 Oct 26:S0165-0327(24)01806-8. doi: 10.1016/j.jad.2024.10.112. Online ahead of print.

ABSTRACT

BACKGROUND: The involvement of cytochrome P450 3A5 (CYP3A5) in the metabolism of quetiapine has been proposed, though conclusive evidence is lacking. This study aimed to quantitatively assess the impact of CYP3A5 genetic variability on quetiapine exposure in a Chinese patient population.

METHODS: Patient data were retrospectively collected from the database of the Mental Health Centre at the First Hospital of Hebei Medical University, covering the period from September 1, 2019, to July 1, 2023. The study included patients genotyped for CYP3A5 who were treated with quetiapine. Inclusion criteria for the analysis of pharmacokinetic parameters, such as serum concentrations of the drug and its metabolites, included oral administration of quetiapine, availability of information on the prescribed daily dose and concomitant medications, and the determination of steady-state blood levels at the time of sampling (after at least 3 days of continuous administration at the same dose). Exclusion criteria comprised polypharmacy with known CYP3A4 inducers or inhibitors, as well as patients with hepatic or renal insufficiency. The primary endpoint was the exposure to quetiapine and N-dealkylquetiapine, measured using dose-corrected concentrations (C/D). The secondary endpoint was the metabolism of quetiapine to N-dealkylquetiapine, assessed by the ratio of metabolite to parent drug concentrations. The third endpoint is the differences in adverse reactions, QTc intervals, and biochemical parameters among patients with different CYP3A5 genotypes.

RESULT: Based on the inclusion and exclusion criteria, clinical data from 207 patients were ultimately included in the study. Of these, 20 patients had the CYP3A5*1/*1 genotype, 78 had the CYP3A5*1/*3 genotype, and 109 had the CYP3A5*3/*3 genotype.The CYP3A5*3 variant was found to significantly impact the metabolism of quetiapine. The C/D values for both quetiapine and dealkylated quetiapine were notably higher in individuals with the *3/*3 genotype compared to those with the *1/*1 and *1/*3 genotypes (P1 <0.001 and P2 = 0.002, respectively). A comparison of the variability in metabolic ratios among different genotype groups revealed no significant difference (P = 0.067). However, a post hoc analysis indicated that the metabolic ratio in poor metabolizers was significantly lower than that in intermediate metabolizers (P = 0.021). The analysis of adverse reaction incidence and QTc intervals among different genotypes showed no statistically significant differences (P = 0.652, P = 0.486). However, comparison of biochemical parameters across different genotype groups revealed that alanine aminotransferase, uric acid, hemoglobin, and gamma-glutamyl transferase levels were significantly higher in patients with the CYP3A5*3/*3 genotype compared to those with the CYP3A5*1/*1 and CYP3A5*1/*3 genotypes.

CONCLUSION: The results indicated that the genetic polymorphism of CYP3A5*3 significantly influences the metabolism of quetiapine. Specifically, carriers of the CYP3A5*3/*3 genotype exhibited higher blood levels of quetiapine, with a greater likelihood of these levels exceeding the therapeutic range. This finding underscores the need for clinicians to carefully monitor and potentially adjust the dosage for patients with this genotype to avoid adverse effects. This finding underscores the need for clinicians to pay special attention to the efficacy and occurrence of adverse reactions when prescribing quetiapine to patients carrying the CYP3A5*3/*3 genotype.

PMID:39490424 | DOI:10.1016/j.jad.2024.10.112

Sci Rep. 2024 Nov 3;14(1):26543. doi: 10.1038/s41598-024-77935-0.

ABSTRACT

This study aimed to measure relative telomere length (RTL) in blood leukocytes of advanced-stage NSCLC patients either with or without Osimertinib-induced ADRs and determine whether RTL could serve as a biomarker of Osimertinib-induced ADRs. Blood leukocytes RTL were measured in 63 advanced-stage NSCLC patients and 62 age-matched healthy controls using real-time polymerase chain reaction. In patients with advanced-stage NSCLC, RTL was significantly shorter than that in healthy controls (P < 0.001). Compared to patients without ADRs and those with mild/moderate ADRs, patients with severe ADRs exhibited significantly decreased RTL (P < 0.001, P < 0.001, respectively). ROC curve analysis uncovered a diagnostic value of RTL as a biomarker of Osimertinib-induced ADRs (AUC = 1.000, P < 0.001). Kaplan-Meier analysis revealed a significant association between shorter RTL and increased cumulative incidence of Osimertinib-induced ADRs in patients with advanced-stage NSCLC (P < 0.001). Shorter RTL in blood leukocytes would reflect the occurrence of Osimertinib-induced ADRs and might emerge as a promising biomarker for identifying advanced-stage NSCLC patients who are at risk of experiencing Osimertinib-induced ADRs, particularly those with severe ADRs.

PMID:39489788 | DOI:10.1038/s41598-024-77935-0

Transl Psychiatry. 2024 Nov 1;14(1):458. doi: 10.1038/s41398-024-03160-y.

NO ABSTRACT

PMID:39487122 | PMC:PMC11530542 | DOI:10.1038/s41398-024-03160-y

Atherosclerosis. 2024 Oct 18:118624. doi: 10.1016/j.atherosclerosis.2024.118624. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Statin-associated muscle symptoms (SAMS) are a major cause of treatment discontinuation. Clinical Pharmacogenetics Implementation Consortium (CPIC) recommend dose adjustment for statin treatment according to known SLCO1B1 genotype to reduce SAMS. We hypothesized that the association between SLCO1B1 genotype and SAMS is misestimated because of publication bias.

METHODS: We searched published systematic reviews on the association between SLCO1B1 genotype and SAMS. To assessed publication bias, we used funnel plot visual inspection, Egger's test, and the Bayes Factor (BFPublication-bias) from Robust Bayesian Meta-Analysis (RoBMA). We compared the odds ratios (ORUncorrected) from meta-analyses before and after correcting for publication bias using trim-and-fill (ORTrim&Fill) and RoBMA (ORRoBMA) methods.

RESULTS: We included 8 cohort and 11 case-control studies, totaling 62 OR of three SLCO1B1 genotypes and six statin drugs. In the primary analysis, the funnel plot was suggestive of publication bias, confirmed by Egger's test (p=0.001) and RoBMA (BFPublication-bias = 18). Correcting the estimate for publication bias resulted in loss of the association, from a significant ORUncorrected (1.31 95%CI [1.13-1.53]) to corrected ORs suggesting no difference: ORTrim&Fill (1.07 95%CI [0.89-1.30]) and ORRoBMA (1.02 95%CI [1.00-1.33]). This suggested that publication bias overestimated the association by 18 % and 23 %, respectively. Similar results were found for genotype rs4149056, simvastatin and atorvastatin.

CONCLUSIONS: The effect of the SLCO1B1 genotype on the risk of developing SAMS is overestimated in the published literature, especially rs4149056. This could lead prescribers to incorrectly decreasing statin doses or even avoiding statin use, leading to a loss of the potential cardiovascular benefit of statins.

PMID:39488449 | DOI:10.1016/j.atherosclerosis.2024.118624

Complement Ther Med. 2024 Oct 31:103107. doi: 10.1016/j.ctim.2024.103107. Online ahead of print.

ABSTRACT

BACKGROUND: Long COVID have posed a global health burden since the COVID-19 pandemic. This study aimed to evaluate the efficacy and safety of a combined plant extract (CPE) formulation, containing Citrus aurantifolia, Tiliacora triandra, Cannabis sativa, Alpinia galanga, and Piper nigrum, in participants with long COVID. A newly developed long COVID symptom questionnaire was used to evaluate outcomes.

METHODS: This randomized, double-blinded, placebo-controlled trial was conducted at the College of Pharmacy, Rangsit University, Thailand. Participants were randomly assigned to receive either a CPE supplement (4,500mg/day) or a placebo for 7 days. Primary outcomes were changes in C-reactive protein (CRP) levels and the total symptom score (ranging from 0 to 57 points). Secondary outcomes included full recovery/improvement of long COVID symptoms, health-related quality of life (HRQOL), and adverse events.

RESULTS: A total of 66 participants were enrolled, with 33 in each group. The CPE supplement did not significantly reduce CRP levels, with a median difference (MD) (95% CI) of -0.05 (-0.49, 0.39) mg/L compared to placebo. However, the CPE group showed a reduction in the total symptom score [MD (95% CI) of -4.00 (-7.58, -0.42)], and a reduction in overall moderate to severe symptoms [RR (95% CI) of 0.57 (0.35, 0.91)], moderate to severe fatigue [RR (95% CI) of 0.25 (0.08, 0.81)], and moderate to severe post-exertional malaise (PEM) [RR (95% CI) of 0.35 (0.16, 0.78)]. Changes in HRQOL scores did not differ significantly between groups. Adverse events were mostly mild and resolved by the end of the follow-up period.

CONCLUSIONS: Our study suggests potential benefits of the CPE in alleviating moderate to severe long COVID symptoms, particularly fatigue and PEM, with an acceptable safety profile. However, larger-scale trials are necessary to validate these findings, and assessing the reliability of the long COVID symptom questionnaire is essential before its application in future studies.

PMID:39488240 | DOI:10.1016/j.ctim.2024.103107

Comput Biol Med. 2024 Nov 1;183:109324. doi: 10.1016/j.compbiomed.2024.109324. Online ahead of print.

ABSTRACT

BACKGROUND: Cisplatin-induced ototoxicity remains a significant concern in pediatric cancer treatment due to its permanent impact on quality of life. Previously, genetic association analyses have been performed to detect genetic variants associated with this adverse reaction.

METHODS: In this study, a combination of interpretable neural networks and Generative Adversarial Networks (GANs) was employed to identify genetic markers associated with cisplatin-induced ototoxicity. The applied method, BRI-Net, incorporates biological domain knowledge to define the network structure and employs adversarial training to learn an unbiased representation of the data, which is robust to known confounders. Leveraging genomic data from a cohort of 362 cisplatin-treated pediatric cancer patients recruited by the CPNDS (Canadian Pharmacogenomics Network for Drug Safety), this model revealed two statistically significant single nucleotide polymorphisms to be associated with cisplatin-induced ototoxicity.

RESULTS: Two markers within the CERS6 (rs13022792, p-value: 3 × 10-4) and TLR4 (rs10759932, p-value: 7 × 10-4) genes were associated with this cisplatin-induced adverse reaction. CERS6, a ceramide synthase, contributes to elevated ceramide levels, a known initiator of apoptotic signals in mouse models of inner ear hair cells. TLR4, a pattern-recognition protein, initiates inflammation in response to cisplatin, and reduced TLR4 expression has been shown in murine hair cells to confer protection from ototoxicity.

CONCLUSION: Overall, these findings provide a foundation for understanding the genetic landscape of cisplatin-induced ototoxicity, with implications for improving patient care and treatment outcomes.

PMID:39488053 | DOI:10.1016/j.compbiomed.2024.109324

Bratisl Lek Listy. 2024;125(11):701-705. doi: 10.4149/BLL_2024_106.

ABSTRACT

BACKGROUND: The pathophysiology of mental illnesses is not fully understood, leading to insufficient remission, frequent adverse drug reactions, and treatment resistance. Pharmacogenetic (PGx) testing, a personalized approach recently adopted also in psychiatry, can guide effective drug therapy and minimize side effects. The objective of this study was to determine the perspective of Slovak clinicians regarding the integration of PGx testing in psychiatric clinical practice.

METHODS: Questionnaires covering various aspects such as prior experience with PGx testing, self-perceived competence, perceived utility, potential risks and challenges were distributed directly to attendees at two psychiatric conferences held in Slovakia in 2023 and their responses were statistically analysed.

RESULTS: Out of 54 respondents, only 7.4% had previous experience with PGx in clinical practice. The most clinicians felt that they should possess the skills to apply PGx testing in psychiatric clinical practice and were enthusiastic about increasing their expertise. They found PGx useful in medication selection, adverse effect management, and treatment-resistant depression. The primary concerns centered around the lack of well-defined guidelines and the financial considerations linked to the testing.

CONCLUSIONS: Considering the participants' interest in PGx and its integration into clinical practice, educational programmes based on recommendations, guidelines, and convincing evidence could be organized (Tab. 4, Ref. 30). Text in PDF www.elis.sk Keywords: pharmacogenetics, pharmacogenomics, psychiatry, personalized treatment, Slovakia, perspective.

PMID:39487839 | DOI:10.4149/BLL_2024_106

Eur J Pharmacol. 2024 Oct 30:177076. doi: 10.1016/j.ejphar.2024.177076. Online ahead of print.

ABSTRACT

Understanding the capability of a drug to penetrate the blood-brain barrier (BBB) is an unmet medical need in patients with positive human epidermal growth factor receptor 2 (HER2 positive) and brain metastases. The National Comprehensive Cancer Network (NCCN) guidelines recommend the use of tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib in co-administration with monoclonal antibodies or chemotherapy drugs and the antibody-drug conjugates (ADCs) trastuzumab-deruxtecan and trastuzumab-emtansine. Predicting the BBB permeability of these therapeutic agents is a pharmacological challenge due to the various factors involved in the barrier functions. In this review article, we discuss about the molecular and cellular features of the barriers located in the central nervous system and the pharmacological parameters found to be important in predicting BBB permeability in human normal brain and in the presence of brain metastases. Finally, we reported the clinical outcomes and intracranial response of patients with HER2-positive breast cancer with brain metastases treated with targeted TKIs and ADCs.

PMID:39486766 | DOI:10.1016/j.ejphar.2024.177076

Eur J Drug Metab Pharmacokinet. 2024 Nov 1. doi: 10.1007/s13318-024-00925-0. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: The commonly used antiseizure medication lamotrigine is a substrate to ATP binding cassette subfamily G member 2 (ABCG2) transporter. The objective of this study was to evaluate the effect of the common loss-of-function polymorphism ABCG2 c.421C>A (rs2231142) on the lamotrigine trough concentrations at steady state in adults with epilepsy.

METHODS: In two consecutive studies (Study 1, Study 2) in patients on lamotrigine monotherapy, carriers of the variant ABCG2 c.421C>A allele (CA/AA) were considered exposed, and wild-type homozygotes (CC) were considered controls. They were mutually balanced on covariates (age, sex, body weight, several polymorphisms in genes encoding other transporter proteins and lamotrigine-metabolizing enzymes that have been suggested to affect exposure to lamotrigine) to estimate the exposure effect (geometric means ratios, GMRs) in each study separately and overall (individual patient data meta-analysis). The overall estimate was evaluated for sensitivity to residual confounding.

RESULTS: In both studies (exposed n = 28 vs. controls n = 103; exposed n = 44 vs. controls n = 153, in Study 1 and Study 2, respectively) and overall (exposed n = 72 vs. controls n = 256), dose-corrected lamotrigine trough concentrations were moderately lower in the exposed patients: frequentist GMR [95% CI] = 0.82 [0.63-1.08]; GMR = 0.69 [0.60-0.81] and GMR = 0.72 [0.63-0.83] in Study 1, Study 2 and overall, respectively; Bayes GMR [95% CrI] = 0.83 [0.68-1.00]; GMR = 0.69 [0.58-0.83] and GMR = 0.75 [0.65-0.86] in Study 1, Study 2 and overall, respectively. Estimates appeared resistant to unmeasured confounding-the E-values for the pooled point estimates were high, and estimates corrected for a strong hypothetical bias were GMR = 0.78 [0.68-0.90] frequentist and GMR = 0.81 [0.70-0.93] Bayes.

CONCLUSION: Polymorphism ABCG2 c.421C>A moderately reduces lamotrigine concentrations in adults with epilepsy.

PMID:39485627 | DOI:10.1007/s13318-024-00925-0

Pharmacogenet Genomics. 2024 Oct 4. doi: 10.1097/FPC.0000000000000547. Online ahead of print.

ABSTRACT

Pharmacogenetics promises to optimize treatment-related outcomes by informing optimal drug selection and dosing based on an individual's genotype in conjunction with other important clinical factors. Despite significant evidence of genetic associations with drug response, pharmacogenetic testing has not been widely implemented into clinical practice. Among the barriers to broad implementation are limited guidance for how to successfully integrate testing into clinical workflows and limited data on outcomes with pharmacogenetic implementation in clinical practice. The Pharmacogenomics Global Research Network Implementation Working Group seeks to engage institutions globally that have implemented pharmacogenetic testing into clinical practice or are in the process or planning stages of implementing testing to collectively disseminate data on implementation strategies, metrics, and health-related outcomes with the use of genotype-guided drug therapy to ultimately help advance pharmacogenetic implementation. This paper describes the goals, structure, and initial projects of the group in addition to implementation priorities across sites and future collaborative opportunities.

PMID:39485373 | DOI:10.1097/FPC.0000000000000547

Genet Med. 2024 Oct 28:101308. doi: 10.1016/j.gim.2024.101308. Online ahead of print.

ABSTRACT

PURPOSE: Better understanding patient uptake of pharmacogenomic (PGx) testing may inform its implementation and maximize the benefits that such testing can confer. This study examined patient and provider factors associated with PGx test ordering in a national healthcare system where panel-based testing was implemented as part of routine care.

METHODS: We used a retrospective matched cohort design and data from the Veterans Health Administration Corporate Data Warehouse. A conditional logistic model was used to identify factors associated with a PGx order receipt and estimate odds ratios and 95% confidence intervals.

RESULTS: The following patient factors predicted receipt of a PGx test order: younger age, married status, rural residence, non-Hispanic Black or Hispanic race/ethnicity, PGx educational mailer receipt, depression diagnosis, allergy to a drug on the panel, prescriptions for drugs on the panel, and specialty care visits (p<0.05). Additionally, patients whose providers were female, younger, a nurse practitioner/physician assistant or pharmacist, or participated in an educational mailer program were more likely to receive an order (p<0.05).

CONCLUSION: This study highlights factors that may facilitate or hinder the widespread and equitable implementation of PGx testing in a large national healthcare system. The information is being used to further refine the program.

PMID:39484796 | DOI:10.1016/j.gim.2024.101308

bioRxiv [Preprint]. 2024 Oct 25:2024.10.22.619113. doi: 10.1101/2024.10.22.619113.

ABSTRACT

DNA transactions introduce torsional constraints that pose an inherent risk to genome integrity. While topoisomerase 1 (TOP1) activity is essential for removing DNA supercoiling, aberrant stabilization of TOP1:DNA cleavage complexes (TOP1ccs) can result in cytotoxic DNA lesions. What protects genomic hot spots of topological stress from aberrant TOP1 activity remains unknown. Here, we identify chromatin context as an essential means to coordinate TOP1cc resolution. Through its ability to bind poly(ADP-ribose) (PAR), a protein modification required for TOP1cc repair, the histone variant macroH2A1.1 establishes a TOP1-permissive chromatin environment, while the alternatively spliced macroH2A1.2 isoform is unable to bind PAR or protect from TOP1ccs. By visualizing transcription-induced topological stress in single cells, we find that macroH2A1.1 facilitates PAR-dependent recruitment of the TOP1cc repair effector XRCC1 to protect from ssDNA damage. Impaired macroH2A1.1 splicing, a frequent cancer feature, was predictive of increased sensitivity to TOP1 poisons in a pharmaco-genomic screen in breast cancer cells, and macroH2A1.1 inactivation mirrored this effect. Consistent with this, low macroH2A1.1 expression correlated with improved survival in cancer patients treated with TOP1 inhibitors. We propose that macroH2A1 alternative splicing serves as an epigenetic modulator of TOP1-associated genome maintenance and a potential cancer vulnerability.

PMID:39484415 | PMC:PMC11526978 | DOI:10.1101/2024.10.22.619113

Front Pharmacol. 2024 Oct 17;15:1414059. doi: 10.3389/fphar.2024.1414059. eCollection 2024.

ABSTRACT

INTRODUCTION: Ezetimibe inhibits cholesterol uptake by modulation of intestinal sterol absorption. Currently, although some studies have shown alterations in ezetimibe levels caused by alterations in the ABCG5, ABCG8, NPC1L1 or UGT1A1 genes, there are no pharmacogenetic guidelines to confirm these biomarkers. The aim of this work was to evaluate the effect of 49 variants in 22 pharmacogenes related to metabolism and transport.

METHODS: A total of 96 healthy volunteers from four bioequivalence clinical trials of ezetimibe as monotherapy or in combination with simvastatin were studied. Blood samples were extracted for unconjugated ezetimibe plasma quantification and genotyping.

RESULTS AND DISCUSSION: No association of metabolizing enzyme variants with ezetimibe pharmacokinetic parameters was found. The results show some trends in the univariate analysis for ABCB1 rs2032582 or ABCC2 rs2273697 and Cmax (p univariate (p uv ) = 0.056 and 0.087, respectively), which finally reach significance in the multivariate analysis (p multivariate (p mv ) = 0.049 and 0.048, respectively). Nevertheless, these results need to be validated in future studies.

PMID:39484171 | PMC:PMC11524821 | DOI:10.3389/fphar.2024.1414059

Ther Adv Med Oncol. 2024 Oct 18;16:17588359241287658. doi: 10.1177/17588359241287658. eCollection 2024.

ABSTRACT

Medical oncology, through conventional chemotherapy as well as targeted drugs, remains an important component of cancer patient management, particularly for systemic disease. Despite advances in all areas of medical oncology, certain challenges persist in the form of drug resistance and severe normal tissue toxicity. These unwanted effects can be counteracted through a patient-tailored treatment approach, which in chemotherapy is translated as pharmacogenomics. This research field investigates the way genetic makeup influences a patient's response to various drugs with the aim to minimize trial-and-error associated with drug administration. The paper introduces the role, advances and challenges of pharmacogenomics, highlighting the importance of Big Data mining to reveal the mechanisms behind drug-gene pair interaction for better patient outcomes. International consortiums have prioritized their focus on the clinical implementation of pharmacogenomics while tackling the challenges ahead: data standardization, ethical aspects and the education of physicians and patients alike to comprehend the power of pharmacogenomics to transform medical oncology.

PMID:39483136 | PMC:PMC11526290 | DOI:10.1177/17588359241287658