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Genes May 2024Over the last few decades, the implementation of pharmacogenomics (PGx) in clinical practice has improved tailored drug prescriptions [...].
Over the last few decades, the implementation of pharmacogenomics (PGx) in clinical practice has improved tailored drug prescriptions [...].
Topics: Pharmacogenetics; Humans; Precision Medicine
PubMed: 38927650
DOI: 10.3390/genes15060714 -
British Journal of Clinical Pharmacology Jun 2024The aim of the present study was to investigate the impact of CYP2D6 genotype on exposure and metabolism of escitalopram in patients stratified by CYP2C19 genotype in a...
AIMS
The aim of the present study was to investigate the impact of CYP2D6 genotype on exposure and metabolism of escitalopram in patients stratified by CYP2C19 genotype in a large real-world population.
METHODS
Patients were included from a therapeutic drug monitoring service if they had measured serum concentration of escitalopram and the metabolite, N-desmethyl escitalopram, and performed CYP2C19 and CYP2D6 genotyping. Patients were divided into 16 combined genotype-predicted phenotype subgroups (poor [PM], intermediate [IM], normal [NM] and ultrarapid metabolizers [UM]) of CYP2C19/CYP2D6. The concentration-to-dose (CD) ratio and metabolite-to-parent ratio (metabolic ratio) of escitalopram were compared across subgroups using the Kruskal-Wallis test followed by Dunn's test with CYP2D6 NMs as the reference group.
RESULTS
A total of 5067 patients were included in the study. A stepwise increase in escitalopram CD ratio by decreasing CYP2D6 activity was observed in all CYP2C19 subgroups, except for in CYP2C19 UMs. The percentage differences in escitalopram CD ratio between CYP2D6 PMs and NMs were 24% in CYP2C19 NMs (P < .001), 28% in CYP2C19 IMs (P < .001) and 31% in CYP2C19 PMs (P = .04). As for the CD ratio, CYP2D6 genotype effect on metabolic ratio increased stepwise by decreasing CYP2C19 metabolism.
CONCLUSIONS
CYP2D6 genotype is of significant importance for the individual variation in escitalopram pharmacokinetics. The most relevant increase in escitalopram concentration is seen in individuals with decreased and/or absent CYP2C19 activity. By combining CYP2C19 and CYP2D6 genotypes, the optimal dose for patients may be predicted with greater precision than for CYP2C19 genotype alone.
PubMed: 38925553
DOI: 10.1111/bcp.16156 -
Clinical and Translational Science Jun 2024Next-generation sequencing (NGS) significantly enhances precision medicine (PM) by offering personalized approaches to diagnosis, treatment, and prevention of unmet... (Review)
Review
Next-generation sequencing (NGS) significantly enhances precision medicine (PM) by offering personalized approaches to diagnosis, treatment, and prevention of unmet medical needs. Little is known about the current situation of PM in Asia. Thus, we aimed to conduct an overview of the progress and gaps in PM in Asia and enrich it with in-depth insight into the possibilities of future PM in Thailand. This scoping review focused on Asian countries starting with non-cancer studies, including rare and undiagnosed diseases (RUDs), non-communicable diseases (NCDs), infectious diseases (IDs), and pharmacogenomics, with a focus on NGS. Subsequent in-depth interviews with experts in Thailand were performed, and a thematic analysis served as the main qualitative methodology. Out of 2898 searched articles, 387 studies were included after the review. Although most of the studies focused on cancer, 89 (23.0%) studies were related to RUDs (17.1%), NCDs (2.8%), IDs (1.8%), and pharmacogenomics (1.3%). Apart from medicine and related sciences, the studies were mostly composed of PM (61.8%), followed by genetics medicine and bioinformatics. Interestingly, 28% of articles were conducted exclusively within the fields of medicine and related sciences, emphasizing interdisciplinary integration. The experts emphasized the need for sustainability-driven political will, nurturing collaboration, reinforcing computational infrastructure, and expanding the bioinformatic workforce. In Asia, developments of NGS have made remarkable progress in PM. Thailand has extended PM beyond cancer and focused on clinical implementation. We summarized the PM challenges, including equity and efficiency targeting, guided research funding, sufficient sample size, integrated collaboration, computational infrastructure, and sufficient trained human resources.
Topics: Humans; Precision Medicine; Thailand; High-Throughput Nucleotide Sequencing; Pharmacogenetics; Interviews as Topic; Neoplasms
PubMed: 38924657
DOI: 10.1111/cts.13868 -
Clinical and Translational Science Jun 2024For the same age, sex, and dosage, there can be significant variation in fertility outcomes in childhood cancer survivors. Genetics may explain this variation. This...
For the same age, sex, and dosage, there can be significant variation in fertility outcomes in childhood cancer survivors. Genetics may explain this variation. This study aims to: (i) review the genetic contributions to infertility, (ii) search for pharmacogenomic studies looking at interactions of cancer treatment, genetic predisposition and fertility-related outcomes. Systematic searches in MEDLINE Ovid, Embase Classic+Embase, and PubMed were conducted using the following selection criteria: (i) pediatric, adolescent, and young adult cancer survivors, below 25 years old at the time of diagnosis, (ii) fertility outcome measures after cancer therapy, (iii) genetic considerations. Studies were excluded if they were (i) conducted in animal models, (ii) were not published in English, (iii) editorial letters, (iv) theses. Articles were screened in Covidence by at least two independent reviewers, followed by data extraction and a risk of bias assessment using the Quality in Prognostic Studies tool. Eight articles were reviewed with a total of 29 genes. Outcome measures included sperm concentration, azoospermia, AMH levels, assessment of premature menopause, ever being pregnant or siring a pregnancy. Three studies included replication cohorts, which attempted replication of SNP findings for NPY2R, BRSK1, FANCI, CYP2C19, CYP3A4, and CYP2B6. Six studies were rated with a high risk of bias. Differing methods may explain a lack of replication, and small cohorts may have contributed to few significant findings. Larger, prospective longitudinal studies with an unbiased genome-wide focus will be important to replicate significant results, which can be applied clinically.
Topics: Adolescent; Child; Female; Humans; Male; Young Adult; Antineoplastic Agents; Cancer Survivors; Fertility; Infertility; Neoplasms; Pharmacogenetics; Pharmacogenomic Testing
PubMed: 38924306
DOI: 10.1111/cts.13827 -
Annals of the Academy of Medicine,... Mar 2024
Topics: Warfarin; Humans; Singapore; Algorithms; Anticoagulants; Pharmacogenetics; Male; International Normalized Ratio; Female; Cytochrome P-450 CYP2C9; Middle Aged; Aged; Vitamin K Epoxide Reductases
PubMed: 38920246
DOI: 10.47102/annals-acadmedsg.2023186 -
Current Neuropharmacology Jun 2024Excessive free radicals are implicated in the pathophysiology of tardive dyskinesia (TD), and Ginkgo biloba extract (EGb761) scavenges free radicals, thereby enhancing...
BACKGROUND
Excessive free radicals are implicated in the pathophysiology of tardive dyskinesia (TD), and Ginkgo biloba extract (EGb761) scavenges free radicals, thereby enhancing antioxidant enzymes such as mitochondrial manganese superoxide dismutase (MnSOD). This study examined whether EGb761 treatment would improve TD symptoms and increase MnSOD activity, particularly in TD patients with specific MnSOD Val-9Ala genotype.
METHODS
An EGb761 (240 mg/day) 12-week double-blind clinical trial with 157 TD patients was randomized. The severity of TD was measured by the Abnormal Involuntary Movement Scale (AIMS) and plasma MnSOD activity was assayed before and after 12 weeks of treatment. Further, in an expanded sample, we compared MnSOD activity in 159 TD, 227 non-TD and 280 healthy controls, as well as the allele frequencies and genotypes for the MnSOD Ala-9Val polymorphism in 352 TD, 486 non-TD and 1150 healthy controls.
RESULTS
EGb761 significantly reduced TD symptoms and increased MnSOD activity in TD patients compared to placebo (both p < 0.01). Moreover, we found an interaction between genotype and treatment response (p < 0.001). Furthermore, in the EGb761 group, patients carrying the Ala allele displayed a significantly lower AIMS total score than patients with the Val/Val genotype. In addition, MnSOD activity was significantly lower at baseline in TD patients compared with healthy controls or non-TD patients.
CONCLUSION
EGb761 treatment enhanced low MnSOD activity in TD patients and produced greater improvement in TD symptoms in patients with the Ala allele of the MnSOD Ala-9Val polymorphism.
PubMed: 38919004
DOI: 10.2174/1570159X22666240530095721 -
Critical Reviews in Oncology/hematology Jun 2024The presence of FLT3 mutations, including the most common FLT3-ITD (internal tandem duplications) and FLT3-TKD (tyrosine kinase domain), is associated with an... (Review)
Review
The presence of FLT3 mutations, including the most common FLT3-ITD (internal tandem duplications) and FLT3-TKD (tyrosine kinase domain), is associated with an unfavorable prognosis in patients affected by Acute Myeloid Leukemia (AML). In this setting, in recent years, new FLT3-inhibitors have demonstrated efficacy in improving survival and treatment response. Nevertheless, the development of primary and secondary mechanisms of resistance poses a significant obstacle to their efficacy. Understanding these mechanisms is crucial for developing novel therapeutic approaches to overcome resistance and improve the outcomes of patients. In this context, the use of novel FLT3 inhibitors and the combination of different targeted therapies have been studied. This review provides an update on the molecular alterations involved in FLT3 AML mechanisms of resistance, exploring how the molecular monitoring may be used to guide treatment strategy in FLT3-mutated AML.
PubMed: 38917943
DOI: 10.1016/j.critrevonc.2024.104424 -
Pharmacopsychiatry Jun 2024Little is known about the interplay between genetics and epigenetics on antidepressant treatment (1) response and remission, (2) side effects, and (3) serum levels. This...
INTRODUCTION
Little is known about the interplay between genetics and epigenetics on antidepressant treatment (1) response and remission, (2) side effects, and (3) serum levels. This study explored the relationship among single nucleotide polymorphisms (SNPs), DNA methylation (DNAm), and mRNA levels of four pharmacokinetic genes, , , , and , and its effect on these outcomes.
METHODS
The Canadian Biomarker Integration Network for Depression-1 dataset consisted of 177 individuals with major depressive disorder treated for 8 weeks with escitalopram (ESC) followed by 8 weeks with ESC monotherapy or augmentation with aripiprazole. DNAm quantitative trait loci (mQTL), identified by SNP-CpG associations between 20 SNPs and 60 CpG sites in whole blood, were tested for associations with our outcomes, followed by causal inference tests (CITs) to identify methylation-mediated genetic effects.
RESULTS
Eleven SNP-CpG pairs (q<0.05) constituting four unique SNPs were identified. Although no significant associations were observed between mQTLs and response/remission, rs4244285 was associated with treatment-related weight gain (=0.027) and serum concentrations of ESC (<0.001). Between weeks 2-4, 6.7% and 14.9% of those with *1/*1 (normal metabolizers) and *1/*2 (intermediate metabolizers) genotypes, respectively, reported ≥2 lbs of weight gain. In contrast, the *2/*2 genotype (poor metabolizers) did not report weight gain during this period and demonstrated the highest ESC concentrations. CITs did not indicate that these effects were epigenetically mediated.
DISCUSSION
These results elucidate functional mechanisms underlying the established associations between rs4244285 and ESC pharmacokinetics. This mQTL SNP as a marker for antidepressant-related weight gain needs to be further explored.
PubMed: 38917846
DOI: 10.1055/a-2313-9979 -
Pharmacogenetics and Genomics Jun 2024This study aims to understand patient and healthcare provider perspectives on the integration and application of pharmacogenetics (PGx) testing in routine clinical...
OBJECTIVE
This study aims to understand patient and healthcare provider perspectives on the integration and application of pharmacogenetics (PGx) testing in routine clinical practice.
METHODS
Two anonymous online surveys were distributed globally for healthcare providers and patients respectively on the Qualtrics platform (version 3.24). The surveys were distributed through social platforms, email, and posters with QR codes from 27 October 2023 to 7 March 2024. The surveys evaluated participant familiarity with PGx, previous experience with PGx testing, perceived implementation challenges, and opinions on point-of-care (PoC) PGx testing devices.
RESULTS
This study collected 78 responses from healthcare providers and 98 responses from patients. The results revealed that 64% of healthcare providers had some level of familiarity with PGx, however, PGx testing in clinical practice was low. The primary challenges identified by healthcare providers included limited access to testing and lack of knowledge on PGx test interpretation. In contrast, 52% of patient respondents were aware of PGx testing, with a significant association between awareness and positive opinions toward PGx. Both healthcare providers and patients recognized the value of PoC PGx testing devices, with 98% of healthcare providers and 71% of patients believing PoC devices would improve the accessibility and implementation of PGx testing. Comparative analysis revealed a statistically significant difference in PGx awareness between healthcare providers and patients, with providers being more informed.
CONCLUSION
Improved PGx awareness, training, clinical guidelines, and PoC PGx testing devices may help promote the implementation of PGx-guided treatments in routine clinical practice.
PubMed: 38917295
DOI: 10.1097/FPC.0000000000000541 -
International Journal of... Apr 2024Pharmacogenetic research has led to significant progress in understanding how genetic factors influence drug response in tuberculosis (TB) treatment. One ongoing...
BACKGROUND
Pharmacogenetic research has led to significant progress in understanding how genetic factors influence drug response in tuberculosis (TB) treatment. One ongoing challenge is the variable occurrence of adverse drug reactions in some TB patients. Previous studies have indicated that genetic variations in the N-acetyltransferase 2 (NAT2) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) genes can impact the blood concentrations of the first-line anti-TB drugs isoniazid (INH) and rifampicin (RIF), respectively. This study aimed to investigate the influence of pharmacogenetic markers in the NAT2 and SLCO1B1 genes on TB treatment outcomes using whole-exome sequencing (WES) analysis.
METHODS
DNA samples were collected from 30 healthy Iranian adults aged 18-40 years. The allelic frequencies of single-nucleotide polymorphisms (SNPs) in the NAT2 and SLCO1B1 genes were determined through WES.
RESULTS
Seven frequent SNPs were identified in the NAT2 gene (rs1041983, rs1801280, rs1799929, rs1799930, rs1208, rs1799931, rs2552), along with 16 frequent SNPs in the SLCO1B1 gene (rs2306283, rs11045818, rs11045819, rs4149056, rs4149057, rs2291075, rs201722521, rs11045852, rs11045854, rs756393362, rs11045859, rs74064211, rs201556175, rs34671512, rs71581985, rs4149085).
CONCLUSION
Genetic variations in NAT2 and SLCO1B1 can affect the metabolism of INH and RIF, respectively. A better understanding of the pharmacogenetic profile in the study population may facilitate the design of more personalized and effective TB treatment strategies. Further research is needed to directly correlate these genetic markers with clinical outcomes in TB patients.
Topics: Humans; Arylamine N-Acetyltransferase; Liver-Specific Organic Anion Transporter 1; Adult; Antitubercular Agents; Male; Young Adult; Mycobacterium tuberculosis; Polymorphism, Single Nucleotide; Rifampin; Adolescent; Female; Isoniazid; Iran; Tuberculosis; Gene Frequency; Exome Sequencing; Pharmacogenomic Testing; Pharmacogenetics
PubMed: 38916393
DOI: 10.4103/ijmy.ijmy_106_24