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Biomedicine & Pharmacotherapy =... Sep 2022Multiple sclerosis is a chronic inflammatory neurological disease, and siponimod (Mayzent) is the first oral treatment option for adult patients with secondary... (Review)
Review
Multiple sclerosis is a chronic inflammatory neurological disease, and siponimod (Mayzent) is the first oral treatment option for adult patients with secondary progressive multiple sclerosis. We performed a systematic review of the pharmacogenetics of Siponimod, and we found that (430 C>T; rs1799853) and CYP2C9 * 3 (1075 A>C; rs1057910), both translated no-function alleles, have been related to a lower metabolism of siponimod by CYP2C9 enzyme. The FDA-approved drug label and EMA risk management plan for siponimod require testing patients for CYP2C9 genotype before treatment starts. The FDA drug label states that siponimod is contraindicated in patients carrying a CYP2C9 * 3/* 3 genotype, and a daily maintenance dose of 1 mg in patients with CYP2C9 * 1/* 3 and * 2/* 3 genotypes. The EMA reported the potential long-term safety implications in CYP2C9 poor metabolizer patients treated with this drug. Based on this systematic review we concluded that CYP2C9 SNPs influence on siponimod response might be stated by assessing not only CYP2C9 * 2 and CYP2C9 * 3 but other genetic variants resulting in CYP2C9 IM/PM status. CYP2C9 IM phenotype translated from the CYP2C9 * 2 genotype should be revised since it is contradictory compared to other CYP2C9 no-function alleles, and CYP2C9 * 2 might be excluded from PGx testing recommendation before treatment starts with siponimod since it is not translated into a therapeutic recommendation.
Topics: Azetidines; Benzyl Compounds; Cytochrome P-450 CYP2C9; Genotype; Pharmacogenetics
PubMed: 36076616
DOI: 10.1016/j.biopha.2022.113536 -
Frontiers in Medicine 2022Several healthcare organizations have developed pre-emptive pharmacogenetic testing programs, where testing is undertaken prior to the prescription of a medicine. This...
Several healthcare organizations have developed pre-emptive pharmacogenetic testing programs, where testing is undertaken prior to the prescription of a medicine. This review characterizes the barriers and facilitators which influenced the development of these programs. A bidirectional citation searching strategy identified relevant publications before a standardized data extraction approach was applied. Publications were grouped by program and data synthesis was undertaken using the Consolidated Framework for Implementation Research (CFIR). 104 publications were identified from 40 programs and 4 multi-center initiatives. 26 (66%) of the programs were based in the United States and 95% in high-income countries. The programs were heterogeneous in their design and scale. The Characteristics of the Intervention, Inner Setting, and Process domains were referenced by 92.5, 80, and 77.5% of programs, respectively. A positive institutional culture, leadership engagement, engaging stakeholders, and the use of clinical champions were frequently described as facilitators to implementation. Clinician self-efficacy, lack of stakeholder knowledge, and the cost of the intervention were commonly cited barriers. Despite variation between the programs, there were several similarities in approach which could be categorized the CFIR. These form a resource for organizations planning the development of pharmacogenetic programs, highlighting key facilitators which can be leveraged to promote successful implementation.
PubMed: 36059837
DOI: 10.3389/fmed.2022.945352 -
European Journal of Human Genetics :... Feb 2024The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize...
The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the gene-drug interaction of ABCG2 with allopurinol, HLA-B with allopurinol, MTHFR with folic acid, and MTHFR with methotrexate, relevant for the treatment of gout, cancer, and rheumatoid arthritis. A systematic review was performed based on which pharmacotherapeutic recommendations were developed. Allopurinol is less effective in patients with the ABCG2 p.(Gln141Lys) variant. In HLA-B*58:01 carriers, the risk of severe cutaneous adverse events associated with allopurinol is strongly increased. The DPWG recommends using a higher allopurinol dose in patients with the ABCG2 p.(Gln141Lys) variant. For HLA-B*58:01 positive patients the DPWG recommends choosing an alternative (for instance febuxostat). The DPWG indicates that another option would be to precede treatment with allopurinol tolerance induction. Genotyping of ABCG2 in patients starting on allopurinol was judged to be 'potentially beneficial' for drug effectiveness, meaning genotyping can be considered on an individual patient basis. Genotyping for HLA-B*58:01 in patients starting on allopurinol was judged to be 'beneficial' for drug safety, meaning it is advised to consider genotyping the patient before (or directly after) drug therapy has been initiated. For MTHFR-folic acid there is evidence for a gene-drug interaction, but there is insufficient evidence for a clinical effect that makes therapy adjustment useful. Finally, for MTHFR-methotrexate there is insufficient evidence for a gene-drug interaction.
Topics: Humans; Allopurinol; ATP Binding Cassette Transporter, Subfamily G, Member 2; Drug Interactions; Folic Acid; Gout Suppressants; HLA-B Antigens; Methotrexate; Methylenetetrahydrofolate Reductase (NADPH2); Neoplasm Proteins; Pharmacogenetics
PubMed: 36056234
DOI: 10.1038/s41431-022-01180-0 -
Clinical Pharmacology and Therapeutics May 2023Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with development of acute hemolytic anemia in the setting of oxidative stress, which can be caused by... (Review)
Review
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with development of acute hemolytic anemia in the setting of oxidative stress, which can be caused by medication exposure. Regulatory agencies worldwide warn against the use of certain medications in persons with G6PD deficiency, but in many cases, this information is conflicting, and the clinical evidence is sparse. This guideline provides information on using G6PD genotype as part of the diagnosis of G6PD deficiency and classifies medications that have been previously implicated as unsafe in individuals with G6PD deficiency by one or more sources. We classify these medications as high, medium, or low to no risk based on a systematic review of the published evidence of the gene-drug associations and regulatory warnings. In patients with G6PD deficiency, high-risk medications should be avoided, medium-risk medications should be used with caution, and low-to-no risk medications can be used with standard precautions, without regard to G6PD phenotype. This new document replaces the prior Clinical Pharmacogenetics Implementation Consortium guideline for rasburicase therapy in the context of G6PD genotype (updates at: www.cpicpgx.org).
Topics: Humans; Glucosephosphate Dehydrogenase; Glucosephosphate Dehydrogenase Deficiency; Pharmacogenetics; Hemolysis; Genotype
PubMed: 36049896
DOI: 10.1002/cpt.2735 -
BMC Psychiatry Aug 2022The main goal of this work was to identify, describe, characterize, and classify the scientific evidence regarding the use of pharmacogenomic biomarkers in...
OBJECTIVE
The main goal of this work was to identify, describe, characterize, and classify the scientific evidence regarding the use of pharmacogenomic biomarkers in antidepressant treatment.
METHODS
The work was developed in two phases: i) a search for pharmacogenomic biomarkers in summaries of antidepressant drugs with marketing authorization in Portugal; and ii) a systematic literature review based on the data obtained in the first phase, with the main objective of finding international literature that could describe and characterize previously reported biomarkers and identify other relevant biomarkers. Finally, the levels of evidence and recommendation grades were classified.
RESULTS
Among the 26 drugs with marketing authorization in Portugal, only 16 had pharmacogenomic information. The most widely studied pharmacogenomic biomarker was CYP2D6. These results were mostly supported by the systematic literature review, which yielded 103 papers, 63 of which were ultimately included in the review. The systematic literature review also revealed the existence of other relevant biomarkers. Most of the included studies show a good level of evidence, which guarantees reliability and good recommendation grades. For the database (built during phase i), the results were informative but resulted in no specific recommendations.
CONCLUSIONS
Most pharmacogenomic variants are not studied or acknowledged by genetic tests, and more scientific research is needed to confirm their usefulness. Therefore, only a small number of variants are considered when prescribing antidepressant drugs. In addition, genotyping of patients is not common in clinical practice.
Topics: Antidepressive Agents; Biomarkers; Genetic Testing; Humans; Pharmacogenetics; Reproducibility of Results
PubMed: 36042420
DOI: 10.1186/s12888-022-04225-2 -
Antioxidants (Basel, Switzerland) Aug 2022The coronavirus disease (COVID-19) pandemic is a leading global health and economic challenge. What defines the disease's progression is not entirely understood, but... (Review)
Review
The coronavirus disease (COVID-19) pandemic is a leading global health and economic challenge. What defines the disease's progression is not entirely understood, but there are strong indications that oxidative stress and the defense against reactive oxygen species are crucial players. A big influx of immune cells to the site of infection is marked by the increase in reactive oxygen and nitrogen species. Our article aims to highlight the critical role of oxidative stress in the emergence and severity of COVID-19 and, more importantly, to shed light on the underlying molecular and genetic mechanisms. We have reviewed the available literature and clinical trials to extract the relevant genetic variants within the oxidative stress pathway associated with COVID-19 and the anti-oxidative therapies currently evaluated in the clinical trials for COVID-19 treatment, in particular clinical trials on glutathione and N-acetylcysteine.
PubMed: 36009328
DOI: 10.3390/antiox11081609 -
Expert Review of Clinical Pharmacology Jul 2022Clopidogrel is an antiplatelet agent recommended for secondary prevention of ischemic stroke (IS) and transient ischemic attack (TIA). Conversion of clopidogrel to its...
INTRODUCTION
Clopidogrel is an antiplatelet agent recommended for secondary prevention of ischemic stroke (IS) and transient ischemic attack (TIA). Conversion of clopidogrel to its active metabolite by hepatic cytochrome P450-2C19 (CYP2C19) is essential for the inhibition of the P2Y12 receptor and subsequent platelet aggregation to prevent thrombotic events. is highly polymorphic, with over 30 loss of function (LoF) alleles. This review considers whether there is sufficient data to support genotype guided antiplatelet therapy after stroke.
AREAS COVERED
A systematic literature review retrieved articles, which describe the interaction between genotype and clinical outcomes following IS or TIA when treated with clopidogrel. The review documents efforts to identify optimal antiplatelet regimens and explores the value genotype guided antiplatelet therapy. The work outlines the contemporary understanding of clopidogrel metabolism and appraises evidence linking LoF variants with attenuated platelet inhibition and poorer outcomes.
EXPERT OPINION
There is good evidence that LoF allele carriers of Han-Chinese ancestry have increased risk for further vascular events following TIA or IS when treated with clopidogrel. The evidence base is less certain in other populations. The expansion of pharmacogenetics into routine clinical practice will facilitate further research and help tailor other aspects of secondary prevention.
Topics: Clopidogrel; Cytochrome P-450 CYP2C19; Genotype; Humans; Ischemic Attack, Transient; Ischemic Stroke; Platelet Aggregation Inhibitors; Stroke; Ticlopidine; Treatment Outcome
PubMed: 35912831
DOI: 10.1080/17512433.2022.2108401 -
Clinical and Translational Science Oct 2022Taxane-based chemotherapy regimens are used as first-line treatment for breast cancer. Neurotoxicity, mainly taxane-induced peripheral neuropathy (TIPN), remains the... (Meta-Analysis)
Meta-Analysis
Taxane-based chemotherapy regimens are used as first-line treatment for breast cancer. Neurotoxicity, mainly taxane-induced peripheral neuropathy (TIPN), remains the most important dose-limiting adverse event. Multiple genes may be associated with TIPN; however, the strength and direction of the association remain unclear. For this reason, we systematically reviewed observational studies of TIPN pharmacogenetic markers in breast cancer treatment. We conducted a systematic search of terms alluding to breast cancer, genetic markers, taxanes, and neurotoxicity in Ovid, ProQuest, PubMed, Scopus, Virtual Health, and Web of Science. We assessed the quality of evidence and bias profile. We extracted relevant variables and effect measures. Whenever possible, we performed random-effects gene meta-analyses and examined interstudy heterogeneity with meta-regression models and subgroup analyses. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and STrengthening the REporting of Genetic Association Studies (STREGA) reporting guidance. A total of 42 studies with 19,431 participants were included. These evaluated 262 single-nucleotide polymorphisms (SNPs) across 121 genes. We conducted meta-analyses on 23 genes with 60 SNPs (19 studies and 6246 participants). Thirteen individual SNPs (ABCB1-rs2032582, ABCB1-rs3213619, BCL6/-rs1903216, /CAND1-rs17781082, CYP1B1-rs1056836, CYP2C8-rs10509681, CYP2C8-rs11572080, EPHA5-rs7349683, EPHA6-rs301927, FZD3-rs7001034, GSTP1-rs1138272, TUBB2A-rs9501929, and XKR4-rs4737264) and the overall SNPs' effect in four genes (CYP3A4, EphA5, GSTP1, and SLCO1B1) were statistically significantly associated with TIPN through meta-analysis. In conclusion, through systematic review and meta-analysis, we found that polymorphisms, and particularly 13 SNPs, are associated with TIPN, suggesting that genetics does play a role in interindividual predisposition. Further studies could potentially use these findings to develop individual risk profiles and guide decision making.
Topics: Female; Humans; Breast Neoplasms; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Genetic Markers; Liver-Specific Organic Anion Transporter 1; Neurotoxicity Syndromes; Paclitaxel; Peripheral Nervous System Diseases; Pharmacogenetics; Polymorphism, Single Nucleotide; Taxoids
PubMed: 35892315
DOI: 10.1111/cts.13370 -
Journal of Personalized Medicine Jun 2022Pharmacogenetics research on leukotriene modifiers (LTMs) for asthma has been developing rapidly, although pharmacogenetic testing for LTMs is not yet used in clinical...
Pharmacogenetics research on leukotriene modifiers (LTMs) for asthma has been developing rapidly, although pharmacogenetic testing for LTMs is not yet used in clinical practice. We performed a systematic review and meta-analysis on the impact of pharmacogenomics on LTMs response. Studies published until May 2022 were searched using PubMed, EMBASE, and Cochrane databases. Pharmacogenomics/genetics studies of patients with asthma using LTMs with or without other anti-asthmatic drugs were included. Statistical tests of the meta-analysis were performed with Review Manager (Revman, version 5.4, The Cochrane Collaboration, Copenhagen, Denmark) and R language and environment for statistical computing (version 4.1.0 for Windows, R Core Team, Vienna, Austria) software. In total, 31 studies with 8084 participants were included in the systematic review and five studies were also used to perform the meta-analysis. Two included studies were genome-wide association studies (GWAS), which showed different results. Furthermore, none of the SNPs investigated in candidate gene studies were identified in GWAS. In candidate gene studies, the most widely studied SNPs were ALOX5 (tandem repeats of the Sp1-binding domain and rs2115819), LTC4S-444A/C (rs730012), and SLCO2B1 (rs12422149), with relatively inconsistent conclusions. LTC4S-444A/C polymorphism did not show a significant effect in our meta-analysis (AA vs. AC (or AC + CC): −0.06, 95%CI: −0.16 to 0.05, p = 0.31). AA homozygotes had smaller improvements in parameters pertaining to lung functions (−0.14, 95%CI: −0.23 to −0.05, p = 0.002) in a subgroup of patients with non-selective CysLT receptor antagonists and patients without inhaled corticosteroids (ICS) (−0.11, 95%CI: −0.14 to −0.08, p < 0.00001), but not in other subgroups. Variability exists in the pharmacogenomics of LTMs treatment response. Our meta-analysis and systematic review found that LTC4S-444A/C may influence the treatment response of patients taking non-selective CysLT receptor antagonists for asthma, and patients taking LTMs not in combination with ICS for asthma. Future studies are needed to validate the pharmacogenomic influence on LTMs response.
PubMed: 35887565
DOI: 10.3390/jpm12071068 -
Antioxidants (Basel, Switzerland) Jul 2022Alcohol use disorder (AUD) is a highly prevalent, comorbid, and disabling disorder. The underlying mechanism of ethanol neurotoxicity and the involvement of oxidative... (Review)
Review
Alcohol use disorder (AUD) is a highly prevalent, comorbid, and disabling disorder. The underlying mechanism of ethanol neurotoxicity and the involvement of oxidative stress is still not fully elucidated. However, ethanol metabolism has been associated with increased oxidative stress through alcohol dehydrogenase, the microsomal ethanol oxidation system, and catalase metabolic pathways. We searched the PubMed and genome-wide association studies (GWAS) catalog databases to review the literature systematically and summarized the findings focusing on AUD and alcohol abstinence in relation to oxidative stress. In addition, we reviewed the ClinicalTrials.gov resource of the US National Library of Medicine to identify all ongoing and completed clinical trials that include therapeutic interventions based on antioxidants. The retrieved clinical and preclinical studies show that oxidative stress impacts AUD through genetics, alcohol metabolism, inflammation, and neurodegeneration.
PubMed: 35883865
DOI: 10.3390/antiox11071374