CYP2C19 Gene Research Articles

Precision medicine as a predictive factor for risk of hospitalization of recurrent ischemic stroke patients treated with low dose aspirin. A pilot study

ABSTRACT Recurrent ischemic stroke risk after transient ischemic attack was underestimated by most of epidemiological studies due to the widespread use of very different and sometimes restrictive definitions for recurrent stroke instead of a standard definition, making it difficult to assess the benefit of early prevention of recurrence. Knowing that early intervention by treatment with aspirin reduced fatal recurrent stroke and proved to be cost effective by reducing hospital admission, it was worthwhile studying the pharmacogenetics association as well as biological risk factors of aspirin intolerance for patients with recurrent ischemic stroke. Accordingly, our primary outcome was to investigate the association of CYP2C9*3 (Rs1057910) polymorphism as well as other factors such as diabetes, hypertension and smoking with aspirin intolerance for these patients. The secondary outcome was to study the correlation between TNF-alpha as an inflammatory mediator and the prognosis of ischemic stroke for these patients. Our results showed that although smoking and heterozygous A/C of Rs1057910 still have a higher prevalence however statistically insignificant risk for ischemic stroke recurrence compared with other risk factors; OR1.69 and 1.9, 95%CI (0.471–1.695) and (0.321–11.257) respectively. Also, our results suggest that there is a borderline statistically significant correlation between recurrent stroke prognosis and TNF alpha (p = 0.043). Conclusion: This study failed to detect association of Rs1057910 variant of CYP2C9 gene with preventive aspirin for patients with ischemic stroke. However, a somehow significant association was detected between ischemic stroke prognosis and TNF- α as an inflammatory marker. Further research investigations on larger sample size population are encouraged.

Novel Cytochrome P450 2C94 Functionally Metabolizes Diclofenac and Omeprazole in Dogs.

Cytochromes P450 (P450s or CYPs) are important drug-metabolizing enzymes. Because dogs are frequently used in drug metabolism studies, knowledge of dog CYP2C enzymes is essential because in humans these enzymes are abundant and play major roles in liver and intestine. The present study identified and characterized novel dog CYP2C94 along with previously identified dog CYP2C21 and CYP2C41. Dog CYP2C21, CYP2C41, and CYP2C94 cDNAs, respectively, contained open reading frames of 490, 489, and 496 amino acids and shared high-sequence identities (70%, 75%, and 58%) with human CYP2Cs. Dog CYP2C94 mRNA was preferentially expressed in liver, just as dog CYP2C21 and CYP2C41 mRNAs were. In dog liver, CYP2C21 mRNA was the most abundant, followed by CYP2C94 and CYP2C41 mRNAs. Moreover, the hepatic expressions of all three dog CYP2C mRNAs varied in four individual dogs, two of which did not express CYP2C41 mRNA. The three dog CYP2C genes had similar gene structures, and CYP2C94, although located on the same chromosome, was in a genomic region far from the gene cluster containing CYP2C21 and CYP2C41 Metabolic assays with recombinant proteins showed that dog CYP2C94, along with CYP2C21 and CYP2C41, efficiently catalyzed oxidations of diclofenac, warfarin, and/or omeprazole, indicating that dog CYP2C94 is a functional enzyme. Novel dog CYP2C94 is expressed abundantly in liver and encodes a functional enzyme that metabolizes human CYP2C substrates; it is, therefore, likely responsible for drug clearances in dogs. SIGNIFICANCE STATEMENT: Novel dog cytochrome P450 2C94 (CYP2C94) was identified and characterized along with dog CYP2C21 and CYP2C41. Dog CYP2C94, isolated from liver, had 58% sequence identity and a close phylogenetic relationship with its human homologs and was expressed in liver at the mRNA level. Dog CYP2C94 (and CYP2C21 and CYP2C41) catalyzed oxidations of diclofenac and omeprazole, human CYP2C9 and CYP2C19 substrates, respectively, but CYP2C41 also hydroxylated warfarin. CYP2C94 is therefore a functional drug-metabolizing enzyme likely responsible for drug clearances in dogs.

Clinical Impact of the CYP2C19 Gene on Diazepam for the Management of Alcohol Withdrawal Syndrome.

Diazepam is a benzodiazepine widely prescribed for the management of patients with severe alcohol withdrawal syndrome to prevent agitation, withdrawal seizures, and delirium tremens. Despite standard dosing of diazepam, a subset of patients experience refractory withdrawal syndromes or adverse drug reactions, such as impaired motor coordination, dizziness, and slurred speech. The CYP2C19 and CYP3A4 enzymes play a key role in the biotransformation of diazepam. Given the highly polymorphic nature of the CYP2C19 gene, we reviewed the clinical impact of variants in the CYP2C19 gene on both the pharmacokinetics of diazepam and treatment outcomes related to the management of alcohol withdrawal syndrome.

РОЛЬ ПОЛИМОРФИЗМОВ ГЕНОВ СИСТЕМЫ БИОТРАНСФОРМАЦИИ КСЕНОБИОТИКОВ И АНТИОКСИДАНТНОЙ ЗАЩИТЫ В РАЗВИТИИ ДИАБЕТИЧЕСКОЙ НЕФРОПАТИИ

Introduction.The main etiopathogenetic mechanisms of the development of multifactorial diseases are genetic predisposition and environmental factors. A special role in the prognosis of type 1 diabetes mellitus is played by diabetic nephropathy, which leads to chronic kidney disease in its outcome. In the conditions of modern technogenic civilization, it is believed that the most significant contribution to the formation of predisposition to socially significant human diseases can be made by genes of enzymes of protective and adaptive systems of the body – these are, first of all, genes of enzymes of antioxidant protection and biotransformation of xenobiotics. The aim of the study was to study the role of polymorphic variants of genes of the xenobiotic biotransformation system and antioxidant protection (G681A in the CYP2C19 gene; G1293C in the CYP2E1 gene) in the development of diabetic nephropathy in patients with type 1 diabetes mellitus. Material and methods. The study included patients with type 1 diabetes mellitus (50 people) and healthy individuals (20 people). Molecular-genetic, clinical-laboratory and biochemical research methods were used. The reliability of differences in the distribution of genotype frequencies between groups of patients and healthy individuals was assessed by the test2, by the method of conjugate tables (four-field table). Results and discussion. The activity of the processes of free radical oxidation and lipid peroxidation increases many times in type 1 diabetes mellitus, which is confirmed in our study by an increase in the content of malondialdehyde products against the background of an increase in the activity of enzymes of the antioxidant defense system. This is especially evident in individuals carrying heterozygous polymorphism of the CYP2C19 (G681A) and CYP2E1 (G1293C) genes, which is also combined with a more pronounced decrease in kidney function in these patients compared with carriers of other polymorphic variants of the studied genes. Conclusion. Heterozygous polymorphism of the CYP2C19 (G681A) and CYP2E1 (G1293C) genes in combination with increased activity of antioxidant defense enzymes and xenobiotic biotransformation enzymes leads to a more severe course of diabetic nephropathy in patients with type 1 diabetes mellitus.

46P Long-term residual chemotherapy-induced peripheral neuropathy (CIPN) and relationship with single nucleotide polymorphisms (SNPs) in ovarian cancer patients free of disease in the GINECO Vivrovaire study

Paclitaxel and carboplatin remains a backbone treatment of ovarian cancer (OC) inducing peripheral neuropathy in a significant proportion of patients. Meanwhile, long term survival of OC has dramatically increased with the recent therapeutic progress. Predictive factors for long-term CIPN are needed considering the impact on quality of life (Qol) of patients. We investigated the link between the incidence of CIPN and selected genetic polymorphisms in a cohort of ovarian cancer survivors. Vivrovaire is a French multi-center long-standing cohort of ovarian cancer patients free of disease 3 years after the end of the primary treatment. Long-term analysis of Qol in linked with neuropathy was performed including peripheral neuropathy assessed by the FACT/GOG-Ntx4 self-questionnaire. CIPN scores were correlated with SNPs in the selected CYP2C8, CYP3A4, ERCC1 and XPC genes. 130 patients were included with a median time from the end of chemotherapy of 63 months [35-180]. Median CIPN score was 37 [18-44] with 35 patients (27 %) having a severe score (< 33). SNPs (homozygotous/heterozygotous) were identified as follows: CYP2C8 [n=32 (24.6%)/ n=99 (76%)]; CYP3A4 [n=0 (0%)/ n=8 (6.1%)], ERCC1 [n=21 (16.1%)/ n=57 (43.8%)] and XPC [n=45 (34.6%)/ n=66 (50.8%)]. In univariate analysis, homozygous SNP (ho SNP) in any of the selected genes was associated with CIPN score as a continuous variable (p=0.045) but not with severe score (< 33) (OR: 1.66; 95% CI [0.74-3.88], p=0.22). Patients with CYP2C8_rs1934951 SNP tend to have CIPN score <33, (OR: 2.22; 95% CI [0.98-5.02], p=0.057). In multivariate analyses including age, interval from the end of chemotherapy, type and number of chemotherapy courses, identification of homozygotous or heterozygotous CYP2C8_rs1934951 SNP was associated with a severe CIPN score (OR: 2.41; 95% CI [1.02-5.70], p=0.043). Our study shows that residual CIPN is a frequent concern for ovarian cancer survivors. CYP2C8_rs1934951 SNP may be associated with severe residual CIPN in long-term survivors of ovarian cancer.

The role of CYP2C9*2, CYP2C9*3 and VKORC1-1639 variants on the susceptibility of upper gastrointestinal bleeding: A full case-control study.

Purpose: To investigate whether interindividual variability in the CYP2C9 (*2 and *3 alleles) and VKORC1 (rs9923231) genes is associated with increased risk of upper gastrointestinal bleeding (UGIB) in users of non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin (LDA). Methods: A full case-control study including 200 cases of patients diagnosed with UGIB and 706 controls was conducted in a Brazilian hospital complex. To perform an analysis of NSAIDs dose-effect, the defined daily dose (DDD) for NSAIDs was calculated in the 7-day etiologic window preceding the data index. Three categories of DDD, considering the genotypes of the genetic variants, were established: non-users of NSAIDs (DDD = 0), DDD ≤0.5, and DDD >0.5. Genetic variants and LDA or NSAIDs use synergism was estimated through Synergism Index (SI) and Relative Excess Risk Due To Interaction (RERI). Results: For DDDs of NSAIDs upward of 0.50, a risk of UGIB was identified in carriers of the *3 allele (OR: 15,650, 95% CI: 1.41-174.10) and in carriers of the variant homozygous genotype (TT) of rs9923231 (OR: 38,850, 95% CI: 2.70-556.00). In LDA users, the risk of UGIB was observed to be similar between carriers of the wild type homozygous genotype and carriers of the variant alleles for the CYP2C9 and VKORC1 genes. No synergism was identified. Conclusion: Our findings suggest an increased risk of UGIB in carriers of the variant allele of rs9923231 and in carriers of the *3 allele associated with doses of NSAIDs greater than 0.5. Hence, the assessment of these variants might reduce the incidence of NSAIDs-related UGIB and contribute to the safety of the NSAIDs user.

Polymorphisms Affecting the Response to Novel Antiepileptic Drugs.

Epilepsy is one of the most frequent chronic neurologic disorders that affects nearly 1% of the population worldwide, especially in developing countries. Currently, several antiepileptic drugs (AEDs) are available for its therapy, and although the prognosis is good for most patients, 20%-30% amongst them do not reach seizure freedom. Numerous factors may explain AED-resistance such as sex, age, ethnicity, type of seizure, early epilepsy onset, suboptimal dosing, poor drug compliance, alcohol abuse, and in particular, genetic factors. Specifically, the interindividual differences in drug response can be caused by single nucleotide polymorphisms (SNPs) in genes encoding for drug efflux transporters, for the brain targets of AEDs, and for enzymes involved in drug metabolism. In this review, we used the PubMed database to retrieve studies that assessed the influence of SNPs on the pharmacokinetic (PK), pharmacodynamic (PD), and efficacy of new antiepileptic drugs. Our results showed that polymorphisms in the ABCB1, ABCC2, UGT1A4, UGT2B7, UGT2B15, CYP2C9, and CYP2C19 genes have an influence on the PK and efficacy of AEDs, suggesting that a genetic pre-evaluation of epileptic patients could help clinicians in prescribing a personalized treatment to improve the efficacy and the safety of the therapy.

Platelet reactivity index after treatment of clopidogrel versus ticagrelor based on CYP2C19 genotypes among patients undergoing percutaneous coronary intervention: results of a randomized study

Abstract Funding Acknowledgements Type of funding sources: None. Background Although clopidogrel is the basic drug for antiplatelet therapy in patients with coronary artery disease (CAD). However, loss of function (LOF) allelic variants located within the CYP2C19 gene may reduce the production of clopidogrel active metabolites and weaken the antiplatelet effect, increasing platelet rates reactivity and associated with increased rates of adverse events after percutaneous coronary intervention (PCI). Thus, drug regulatory authorities have warned of clopidogrel's reduced efficacy and suggested using alternative treatments (such as ticagrelor). However, in clinical practice, the strategy of genotype-guided selection for antiplatelet therapy has been limited by the lack of access to immediately available results. Purpose We sought to evaluate the effect of point-of-care genetic testing for CYP2C19 genotypes on the antiplatelet choice of therapy (i.e., clopidogrel vs ticagrelor), using platelet reactivity index (PRI) as a proxy of clinical outcome Method This study was a prospective, randomized, parallel design, an open-label investigation conducted among Malaysian patients with stable coronary artery disease (SCAD) undergoing PCI. Patients underwent rapid point-of-care genetic testing using the nested allele-specific multiplex PCR assay, which defines CYP2C19 genetic status within 3 hours, allowing patients to be genotyped on the same day before PCI. Patients who were carriers of at least one +LOF or -LOF (*2 or *3) allele was randomized to receive either clopidogrel [600mg loading dose (LD) - 75mg/day maintenance dose (MD)] or ticagrelor (180mg LD - 90mg MD). The induced platelet reactivity index (PRI) was assessed by Vasodilator-Associated Stimulated Phosphoprotein (VASP) Assay to whole blood at one standardized time point after 4 hours of LD. All patients were treated with aspirin. The primary endpoint of the study was the non-inferiority in platelet reactivity, measured as PRI, at 4 hours of clopidogrel vs ticagrelor in +LOF or -LOF allele carriers Result In 1638 SCAD patients, 94 underwent PCI and were genotyped and randomized to receive either clopidogrel (n=44) or ticagrelor (n=50). A total of 42 (44.68%) were carriers of at least one +LOF. PRI levels at 4 hours for clopidogrel vs ticagrelor 44 and 40, respectively (mean difference = 23.08; 95% CI: 17 to 30; p=&amp;lt;0.001); this will meet the primary endpoint of superiority in a non-inferiority. Ticagrelor significantly reduced PRI more than clopidogrel. The cross-tabulation of the response classification showed that ticagrelor is superior to clopidogrel based on the -LOF and +LOF (P= 0.005 and &amp;lt;0.001, respectively) Conclusion A rapid point-of-care genetic test using a nested allele-specific multiplex PCR assay can be used to personalize antiplatelet therapy and provides timely results for patients undergoing PCI. In addition, the results showed that ticagrelor was superior to clopidogrel in the level of platelet inhibition in both groups (+LOF or -LOF)

Influence of CYP2C19 genetic variants and smoking on dual antiplatelet efficacy in patients with coronary artery disease.

This study aimed to investigate the effects of smoking and CYP2C19 gene polymorphism on antiplatelet therapy to specify the most optimized and accurate antiplatelet therapy for different populations. This study included 6,353 patients with coronary artery disease (CAD). In total, 2,256 (35.5%) were smokers and 4,097 (64.5%) were non-smokers. Patients carrying a CYP2C19*2 or *3 allele were considered loss-of-function (LOF) allele carriers. The medical history of patients who had undergone percutaneous coronary intervention (PCI) at Beijing Anzhen Hospital was recorded. The primary endpoint was major adverse cardiovascular or cerebrovascular events (MACCE) during the 6-month follow-up period. A Cox regression model was used to assess the interactions between antiplatelet efficacy and CYP2C19 LOF allele carrier status, stratified by smoking status. Compared to clopidogrel plus aspirin, ticagrelor plus aspirin reduced the MACCE recurrence risk in non-smokers (carrier: 6.0 vs. 2.0%, hazard ratio 0.298, 95% confidence interval 0.204-0.635, P < 0.0001; non-carrier: 5.8 vs. 2.1%, hazard ratio 0.358, 95% confidence interval 0.189-0.678, P = 0.002), and not in smokers. Similar results were discovered regarding the recurrence rate for hospitalization for ischemic cardiac events in non-smokers. No apparent difference was discovered in the bleeding events in either group. There were no significant associations between antiplatelet medication and CYP2C19 LOF allele carrier status for the MACCE recurrence risk among smokers (P = 0.943, respectively) or non-smokers (P = 0.774, respectively). In patients with CAD after PCI, ticagrelor plus aspirin lowered the MACCE recurrence risk in CYP2C19 LOF allele carriers and non-carriers compared with clopidogrel plus aspirin alone among non-smokers. The efficacy of antiplatelet therapy varies between CYP2C19 LOF allele carrier status. No significant interaction between CYP2C19 LOF allele carrier status and antiplatelet effectiveness was observed. However, caution should be used to interpret our results considering the many limitations of our investigation.

Pharmacokinetics and bioequivalence evaluation of omeprazole and sodium bicarbonate dry suspensions in healthy Chinese volunteers

Omeprazole and sodium bicarbonate dry suspension are effective treatments for acid-related disorders. This study compared the bioequivalence and safety of the two formulations of omeprazole and sodium bicarbonate powder and assessed how CYP2C19 gene polymorphisms affect pharmacokinetics (PK). A single-center, randomized, single-dose, 2-sequence and 2-period crossover method was performed in forty healthy Chinese subjects. Blood samples were collected after a single dose for PK (AUC0–∞, AUC0–t, and Cmax) analysis. The concentrations of Omeprazole in human plasma were determined by HPLC–MS/MS. Besides, the gene polymorphisms of CYP2C19 were assessed by Sanger sequencing. The geometric mean ratios (90% confidence interval) [GMR (95% CI)] of Test/Reference preparation for Cmax: 95.2% (88.48%, 102.43%), AUC0–t: 97.47% (94.4%, 101.02%), AUC0–∞: 97.68% (94.27%, 101.21%) were within the range of 80.00–125.00%. The non-parametric test showed no statistical difference in Tmax between the two groups (p > 0.05). All drugs were well tolerated, no severe adverse reactions occurred, and no significant differences in adverse events between the two drugs. For CYP2C19 gene polymorphisms, the results showed that of 40 subjects, 12 subjects were extensive metabolizers, 24 were intermediate metabolizers, and 4 were poor metabolizers, the frequency of metabolic genotypes were 30%, 60%, and 10%. And the allele distributions for CYP2C19 were *1, *2, and *3 at 60%, 38.75%, and 1.25%. Both the CYP2C19 alleles and metabolic genotypes were consistent with other studies in Chinese. The results of PK parameters showed that different genotypes of CYP2C19 lead to significant differences in t1/2, AUC0–t, AUC0–∞ and Cmax, but no significant differences in Tmax in each group. At the same time, we confirmed that the PK parameters of the test and reference had no differences between the males and females. This study has shown that the pharmacokinetic parameters of the two formulations are not significantly different, which showed bioequivalence and exemplary safety. CYP2C19 gene polymorphism significantly differed in the PK parameters of omeprazole sodium bicarbonate powder.

SNPs Sets in Codifying Genes for Xenobiotics-Processing Enzymes Are Associated with COPD Secondary to Biomass-Burning Smoke.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide; the main risk factors associated with the suffering are tobacco smoking (TS) and chronic exposure to biomass-burning smoke (BBS). Different biological pathways have been associated with COPD, especially xenobiotic or drug metabolism enzymes. This research aims to identify single nucleotide polymorphisms (SNPs) profiles associated with COPD from two expositional sources: tobacco smoking and BBS. One thousand-five hundred Mexican mestizo subjects were included in the study and divided into those exposed to biomass-burning smoke and smokers. Genome-wide exome genotyping was carried out using Infinium Exome-24 kit arrays v. 1.2. Data quality control was conducted using PLINK 1.07. For clinical and demographic data analysis, Rstudio was used. Eight SNPs were found associated with COPD secondary to TS and seven SNPs were conserved when data were analyzed by genotype. When haplotype analyses were carried out, five blocks were predicted. In COPD secondary to BBS, 24 SNPs in MGST3 and CYP family genes were associated. Seven blocks of haplotypes were associated with COPD-BBS. SNPs in the ARNT2 and CYP46A1 genes are associated with COPD secondary to TS, while in the BBS comparison, SNPs in CYP2C8, CYP2C9, MGST3, and MGST1 genes were associated with increased COPD risk.

The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia.

CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia. The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride. CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice. Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.

Association of Breast Cancer with Single Nucleotide Polymorphism of CYP2C9 Gene for Women Patients in Baghdad, Iraq

Breast cancer (BC) is a very varied disease, with several subtypes that exhibit different biological, molecular, and clinical characteristics. Standard information on tumor biology and clinicopathology can be identified by gene expression profile; have provided enhanced prognostic and predictive information. This study included 37 patients suffering from breast cancer and 15 healthy subjects. DNA has been extracted from all samples and then real-time PCR has been performed to analyze the genotyping of Rs1799853. The results showed higher frequency of CT genotype in the control subjects than the patients (73.3 and 43.2, respectively) and this difference was significant (0dd= 0.28, p-value= 0.038). The CC genotype showed a non-significant higher frequency in patients than in control (24.3 and 6.7, respectively. P-Value= 0.247). The TT genotype also showed higher frequency in patients than in control (32.4 and 20, respectively. P-Value= 0.506). In conclusion, the genotype CT of the SNP Rs1799853 for CYP2C9 gene may have a great defense role against the breast cancer.

Association of Breast Cancer with Single Nucleotide Polymorphism of CYP2C9 Gene for Women Patients in Baghdad, Iraq

Association of Breast Cancer with Single Nucleotide Polymorphism of CYP2C9 Gene for Women Patients in Baghdad, Iraq

VARIANTS OF THE FORMATION AND COURSE OF DRUG-RESISTANT EPILEPSY IN CHILDREN WITH GENETIC POLYMORPHISMS OF CYP2C9, CYP2C19, CYP3A4.

The aim: To clarify the frequency with which various variants of the formation and course of drug-resistant epilepsy occur in children with genetic polymor¬phisms of cytochromes CYP2C9, CYP2C19, CYP3A4. Materials and methods: The genotyping of CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP3A4*1B by the allele-specific polymerase chain reaction was performed in 116 children with drug-resistant epilepsy aged from 2 to 17 years. Thirty cases (boys-15; girls-15) with a follow-up period of more than 5 years were analyzed in detail. Results: Of 30 cases analyzed, polymorphisms were not detected in 8 (26.67%) children, and 22 (73.33%) had polymorphisms of the CYP2C9, CYP2C19 and CYP3A4 genes associated with a slow metabolism of AED. In children with polymorphisms of the CYP450 genes, the wave-like course of the disease with the periods of remission and its failures was characteristic, while for children with a presumably normal metabolism there was the initial resistance to the treatment with AED. Conclusions: Individual changes in the AED metabolism affect the course of drug-resistant epilepsies. For patients with a slow metabolism of AED the wave-like course of the disease and the "slipping off" phenomenon were more characteristic.

Fibrinogen-Aα THR312ALA Polymorphism is Associated to Chronic Thromboembolic Pulmonary Hypertension in Turkey.

Chronic thromboembolic pulmonary hypertension is a condition that occurs after mechanical obstruction of the pulmonary arteries by thrombus. Since the frequency and demographics of chronic thromboembolic pulmonary hypertension differ between countries, it is thought that genetic factors may play a role in its development. The aim of this study is to reveal the status of VKORC1, CYP2C9*3, CYP2C9*7, and fibrinogen-Aα THR312ALA gene polymorphisms in chronic thromboembolic pulmonary hypertension patients in Turkey. In this prospective cross-sectional study, a total of 46 chronic thromboembolic pulmonary hypertension patients and 106 healthy volunteers were included. Polymerase chain reaction-restriction fragment length polymorphism method was used to determine candidate gene polymorphisms for chronic thromboembolic pulmonary hypertension. The general population parameters of each locus were calculated, and the relationship between dominant, codominant, and recessive genotype models and chronic thromboembolic pulmonary hypertension was analyzed. For the fibrinogen-Aα gene, those with the THR/THR genotype were found to have a 13.51 (95% CI: 2.688-33.333) times less susceptibility rate to the disease than those with the ALA/THR genotype, the susceptibility of THR/ALA genotype to the disease was 5.026 (95% CI: 1.774-14.242) times more than those with ALA/ALA genotype. There was no difference between patient groups for VKORC1, CYP2C9*3 genes (P >.05). Since the CYP2C9*7 patient group was monomorphic for the ILE allele, the patient/control odds ratio and 95% CI could not be calculated. This study shows that there is an association between the fibrinogen-Aα gene ALA polymorphism at the amino acid position of 312 and the development of chronic thromboembolic pulmonary hypertension, but not between the CYP2C9 and VKORC1 gene polymorphisms.

ASSOCIATION BETWEEN CYP2C19 GENE POLYMORPHISMS AND CARDIOVASCULAR RISK FACTORS IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION

This study aims to investigate CYP2C19 gene polymorphisms and the association between gene polymorphisms with cardiovascular risk factors and major adverse cardiovascular events (MACE) in patients with acute myocardial infarction (AMI). A prospective cross-sectional analysis study involved 86 AMI patients enrolled and assessed CYP2C19 gene polymorphisms with MACE evaluated after three months of AMI treatment. CYP2C19*1*1 genotype accounted for the highest prevalence at 54.7%, which means normal metabolizers phenotype prevalence was the highest. The prevalence of patients with circumflex artery stenting, medical history of taking clopidogrel, percutaneous coronary intervention (PCI), and hypertension in patients with CYP2C19 polymorphism was significantly higher than in those without CYP2C19 polymorphism, 35.9 vs. 10.6, 46.2 vs. 14.9,10.3 vs., and 9.49 vs. 74.5, respectively (p&lt;0.05). In patients with CYP2C19 polymorphisms, using a combination of clopidogrel and aspirin regimen had a 13.6% of cardiovascular mortality, while using ticagrelor and aspirin regimen was 0% (p&gt;0.05). The relationship between CYP2C19 gene polymorphisms and MACE after three months of AMI treatment was not associated. CYP2C19 gene polymorphism is associated with hypertension, medical history of PCI, taking clopidogrel, and circumflex artery stenting injury. This study established the relationship between CYP2C19 gene polymorphism and cardiovascular risk factors in patients with acute myocardial infarction who require testing for this gene polymorphism when suffering from acute myocardial infarction to have a medicine adaptation method. Keywords: Polymorphism, CYP2C19 , Acute Myocardial Infarction, Major Adverse Cardiovascular Events, Percutaneous Coronary Intervention DOI： https://doi.org/10.35741/issn.0258-2724.58.3.11

Efficacy and safety of vonoprazan-amoxicillin dual therapy for Helicobacter pylori first-line treatment: a single-center, randomized, controlled trial.

With the increase in antibiotic resistance, the success rate of Helicobacter pylori (H. pylori) eradication therapy has declined in recent years. Vonoprazan-amoxicillin (VA) dual therapy has been reported to be a promising regimen. To compare the efficacy and safety of VA dual therapy and bismuth quadruple therapy containing amoxicillin and clarithromycin for H. pylori first-line eradication, and to further analyze the effects of clarithromycin resistance on eradication rate. This study was a single-center, open-label, randomized controlled trial. Treatment-naïve H. pylori-infected patients were randomly allocated 1:1 to the VA group (vonoprazan 20 mg twice daily and amoxicillin 750 mg four times daily, for 14 days) or the RBAC group (rabeprazole 10 mg, bismuth potassium citrate 220 mg, amoxicillin 1000 mg and clarithromycin 500 mg twice daily, for 14 days). H. pylori clarithromycin resistance and CYP2C19 gene polymorphisms were detected with real-time polymerase chain reaction (PCR) technique. The eradication rates and adverse events were analyzed. A total of 151 patients were enrolled. The intention-to-treat (ITT), modified intention-to-treat (mITT), and per-protocol (PP) eradication rates and their 95% confidence intervals (95% CIs) were 94.6% (86.0-98.3%), 98.6% (91.3-99.9%), and 98.5% (90.9-99.9%) for VA group and 87.0% (77.0-93.3%), 91.8% (82.3-96.6%), and 93% (83.7-97.4%) for RBAC group. The eradication rate of the VA group was noninferior to the RBAC group in ITT, mITT, and PP analyses (p < 0.0001). In patients infected with strains of clarithromycin resistance point mutation, the eradication rate of the RBAC group decreased to lower than 90%, but the difference from the VA group did not achieve statistical significance (ITT eradication rate: 81.5% in the RBAC group and 96.2% in the VA group, p = 0.192). The incidence of adverse events in the VA group was 39.2%, which was significantly lower than that in the RBAC group (79.2%, p = 0.000). The efficacy of VA dual therapy is noninferior to RBAC in H. pylori first-line eradication, with fewer adverse reactions. This study was registered at the Chinese Clinical Trial Registry (ChiCTR2100052550) on 30 October 2021.

CYP2C8 and CYP2J2 gene variations increase the risk of hypertensive intracerebral hemorrhage

PurposeMany studies have shown that cytochrome P450 (CYP) gene polymorphisms are usually associated with an increased risk of cardiovascular and cerebrovascular diseases. To explore the association of CYP2C8 and CYP2J2 gene polymorphisms with hypertensive intracerebral hemorrhage (HICH) in the Han Chinese population. MethodsForty HICH patients and 40 control subjects were recruited for this study. Two single nucleotide polymorphisms (SNP) (rs1058932, rs2275622) in the CYP2C8 gene and two SNPs (rs2271800, rs1155002) in the CYP2J2 gene were selected for genotyping by direct sequencing. Statistical analysis was applied to examine the effect of genetic variation on HICH. ResultsWe found that variant alleles of CYP2C8 rs1058932 (A) and rs2275622 (C) were both significantly associated with HICH, especially in females. We also found significant associations of CYP2C8 rs1058932 (A) and rs2275622 (C) variant alleles with poor outcomes in HICH patients, especially in males. ConclusionsCYP2C8 gene polymorphisms might increase the risk of HICH in the Han Chinese population and might lead to poor outcomes. This finding adds to the body of literature supporting novel therapeutic strategies for HICH.

Detection of The Effect of CYP2C19*4 Mutation on Clopidogrel Response by In Silico Methods

Single nucleotide polymorphisms cause amino acid change, and protein structure and function are changed. Thus, the patient improves drug resistance and does not respond to therapy. Clopidogrel is an antiplatelet drug and is used for cardiovascular disease therapy such as heart failure, atherosclerosis, and myocardial infarction.CYP2C19 gene is a CYP450 enzyme and metabolizes clopidogrel. Polymorphism of the CYP2C19 gene causes clopidogrel response. A homology modeling study was carried out using the Swiss-Model database and the Chimera program. The selection of models was made with the evaluation of the QMEAN values of the three-dimensional structures. The physicochemical properties of the wild type and CYP2C19*4 mutant type were analyzed by the ExPASy-ProtParam Portal. The effects of the mutation on the protein structure were performed by the HOPE database. The HDock program was used to demonstrate interactions between clopidogrel and wild-type protein and, mutant type protein. Mutation of the residue might disturb this function. This mutation causes the loss of interactions and affects the drug response. In this study, it was shown that Clopidogrel drug interactions between mutant type protein by docking study. Possible drug conformation is designed for the effective treatment of patients carrying the common mutation.