Exploring Risk Factors for Adverse Reactions in Children with an Acute Psychotic Episode Using the Global Trigger Tool: Does Age Matter?

Aim: To establish significant risk factors for the development of adverse drug effects (ADEs) in children and adolescents with an acute psychotic episode taking antipsychotics. Materials and Methods: The research team randomly selected 15 patient records each month for 3 years (2016-2018). Overall, 450 patient records were included (223 boys and 227 girls, mean age was 14.52 ± 2.21 years). Adverse effects were identified using the standard algorithm of the Global Trigger Tool method. A "trigger" is an indication that an adverse reaction is likely to occur, e.g., an antihistamine prescription on a prescribing list. When a trigger was detected, the case history was studied in further detail to confirm the occurrence of ADEs. We divided patients into two groups: the "children" group (under 12 years old) and the "adolescents" group (13 years and older). Data were analyzed using the statistical package IBM SPSS Statistics 23.0. Results: Of the 450 patient records, 402 (89.3%) had at least one trigger detected. In total, 126 case histories contained evidence of ADE (28%). The total number of ADEs per 1000 patient days was 5.39 and the number of ADEs per 100 admissions was 32.0. Among adolescents, two or more triggers per patient were significantly more frequently identified (61.3% vs. 44.6%; p = 0.001). ADEs were rare in "Children" compared with "Adolescents" (13.8% vs. 30.4%; p = 0.006). The logistic regression analysis confirmed high predictive role of "Adolescence" (odds ratio [OR] = 2.58; 95% confidence interval [CI] 1.22-5.4; p = 0.013), "Polypharmacy" (OR = 1.96; 95% CI 1.23-3.1; p = 0.004), and "First-life hospitalization" (OR = 2.17; 95% CI 1.34-3.48; p = 0.001) for ADE fact in patient records. Conclusion: We found that significant risk factors for ADEs to antipsychotics in patients with acute psychotic episode were adolescence (13 years and older), polypharmacy, and first-life hospitalization. The fact that children (i.e., younger than 13 years of age) are less likely to experience ADEs was not associated with high-risk drugs or higher doses in our study.

Genetic markers associated with adverse reactions of radioiodine therapy in thyroid cancer patients.

OBJECTIVES: Radioactive iodine therapy is considered for patients with certain clinicopathological factors that predict a significant risk of recurrence, distant metastases of thyroid cancer or disease-specific mortality. The aim of the study was to investigate the association between polymorphisms of genes, products of which are involved in the processes of DNA damage response and autophagy, and the adverse reactions of radioiodine therapy in thyroid cancer patients. METHODS: The study included 181 patients (37 men, 144 women; median age 56 [41; 66.3] years) with histologically confirmed thyroid cancer and a history of thyroidectomy who received radioiodine therapy. NFKB1, ATM, ATG16L2, ATG10, TGFB1, and TNF polymorphisms were determined by allele-specific realtime-PCR. RESULTS: The frequency of adverse reactions was the following: gastrointestinal symptoms - 57.9 %, local symptoms - 65.8 %, cerebral symptoms - 46.8 %, fatigue - 54.4 %; signs of sialoadenitis six months after radioiodine therapy - 25.2 %. TT genotype carriers of ATG10 rs1864183 had higher frequency of gastrointestinal symptoms (vs. CC+CT), the CC genotype carriers of ATG10 rs10514231 had significantly more frequent cerebral symptoms (vs. CT+TT), as well as AA genotype carriers of TGFB1 rs1800469 (vs. AG+GG). CC genotype of ATG10 rs10514231 increased the incidence of radioiodine-induced fatigue, whereas GA genotype of the ATM rs11212570 had a protective role against fatigue. TGFB1 rs1800469 was associated with signs of sialoadenitis six months after radioiodine therapy. CONCLUSIONS: Genetic factors may contribute to the occurrence of adverse reactions of radioiodine therapy in thyroid cancer patients.

Genetic markers associated with adverse reactions of radioiodine therapy in thyroid cancer patients.

OBJECTIVES: Radioactive iodine therapy is considered for patients with certain clinicopathological factors that predict a significant risk of recurrence, distant metastases of thyroid cancer or disease-specific mortality. The aim of the study was to investigate the association between polymorphisms of genes, products of which are involved in the processes of DNA damage response and autophagy, and the adverse reactions of radioiodine therapy in thyroid cancer patients. METHODS: The study included 181 patients (37 men, 144 women; median age 56 [41; 66.3] years) with histologically confirmed thyroid cancer and a history of thyroidectomy who received radioiodine therapy. NFKB1, ATM, ATG16L2, ATG10, TGFB1, and TNF polymorphisms were determined by allele-specific realtime-PCR. RESULTS: The frequency of adverse reactions was the following: gastrointestinal symptoms - 57.9 %, local symptoms - 65.8 %, cerebral symptoms - 46.8 %, fatigue - 54.4 %; signs of sialoadenitis six months after radioiodine therapy - 25.2 %. TT genotype carriers of ATG10 rs1864183 had higher frequency of gastrointestinal symptoms (vs. CC+CT), the CC genotype carriers of ATG10 rs10514231 had significantly more frequent cerebral symptoms (vs. CT+TT), as well as AA genotype carriers of TGFB1 rs1800469 (vs. AG+GG). CC genotype of ATG10 rs10514231 increased the incidence of radioiodine-induced fatigue, whereas GA genotype of the ATM rs11212570 had a protective role against fatigue. TGFB1 rs1800469 was associated with signs of sialoadenitis six months after radioiodine therapy. CONCLUSIONS: Genetic factors may contribute to the occurrence of adverse reactions of radioiodine therapy in thyroid cancer patients.

Effect of CYP2D6*4, CYP2D6*10 polymorphisms on the safety of treatment with timolol maleate in patients with glaucoma.

OBJECTIVES: Timolol maleate is used for the treatment of glaucoma and metabolized by cytochrome CYP2D6 in the liver. The aim of this study was the evaluation of the influence of CYP2D6*4 and CYP2D6*10 gene polymorphisms on the safety of medications containing 0.5% of timolol maleate as glaucoma treatment in patients with primary open-angle glaucoma (POAG). METHODS: 105 patients with POAG were prescribed glaucoma medications, containing 0.5% timolol maleate. The safety of glaucoma treatment was determined by electrocardiography (ECG) (to assess heart rate (HR) and PQ interval) and blood pressure (BP) measurements. The real-time polymerase chain reaction method was used for the detection of single nucleotide polymorphisms (SNP). RESULTS: The risk of adverse drug reactions was higher in patients with the CYP2D6*4 GA genotype compared with GG: mean HR change at 1 month (2.88 ± 4.68 and 6.44 ± 5.57, p<0.001) and 6 months (5.14 ± 8.93 and 7.88 ± 5.65, p<0.001), mean PQ interval change at 1 (0.01 ± 0.031 and 0.02 ± 0.022, p=0.003) and 6 months (0.01 ± 0.032 and 0.02 ± 0.024, p=0.003). The risk of adverse drug reactions was higher in patients with the CYP2D6*10 CT genotype compared with CC: mean HR change at 1 month (2.94 ± 4.65 and 6.34 ± 5.66, p<0.001) and 6 months (5.20 ± 8.90 and 7.78 ± 5.75, p<0.001), mean PQ interval change at 1 (0.01 ± 0.032 and 0.02 ± 0.021, p=0.014) and 6 months (0.01 ± 0.033 and 0.02 ± 0.022, p=0.014). CONCLUSIONS: CYP2D6*4 and CYP2D6*10 gene polymorphisms may affect a higher risk of timolol-induced bradycardia and increased PQ interval of treatment medications containing 0.5% of timolol maleate in patients with POAG.

Influence of Clinically Significant Genes on Antiplatelet Effect of Clopidogrel and Clinical Outcomes in Patients with Acute Coronary Syndrome and Atrial Fibrillation.

INTRODUCTION: The interindividual variability of the antiplatelet effect of clopidogrel is determined by multiple clinical and genetic factors. A lot of genotype-oriented studies have concentrated on the impact of CYP2C19 gene polymorphisms on platelet aggregation in patients receiving clopidogrel. However, the influence of this polymorphism may be only 12-20%, so other genetic markers should also be investigated. The aim of this work was to study the impact of carriage of CES1, PON1, ABCG2, CYP4F2, CYP3A4, IGTB3, P2Y12, PEAR1, and B4GALT2 polymorphisms on antiplatelet effect of clopidogrel and clinical outcomes in patients with acute coronary syndrome (ACS) and atrial fibrillation (AF). METHODS: 103 patients who underwent ACS with or without percutaneous coronary intervention and concomitant nonvalvular AF were included in an open multicenter prospective study to assess efficacy and safety of combined antithrombotic therapy. The study assessed the frequency of different primary clinical outcomes (incidence of major bleeding, hospital mortality, cardiovascular mortality, stroke and transient ischemic attacks (TIAs), renal mortality) and secondary outcomes (resistance to therapy - high residual platelet reactivity, excessive platelet suppression). Residual platelet reactivity was examined using the VerifyNow system (Accumetrics, Latham, NY, USA). RESULTS: None of the studied genetic markers had no statistically significant effect on the antiaggregant response to clopidogrel in patients with ACS and AF. However, CYP4F2 C(Val433Met) T, PEAR1 rs41273215 C>T were statistically significantly associated with an increased frequency of bleeding on antithrombotic therapy. B4GALT2 rs1061781 was statistically significantly associated with increased frequency of strokes and TIA. CONCLUSION: In our study, we determined that carriers of CYP4F2 gene polymorphisms C(Val433Met)T, PEAR1 rs41273215 C>T (CT+TT) were associated with lower safety of antithrombotic therapy in patients with ACS and AF. And, the B4GALT2 rs1061781 gene polymorphism was associated with a greater risk of insufficient efficacy of the therapy. The data obtained in our study may improve the understanding of the effect of less studied genetic markers on the efficacy and safety of antithrombotic therapy in patients with ACS and AF.

CYP2D6 phenotype and ABCB1 haplotypes are associated with antipsychotic safety in adolescents experiencing acute psychotic episodes.

OBJECTIVES: To identify possible associations of CYP2D6, CYP3A4/5, and ABCB1 gene polymorphisms with the efficacy and safety of antipsychotics in adolescents with acute psychotic episodes. METHODS: We examined the associations of pharmacogenetic factors with the efficacy and safety of antipsychotics in 101 adolescents with acute psychotic episodes. The diagnosis on admission was "Brief psychotic disorder" (F23.0-23.9 by ICD-10). All patients were administered antipsychotics for 14 days. Treatment efficacy and safety were assessed using the PANSS, CGAS, CGI-S(I), UKU SERS, BARS, and SAS scales. Pharmacokinetic genotyping was performed for the CYP2D6*4, *10, ABCB1 1236C>T, 2677G>T, and 3435C>T genes. RESULTS: CYP2D6 intermediate metabolisers had "Micturition disturbances" more often than extensive metabolisers (24.2 vs. 7.4%; p=0.026). "Wild" homozygote ABCB1 3435C>T CC was associated with more prominent akathisia. Haplotype analysis of three ABCB1 polymorphisms revealed that the "wild" alleles "C-G-C" (ABCB1 1236-2677-3435) were associated with higher risk of "Reduced salivation" (OR=2.95; 95% CI=1.35-6.45; p=0.0078). CONCLUSIONS: CYP2D6 intermediate metabolism was associated with the risk of urinary difficulties under treatment with antipsychotics. We found that "wild" homozygotes ABCB1 1236C>T, 2677G>T, and 3435C>T were predictors of adverse drug effects caused by treatment with antipsychotics.

CYP2D6 phenotype and ABCB1 haplotypes are associated with antipsychotic safety in adolescents experiencing acute psychotic episodes.

OBJECTIVES: To identify possible associations of CYP2D6, CYP3A4/5, and ABCB1 gene polymorphisms with the efficacy and safety of antipsychotics in adolescents with acute psychotic episodes. METHODS: We examined the associations of pharmacogenetic factors with the efficacy and safety of antipsychotics in 101 adolescents with acute psychotic episodes. The diagnosis on admission was "Brief psychotic disorder" (F23.0-23.9 by ICD-10). All patients were administered antipsychotics for 14 days. Treatment efficacy and safety were assessed using the PANSS, CGAS, CGI-S(I), UKU SERS, BARS, and SAS scales. Pharmacokinetic genotyping was performed for the CYP2D6*4, *10, ABCB1 1236C>T, 2677G>T, and 3435C>T genes. RESULTS: CYP2D6 intermediate metabolisers had "Micturition disturbances" more often than extensive metabolisers (24.2 vs. 7.4%; p=0.026). "Wild" homozygote ABCB1 3435C>T CC was associated with more prominent akathisia. Haplotype analysis of three ABCB1 polymorphisms revealed that the "wild" alleles "C-G-C" (ABCB1 1236-2677-3435) were associated with higher risk of "Reduced salivation" (OR=2.95; 95% CI=1.35-6.45; p=0.0078). CONCLUSIONS: CYP2D6 intermediate metabolism was associated with the risk of urinary difficulties under treatment with antipsychotics. We found that "wild" homozygotes ABCB1 1236C>T, 2677G>T, and 3435C>T were predictors of adverse drug effects caused by treatment with antipsychotics.

Pharmacogenetics of antipsychotics in adolescents with acute psychotic episode during first 14 days after admission: effectiveness and safety evaluation.

OBJECTIVES: Prediction of the antipsychotic's effectiveness is a relevant topic in the field of personalized medicine. METHODS: The research design of this study is a prospective observation with posthoc analysis of associations of genetic polymorphisms with safety parameters and effectiveness of antipsychotic therapy. We observed 53 adolescents with an acute psychotic episode which were prescribed antipsychotics for 14 days. We evaluated the effectiveness of antipsychotics with the Positive and Negative Symptoms Scale and the safety with the UKU Side Effects Rating Scale, Simpson-Angus Scale, and Barnes Akathisia rating scale. We genotyped CYP3A4*22 (rs2740574), CYP3A5*3 (6986A>G, rs7767746), CYP2D6*4, *9, *10 (rs3892097, rs1065852), ABCB1 1236C>T (rs1128503), 2677G>T/A (rs2032582), 3435C>T (rs1045642), DRD2 (rs1800497), DRD4 (rs1800955), HTR2A (rs6313) by the real-time polymerase chain reaction method. RESULTS: We found significantly more frequent "increased dream activity" between CYP2D6 intermediate metabolizers and normal metabolizers (54 vs. 22%; p=0.043). The «increased duration of sleep¼ was more often observed in homozygotes TT of ABCB1 2677G>T/A (50 vs. 15.8%, p=0.006) and TT of 3435C>T (41.7 vs. 8.2%, p=0.007). CONCLUSIONS: We found that CYP2D6 and ABCB1 polymorphisms were associated with the safety of antipsychotics in adolescents with an acute psychotic episode.

Pain pharmacogenetics.

Pain is a significant problem in medicine. The use of PGx markers to personalize postoperative analgesia can increase its effectiveness and avoid undesirable reactions. This article describes the mechanisms of nociception and antinociception and shows the pathophysiological mechanisms of pain in the human body. The main subject of this article is pharmacogenetic approach to the selection of anesthetics. Current review presents data for local and general anesthetics, opioids, and non-steroidal anti-inflammatory drugs. None of the anesthetics currently has clinical guidelines for pharmacogenetic testing. This literature review summarizes the results of original research available, to date, and draws attention to this area.

Effect of CES1 and ABCB1 genotypes on the pharmacokinetics and clinical outcomes of dabigatran etexilate in patients with atrial fibrillation and chronic kidney disease.

Background Despite the well-studied safety profile of dabigatran, its interactions with genetic polymorphism parameters are poorly understood, especially in patients with moderate chronic kidney disease (CKD). The study assessed whether genetic factors can contribute to CKD and alter dabigatran concentration. Methods Patients with atrial fibrillation (AF) and stage 3 CKD treated with dabigatran 110 or 150 mg have been included in the study. Real-time polymerase chain reaction was used to evaluate single-nucleotide polymorphisms of the ABCB1 gene (rs1045642 and rs4148738) and CES1 gene (rs2244613). A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index. Results A total of 96 patients aged 51-89 years (median age: 75 years) were evaluated. Patients on a reduced regimen of 110 mg twice a day were older (79.8 vs. 67.9, p < 0.0001) and had lower creatinine clearance (49.7 vs. 62.3 mL/min/1.73 m2, p = 0.015). Patients with the rs2244613 CC genotype had lower C/D values (70% reduction in the mean C/D vs. AA genotype, p = 0.001). Linear stepwise regression has shown the CKD epidemiology collaboration to be the only significant predictor of C/D among genetic factors and kidney function characteristics. During the median follow-up of 15 months, there were 15 bleedings in 13 patients. Conclusions Polymorphism of CES1 rs2244613 can contribute to the safety of dabigatran in patients with AF and CKD. There was no influence of the aforementioned polymorphisms of ABCB1 on dabigatran trough plasma concentrations and C/D. Kidney function is a mainstay of clinical decision-making on direct oral anticoagulant (DOAC) dose, and further knowledge should be accumulated on the role of genetic factors.

Global trigger tool in child psychiatry: Treatment safety evaluation in adolescents with an acute psychotic episode.

OBJECTIVE: To analyse the frequency, structure and risk factors of adverse drug effects in adolescents with acute psychotic episode by the methods of global triggers - Paediatric All-Cause Harm Measurement Tool (PACHMT) and Global Assessment of Paediatric Patient Safety Tool (GAPPS). PATIENTS AND METHODS: We used 151 completed case histories of patients who were admitted to a psychiatric hospital with acute psychotic episode. We applied Global Trigger Tool algorithm to each case retrospectively: we developed a special trigger list for psychiatric patients based on PACHMT, GAPPS and general Global Trigger Tool. We also calculated the Medical Appropriateness Index (MAI) for each case. We applied trigger tool analysis for calculation of treatment safety parameters. Statistical analyses included Pearson's Chi-square, Mann-Whitney U, and Kruskal-Walles tests. RESULTS: We identified a total of 261 triggers among 151 analysed cases, 51 of which were accompanied by adverse drug effects (ADEs) (overall positive prediction value = 19.54%). The value of ADEs per 1000 bed days was 4.73, ADEs per 100 admissions was 33.77%. Extrapyramidal reactions to antipsychotics (58.8%) were the most common ADEs, followed by an abrupt medication stop of one or more drugs due to ADEs (25.5%). Significant predictors of antipsychotic-induced extrapyramidal symptoms were age, MAI score and total number of hospital admissions. CONCLUSION: We recommend three triggers, "Abrupt medication stop", "Prescribing of extrapyramidal symptoms corrector", and "Hospital readmission within 30 days", with reasonable positive predictive value for incorporation into routine systems for patient safety monitoring in adolescents with an acute psychotic episode. Antipsychotic-induced extrapyramidal symptoms were more prevalent in older adolescents and patients with fewer lifetime hospital admissions. These patients need to be carefully monitored to ensure patient safety.

Which cytochrome P450 metabolizes phenazepam? Step by step in silico, in vitro, and in vivo studies.

BACKGROUND: Phenazepam (bromdihydrochlorphenylbenzodiazepine) is the original Russian benzodiazepine tranquilizer belonging to 1,4-benzodiazepines. There is still limited knowledge about phenazepam's metabolic liver pathways and other pharmacokinetic features. METHODS: To determine phenazepam's metabolic pathways, the study was divided into three stages: in silico modeling, in vitro experiment (cell culture study), and in vivo confirmation. In silico modeling was performed on the specialized software PASS and GUSAR to evaluate phenazepam molecule affinity to different cytochromes. The in vitro study was performed using a hepatocytes' cell culture, cultivated in a microbioreactor to produce cytochrome P450 isoenzymes. The culture medium contained specific cytochrome P450 isoforms inhibitors and substrates (for CYP2C9, CYP3A4, CYP2C19, and CYP2B6) to determine the cytochrome that was responsible for phenazepam's metabolism. We also measured CYP3A activity using the 6-betahydroxycortisol/cortisol ratio in patients. RESULTS: According to in silico and in vitro analysis results, the most probable metabolizer of phenazepam is CYP3A4. By the in vivo study results, CYP3A activity decreased sufficiently (from 3.8 [95% CI: 2.94-4.65] to 2.79 [95% CI: 2.02-3.55], p=0.017) between the start and finish of treatment in patients who were prescribed just phenazepam. CONCLUSIONS: Experimental in silico and in vivo studies confirmed that the original Russian benzodiazepine phenazepam was the substrate of CYP3A4 isoenzyme.

Pharmacogenetic testing by polymorphic markers 681G>A and 636G>A CYP2C19 gene in patients with acute coronary syndrome and gastric ulcer in the Republic of Sakha (Yakutia).

BACKGROUND: The focus of the study is to determine the prevalence of CYP2C19 alleles, associated with the risk of changes in the pharmacological response to clopidogrel and proton pump inhibitors in patients with acute coronary syndrome (ACS) and gastric ulcer from Russian and Yakut ethnic groups. METHODS: The research included 411 patients with ACS (143 Russians and 268 Yakuts) and 204 patients with histologically confirmed gastric ulcer (63 Russians and 141 Yakuts). Genotyping of 681G>A and 636G>A polymorphisms was performed by using polymerase real-time chain reaction. RESULTS: In both ethnic groups, Hardy-Weinberg equilibrium was followed in a distribution of alleles and genotypes in the population (p>0.05). The 681A allele frequency in the Yakut ethnic group was higher than in the Russian group: 17.53% vs. 8.39% (p=0.001). No statistically significant difference was found in the frequency of 636A in Yakuts and Russians with ACS: 3.92% vs. 3.50% (p=0.840). While comparing the frequency distribution of alleles 681A (13.49% vs. 14.54%, p=0.878) and 636A (7.94% vs. 7.80%, p=1) in patients with a gastric ulcer from Russian and Yakut ethnic groups, no significant difference was found in carrier frequency. CONCLUSIONS: The results of the present study may be helpful for developing guidelines for CYPC19 genotype-directed antiplatelet therapy for Yakut and Russian patients.

Role of nitric oxide and related molecules in schizophrenia pathogenesis: biochemical, genetic and clinical aspects.

Currently, schizophrenia is considered a multifactorial disease. Over the past 50 years, many investigators have considered the role of toxic free radicals in the etiology of schizophrenia. This is an area of active research which is still evolving. Here, we review the recent data and current concepts on the roles of nitric oxide (NO) and related molecules in the pathogenesis of schizophrenia. NO is involved in storage, uptake and release of mediators and neurotransmitters, including glutamate, acetylcholine, noradrenaline, GABA, taurine and glycine. In addition, NO diffuses across cell membranes and activates its own extrasynaptic receptors. Further, NO is involved in peroxidation and reactive oxidative stress. Investigations reveal significant disturbances in NO levels in the brain structures (cerebellum, hypothalamus, hippocampus, striatum) and fluids of subjects with schizophrenia. Given the roles of NO in central nervous system development, these changes may result in neurodevelopmental changes associated with schizophrenia. We describe here the recent literature on NOS gene polymorphisms on schizophrenia, which all point to consistent results. We also discuss how NO may be a new target for the therapy of mental disorders. Currently there have been 2 randomized double-blind placebo-controlled trials of L-lysine as an NOS inhibitor in the CNS.

The frequency of CYP2C9, VKORC1, and CYP4F2 polymorphisms in Russian patients with high thrombotic risk.

BACKGROUND AND OBJECTIVE: VKORC1, CYP2C9, and CYP4F2 are known to be responsible for the metabolism of warfarin. The aim was to explore the frequencies of these genotypes in the Russian population and compare the results with those for other populations. MATERIAL AND METHODS: In total, 91 Caucasian subjects with a mean age of 66.17 years (SD, 10.9) were recruited into the study. Of them, 40 patients (48.2%) were men. In order to obtain necessary clinical data, the medical records of the patients were reviewed. Blood (5 mL) was taken from each subject, and DNA was isolated and used for identification of the CYP2C9 allele *1, *2, *3, -1639G/A VKORC1, and CYP4F2 V433M rs2108622 C>T, using the real-time polymerase chain reaction-restriction fragment length polymorphism assay. RESULTS: The CYP2C9*1/*1 genotype was detected in 67.0%, CYP2C9*1/*2 in 9.9%, CYP2C9*1/*3 in 11.0%, CYP2C9*2/*2 in 2.2%, CYP2C9*2/*3 in 8.8%, and CYP2C9*3/*3 in 1.1% of the patients. The results for VKORC1 were as follows: 49.5% (GG), 28.6% (GA), and 22.0% (AA); meanwhile, those for the genotype CYP4F2 were 57.1% (CC), 34.1% (CT), and 7.7% (TT). No significant deviations from the Hardy-Weinberg equilibrium were observed. The frequency of the polymorphisms in the Russian population was found to differ from Asian and close to Caucasian. There were no significant interethnic variations in the frequency of CYP4F2 among Russian, Asian, and Caucasian populations. CONCLUSION: The frequency of CYP2C9, CYP4F2, and VKORC1 polymorphisms in Russian patients is comparable with other European ethnic groups.