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Margarita N Dorofeeva,1 Evgenia V Shikh,2 Zhanna M Sizova,1 Alisa V Tarasenko,3 Natalia P Denisenko,4,5 Valeriy V Smirnov,6,7 Kristina A Ryzhikova,4 Zhannet A Sozaeva,4 Elena A Grishina,4 Dmitriy A Sychev5 1Department of Social Expertise, Urgent and Outpatient Therapy, First Moscow State Medical University (Sechenov University), Ministry of Healthcare, Moscow, Russia; 2Department of Clinical Pharmacology and Propedeutics of Internal Diseases, First Moscow State Medical University (Sechenov University), Ministry of Healthcare, Moscow, Russia; 3Medicine of the Future, First Moscow State Medical University (Sechenov University), Ministry of Healthcare, Moscow, Russia; 4Research Institute, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia; 5Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia; 6Department of Pharmaceutical and Toxicological Chemistry, First Moscow State Medical University (Sechenov university), Ministry of Healthcare, Moscow, Russia; 7Laboratory of Clinical Pharmacology, National Research Centre - Institute of Immunology, Federal Medical Biological Agency, Moscow, RussiaCorrespondence: Natalia P DenisenkoResearch Institute, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Barrikadnaja Street, 2/1, Moscow 125993, RussiaTel +7 495 945 81 39Email natalypilipenko3990@gmail.comBackground: CYP2C19 and CYP3A are the main enzymes involved in omeprazole metabolism, while CYP3A is the principal enzyme family for amlodipine biotransformation. Concomitant use of these drugs in patients with hypertension and acid-related disorders (ARD) might lead to drug–drug interaction.Purpose: The aim of the study was to find if adding omeprazole for treating ARD to amlodipine long-term therapy of hypertension influenced blood pressure of CYP2C19 polymorphism carriers.Patients and methods: Fifty-one patients diagnosed with hypertension and ARD were enrolled in the study. Evaluation of antihypertensive therapy was performed by office (OBPM) and ambulatory (ABPM) blood pressure monitoring. Peripheral venous blood was collected for DNA extraction and real-time polymerase chain reaction was performed for CYP2C19*2G681A (rs4244285), CYP2C19*3G636A (rs4986893) and CYP2C19*17C−806T (rs12248560) polymorphisms analysis.Results: Of 51 patients there were 21 extensive metabolizers (EMs), 18 ultrarapid metabolizers (UMs) and 12 intermediate metabolizers (IMs). The results of OBPM showed that antihypertensive effect was significantly more pronounced in IMs compared to EMs or UMs and the average group value in the following parameters: average office systolic blood pressure (BP), dynamics of the average office systolic BP. According to dynamics of diastolic BP, the antihypertensive effect was also significantly higher in IMs than in UMs and the average group value. The results of ABPM revealed that there was a significantly more pronounced antihypertensive effect in IMs compared to all other analyzed groups according to the dynamics of both daytime systolic and 24 hr diastolic BP. The average daytime diastolic BP and its dynamics, the average 24 hr systolic BP and its dynamics were higher in IMs compared to EMs and UMs.Conclusion: Adding omeprazole to long-term amlodipine therapy in patients with hypertension and ARD may lead to a significantly more pronounced antihypertensive effect in patients genotyped CYP2C19 IMs.Keywords: CYP2C19, CYP3A, pharmacogenetics, proton pump inhibitor

Introduction According to various data, 25–50% of all patients with schizophrenia suffer from treatment resistance. It is believed that patients with treatment-resistant schizophrenia (TRS) have reduced cognitive skills, compared to the patients with a more favourable type of schizophrenia. However, according to some authors, there is limited evidence-based research on this topic at present. Materials and methods The total number of patients included 130 patients with a diagnosis of schizophrenia (F20 according to ICD 10). All patients were examined according to the following scales: Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF), Brief Assessment of Cognition in Schizophrenia (BACS). Results Our results showed that patients with TRS as a whole had worse cognitive functions than nTRS patients (p = 0.357). In the group of patients with TRS, polymorphism CYP2D6*4 showed an effect on executive functions. Carriers of the heterozygous GA genotype had higher values of executive functions (p = 0.043). No association between the studied gene polymorphic variants and TRS was found in this research. Conclusion The polymorphic variant CYP2D6*4 showed an effect on cognitive function in the TRS group, regardless of their mental state and the effect of pharmacotherapy. In the future, it will be necessary to conduct larger prospective studies with a greater number of patients and a greater number of polymorphic variants of genes. Further identification of genetic predictors of cognitive impairment will improve researchers’ understanding of their causes and possibly move closer to more targeted therapy for schizophrenia.

Tamoxifen is the selective modulator of estrogen receptors. Nowadays, it is widely used for treatment of premenopausal women with ER(+) breast cancer likewise for postmenopausal women with treatment contraindications to aromatase inhibitors. Tamoxifen is a prodrug which is metabolized by cytochrome P450 (CYP): CYP2D6, CYP3A4, CYP3A5, CYP2C9, CYP2C19 to active metabolites. There is high variability in the CYP genes therefore differences in tamoxifen metabolism, tamoxifen individual response and efficacy are observed among patients. This article presents two clinical case reports. Both patients have breast cancer luminal A subtype, similar prognosis and are administered tamoxifen but they have diverse clinical effects. Patients responded to the survey questionnaire, then samples of buccal epithelium were taken for genetic analysis of CYP2D6*4, CYP3A5*3, CYP3A4*17, CYP2C9*2,3, CYP2C19*2,3, ABCB1 gene mutations by use of real time PCR. In patient A samples were detected significant mutations in CYP2D6 (*1/*4), CYP3A5 (*3/*3) и CYP2С9 (*2/*3), but there were no mutations detected in patient B. It is interesting that patient B has had prominent tamoxifen adverse effects, such as flushes, ostealgia, faintness, after 1 month of tamoxifen therapy. Patient A has taken tamoxifen for 19 months without any adverse effects. Also there is a review in this article about clinical value of different CYP2D6, CYP3A5, CYP2C9 polymorphisms. Additionally, we make a suggestion about the role of polymorphisms in tamoxifen adverse effects and the way of solution for problems of tamoxifen resistance. We suppose that routine genetic study before tamoxifen administration would help to predict individual intolerance and increase the efficacy of treatment.

Introduction. Bromdihydrochlorphenylbenzodiazepine is the Russian original tranquilizer which widely using in psychiatry, narcology, neurology and general medicine. Particularly, that drug prescribing for patients with alcohol withdrawal syndrome (AWS). Isoenzyme CYP2C19 takes part in metabolism of the most of benzodiazepines, so the gene CYP2C19 might be included into pharmacogenetics study of bromdihydrochlorphenylbenzodiazepine. There was no study of CYP2C19 polymorphisms as biomarkers of bromdihydrochlorphenylbenzodiazepine’s safety. Methods. 102 male patients with non-comlicated AWS (F 10.3 by ICD-10) were involved into the study. During 6 days of dynamic observation each participant was prescribed bromdihydrochlorphenylbenzodiazepine (Phenazepam). 5 ml of venous blood was collected from each participant for genotyping. 38 participants were added Pagluferal (contains phenobarbitalum, natrium coffeine-benzoate, bromisoval, papaverine) and/or Carbamazepine. Blood samples were analyzed to detect the CYP2C19*2 (rs4244285), *3 (rs4986893) и *17 (rs12248560) polymorphisms. Safety of therapy was evaluated with UKU Side Effects Rating Scale. Data analysis was performed with SPSS Statistics 21.0. Results. Carriers of CYP2C19*2 GA+AA genotypes compared to GG homozygous significantly more often had such adverse effects as «Polyuria/polydipsia» in mean grade of penetration (33,3% vs 9%, p=0,016) and “Palpitations/Tachycardia” (16,7% vs 3,8%, p=0,018). Observed relationship between «Polyuria/polydipsia» and CYP2C19*2 GA+AA genotypes was confirmed in the subgroup “Combined pharmacotherapy” (37,5% vs 0%, p=0,006). CYP2C19*17 polymorphism in tendency to significance was associated with less frequent AE «Polyuria/polydipsia» among patients taking bromdihydrochlorphenylbenzodiazepine as monotherapy carriers of allele T had that AE in 16,9%, and CC homozygous in 24,2% (p=0,067). Conclusion. Significant associations between CYP2C19*2 polymorphism and several AE in patients with alcohol withdrawal syndrome taking bromdihydrochlorphenylbenzodiazepine. Substantial role of CYP2C19*17 as predictor of AE associated with bromdihydrochlorphenylbenzodiazepine was not confirmed. Gene CYP2C19 is the sufficient biomarker of bromdihydrochlorphenylbenzodiazepine’s safety profile and needs further research.

Natalia P Denisenko,1–3 Dmitriy A Sychev,2 Zhanna M Sizova,3 Valeriy V Smirnov,4,5 Kristina A Ryzhikova,1 Zhannet A Sozaeva,1 Elena A Grishina1 1Research Center, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia; 2Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia; 3Department of Social Expertise, Urgent and Outpatient Therapy, First Moscow State Medical University (Sechenov University), Ministry of Healthcare, Moscow, Russia; 4Department of Pharmaceutical and Toxicological Chemistry, First Moscow State Medical University (Sechenov University), Ministry of Healthcare, Moscow, Russia; 5Laboratory of Clinical Pharmacology, National Research Centre, Institute of Immunology, Federal Medical Biological Agency, Moscow, Russia Background: CYP2C19 is known to be the main enzyme of biotransformation of proton pump inhibitors (PPIs), whereas the CYP2C19 gene is highly polymorphic. Genotyping and phenotyping together represent more reliable data about patient’s CYP2C19 activity.Purpose: The aim of the study was to investigate the applicability of urine metabolic ratio of omeprazole for CYP2C19 phenotyping in Russian peptic ulcer patients with different CYP2C19 genotypes.Patients and methods: A total of 59 patients (19 men and 40 women) aged 18–91years (mean age 53.5±15.1years) from four Moscow clinics who were diagnosed with an endoscopically and histologically proven peptic ulcer or had a history of endoscopically and histologically proven ulcers in the past were recruited. Peripheral venous blood (6mL) was collected for DNA extraction, and real-time polymerase chain reaction was performed for the analysis of CYP2C19*2G681A (rs4244285), CYP2C19*3G636A (rs4986893) and CYP2C19*17C-806T (rs12248560) polymorphisms. Urine samples of patients were collected in the morning between 6 am and 9 am, before food or drug intake, after at least 3 days of twice daily (b.i.d.) omeprazole intake. Omeprazole and 5-hydroxyomeprazole concentrations in the urine were measured using high-performance liquid chromatography with mass spectrometry.Results: Of the 59 patients, there were 27 (45.8%) extensive metabolizers (EMs; CYP2C19*1/*1), 16 (27.1%) ultrarapid metabolizers (UMs; CYP2C19*1/*17, CYP2C19*17/*17), 14 (23.7%) intermediate metabolizers (IMs; CYP2C19*1/*2, CYP2C19*2/*17, CYP2C19*3/*17) and two (3.4%) poor metabolizers (PMs; CYP2C19*2/*2). Median metabolic ratio (25%–75% percentiles) were 1.03 (0.69–1.36) for EMs, 1.95 (1.33–2.68) for UMs, 1.40 (0.78–2.13) for IMs+PMs and 1.26 (0.82–1.99) for the whole sample. A statistically significant difference in metabolic ratio (Mann–Whitney U test) was found between UMs and EMs (p=0.001) and in the multiple comparison Kruskal–Wallis test (p=0.005).Conclusion: We found a connection between particular CYP2C19 genotypes and urine metabolic ratio of omeprazole in Russian peptic ulcer patients. This method needs to be improved as in our modification it worked mainly for UMs and did not differentiate all patients according to omeprazole biotransformation activity. Keywords: pharmacogenetics, phenotyping, metabolomics, proton pump inhibitor

Retinal vessel occlusion (RVO) is an eye disease that leads to decreased visual acuity, ultimately resulting in blindness. It is observed in 1%-2% of individuals above the age of 40 years. The etiology of RVO still remains unclear. However, the most widely recognized risk factors include age, hypertension, hyperlipidemia, atherosclerosis, cardiovascular diseases, and diabetes. The number of patients with RVO among the young population has increased in recent years; hence, more attention has been focused on the genetic factors. Polymorphisms in the genes encoding proteins involved in the vitamin K cycle are among the genetic factors that may influence RVO. According to literature, the G1639A polymorphism in the vitamin K epoxide reductase complex subunit 1 (vKoRc1) is a possible risk factor for RVO. Purpose. To estimate the association between carriers of the G1639A form of vKoRc1 and the development of venous RVO (VRVO) and arterial RVO (ARVO). Materials and methods. The study included 126 patients aged between 40 and 80 years, mean age 61.5 years. Genotyping for the presence of the G1639A polymorphism of vKoRc1 was performed using polymerase chain reaction, and statistical analysis was performed using the Instat program. Results. The GG genotype of G1639A was found to be significantly more common in patients with VRVO or ARVO than in those of the control group (VRVO, 42.6%; ARVO, 60%; control group, 32%; p = 0.0449 for VRVO, and p = 0.0925 for ARVO). However, the AA genotype was significantly less common in patients with VRVO or ARVO than in those of the control group (VRVO, 9.8%; ARVO, 6.7%; control group, 28%; p = 0.0238 for VRVO and p = 0.1593 for ARVO, RR 2.015, 95% confidence interval 1.011-4.16). Conclusions. Our study demonstrates that the GG genotypic form of the G1639A polymorphism of VKORC1 is associated with the development of VRVO and possibly ARVO. However, the AA genotypic form of this polymorphism is not closely associated with the development of VRVO or ARVO.

AIM The aim of this study was to determine the impact of CYP2C19 and ABCB1 gene polymorphisms and CYP3A4 isoenzyme activity on stent implantation complications among patients with an acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI). PATIENTS AND METHODS Seventy-six patients (median age 63, range 37-91 years) with an ACS who underwent PCI were screened for CYP2C19 and ABCB1 gene polymorphisms with real-time polymerase chain reaction: CYP2C19*2, CYP2C19*17, and ABCB1 3435. CYP3A4 isoenzyme activity was determined by urine cortisol and 6-beta-hydroxycortisol levels. Stent implantation complications such as stent thrombosis (n=2) and restenosis (n=1) were observed among drug-eluting stent recipients. RESULTS Low mean 6-beta-hydroxycortisol/cortisol ratio is indicative of impaired CYP3A4 activity and was associated with higher risk of thrombosis (b coefficient=0.022, SE 0.009, p=0.021 in the linear regression model). The increase in the length of the implanted stent was associated with higher risk of restenosis (b coefficient=0.006, SE=0.002, p=0.001 in the linear regression model). The presence of the CYP2C19*2 polymorphism did not affect the incidence of stent thrombosis (b coefficient=-1.626, SE=1.449, p=0.262 in the logistic regression model), nor did the CYP2C19*17 (b coefficient=-0.907, SE=1.438, p=0.528 in the logistic regression model) and ABCB1 3435 polymorphisms (b coefficient=1.270, SE=1.442, p=0.378 in the logistic regression model). CONCLUSION We did not find evidence that the presence of CYP2C19*2, CYP2C19*17, and ABCB1 3435 polymorphisms may jeopardize the safety of stent implantation in patients with an ACS. Patients with low CYP3A4 isoenzyme activity may have increased risk of stent thrombosis.

Natalia P Denisenko,1–3 Dmitriy A Sychev,2 Zhanna M Sizova,3 Valeriy V Smirnov,4,5 Kristina A Ryzhikova,1 Zhannet A Sozaeva,1 Elena A Grishina1 1Research Center, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia; 2Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia; 3Department of Social Expertise, Urgent and Outpatient Therapy, First Moscow State Medical University (Sechenov University), Ministry of Healthcare, Moscow, Russia; 4Department of Pharmaceutical and Toxicological Chemistry, First Moscow State Medical University (Sechenov University), Ministry of Healthcare, Moscow, Russia; 5Laboratory of Clinical Pharmacology, National Research Centre – Institute of Immunology, Federal Medical Biological Agency, Moscow, Russia Background: Proton pump inhibitors (PPIs) are metabolized by cytochrome P450. CYP2C19 is the main isoenzyme for the majority of PPI, whereas CYP3A family is a secondary enzyme for PPI biotransformation. Purpose: The aim of the study was to find if CYP3A4*22, CYP3A5*3, CYP2C19*2, CYP2C19*3, and CYP2C19*17 genotypes are connected with CYP3A and CYP2C19 activities in Russian peptic ulcer patients taking omeprazole. Patients and methods: Forty-eight gastric or duodenal ulcer patients (15 men, 33 women; mean age 55.0±15.3 years, age range 18–91 years) from Moscow region of Russia were enrolled. Peripheral venous blood was collected for DNA extraction, and real-time polymerase chain reaction was performed for CYP3A5*3 A6986G (rs776746), CYP3A4*22 C>T in intron 6 (rs35599367), CYP2C19*2G681A (rs4244285), CYP2C19*3G636A (rs4986893), and CYP2C19*17C-806T (rs12248560) polymorphism analyses. Urine samples of patients were collected in the morning between 6 and 9 am before food or drug intake. Urine cortisol and 6β-hydroxycortisol concentrations (for CYP3A activity) and omeprazole and 5-hydroxyomeprazole concentrations (for CYP2C19 activity) were measured using high-performance liquid chromatography/mass spectroscopy. Results: We found a connection between CYP2C19 genotypes and CYP3A activity. Median metabolic ratios 6β-hydroxycortisol/cortisol (25%–75% percentiles) were 2.84 (1.99–4.39) for CYP2C19 extensive metabolizers (EMs), 2.51 (1.86–4.73) for CYP2C19 ultra-rapid metabolizers (UMs), and 1.45 (1.12–2.16) for CYP2C19 intermediate metabolizers (IMs) + poor metabolizers (PMs). A statistically significant difference in CYP3A activity (Mann–Whitney test) was found between CYP2C19 EMs vs CYP2C19 IMs+PMs (p=0.006), between CYP2C19 UMs vs CYP2C19 IMs+PMs (p=0.018), and in multiple comparison Kruskal–Wallis test (p=0.014). Conclusion: In CYP2C19 IMs+PMs, CYP3A activity was significantly lower than in CYP2C19 EMs and UMs. Keywords: pharmacogenetics, phenotyping, metabolomics, proton pump inhibitor

CYP2C19, ABCB1 loss-of-function variant carriers are subject to diminished platelet response to clopidogrel. This may result in complications associated with suboptimal blood-thinning levels, such as stent thrombosis as well as other major adverse cardiovascular events. The purpose of this study was