[CYP2C9 and VKORC1 gene polymorphism and acenocoumarol anticoagulant activity in Russian patients at high risk of thromboembolic complications].

The study included 25 patients at high risk of thromboembolic complications. All of them were treated with acenocoumarol for 6 months under control of the frequency of hemorrhage and episodes of severe hypocoagulation (a more than 3-fold rise in INR). All the patients underwent CYP2C9 and VKORC1 genotyping. It was shown that the presence of CYP2C9*2 and CYP2C9*3 alleles in the CYP2C9 locus and the AA genotype of the polymorphous G-1639(3673)A marker of the VKORC1 gene was not associated with the development of severe hypocoagulation episodes (p = 0.261--for CYP2C9, p = 0.616 and 0.361 for VKORC1 in the total group and a subgroup of patients having the CYP2C9*1/*1 genotype respectively and treated with acenocoumarol. The search for other genetic markers of efficacy and safety of this drug should be continued.

[Anticoagulant action and safety of warfarin dosing based on pharmacogenetic testing: results of the first Russian prospective pilot study].

Aim of the study was to compare numbers of episodes of excess hypocoagulation and bleeding with warfarin dosing based on pharmacogenetic testing and traditional method in patients with high risk of thromboembolic complications. In 76 patients (43 men and 33 women aged 60.3 +/- 12.3 years) warfarin was administered starting with the dose calculated according to the gage algorithm with consideration of results of pharmacogenomic testing (genotyping of CYP2C9 and VKORC1). Control group comprised 78 patients aged 63.4 +/- 9.4 years who had participated in an earlier retrospective study in which they received warfarin according to traditional scheme with starting dose of 5 mg/day. In both groups we analyzed data obtained during 6 months after start of drug administration. Genotyping was carried out by polymerase chain reaction. Episodes of excess hypocoagulation (international normalized ratio above therapeutic range) and bleeding accurred more rarely with the use of pharmacogenetic approach to dosing of warfarin compared with standard method (17.1 vs 56.4%, p = 4.1 x10(-7), and 4 vs 18%, p = 0.009 respectively).

[Efficacy and safety of bisoprolol in pregnant women with chronic arterial hypertension do not depend on genetic CYP2D6 polymorphism].

The investigation has been conducted with the aim of studying association between polymorphic marker G1846A of CYP2D6 gene and efficacy and safety of bisoprolol in 64 pregnant women with chronic stage I and II hypertension. These women have been under observation during trimesters II and III of pregnancy. Results of the study evidence for the absence of differences in frequencies of alleles and genotypes of polymorphic marker CYP2D6 of CYP2D6 gene between groups with various regimens of antihypertensive therapy. An important conclusion has been formulated that in pregnant women with chronic arterial hypertension receiving antihypertensive therapy with bisoprolol and nifedipine polymorphic marker CYP2D6 of CYP2D6 gene is not associated with prognostically unfavorable hemodynamic changes in maternal-placental-fetal-compartment - altered parameters of dopplerometry of maternal-placental blood flow and cardioflowgraphy.

[Cytochrome P4502C9(CYP2C9) gene polymorphism and safety of therapy with warfarin].

Aim of the study was to investigate frequency and influence of alleles CYP2C9*2 and CYP2C9*3 on pharmacokinetics, pharmacodynamics and dosing regimen of warfarin and on development of hemorrhagic complications. We included 84 patients (mean age 62,8 +/- 10,5 years). Duration of follow-up varied between 1 month and 1 year. Carriage of allele variants was determined by polymerase chain reaction, measurement of plasma wafarin concentration was carried out with the help of high performance liquid chromatography. Wild type (CYP2C9*1/*1) was found in 68% of patients; overall frequency of 2C9*1/*1, *l/*3, *2/*2, *3/*3, *2/*3 genotypes was 32%. Average maintenance doses of warfarin for patients with allele variants CYP 2C9 *2 and 2C9 *3 were 3.6 and 3.1 mg/day, respectively, what was significantly lower than in wild type homozygotes (6.1 mg/day). Wild type homozygotes (1) had the highest warfarin clearance (3,51 ml/min). In carriers of 2C9 *2(2) and 2C9 *3(3) warfarin clearance was significantly lower (2.42 and 1.82 ml/min; p1 - 2 = 0,05; p1 - 3 = 0,0008). In carriers of allele variants CYP2C9*2, CYP2C9*3 values of international normalized ratio > 3,0 were met more often, especially in carriers of CYP2C9*3 (in 100% of cases) vs. 28% in wild type homozygotes (p=0,02). Carriers of CYP2C9*3 compared with wild type homozygotes had more hemorrhagic complications (67% and 16%, respectively, p=0,0008). Thus cytochrome P450 2C9 gene polymorphism influences frequency of development of hemorrhagic complications, metabolic clearance, and magnitude of warfarin maintenance dose.

[Importance of genetic polymorphism of cytochrome P450 isoenzymes for the choice and regimes of antidepressant and antipsychotic dosing on an individual basis].

Polymorphism of P450 2D6 (CYP2D6) gene is one of the causes of altered activity of enzymes controlling metabolism of medicinal products (MP), specifically increasing and decreasing biotransformation of xenobiotics. These changes result either in a rise or in a fall of plasma MP; in the former case adverse effects (AE) of MPs are likely to arise, in the latter xenobiotic therapy may prove inefficient. Drug interactions also contribute to variation of MP levels in plasma and undesirable changes of their pharmacological action that may require correction of the therapeutic regime. This paper presents results of original studies and reviews domestic and foreign publications on polymorphism of genes encoding isoenzymes involved in biotransformation processes, such as CYP2D6. This issue is of importance for psychiatric and psychosomatic practice. Algorithms for the rational choice of antidepressants and antipsychotics are proposed with a view to enhancing efficiency and safety of therapy with the use of these MPs.

[The influence of CYP2C9 genetic polymorphism on the pharmacokinetics and pharmacodynamics of warfarin in patients with constant atrial fibrillation].

CYP2C9 is the main enzyme participating in warfarin metabolism, of which genetic polymorphism is typical. The aim of the study was to investigate the influence of having allelic variants CYP2C9*2 and CYP2C9*3 on the pharmacokinetics, dosage regimen, and the rate of hemorrhage in patients with constant atrial fibrillation taking warfarin. Eighty-two patients with constant atrial fibrillation taking warfarin were included in the study. It was shown that in patients with CYP2C9*2 and CYP2C9*3 the clearance of warfarin and its dose were lower, while the episodes of excessive hypocoagulation and hemorrhage associated with warfarin were more frequent than in patients without these allelic variants. Basing on the results of the study, the authors propose an algorithm of choosing the initial warfarin dose depending on CYP2C9 genotype.

[Pharmacogenetics of indirect anticoagulants: value of genotype for improvement of efficacy and safety of therapy].

The review is devoted to the contemporary state of the problem of pharmacogenetics of indirect anticoagulants. At present there are data about effects of allele variants of CYP2C9, VKORC1, APOE genes on efficacy and safety of therapy with indirect anticoagulants. Detection of these variants is a perspective way to individualization of therapy with indirect anticoagulants.

[The clinical pharmacology of beta-adrenoblockers].

Beta-adrenoblockers (BAB) are highly-effective pharmaceuticals used broadly in treatment of cardial diseases. Response to BABs is known to display interindividual variability; pre-treatment analysis of allelic gene variants responsible for BAB pharmacokinetics, allows dose correction according to the genetic features of an individual patient. Pharmacogenetics is a young science, but it has already proven its practical significance in term of individualization of pharmacotherapy, which in some cases makes it possible to increase the effectiveness of the pharmaceuticals and avoid undesirable effects.

[Clinical genetic determinants of carbohydrate metabolism disturbances in patients with hypertension and excessive weight].

AIM: To elucidate associations of polymorphic markers of PPAR, PPARG2, IRS1, IRS2 genes with disturbances of carbohydrate metabolism in patients with hypertension and excessive weight. MATERIAL: Patients (n=145, 53 men and 92 women, age 40-75 years) with untreated stage 1 hypertension (systolic BP 140-159 and diastolic BP <100 mm Hg) and excessive weight or obesity (body mass index >27 kg/m(2)) were divided into 2 groups: with (group 1, n=124) and without (group II, n=21) disturbances of carbohydrate metabolism. Group I comprised patients with insulin resistance, abnormal fasting blood glucose or glucose tolerance, type 2 diabetes. Results of oral glucose tolerance test were normal in 25 and abnormal in 99 of these patients. RESULTS: Carriers of Pro allele compared with carriers of Ala allele of PPARG2 gene had higher frequency of insulin resistance. No association was found between insulin resistance and alleles and genotypes of PPAR, IRS1, and IRS2 genes. There was an association between diastolic BP and polymorphic markers Pro12Ala of PPARG2 gene and C24313G of PPARA gene. Carriers of C allele of PPARA gene and Ala allele of PPARG2 gene had higher diastolic BP. No association was found between systolic BP and alleles and genotypes of polymorphic markers of PPARG2 and PPARA genes.

[Clinicogenetic aspects of carbohydrate metabolism disorders and efficacy of their correction with moxonidine and metformine in patients with arterial hypertension].

AIM: To study effects of monotherapy with moxonidine and metformine on metabolic parameters in hypertensive patients with carbohydrate dysbolism (CD) regarding polymorphic markers of genes PPARalpha, PPARgamma and IRS type 1 and 2. MATERIAL AND METHODS: A total of 83 patients (31 male and 52 female patients aged 40-75 years) with untreated arterial hypertension stage I, obesity and CD (by glucose tolerance test) entered the trial. The patients were randomized into two groups. Patients of group I (n=42) received moxonidin in a dose 0.4 mg/day, of group 2 (n=41)--metformin in a dose 1000 mg/day. Measurement of arterial pressure, blood count and biochemistry, oral test for glucose tolerance with glucose and insulin measurement before meal and 1, 2 and 3 hours later was made initially and on the treatment week 16 Genotypes of polymorphic markers of genes PPARA, PPARG2, IRS1 and IRS2 were defined in all the patients. RESULTS: Changes in basic hemodynamic and metabolic indices in therapy with moxonidine depending on polymorphic markers of genes PPARA, PPARG2, IRS1 and IRS2 in patients with AH and CD showed that G allele PPARG2 is associated with greater weight loss, G allele PPARA--with weight loss, C allele PPARA--with maximal fall of diastolic blood pressure. CONCLUSION: Genetic factors participate in development of metabolic disturbances in hypertensive patients, obesity and CD and determine treatment efficacy in each individual patient.

[Association of the complex of polymorphic markers of ACE genes, aldosteron synthetase and endothelial synthetase of nitric oxide with progression of chronic glomerulonephritis]. / Assotsiatsiia kompleksa polimorfnykh markerov genov angiotenzinprevrashchaiushchego fermanta, sintazy al'dosterona i éndotelial'noi sintetazy okisi azota s progressirovaniem khronicheskogo glomerulonfrita.

AIM: To study association of the complex of polymorphic markers of ACE genes (ACE complex), aldosteron synthetase gene (CYP11B2) and endothelial synthetase of nitric oxide (NOS3) with onset, course and progression of chronic glomerulonephritis (CGN). MATERIAL AND METHODS: 117 CGN patients were examined. Genetic predisposition to CGN development was studied by comparison of distributions of alleles and genotypes of polymorphic markers of genes ACE, CYP11B2 and NOS3 in CGN patients and controls (n = 80) free of renal diseases and arterial hypertension (AH). The course of CGN was analysed with consideration of the following factors: AH severity, proteinuria persistence, nephritic level for 6 months and longer, immunosuppressive therapy and response to it, therapy with ACE inhibitors and/or blockers of antiotensin II receptors (ARB). CGN progression rate end point was doubling of initial blood creatinine level. RESULTS: Significant differences in the incidence of the above alleles and genotypes in the patients and controls were not found. The patients were divided into two groups: group 1 consisted of 25 patients carrying the combination of alleles D+C+4a, group 2 consisted of the rest 92 patients. The groups did not differ by CGN course parameters, but renal survival was significantly lower in carriers of the allele combination D+C+4a. Cox's mono- and multifactorial regression analysis has shown that carriage of the allele combination D+C+4a is an independent riskfactor of renal survival deterioration. CONCLUSION: No association was detected between polymorphic markers of genes ACE, CYP11B2 and NOS3 and onset of CGN. Carriage of D+C+4a allele combination is an independent factor of risk for fast progression of chronic renal failure.

[Genetic predictors of left ventricular hypertrophy: do polymorphisms of peroxisome proliferator activated nuclear receptor genes play any role?]. / Geneticheskie prediktory gipertrofii levogo zheludochka: igraet li rol' polimorfizm genov iadernykh retseptorov, aktiviruemykh proliferatorom peroksisom?

AIM: To assess possible associations of polymorphic markers of PPARA and PPARG2 genes with presence of left ventricular hypertrophy (LVH) in patients with hypertension. MATERIAL: Patients with hypertension (n=163, mean age 60.93+/-0.82 years) with (n=110) and without (n=53) LVH. METHODS: Echocardiography was used for evaluation of left ventricular mass and mass index and polymerase chain reaction - for identification of alleles and genotypes of polymorphic markers of ACE, NOS3, PPARA, PPARG2 genes. RESULTS AND CONCLUSION: There was no association between presence of LVH and polymorphic marker Pro12AIa. Carriers of 4a allele of a polymorphic marker ecNOS4a/4b of NOS3 gene, A allale of a polymorphic marker G7831A of ACE gene, and C allele of PPARA gene had significantly greater left ventricular myocardial mass index. Monofactorial regression analysis showed that degree of LVH was significantly related to age, duration of hypertension, maximal systolic blood pressure. No relationship was found between left ventricular mass index and smoking, maximal diastolic blood pressure, habitual systolic and diastolic blood pressure, duration of hypertension, presence of ischemic heart disease, diabetes. According to results of multifactorial analysis A allele of a polymorphic marker G7831A of ACE gene, age and maximal systolic blood pressure were while C allele of PPARA gene was not independently related to the presence of LVH.