[Use of pharmacogenetic testing to prevent adverse drug reactions during statin therapy]. / Ispol'zovanie farmakogeneticheskogo testirovaniia dlia predotvrashcheniia nezhelatel'nykh lekarstvennykh reaktsii pri terapii statinami.

The number of patients receiving statins increases every year and due to the fact that they should take statins during their lives, the problem of their safety use comes to the forefront. The paper analyzes the safety of using the medications of this group and discusses the diagnosis of myopathies induced by statins and the occurrence of immune-mediated statin myopathies. It considers a personalized approach to prescribing statins, analyzes Russian and foreign experience in using pharmacogenetics to reduce the risk of myopathies, publishes the results of the authors' experience in clinically introducing pharmacogenetic testing at hospitals, and analyzes the long-term results of determining the polymorphism of the SLCO1B1 gene for the prediction of the risk of adverse events when using statins and estimating patient compliance to prescribed treatment.

ABCB1 polymorphism and acenocoumarol safety in patients with valvular atrial fibrillation.

BACKGROUND: Oral anticoagulant drugs (AD) are commonly used to treat patients with thromboembolic diseases. The ADs have narrow therapeutic index and wide pharmacokinetic and pharmacodynamic interindividual variability. Some genetic variations could influence interindividual variability in response to AD. Acenocoumarol (AC) is a coumarin, vitamin K derivate with antagonistic activity, used as anticoagulant therapy mainly in Central Europe and Latin America. P - glycoprotein (PGP), a transporter encoded by the ABCB1 gene, plays a major role in the drug disposition [1]. PGP is expressed in normal tissues, where it performs a defensive role against potentially toxic substances in intestinal cells and endothelial cells of the brain capillary endothelium. ABCB1 - is highly polymorphic, C3435T polymorphism in exon 26 has been associated with the expression of PGP [2]. There is some evidence that PGP could influence coumarin sensitivity. OBJECTIVE: To assess effects of the ABCB1 pilymorphisms on safety profile and dosing regimen of acenocoumarol in the patients with valvular atrial fibrillation. METHODS: 50 patients (34 male and 16 female), 40-70 years of age were included. All patients received acenocoumarol at doses of 1-6 mg daily with a target international normalized ratio (INR) of 2.0 to 3.0. Genotyping for polymorphism marker C3435T of ABCB1 gen was performed using PCR and RFLP (restriction fragment length polymorphisms) techniques. Statistics were performed by Fishers exact tests. All enrolled patients provided written informed consent. RESULTS: Genotype CC was found in 10 patients (20%), genotype CT in 25 patients (50%) and genotype TT in 15 patients (30%). In the CC group (n = 10) bleeding was found in 1 patient (2%). There were 19 patients (38%) with bleedings in combined group of CT and TT genotype (p = 0.0366). We compared the average doses of acenocoumarol in groups identified according to their genotypes: CC (3.45 mg/day), CT (2.64 mg/day), TT (3.07 mg/day) and found no significant differences. CONCLUSIONS: ABCB1 CT and TT genotypes were found to be significantly associated with higher risk of bleeding. There was no influence of ABCB1 polymorphisms on dosing regimens of acenocoumarol.

[Relationship between warfarin dosing and activity of CYP2C9 assessed by the content of losartan and its metabolite E-3174 in the urine of patients with mechanical prosthetic heart valves].

We evaluated effect of activity of cytochrome P450 CYP2C9 on maintenance doses of warfarin in 33 patients with implanted artificial heart valves. Losartan test was used for measurement of concentration of active metabolite E-3174 in urine. Concentration of E-3174 below 2500 ng/ml in patients with genotype CYP2C981/*1 with sensitivity 87% and specificity 66% predicted requirement of low doses (< 5 mg/day) of warfarin in the late postoperative period (odds ratio 14, 95% confidence interval 1.135 to 172.75).

[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.

Toxic effects of microbial phenolic acids on the functions of mitochondria.

Low-molecular-weight phenolic acids (PhAs) phenylacetate, phenyllactate, phenylpropionate, p-hydroxyphenyllactate, and p-hydroxyphenylacetate are essentially the products of the degradation of aromatic amino acids and polyphenols by the intestinal microflora. In sepsis, the concentrations of some of these acids in the blood increase tens of times. Assuming that these compounds can cause the mitochondrial dysfunction in sepsis, we examined their effects on respiration, the induction of pore opening, and the production of reactive oxygen species (ROS) in mitochondria. It was found that phenylpropionate and phenylacetate produce a more toxic effect on mitochondria than the other phenolic acids. At concentrations 0.01-0.1 mM they decreased the rate of oxidation of NAD-dependent substrates and activated the Ca2+- and menadione-induced opening of the cyclosporin A-sensitive pore and the production of ROS. The disturbances caused by these PhAs are similar to those observed in mitochondria in sepsis, and hence the rise in their level may be one of the causes of mitochondrial dysfunctions. Phenyllactate, p-hydroxyphenyllactate, and p-hydroxyphenylacetate inhibited the production of ROS and pore opening, acting as antioxidants. Thus, the ability of PhAs to affect the mitochondrial functions, as well as an increase in their concentrations in sepsis (the total concentration of these PhAs in the blood is close to 0.1 mM), suggests that PhAs can be directly involved in the development of mitochondrial failure.

[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 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.