[Initiation of pharmacotherapy as a risk factor for older patients.]

The article presents the literature and original data on the problems of falls in elderly patients. The connection of the fact of falling with initiation of therapy by a number of drugs known to have a negative impact on the risk of falling is considered. The article presents data on the frequency and structure of falls on the example of patients with cardiovascular diseases older than 75 years, treated in a multidisciplinary hospital. The analysis of the data showed a tendency of prevalence of the fact of falling in 1/3 patients (33,8%) in the first 5 days of hospital stay, which may be associated with high drug burden and the appointment of «new¼ drugs for the patient. The study noted that it was on the first day that the selection of therapy took place and additional drugs were often prescribed, leading to a state of polypragmasia. Analysis of individual groups of drugs was able to reliably confirm the relationship between the appointment of drugs that increase.

[Impact of pharmacogenetic testing on the risk of bleedings and excessive hypocoagulation episodes in the use of warfarin: the first meta-analysis of Russian prospective studies].

AIM: To perform a meta-analysis of Russian prospective studies comparing the pharmacogenetic versus conventional warfarin dosing procedures. MATERIALS AND METHODS: Publications were sought in the PubMed and eLibrary through September 30, 2013. Seven prospective studies comparing the pharmacogenetic method of warfarin dosing with consideration for CYP2C9, VKORC1, and CYP4F2 gene polymorphisms with the conventional one were selected. The number of minor and major bleedings and hypocoagulation episodes was taken into account. The meta-analysis was performed using MIX Pro 2.0. RESULTS: Six studies compared the number of bleedings in experimental and control groups. Analysis of statistical heterogeneity showed that extraneous factors did not influence the results of meta-analysis. The pharmacogenetic approach decreases the risk of bleeding. The pooled odds ratio (OR) was significant for minor (OR = 0.49; 95% confidence interval (CI), 0.31 to 0.78; p = 0.002), major (OR = 0.07; 95% CI, 0.008 to 0.54; p = 0.01) and both minor and major bleedings (OR = 0.49; 95% CI, 0.31 to 0.78; p = 0.002). Six studies estimated the number of hypocoagulation cases. There was no evidence for statistical heterogeneity (Q-test p = 0.13; I2 = 40%). Four studies showed a group difference in the number of hypocoagulation cases (p < 0.05). The pooled OR was 0.21 (95% CI, 0.15 to 0.3; p < 0.01). The pharmacogenetic dosing groups had fewer hypocoagulation episodes than the control ones. CONCLUSION: The pharmacogenetic approach decreases the risk of bleeding and the episodes of hypocoagulation. The performed meta-analysis covered only two randomized trials. Improving the metalogic quality and statistical power of Russian studies will be able to get more reliable data on the impact of pharmacogenetic testing on clinical outcomes during warfarin therapy.

CYP2C19*17 May Increase the Risk of Death Among Patients with an Acute Coronary Syndrome and Non-Valvular Atrial Fibrillation Who Receive Clopidogrel and Rivaroxaban.

INTRODUCTION: The aim of this study is to assess the influence of gene CYP2C19, CYP3A4, CYP3A5 and ABCB1 polymorphisms on clopidogrel antiplatelet activity, rivaroxaban concentration equilibrium, and clinical outcomes among patients with acute coronary syndrome and non-valvular atrial fibrillation. METHODS: In the multicenter prospective registry study of the efficacy and safety of a combined antithrombotic therapy 103 patients with non-valvular atrial fibrillation both undergoing or not a percutaneous coronary intervention were enrolled. The trial assessed the primary outcomes (major bleeding, in-hospital death, cardiovascular death, stroke\transient ischaemic attack, death/renal insufficiency) and secondary outcomes (platelet reactivity units (PRU), rivaroxaban concentration). RESULTS: For none of the clinical outcomes when combined with other covariates, the carriership of polymorphisms CYP3A5*3 rs776746, CYP2C19*2 rs4244285;*17 rs12248560, ABCB1 3435 C>T, ABCB1 rs4148738 was significant. None of the markers under study (CYP3A5*3 rs776746, CYP2C19*2 rs4244285, *17 rs12248560, ABCB1 3435 C>T, ABCB1 rs4148738) has proven to affect rivaroxaban equilibrium concentration in blood plasma among patients with atrial fibrillation and acute coronary syndrome. CONCLUSION: In situations of double or triple antithrombotic rivaroxaban and clopidogrel therapy among patients with atrial fibrillation and acute coronary syndrome, the genetic factors associated with bleeding complications risk (CYP2C19*17) may prove to be clinically relevant.

[Evidence-based treatment of acute psychotic episode and schizophrenia in children and adolescents]. / Dokazatel'naia farmakoterapiia ostrogo psikhoticheskogo épizoda i shizofrenii u detei i podrostkov.

Children and adolescents are a special group in the context of psychopharmacotherapy. Given the limited choice of registered antipsychotics permitted in childhood, caution should be exercised in the choice of medication. This literature review reviews the current evidence base for pharmacotherapy of acute psychotic episode and schizophrenia in children and adolescents. The results of major systematic reviews and meta-analyses are compared. Meta-analyses of pharmacotherapy studies of the first psychotic episode are considered separately. Antipsychotics of the first and second generation are comparable in effectiveness for children and adolescents with acute psychotic episode. Olanzapine demonstrates higher efficacy in reducing negative symptoms. Ziprasidone and asenapine are less effective in treating schizophrenia in children and adolescents than other antipsychotics. Compared to adults, children and adolescents are at higher risk of metabolic impairments when taking antipsychotics.

[Combination of DAT and DBH gene polymorphisms with a family history of alcohol use disorders increases the risk of withdrawal seizures and delirium tremens during alcohol withdrawal in alcohol-dependent men]. / Sochetanie polimorfizma genov DAT i DBH s semeinoi otyagoshchennost'yu po alkogol'noi zavisimosti uvelichivaet risk razvitiya sudorozhnykh pristupov i alkogol'nykh psikhozov u muzhchin.

AIM: To explore the genetic influence of a family history of alcohol use disorders and the dopamine transporter SLC6A3 (DAT1) and dopamine beta-hydroxylase (DBH) gene polymorphisms on the risk of severe complications (withdrawal seizures (AWS) and delirium tremens (DT)) during alcohol withdrawal in alcohol-dependent men. MATERIAL AND METHODS: We investigated the effects of 3 previously reported candidate genetic variations: 40-bp variable number tandem repeat (VNTR) polymorphism and C/T exon 15 (rs27072) in the 3' untranslated region (3' UTR) of the SLC6A3(DAT1) gene, and -1021 C/T (rs1611115) of DBH gene in 266 alcohol-dependent Russian male inpatients in two groups by presence (SC group: AWS, DT, AWS+DT, n=130) or absence (n=136) of severe complications diagnosed by ICD-10 during current alcohol withdrawal. Clinically important information and a family history of alcohol use disorders (FH) were obtained by semi-structured interview. RESULTS: Patients in SC group more often have positive FH (54.6% vs. 33%, p=0.001) and their age at first alcohol use (FAU) was lower (16±3.53y.o vs. 17±1.66 y.o, p=0.001). Logistic regression revealed that FH predicts severe complications in total (р=0.001) and DT (р=0.003), FAU independently predicts severe complications in total (р=0.008), AWS (р=0.04), DT (р=0.032), AWS+DT (р=0.048) and every year of delay alcohol use decreases the risk by 18-30%. The gene polymorphisms interact with FAU to decrease the FAU influence on the risk of AWS (T variant of DAT (rs27072), р=0.04), (AWS+DT) and DT (T variant of DBH (rs1611115), р=0.023 and р=0.06). The T variant of DAT (rs27072) is associated with FAU (p=0.007) and increases the risk of (AWS+DT) (р=0.036), but decreases the risk of AWS (р=0.038) and of DT (р=0.021) too, but only in interaction with positive FH. The 9 repeat variant (9R) of DAT VNTR is associated with AWS (p=0.009), but the risk of AWS (р=0.004) and of SC in total (р=0.001) are elevated only in 9R carriers with positive FH. The 9R independently increases the risk of DT (р=0.048) and the effect become more robust in 9R carriers with high density of FH (р=0.014). The gene x gene interaction decreases the risk of DT (р=0.055). According to an analysis of total cohort of patients, the T variant of DBH (rs1611115) is associated with any kind of manifestation of delirium in alcohol-dependent men (p=0.039). CONCLUSION: This study demonstrate the genetic influence of a family history of alcohol use disorders and DAT and DBH gene polymorphisms on the risk of withdrawal seizures and delirium tremens. The interaction of genetic variations with positive family history provides the most robust effect, the interaction of genetic variations with the age at first alcohol use may «protect¼ their carriers from negative influence of this «behavioral¼ risk factor. Replication in large cohorts of patients is necessary to verify these findings for subsequent use in prevention programs.

[Dopamine neurotransmission of peripheral blood lymphocytes is a potential biomarker of psychiatric and neurological disorders].

Current literature on a role of dopamine in the development of mental and neurological disorders suggests that the discovery of endogenous dopamine in peripheral blood lymphocytes gave rise to a new line of research. Dopamine receptors are not only found on cells of the innate immune response (nonspecific), but also on cells of adaptive immune response (specific): T and B lymphocytes. These facts bring a new evidence of interrelationships between the peripheral immune system, neuroinflammation and neurodegeneration and suggest new ways for investigation of the pathogenesis of different mental and neurological disorders, in particular Parkinson's disease, Alzheimer's disease and schizophrenia. There is strong evidence that ligands of dopamine receptors can change the expression of coding genes both in central neurons and in peripheral cells. Thus, peripheral blood lymphocytes may prove a cellular tool to identify dopamine transmission disturbances in neuropsychiatric diseases, as well as to monitor the effects of pharmacological treatment.

[Pharmacogenetic-based risk assessment of antipsychotic-induced extrapyramidal symptoms].

"Typical" antipsychotics remain the wide-prescribed drugs in modern psychiatry. But these drugs are associated with development of extrapyramidal symptoms (EPS). Preventive methods of EPS are actively developed and they concentrate on personalized approach. The method of taking into account genetic characteristics of patient for prescribing of treatment was proven as effective in cardiology, oncology, HIV-medicine. In this review the modern state of pharmacogenetic research of antipsychotic-induced EPS are considered. There are pharmacokinetic and pharmacodynamic factors which impact on adverse effects. Pharmacokinetic factors are the most well-studied to date, these include genetic polymorphisms of genes of cytochrome P450. However, evidence base while does not allow to do the significant prognosis of development of EPS based on genetic testing of CYP2D6 and CYP7A2 polymorphisms. Genes of pharmacodynamics factors, which realize the EPS during antipsychotic treatment, are the wide field for research. In separate part of review research of such systems as dopaminergic, serotonergic, adrenergic, glutamatergic, GABAergic, BDNF were analyzed. The role of oxidative stress factors in the pathogenesis of antipsychotic-induced EPS was enough detailed considered. The system of those factors may be used for personalized risk assessment of antipsychotics' safety in the future. Although there were numerous studies, the pharmacogenetic-based prevention of EPS before prescribing of antipsychotics was not introduced. However, it is possible to distinguish the most perspectives markers for further research. Furthermore, brief review of new candidate genes provides here, but only preliminary results were published. The main problem of the field is the lack of high- quality studies. Moreover, the several results were not replicated in repeat studies. The pharmacogenetic-based research must be standardized by ethnicity of patients. But there is the ethnical misbalance in world literature. These facts explain why the introduction of pharmacogenetic testing for risk assessment of antipsychotic-induced EPS is so difficult to achieve.