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Pharmacodynamic genetic polymorphisms affect adverse drug reactions of haloperidol in patients with alcohol-use disorder.

ABSTRACT: BACKGROUND:Antipsychotic action of haloperidol is due to blockade of D2 receptors in the mesolimbic dopamine pathway, while the adverse drug reactions are associated with striatal D2 receptor blockade. Contradictory data concerning the effects of genetic polymorphisms of genes encoding these receptors and associated structures (catechol-O-methyltransferase [COMT], glycine transporter and gene encoding the density of D2 receptors on the neuronal membrane) are described. OBJECTIVE:The objectives of this study were to evaluate the correlation between DRD2, SLC6A3 (DAT) and COMT genetic polymorphisms and to investigate their effect on the development of adverse drug reactions in patients with alcohol-use disorder who received haloperidol. PATIENTS AND METHODS:The study included 64 male patients (average age 41.38 ± 10.14 years, median age 40 years, lower quintile [LQ] 35 years, upper quintile [UQ] 49 years). Bio-Rad CFX Manager™ software and "SNP-Screen" sets of "Syntol" (Russia) were used to determine polymorphisms rs4680, rs1800497, rs1124493, rs2242592, rs2298826 and rs2863170. In every "SNP-Screen" set, two allele-specific hybridizations were used, which allowed to determine two alleles of studied polymorphism separately on two fluorescence channels. RESULTS:Results of this study detected a statistically significant difference in the adverse drug reaction intensity in patients receiving haloperidol with genotypes 9/10 and 10/10 of polymorphic marker SLC6A3 rs28363170. In patients receiving haloperidol in tablets, the increases in the UKU Side-Effect Rating Scale (UKU) score of 9.96 ± 2.24 (10/10) versus 13 ± 2.37 (9/10; p < 0.001) and in the Simpson-Angus Scale (SAS) score of 5.04 ± 1.59 (10/10) versus 6.41 ± 1.33 (9/10; p = 0.006) were revealed. CONCLUSION:Polymorphism of the SCL6A3 gene can affect the safety of haloperidol, and this should be taken into account during the choice of drug and its dosage regimen.

SUBMITTER: Zastrozhin MS

PROVIDER: S-EPMC5511016 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Pharmacodynamic genetic polymorphisms affect adverse drug reactions of haloperidol in patients with alcohol-use disorder.

Zastrozhin Mikhail Sergeevich MS Zastrozhin Mikhail Sergeevich MS Brodyansky Vadim Markovich VM Skryabin Valentin Yurievich VY Grishina Elena Anatolievna EA Ivashchenko Dmitry Vladimirovich DV Ryzhikova Kristina Anatolievna KA Savchenko Ludmila Mikhaylovna LM Kibitov Alexander Olegovich AO Bryun Evgeny Alekseevich EA Sychev Dmitry Alekseevich DA

Pharmacogenomics and personalized medicine 20170707

<h4>Background</h4>Antipsychotic action of haloperidol is due to blockade of D<sub>2</sub> receptors in the mesolimbic dopamine pathway, while the adverse drug reactions are associated with striatal D<sub>2</sub> receptor blockade. Contradictory data concerning the effects of genetic polymorphisms of genes encoding these receptors and associated structures (catechol-O-methyltransferase [COMT], glycine transporter and gene encoding the density of D<sub>2</sub> receptors on the neuronal membrane) ...[more]

PMID: 28744152

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Project description:Haloperidol is an efficacious antipsychotic drug that has serious, unpredictable motor side effects that limit its utility and cause noncompliance in many patients. Using a drug-placebo diallel of the eight founder strains of the Collaborative Cross and their F1 hybrids, we characterized aggregate effects of genetics, sex, parent of origin, and their combinations on haloperidol response. Treating matched pairs of both sexes with drug or placebo, we measured changes in the following: open field activity, inclined screen rigidity, orofacial movements, prepulse inhibition of the acoustic startle response, plasma and brain drug level measurements, and body weight. To understand the genetic architecture of haloperidol response we introduce new statistical methodology linking heritable variation with causal effect of drug treatment. Our new estimators, "difference of models" and "multiple-impute matched pairs", are motivated by the Neyman-Rubin potential outcomes framework and extend our existing Bayesian hierarchical model for the diallel (Lenarcic et al. 2012). Drug-induced rigidity after chronic treatment was affected by mainly additive genetics and parent-of-origin effects (accounting for 28% and 14.8% of the variance), with NZO/HILtJ and 129S1/SvlmJ contributions tending to increase this side effect. Locomotor activity after acute treatment, by contrast, was more affected by strain-specific inbreeding (12.8%). In addition to drug response phenotypes, we examined diallel effects on behavior before treatment and found not only effects of additive genetics (10.2-53.2%) but also strong effects of epistasis (10.64-25.2%). In particular: prepulse inhibition showed additivity and epistasis in about equal proportions (26.1% and 23.7%); there was evidence of nonreciprocal epistasis in pretreatment activity and rigidity; and we estimated a range of effects on body weight that replicate those found in our previous work. Our results provide the first quantitative description of the genetic architecture of haloperidol response in mice and indicate that additive, dominance-like inbreeding and parent-of-origin effects contribute strongly to treatment effect heterogeneity for this drug.

Project description:BackgroundAlcohol consumption may interfere with absorption, distribution, metabolism, and excretion of medications and increase risk of adverse drug reactions (ADR). Studies report increasing prescription medication use over time, with many U.S. drinkers using alcohol-interactive medication. This study identified trends in incidence of U.S. emergency department (ED) visits for ADR with alcohol involvement (ADR-A), compared characteristics and disposition between ADR-A visits and ADR visits without alcohol involvement (ADR-NA), and examined frequency of implicated medications in such visits for 2005 to 2011.MethodsADR visits were identified through the Drug Abuse Warning Network, a national surveillance system monitoring drug-related ED visits. Analysis accounted for sampling design effects and sampling weights. Estimates are presented for totals (ages 12+), age group, and/or sex. Trends were assessed by joinpoint log-linear regression. Differences between ADR-A and ADR-NA visits were compared using two-tailed Rao-Scott chi-square tests.ResultsFrom 2005 to 2011, incidence of ADR-A visits increased for males and females ages 21 to 34 and females ages 55+. An average of 25,303 ADR-A visits ages 12+ occurred annually. Compared with ADR-NA visits, ADR-A visits were more likely to involve males, patients ages 21 to 54, and 2+ implicated drugs. Alcohol involvement increased odds of more serious outcomes from ADR visits. Central nervous system (CNS) agents were the most common medications in ADR-A visits (59.1%), with nearly half being analgesics (mainly opioid). About 13.8% of ADR-A visits involved psychotherapeutic agents, including antidepressants. Besides CNS and psychotherapeutic agents, ADR-A visits involved a higher percentage of genitourinary-tract agents (mainly for impotence) than ADR-NA visits. Sex and age variations were observed with certain implicated medications.ConclusionsED visits for alcohol-drug interactions can be prevented by avoiding alcohol when taking alcohol-interactive medications. Our results underscore the need for healthcare professionals to routinely ask patients about alcohol consumption and warn of ADR risks before prescribing and dispensing alcohol-interactive medications.

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Pharmacodynamic genetic polymorphisms affect adverse drug reactions of haloperidol in patients with alcohol-use disorder.

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Pharmacodynamic genetic polymorphisms affect adverse drug reactions of haloperidol in patients with alcohol-use disorder.

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