De impact van CYP2D6-polymorfisme op een behandeling met aripiprazol bij kinderen en jongeren: een systematische review

Impact of CYP2D6 polymorphism on children and adolescents treated with aripiprazole: a systematic review Psychotropic drugs show a significant individual variability in efficacy and adverse events. To explain these differences, there is a promising focus on studies which examine the genetic variants of the cytochrome P450 enzyme 2D6 (CYP2D6). The CYP2D6 gene has a large genetic variability with over 100 known allelic variants encoding this protein. These variants contain predictive value for the function of the CYP2D6 enzyme. Aripiprazole is metabolized by the CYP2D6 enzyme, thereby CYP2D6 allelic variants potentially affect the pharmacokinetics of the drug. This systematic literature review summarizes research on that potential influence of CYP2D6 polymorphism on the treatment outcomes of aripiprazole in minors, in terms of pharmacokinetic changes, efficacy and adverse events. Relevant articles were selected according to PRISMA guidelines (‘preferred reporting items for systematic reviews and meta-analyses’) using Embase and PubMed. After applying the inclusion and exclusion criteria, 10 relevant research articles were retained. The available research shows a possible link between genetic variants of the CYP2D6 enzyme on the one hand, and efficacy and adverse events such as hyperprolactinemia or weight gain on the other hand, in minors treated with aripiprazole. However, the number and quality of studies are low. Recommendations for future studies are made since this systematic review offers insight into the relevance of CYP2D6 genotyping in children and adolescents treated with aripiprazole.

Gene Frequency of CYP2D6*4 and *10 Variants in Karachi Population

Background: CYP2D6 is to be considered the most pronounced gene in pharmacegenetic field which is involved in metabolizing ~25% of all clinically used neuroleptic drugs and other antidepressants. We designed a study to evaluate differential expression of CYP2D6*4 and CYP2D6*10 variants which are very prevalent in Asian countries and exhibit variation in drug metabolizing ability that affect therapeutic responses. Objective: The purpose of this study is to determine the genotypic frequencies of CYP2D6 *1 (normal metabolizer), *4 (poor metabolizer) and *10 (intermediate metabolizer) variants among schizophrenic subjects and compared with control group from a sub-set of Karachi population. Method: Genomic deoxyribonucleic acid (DNA ) was extracted and amplified with CYP2D6*4 and *10 primers using polymerase chain reaction (PCR) and digested by Bacillus stereothermophilus (BstN1) and Hemophilus parahemolyticus (Hph1) restriction enzymes. The digested bands were identified as wild type or mutants and their genotypic frequencies were estimated statistically by Hardy-Weinberg equation (HWE) and analyzed further under non-parametric Chi-square test. Results: The results mentioned the frequencies of CYP2D6*1 wild allele (57%) which produces functional enzyme in normal subjects but CYP2D6*4 variant (9%) that produces non-functional enzyme and CYP2D6*10 allele (70%) produces altered enzyme with reduced activity that was most prevalent in schizophrenic patients. Conclusion : Genotyping of CYP2D6 alleles among schizophrenic patients indicated prevalence of *4 and *10 variants in Karachi population producing non-functional and reduced functional drugs metabolizing enzymes respectively that increases the incurability rate of schizophrenia. Therefore, CYP2D6 gene screening program should be conducted routinely in clinical practice to help clinicians to prescribing appropriate doses according to patient’s genotype and minimize the sufferings of schizophrenia. Discussion: In last, drug response is a complex phenomenon that is dependent on genetic and environmental factors. CYP2D6 polymorphism may un-cured the schizophrenia due to improper drug metabolism and protein-proteins interaction that may alter the antipsychotic drugs metabolism among patients with variable drug resposes. Gene testing system need to establish for analyzing maximum patient’s genotypes predicted with poor metabolizer, intermediate metabolizer and ultrarapid metabolizer for the adjustment of antipsychotic drugs.

MATERNAL GRAVES DISEASE AND ABNORMAL CYP2D6 GENOTYPE WITH FETAL HYPERTHYROIDISM

Objective: Fetal hyperthyroidism is a rare yet potentially fatal complication of past or present maternal Graves disease (GD). Our objective was to present a unique case of fetal hyperthyroidism in a mother with a prior history of GD and a cytochrome P450 2D6 (CYP2D6) polymorphism. Methods: The clinical course in addition to serial laboratory and imaging results are presented. These include thyroid-stimulating hormone, free thyroxine, and thyrotropin receptor antibody levels, as well as fetal ultrasound, doppler fetal heart rate, and cordocentesis testing. Results: A 27-year-old with a history of GD previously treated with radioiodine and a known cytochrome P450 polymorphism was referred to an endocrinology clinic at 17 weeks gestation for evaluation and management of fetal thyrotoxicosis. Despite close follow-up with a multidisciplinary care team and an aggressive “block and replace” treatment approach, progressive disease resulted in intrauterine fetal demise at 28 weeks gestation. Conclusion: To our knowledge, this is the first published case report of fetal hyperthyroidism accompanied by a maternal CYP2D6 polymorphism. We hypothesize that the maternal CYP2D6 poor metabolizer phenotype prevents formation of antithyroid drug (ATD) metabolites and thus decreases the efficacy of ATD treatment. We suggest this as an area of future research.

Pharmacogenetics in anesthesiology: what to look for. Review

Individual pharmacogenetic features of patients areactively studied in various fields of medicine and anesthesiology is no exception. The purpose of this article is to unite the available literature data of polymorphisms affecting the perioperative period. The review includes information obtained from SCOPUS, MedLine, PharmGKB. The effects of cytochrome CYP2D6 polymorphism on the metabolism of tramadol, ondansetron and codeine are described. Also the influence of -opioid receptor OPRM1 polimorphism on the doses of narcotic analgesics and ryanodine receptor RYR1 and calcium channels on the probability of malignant hyperthermia are described, and also considered gene polymorphisms that affect the development of anaphylactic reactions