Vol 1, No 1 (2017)

Stages of development and implementation of personalized medicine technologies in clinical practice
Sychev D.A.

In the article, the authors proposed the concept of developing and introducing into the clinical practice the technologies of personalized medicine, and first of all, genomic as well as other «omics» technologies. These are the stages from the choice of the problem, which is solved by personalizing the management of patients on the basis of genomic studies to the formation of a model for the introduction of personalized medicine technologies into clinical practice. The role of medical organizations of the Ministry of Health and scientific institutions of the Russian Academy of Sciences in all the proposed stages is presented.

World Journal of Personalized Medicine. 2017;1(1):1-4
Pharmacodynamic gene polymorphism and adverse drug reactionsthen applying antipsychotic drugs
Zastrozhin M.S., Sychev D.A., Grishina E.A., Savchenko L.M., Bryun E.A.

Application of antipsychotic drugs of both the first and subsequent generations quite often causes adverse side effects, which can reduce the compliance to the treatment of patients, reducing their quality of life. One of the most serious NLRs that occur during the period of application of antipsychotic disorders in patients are extrapyramidal disorders (acute dystonia, dyskinesia), malignant neuroleptic syndrome and tardive dyskinesia. During the year of therapy with the use of antipsychotic drugs of the first generation, signs of late dyskinesia appear in 3 to 5% of patients, and in elderly patients this figure is 5 times higher.

The achievement of recent years in medicine is the application of the pharmacogenetic approach for predicting the patient’s individual response to taking the drug.

Recent advances in medicine is the practice of pharmacogenetic approach to predict the patient’s individual response to receiving the drug. The pharmacogenetic approach to the prescription of medicines is based on the study of the effect of polymorphism of genes encoding the synthesis of isoenzymes of biotransformation and transport of xenobiotics, as well as the synthesis of elements responsible for the pharmacodynamic component.

In this article, we will attempt to describe the main adverse side effects arising from the use of antipsychotic drugs, as well as consider pharmacogenetic aspects of their appearance, to summarize the relevant information currently available. arisingfrom the use of antipsychotic drugs, as well as consider pharmacogenetic aspects of their appearance, to summarize the relevant information currently available.

World Journal of Personalized Medicine. 2017;1(1):5-12
The prospect of pluripotent stem cells for diabetes mellitus treatment
Panova A.V., Goliudsova D.V., Kiselev S.L.

Treatment options are limited for many diseases including diabetes, cancer and neurological and, many patients do not receive adequate therapy. New chemical entities largely developed within the BioPharma industry are not sufficient to satisfy patient’s needs. New gene and modified cell constructs were developed in academia and are expected on the market recently. This review presents describes somatic cells reprogramming technology and its application for the new drug development. We then summarize the progress made in genome editing and its application to cure monogenic hereditary disorders of the endocrine system.

World Journal of Personalized Medicine. 2017;1(1):13-17
Original Studies
Pharmacogenetic evaluation of adverse events’ risk in patients with alcohol withdrawal syndrome taking bromdihydrochlorphenylbenzodiazepine: The role of CYP2C19 gene polymorphisms
Ivashchenko D.V., Ryzhykova K.A., Sozaeva Z.A., Zastrozhin M.S., Grishina E.A., Savchenko L.M., Bryun E.A., Sychev D.A.

Introduction. Bromdihydrochlorphenylbenzodiazepine is the Russian original tranquilizer which widely using in psychiatry, narcology, neurology and general medicine. Particularly, that drug prescribing for patients with alcohol withdrawal syndrome (AWS). Isoenzyme CYP2C19 takes part in metabolism of the most of benzodiazepines, so the gene CYP2C19 might be included into pharmacogenetics study of bromdihydrochlorphenylbenzodiazepine. There was no study of CYP2C19 polymorphisms as biomarkers of bromdihydrochlorphenylbenzodiazepine’s safety.

Methods. 102 male patients with non-comlicated AWS (F 10.3 by ICD-10) were involved into the study. During 6 days of dynamic observation each participant was prescribed bromdihydrochlorphenylbenzodiazepine (Phenazepam). 5 ml of venous blood was collected from each participant for genotyping. 38 participants were added Pagluferal (contains phenobarbitalum, natrium coffeine-benzoate, bromisoval, papaverine) and/or Carbamazepine. Blood samples were analyzed to detect the CYP2C19*2 (rs4244285), *3 (rs4986893) и *17 (rs12248560) polymorphisms. Safety of therapy was evaluated with UKU Side Effects Rating Scale. Data analysis was performed with SPSS Statistics 21.0.

Results. Carriers of CYP2C19*2 GA+AA genotypes compared to GG homozygous significantly more often had such adverse effects as «Polyuria/polydipsia» in mean grade of penetration (33,3% vs 9%, p=0,016) and “Palpitations/Tachycardia” (16,7% vs 3,8%, p=0,018). Observed relationship between «Polyuria/polydipsia» and CYP2C19*2 GA+AA genotypes was confirmed in the subgroup “Combined pharmacotherapy” (37,5% vs 0%, p=0,006). CYP2C19*17 polymorphism in tendency to significance was associated with less frequent AE «Polyuria/polydipsia» among patients taking bromdihydrochlorphenylbenzodiazepine as monotherapy carriers of allele T had that AE in 16,9%, and CC homozygous in 24,2% (p=0,067).

Conclusion. Significant associations between CYP2C19*2 polymorphism and several AE in patients with alcohol withdrawal syndrome taking bromdihydrochlorphenylbenzodiazepine. Substantial role of CYP2C19*17 as predictor of AE associated with bromdihydrochlorphenylbenzodiazepine was not confirmed. Gene CYP2C19 is the sufficient biomarker of bromdihydrochlorphenylbenzodiazepine’s safety profile and needs further research.

World Journal of Personalized Medicine. 2017;1(1):18-26
Perspectives of pharmacogenetics approach to personalized tamoxifen therapy
Savelyeva M.I., Panchenko J.S., Urvantseva I.A., Ignatova A.K., Poddubnaya I.V.

Tamoxifen is the selective modulator of estrogen receptors. Nowadays, it is widely used in the treatment of ER(+) breast cancer and substantially decreases the risks of recurrence and disease progression. However, high interindividual variability in response is observed, calling for a personalized approach to tamoxifen treatment. Tamoxifen is metabolized by cytochrome P450, resulting in the formation of active metabolites, including 4-hydroxy-tamoxifen and endoxifen. The effectiveness and success of treatment depends largely on concentrations of the active tamoxifen metabolites in blood plasma. Polymorphisms in the genes encoding these enzymes are proposed to influence on pharmacokinetics and pharmacodynamics of tamoxifen. Therefore, pharmacogenetic approach may form the basis of personalized treatment of breast cancer. In this systematic review, we analyze all current data about the potential use of genotyping of CYP2D6, CYP3A4/5, CYP2B6 to predict an individual response on tamoxifen treatment.

World Journal of Personalized Medicine. 2017;1(1):27-35
The personalized approach to neonatal diabetes therapy depending on the genetic defect
Tikhonovich Y.V., Zubkova N.A., Tiulpakov A.N.

Neonatal diabetes mellitus (NDM) is defined as a heterogeneous group of genetic disorders with onset before 6 months of age. Mutations in KATP channel genes (KCNJ11, ABCC8) and the insulin gene (INS) are the most common causes of NDM. Accurate molecular diagnosis of NDM has significant clinical importance as it may influence diabetes treatment, explain pleiotropic features and define the prognosis in the examined subject as well as in other family members .

In this report we present the results of a genetic examination of 70 patients with NDM, generalized the experience of using sulfonylurea in patients with KCNJ11 and ABCC8 genes mutations for the period from 2009 to 2016. A correlation is shown between the type of mutation, the course of the disease, and the sensitivity of patients to glibenclamide.

World Journal of Personalized Medicine. 2017;1(1):36-39
Case report
Genotype-based personalized correction of glycemic control in patients with MODY due to mutations in GCK, HNF1A AND HNF4A genes
Zubkova N.A., Gioeva O.A., Tikhonovich Y.V., Petrov V.M., Vasiliev E.V., Tyulpakov A.N., Dedov I.I.

Aims. To demonstrate the principles of personalized treatment of diabetes for example the most common MODY subtypes (1-3) identified by NGS

Methods. We study 312 patients aged from 3 months to 25 years (162 boy/150 girls) with suspected MODY. A targeted next-generation sequencing approach (IonTorrent platform) was used for sequencing of monogenic form of diabetes mellitus candidate 28genes (13 MODY genes-candidates and other genes, associated with diabetes mellitus). Clinical and biochemicalphenotypes of the patients were compared with the type of mutations. Previously undescribed nonsynonymous mutations were considered as «probably pathogenic» with the minor allele frequency of <0.1% and «pathogenic» assessment in ANNOVAR database.

Results. We selected group of patients with mutations in the most common genes-candidates (GCK; HNF1A; HNF4A):99GCK gene mutations detectedin the 129 probands (61,1%) and 77 relatives, in HNF1A – 20 mutations in the 19 probands(9,0%) and 14 relatives, in HNF4A – 8 mutations in 9the probands (4,3%) and 3 relatives. The current therapy wasmodificated account the genotype and have been evaluated its effectiveness.

Conclusion. Molecular genetic confirmation of the monogenic nature of metabolic carbohydratedisorders is the basis of personalized therapy of diabetes.

World Journal of Personalized Medicine. 2017;1(1):40-48

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