Influence of Plasma Concentration of Hsa-Mir-370-3p and Cyp2d6*4 On Equilibrium Concentration of Phenazepam in Patients with Recurrent Depressive Disorder.

Introduction: Phenazepam is commonly administered to patients diagnosed with major depressive disorder. Some proportion of such patients do not show adequate response to treatment regimen containing phenazepam, whereas many of them experience type A adverse drug reactions. Previous studies showed that CYP2D6 IS involved in the biotransformation of phenazepam, the activity of which is highly dependent on the polymorphism of the gene encoding it. Objective. The objective of the study was to evaluate the impact of 1846G>A polymorphism of the CYP2D6 gene on the concentration/dose indicator of phenazepam, using findings on enzymatic activity of CYP2D6 (as evaluated by the 6M-THBC/pinoline ratio measurement) and on CYP2D6 expression level obtained by measuring the hsa-miR-370-3p plasma concentration levels in patients suffering from major depressive disorder. Material and methods: The study enrolled 191 patients with recurrent depressive disorder (age -40.0 ± 16.3 years). Treatment regimen included phenazepam in an average daily dose of 6.0 ± 2.3 mg per day. Treatment efficacy was assessed using the validated psychometric scales. Therapy safety was assessed using the UKU Side-Effect Rating Scale. For genotyping and estimation of the microRNA (miRNA) plasma levels we performed the real-time polymerase chain reaction (PCR Real-time). The activity of CYP2D6 was evaluated using the HPLC-MS/MS method by the content of the endogenous substrate of given isoenzyme and its metabolite in urine (6M-THBC/pinoline). Therapeutic drug monitoring has been performed using HPLC-MS/MS. Results: Our findings didn't reveal the statistically significant results in terms of the treatment efficacy evaluation (HAMA scores at the end of the treatment course): (GG) 6.0 [4.0; 8.0] and (GA) 6.0 [5.0; 7.8], p > 0.999; the statistical significance in the safety profile was not obtained (the UKU scores): (GG) 3.0 [2.0; 4.0] and (GA) 3.0 [3.0; 3.0], p > 0.999. We didn't reveal a statistical significance for concentration/dose indicator of phenazepam in patients with different genotypes: (GG) 0.812 [0.558; 1.348] and (GA) 0.931 [0.630; 1.271], p = 0.645). Analysis of the results of the pharmacotranscriptomic part of the study didn't show the statistically significant difference in the hsa-miR-370-3p plasma levels in patients with different genotypes: (GG) 22.5 [16.9; 29.8], (GA) 22.7 [15.7; 31.5], p = 0.695. At the same time, correlation analysis didn't reveal a statistically significant relationship between the phenazepam efficacy profile evaluated by changes in HAMA scale scores and the hsa-miR-370-3p plasma concentration: rs = -0.01, p = 0.866. Also, we didn't reveal the correlation between the miRNA concentration and safety profile: rs = 0.07, p = 0.348. Also we did not reveal the relationship between the CYP2D6 enzymatic activity (as evaluated by 6M-THBC/pinoline ratio measurement) and the hsa-miR-370-3p plasma concentration: rs = -0.14, p = 0.056. At the same time, correlation analysis did not reveal a statistically significant relationship between the phenazepam concentration and the hsa-miR-370-3p plasma concentration: rs = -0.05, p = 0.468. Conclusion: The effect of genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of phenazepam was not demonstrated in a group of 191 patients with recurrent depressive disorder. At the same time, hsa-miR-370-3p does not remain a promising biomarker for assessing the level of CYP2D6 expression, because it does not correlate with encoded isoenzyme activity.

[Age-dependent reconstruction of element status in Magadan inhabitants]. / Vozrastnye perestroi élementnogo statusa zhitelei Magadana.

On the base of macro- and microelements' concentration in hair of Magadan's inhabitants there were analyzed the changes of aged people's element status. It has been shown that with age, differently directed reconstruction happened, leading to accumulation of one elements and decrease of concentration of others in inhabitants' hair. Elements, undergoing natural age reconstruction, may be considered as indicators and initiators of aging. We have allocated two groups of elements, in dependence on changes' direction. The first group is the main one; Na, K, Ca, Se, As, Mg, Mn, Fe, Zn belong to this group; their level in hair is increasing with age. Taking into account the excretory function of hair, accumulation of named elements is considered as aged removing of these elements out of organism. The exception is the toxic As: its superfluous concentrations in hair reflect the accumulation As in the internal environment of organism. Elements (Cr, Si), concentration of which in hair is decreasing with age, belong to the second group. On the base of literary data, the decreasing of named elements in hair must be interpreted as their programmed decreasing in the organism of aged people. Hence, in aged people there is seen the generalized decreasing of the most studied essential macro- and microelements in the organism. The exception is As, concentration of which is increasing in aged people. The age disorder of element homeostasis may serve as a predictor of "normal" diseases and may be one of pathophysiological mechanisms of aging.

[Features of tissue differentiation of the thyroid gland in residents of Magadan]. / Osobennosti tkanevoi differentsirovki shchitovidnoi zhelezy u zhitelei Magadana.

The histological structure and morphometric parameters of the thyroid gland were examined in fetuses, newborns and infants during the early postnatal period to assess the peculiarities of thyroid differentiation in Magadan goiter endemic region. It was demonstrated that fetal thyroid gland remained immature. Functional strain of thyroid structures was shown in neonatal period that is considered to be the manifestation of the adaptive responses of the newborn. In infants aged 2-3 months thyroid gland attained definitive morphometric parameters that indicated its functional maturity. Low rate of tissue differentiation in the thyroid gland during prenatal period may result from iodine deficiency in both mother and fetus, which is aggravated by the unfavorable natural climatic factors of the North.