Relationship of the 1846G > A Polymorphism of the CYP2D6 Gene to the Equilibrium Concentration Levels of Haloperidol in Patients with Acute Alcoholic Hallucinosis.

Haloperidol is currently used in addictology for the treatment of acute psychotic disorders, including acute alcoholic hallucinosis. The use of haloperidol is often accompanied by the occurrence of adverse drug reactions (ADRs). There is evidence that CYP2D6 isoenzyme is involved in the biotransformation of haloperidol. Aim: The study aimed to evaluate the relationship of 1846G > A polymorphism of the CYP2D6 gene to the equilibrium concentration levels of haloperidol in patients with acute alcoholic hallucinosis. Material and Methods: The study was conducted on 100 male patients with acute alcoholic hallucinosis (mean age 41.4 ± 14.4 years). The efficacy profile was evaluated using the PANSS (Positive and Negative Syndrome Scale) scale. The safety of therapy was assessed using the UKU Side-Effect Rating Scale and the SAS (Simpson-Angus Scale for Extrapyramidal Symptoms) scale. Genotyping was performed using the real-time polymerase chain reaction (Real-time PCR). Equilibrium plasma concentration levels of haloperidol were investigated using the high-performance liquid chromatography with mass spectrometry (HPLC with MS/MS). Results: No statistically significant results were obtained during the therapy efficacy assessment (dynamics of the PANSS score: GG genotype (-13.00 [-16.00; -16.00; -11.00]), GA genotype (-15.00 [-16.75; -13.00], p = 0.728). There was a statistically significant difference in safety assessment scores (dynamics of the UKU score: GG genotype (8.00 [7.00; 10.00]), GA genotype (15.00 [9.25; 18.00], p < 0.001); dynamics of the SAS score: GG genotype (11.00 [9.00; 14.00]), GA genotype (14.50 [12.00; 18.00], p < 0.001). The pharmacokinetic study results showed a statistically significant difference: GG (3.13 [2.32; 3.95]), GA (3.89 [2.92; 5.26], p = 0.010). Thus, a study conducted on a group of 100 patients with acute alcoholic hallucinosis demonstrated an association between the 1846G > A polymorphism of the CYP2D6 gene (rs3892097) and the safety profile of haloperidol therapy. We also revealed the presence of statistically significant difference in the equilibrium concentration levels of haloperidol in patients with the GG and AG genotypes. Conclusion: It can be concluded that patients with the GA genotype have a higher risk of ADRs compared to patients carrying the GG genotype. It is shown that 1846G > A polymorphism of the CYP2D6 gene (rs3892097) has a statistically significant effect on the equilibrium concentration levels of haloperidol.

Relationship of CYP3A4*1B Single Nucleotide Polymorphism to the Efficiency and Safety Profiles of Haloperidol in Patients Enduring Acute Alcoholic Hallucinosis.

To date, haloperidol has been widely used to treat patients with acute alcoholic hallucinosis. There is strong evidence that haloperidol therapy is commonly associated with adverse drug reactions (ADRs). The 392A > G polymorphism of the CYP3A4*1B gene (rs2740574) is known to affect the metabolism rates of haloperidol; hence it correlates with both therapy efficacy and safety parameters. Objective: The study objective was to investigate the effect of 392A > G polymorphism of the CYP3A4*1B gene (rs2740574) on the efficacy and safety profiles of haloperidol in patients with acute alcoholic hallucinosis. Methods: This study enrolled 100 male patients suffering from acute alcoholic hallucinosis (mean age 41.4 ± 14.4 years). The efficacy profile of haloperidol was assessed using the PANSS (Positive and Negative Syndrome Scale) validated psychometric scale. The safety profile of therapy was assessed with the UKU Side-Effect Rating Scale and the SAS (Simpson-Angus Scale for Extrapyramidal Symptoms) scale. Genotyping was performed using the real-time polymerase chain reaction (Real-time PCR). Results: There were no statistically significant results for the efficacy rates (dynamics of the PANSS score: AA genotype -14.00 [-16.00; -12.00], AG genotype -13.00 [-14.00; -10.50], p = 0.306). Similarly, there was no statistically significant difference in the safety profiles (dynamics of the UKU score: AA genotype - 9.00 [7.00; 13.00], AG genotype - 8.50 [7.25; 10.50], p = 0.620; dynamics of the SAS score: AA genotype -12.00 [10.00; 16.75], AG genotype - 10.00 [10.00; 12.25], p = 0.321). Conclusion: The study demonstrated that the 392A > G polymorphism of the CYP3A4*1B gene (rs2740574) in patients with acute alcoholic hallucinosis does not affect the efficacy and safety rates of haloperidol therapy.

Antiallergic Effects of Technologically Processed Antibodies to MHC II.

The risk of developing anaphylactic reactions to medications introduces additional difficulties for effective pharmacotherapy. Using a model of systemic anaphylaxis in mice, we showed that preventive administration of a preparation containing technologically processed antibodies (TPA) to MHC II induces an anti-anaphylactic effect comparable to that of dexamethasone (when assessing the severity of systemic anaphylaxis 30 and 60 min after challenge injection of the model antigen ovalbumin). The revealed activity may be related to the ability of TPA to MHC II to regulate the antigen presentation system and shift the immune response towards the production of IgG instead of IgE typical of anaphylactic reaction.

[Time perspective, sleep and wellbeing of the elderly during COVID-19 pandemic.]

The purpose of this study was to analyze the association between the time perspective and the psychophysiological state of the elderly during the pandemic COVID-19. 433 residents from 11 Russian cities aged 60,8±9,8 years (range - 50-94 years, women - 78,7%) took part in the study. During the online survey, each participant of the study provided personal data (place of residence, sex, age, height, and weight) and completed the Zimbardo Time Perspective Inventory, the Munich Chronotype Questionnaire, the Beck Depression Inventory and the Yale Food Addiction Scale. It was found that elderly people with a balanced time perspective had the lowest level of depression during the pandemic COVID-19 and less expressed sleep inertia at work days, while those with a past negative time perspective had the highest level of depression, high frequency of detection of food addiction and low sleep efficiency. The other types of time perspective (past positive, present hedonistic, present fatalistic and future) had intermediate values of indicators between these two extreme options. Thus, the conducted studies have shown that elderly people with a balanced time perspective showed the highest level of resistance to psychoemotional stress caused by the pandemic COVID-19.

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.

[Identification of factors influencing the texture sensitivity of young healthy volunteers based on a model for distinguishing the hardness of an agar-gelatin gel].

Elucidating the causes of variability in food texture sensitivity is important for understanding the mechanisms underlying food choice and portion size, eating rates, and enjoyment of food. Since texture perception significantly affects eating behavior, it is assumed that ability to recognize food texture, in turn, may depend on eating behavior. The aim of the study was to elucidate the relationship between the ability to recognize the hardness of an agar-gelatin gel, on the one hand, and the nutritional value of the diet, the type of eating behavior and the level of hunger and satiety feelings, on the other hand. Material and methods. In 38 healthy residents of Syktyvkar (15 men, 23 women aged 21 to 31 years) food textural sensitivity was determined by pairwise comparison of the hardness of model agar-gelatin gels and the level of the feeling of stomach fullness at the time of testing. All participants completed a food diary, the Dutch Eating Behavior Questionnaire, the Yale Food Addiction Scale, and assessed the standard organoleptic and hedonic properties of commercial fruit jelly. Statistical processing of the data was performed using non-parametric statistics: the Mann-Whitney U-test, Fisher's exact test, and calculating the Spearman's correlation coefficient. Results. The ability to recognize the hardness of food gel was found to vary significantly among the participants. The percentage of correct answers given by participants with high food textural sensitivity (n=20) was equal to 92 and 82% when comparing agargelatin gels with hardness in the range of 40-300 and 800-1000 kPa, respectively. Participants with low food texture sensitivity (n=18) gave the correct answer in 74 and 31% of cases when tasting soft and hard gels, respectively. Participants with high and low sensitivity to food gel texture did not differ in the type of eating behavior, as well as in the average daily intake of energy, macronutrients and dietary fiber. Correlation analysis revealed a negative relationship (rs=-0.37, p=0.020) between the percentage of correct answers when determining the hardness of the agar-gelatin gel and the level of the stomach fullness among all participants (n=38). In the sensory evaluation of fruit jelly, it was found that the descriptor «hard¼ was chosen by 60 and 22% (p=0.025) of the participants from the groups with high and low textural sensitivity, respectively. Conclusion. The ability to discriminate the hardness of an agar-gelatin gel is higher in people with a low level of stomach fullness feeling. Sensitivity to the texture of food gel is not related to energy value and macronutrient content in the daily diet and does not depend on the type of eating behavior. Participants with high food textural sensitivity are more likely to use the characteristic "hard" when evaluating fruit jelly.

[To the 100th anniversary from birth of professor lev moiseevich bedrin]. / K 100-letiyu so dnya rozhdeniya professora L'va Moiseevicha Bedrina.

Professor L.M. Bedrin - Head of the Department of Forensic Medicine and Law of the Yaroslavl Medical Institute for over 18 years. L.M. Bedrin was the first to develop a new scientific field - study of microcirculation in extreme conditions. L.M. Bedrin is the author of more than 130 scientific works, 100 articles, monographs. Under the supervision of L.M. Bedrin 1 doctoral and 10 master's theses were successfully defended.

Insitu magnesium calcium phosphate cements formation: From one pot powders precursors synthesis to in vitro investigations.

Calcium phosphate cements are of great interest for researchers and their applications in medical practice expanded. Nevertheless, they have a number of drawbacks including the insufficient level of mechanical properties and low degradation rate. Struvite (MgNH4PO4) -based cements, which grew in popularity in recent years, despite their neutral pH and acceptable mechanical performance, release undesirable NH4 + ions during their resorption. This issue could be avoided by replacement of ammonia ions in the cement liquid with sodium, however, such cements have a pH values of 9-10, leading to cytotoxicity. Thus, the main goal of this investigation is to optimize the composition of cements to achieve the combination of desirable properties: neutral pH, sufficient mechanical properties, and the absence of cytotoxicity, applying Na2HPO4-based cement liquid. For this purpose, cement powders precursors in the CaO-MgO-P2O5 system were synthesized by one-pot process in a wide composition range, and their properties were investigated. The optimal performance was observed for the cements with (Ca + Mg)/P ratio of 1.67, which are characterized by newberyite phase formation during setting reaction, pH values close to 7, sufficient compressive strength up to 22 ± 3 MPa (for 20 mol.% of Mg), dense microstructure and adequate matrix properties of the surface. This set of features make those materials promising candidates for medical applications.

Effects of plasma concentration of micro-RNA Mir-27b and CYP3A4*22 on equilibrium concentration of alprazolam in patients with anxiety disorders comorbid with alcohol use disorder.

Alprazolam is used in the treatment of patients with anxiety disorders comorbid with alcohol use disorder. Some proportion of these patients does not respond adequately to treatment with alprazolam, while many of them experience dose-dependent adverse drug reactions. Results of the previous studies have shown that CYP3A is involved in the biotransformation of alprazolam, the activity of which is dependent, inter alia, on the polymorphism of the encoding gene. OBJECTIVE: The objective of our study was to investigate the effect of 99366316G>A polymorphism of the CYP3A4 gene on the concentration/dose indicator of alprazolam in patients with anxiety disorders comorbid with alcohol use disorder, using findings on enzymatic activity of CYP3A (as evaluated by the 6-beta-hydroxy-cortisol/cortisol ratio measurement) and on CYP3A4 expression level obtained by measuring the miR-27b plasma concentration levels in patients with anxiety disorders comorbid with alcoholism. MATERIAL AND METHODS: Our study enrolled 105 patients with anxiety disorders comorbid with alcohol use disorder (age - 37.8±14.6 years). Therapy included alprazolam in an average daily dose of 5.6±2.4 mg per day. Treatment efficacy was evaluated using the 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. The activity of CYP3A was evaluated using the HPLC-MS/MS method by the content of the endogenous substrate of the given isoenzyme and its metabolite in urine (6- beta-hydroxy-cortisol/cortisol). Therapeutic drug monitoring (TDM) has been performed using HPLC-MS/MS. RESULTS: Our study revealed the statistically significant results in terms of the treatment efficacy evaluation (HAMA scores at the end of the treatment course): (GG) 3.0 [2.0; 5.0] and (GA) 4.0 [4.0; 5.0], p = 0.007; at the same time, the statistical significance in the safety profile was not obtained (the UKU scores): (GG) 3.0 [2.0; 3.8] and (GA) 3.0 [1.5; 4.0], p = 0.650. We revealed a statistical significance for concentration/dose indicator of alprazolam in patients with different genotypes: (GG) 1.583 [0.941; 2.301] and (GA) 2.888 [2.305; 4.394], p = 0.001). Analysis of the results of the pharmacotranscriptomic part of the study didn't show the statistically significant difference in the miR-27b plasma levels in patients with different genotypes: (GG) 25.6 [20.4; 28.8], (GA) 25.7 [19.7; 33.1], p = 0.423. At the same time, correlation analysis revealed a statistically significant relationship between the alprazolam efficacy profile evaluated by changes in HAMA scale scores and the miR-27b plasma concentration: rs = 0.20, p = 0.042. Also, we didn't reveal the correlation between the miRNA concentration and safety profile: rs = 0.15, p = 0.127. In addition, we revealed the relationship between the CYP3A enzymatic activity (as evaluated by 6-beta-hydroxycortisol/ cortisol ratio measurement) and the miR-27b plasma concentration: rs = -0.27, p = 0.006. At the same time, correlation analysis revealed a statistically significant relationship between the alprazolam concentration and the miR-27b plasma concentration: rs = 0.28, p = 0.003. CONCLUSION: The effect of genetic polymorphism of the CYP3A4 gene on the efficacy and safety profiles of alprazolam was demonstrated in a group of 105 patients with anxiety disorders comorbid with alcohol use disorder. At the same time, miR-27b remains a promising biomarker for assessing the level of CYP3A4 expression, because it correlates with the encoded isoenzyme's activity.

Incoherent scattering from dielectric metasurfaces under the influence of electromagnetic eigenmodes.

Anomalous optical properties of microscopically inhomogeneous dielectric films placed on a thick metal sublayer are investigated. We study the reflection, scattering, and absorption of the coherent electromagnetic radiation as a function of the incidence angle. Computer simulations show the existence of the incidence angle of the laser beam when the scattering and absorption increase simultaneously for the s-polarization so that almost 60% of the incident light goes in the scattering channel. The critical angle corresponds to the excitation of Fabry-Perot mode. The effect makes it possible to manipulate the reflection from the metafilms.

Effects of CYP2D6 activity on the efficacy and safety of mirtazapine in patients with depressive disorders and comorbid alcohol use disorder.

The objective of the study was to investigate the effects of CYP2D6 activity on the efficacy and safety of mirtazapine in patients with depressive disorders and comorbid alcohol use disorder who received mirtazapine. The study included 109 Russian patients who received mirtazapine at a dose of 30.0 [15.0; 45.0] mg per day. Genotyping of CYP2D6*4 (1846G > A, rs3892097) was performed using real-time polymerase chain reaction with allele-specific hybridization. The activity of CYP2D6 was evaluated by determining the concentration of endogenous substrate of the enzyme and its urinary metabolite - pinoline to 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline ratio, using high-performance liquid chromatography - mass spectrometry. The statistically significant differences between the scores on the Hamilton Depression Rating Scale (HAMD) in patients with different genotypes were revealed by day 16: (GG) 5.0 [3.0; 6.0], (GA) 1.5 [1.0; 3.2] (p < 0.001), and for the The UKU Side Effects Rating Scale (UKU): (GG) 6.0 [6.0; 7.0], (GA) 8.5 [8.0; 10.0] (p < 0.001). The calculation of correlation coefficients between the differences in scale scores and metabolic rate showed the presence of statistically significant weak inverse correlation with the efficacy indicator evaluated by HAMD (r = -0.278, p < 0.05), but not by UKU (r = 0.274, p > 0.05). This study demonstrated that an increased CYP2D6 activity reduces the efficacy of treatment with mirtazapine.

Diversity of PEGylation methods of liposomes and their influence on RNA delivery.

Gene therapy is a promising approach for personalized medicine, but its application in humans requires development of efficient and safe vehicles. PEGylated liposomes are some of the most suitable delivery systems for nucleic acids because of their stability under physiological conditions and prolonged circulation time, compared to conventional and other types of "stealth" liposomes. In vitro/in vivo activity of PEGylated liposomes is highly dependent on PEG motif abundance. The process of "stealth" coverage formation is a very important parameter for efficient transfection assays and further fate determination of the PEG layer after tissue penetration. In this review, we discuss the latest methods of PEGylated liposome preparation.

Structural, rheological and antioxidant properties of pectins from Equisetum arvense L. and Equisetum sylvaticum L.

The pectins were isolated from sterile stems of E. arvense (EA, yield 5.9%) and E. sylvaticum (ES, yield 4.8%) (Equisetaceae) using ammonium oxalate extraction after preliminary treatment with dilute HCl (рH 4.0). The pectins possessed high molecular weight (Mw, 340-360 kDa), high GalA content (ca. 85%), low degrees of methyl-esterification (14-16%) and acetylation (3-8%). NMR analysis indicated extensive regions of partially methyl-etherified and 3-O-acetylated HG and minor regions of low branched RG in the fragment isolated after hydrolysis of pectin EA by pectinase. Pectin EA produced a higher viscosity solution, formed a stronger and more rigid ionotropic hydrogel than pectin ES. The pectins scavenged DPPH and hydroxyl radicals, but not the superoxide radical and hydrogen peroxide. Phenolic compounds (0.11 and 0.23%) associated with polysaccharide moieties were apparently responsible for the differences in the anti-DPPH scavenging activity of pectins EA and ES (63 and 49%). The findings suggested that pectin from E. arvense should be more perspective than pectin from E. sylvaticum on their use as components of wound healing remedies.

Forced oscillations of the string under conditions of 'sonic vacuum'.

We present the results of analytical study of the significant regularities which are inherent to forced nonlinear oscillations of a string with uniformly distributed discrete masses, without its preliminary stretching. It was found recently that a corresponding autonomous system admits a series of nonlinear normal modes with a lot of possible intermodal resonances and that similar synchronized solutions can exist in the presence of a periodic external field also. The paper is devoted to theoretical explanation of numerical data relating to one of possible scenarios of intermodal interaction which was numerically revealed earlier. This is unidirectional energy flow from unstable nonlinear normal mode to nonlinear normal modes with higher wavenumbers under the conditions of sonic vacuum. The mechanism of such a scenario has not yet been clarified contrary to alternative mechanisms consisting in almost simultaneous energy flow to all nonlinear normal modes with breaking the above-mentioned conditions of sonic vacuum. We begin with a description of single-mode manifolds and then show that consideration of arbitrary double mode manifolds is sufficient for solution of the problem. Because of this, the two-modal equations of motion can be reduced to a linear equation which describes a perturbation of initially excited nonlinear normal mode of the forced system in the conditions of sonic vacuum. We have found analytical representation (in the parametric space) of the thresholds for all possible energy transfers corresponding to unidirectional energy flow from unstable nonlinear normal modes. The analytical results are in a good agreement with previous numerical calculations.This article is part of the theme issue 'Nonlinear energy transfer in dynamical and acoustical systems'.

The Role of Interleukin-33 in Pathogenesis of Bronchial Asthma. New Experimental Data.

Interleukin-33 (IL-33) belongs to the IL-1 cytokine family and plays an important role in modulating immune system by inducing Th2 immune response via the ST2 membrane receptor. Epithelial cells are the major producers of IL-33. However, IL-33 is also secreted by other cells, e.g., bone marrow cells, dendritic cells, macrophages, and mast cells. IL-33 targets a broad range of cell types bearing the ST2 surface receptor. Many ST2-positive cells, such as Th2 cells, mast cells, basophils, and eosinophils, are involved in the development of allergic bronchial asthma (BA). This suggests that IL-33 directly participates in BA pathogenesis. Currently, the role of IL-33 in pathogenesis of inflammatory disorders, including BA, has been extensively investigated using clinical samples collected from patients, as well as asthma animal models. In particular, numerous studies on blocking IL-33 and its receptor by monoclonal antibodies in asthma mouse model have been performed over the last several years; IL-33- and ST2-deficient transgenic mice have also been generated. In this review, we summarized and analyzed the data on the role of IL-33 in BA pathogenesis and the prospects for creating new treatments for BA.

[PERSONALIZED MEDICINE IN INTERNAL MEDICINE].

Personalized medicine - a new direction in medicine, which is based on the study of various biomarkers and the use of new methods of molecular analysis (primarily evaluating the activity of isoenzymes of cytochrome P450), allowing individualized approach to the selection of both the drugs and the selection of the dosing regimen for the purpose of maximize the effectiveness and safety of pharmacotherapy. This personalized medicine is to change the development and use of preventive and curative interventions. Genetic polymorphism isozymes of cytochrome P450 may determine the individual activity of a particular isozyme, and thus, to predict the clinical effectiveness, and in some cases, the risk of adverse reactions. The article is an example of the use of information on the activity of cytochrome P450 in clinical practice in matters of diagnosis, treatment and prevention of diseases. The scheme of the five best-known activity of isoenzymes of cytochrome P450 is shown.

X-ray holography with an atomic scatterer.

X-ray holography scheme with reference scatterer consisting of heavy atom as reference center and its link to an object consisting of several light atoms and using controlled variation of the alignment is represented. The scheme can reproduce an object in three dimensions with atomic resolution. The distorting factors of reconstruction are considered.

RNA INTERFERENCE: NEW APPROACH TO THE TREATMENT OF ALLERGIC ASTHMA (A REVIEW).

Asthma is among the most common chronic disorders of airways, which affects both children and adults. Asthma being a common disease among different segments of population, it has a high mortality rate and, in the absence of appropriate care, affects the quality of life and leads to economics losses. In a view of continuing growth in the incidence of asthma, it is important to find relevant biological targets for developing new approaches to astma therapy. Recent advances in molecular immunology, genetics, and bioinformatics allowed genes involved in the pathogenesis of asthma to be identified, which provided prerequisites for the development of new types of drugs that can regulate the activity of pathogenically significant genes. To date, a number of technologies for sequence-specific gene regulation (ASO, ribozymes, DNAzymes, EGS, DNA-decoys, U 1-adapters) are available, but RNA interference is the most promising approach in both terms of efficacy and financial cost. This review focuses on the generalization and analysis of experimental data regarding the use of RNA interference technology for the treatment of astma.

CYP3A4 activity and haloperidol effects in alcohol addicts.

BACKGROUND: Haloperidol is one of the most commonly used typical antipsychotics [2]. It has a powerful antipsychotic activity blocking mesolimbic postsynaptic dopamine receptors. Unwanted adverse effects accompany the use of haloperidol. Therefore alcohol abusers' attitudes towards haloperidol are ambiguous and often negative, which sometimes limits it's use in patients with addictive disorders [3]. Cytosolic carbonyl reductase reduces haloperidol to reduced form, which has 10-20% of the activity of the parent molecule. It is further metabolized by CYP3A4 to a tetrahydropyridine and then conjugated by glucuronidation and sulphation. Reduced haloperidol is back-oxidized to haloperidol by CYP3A4 and CYP2D6. Haloperidol is N-dealkylated by CYP3A4 and CYP2D6 to 4-chlorophenyl-4-hydroxypiperidine and p-fluorobenzoyl propionic acid. The correlation between CYP2D6 and CYP3A4 activity and the rate of biotransformation of haloperidol was demonstrated in a number of studies on patients with schizophrenia [1, 2, 5]. At the same time other studies deny or disaffirm this correlation [4]. OBJECTIVE: To estimate the correlation between CYP3A4 isoenzyme activity and the efficacy and safety of haloperidol in patients with alcohol abuse during the exacerbation of the addiction. METHODS: The study involved 15 men, alcohol abusers, in exacerbation of their addiction, who were hospitalized in Moscow Research and Practical Centre for Narcology of the Departament of Public Health. All 15 patients received haloperidol in tablets and injections. Determination of CYP3A4 activity was performed using high performance liquid chromatography with mass spectrometry (HPLC/ MS) by determination of endogenous substrate of this isoenzyme and its metabolite in urine - the ratio: cortisol/6-beta-hydroxycortisol. We used international psychometric scales to assess efficacy of haloperidol (the scale of determining the severity of addiction of The National Research Center on Addictions of the Ministry of Health Of Russia, Hamilton Anxiety Research Scale (HARS)). The safety of haloperidol was estimated by the UKU Side-Effect Rating Scale. Scales express the clinical picture of the abuse. The higher the score, the more pronounced the addiction is. Calculating the differences in scores of the scales allowed for clinical assessment of haloperidol effects. The larger the difference in scores was, the more pronounced were the changes in clinical picture of abuse, and the higher the efficacy of therapy was assumed. Statistical analysis of the results of the study was performed by non-parametric statistics by the program STATISTICA v10.0 («StatSoft Inc.¼, USA). The normality of sample distribution was estimated by Shapiro-Wilk's W-test, and the homogeneity of dispersion, that was estimated by Fisher's T-test (in case of comparison of two samples). The differences were evaluated as significant in case of p < 0,05 (statistic power >80%). To determine the correlation between the quantitative characteristics Spearman rank R coefficient was calculated. The value of correlation coefficient r from 0,3 to 0,7 (p < 0,05) indicated positive moderate, but significant correlation between the characteristics, r>0,7 (p < 0,05) - strong and significant correlation, negative value of r indicated inverse correlation. RESULTS: Data analysis demonstrated a correlation between the activity of isoenzyme CYP3A4 and the scores of pathological addiction (r1 = -0,36), HARS (r2 = -0,45), UKU Side-Effect Rating Scale (r3 = -0.15) in the entire group (p < 0.05). In a group of patients, who received the higher doses of haloperidol (more than 7.5 mg per day in tablets or 5 mg per day in injections), the following results were received in the same groups of data: r1 = -0.68, r2 = -0.71, r3 = -0.76 (p < 0.05). CONCLUSIONS: The results demonstrate the correlation between CYP3A4 activities and the efficacy and safety of haloperidol in alcohol abusers during the exacerbation of the addiction. The inverse correlation indicates that the higher the activity of CYP3A4 is, the lower the efficacy of haloperidol is. Also it can be assumed that the presence of strong correlation between the activity of CYP3A4 and the efficacy of haloperidol in group of patients, who received higher doses of haloperidol, may indicate that CYP3A4 is involved in haloperidol metabolism when it is used at higher doses. LIMITATIONS OF THE STUDY: It should be noted that in this research the activity of CYP3A4 was determined using high performance liquid chromatography with mass spectrometry (HPLC/MS) by determination the ratio of cortisol/6-beta-hydroxycortisol for the fist time. To increase the level of our confidence in the results further studies with a larger number of people are necessary.