[Treatment of attention deficit hyperactivity disorder in children: results of a multicenter, randomized, double-blind, placebo-controlled clinical trial]. / Terapiya sindroma defitsita vnimaniya s giperaktivnost'yu u detei: rezul'taty mnogotsentrovogo randomizirovannogo dvoinogo slepogo platsebo-kontroliruemogo klinicheskogo issledovaniya.

OBJECTIVE: Evaluation of the efficacy and safety of the new drug Prospekta in the treatment of attention deficit hyperactivity disorder (ADHD) in patients aged 7-12 years. MATERIAL AND METHODS: A multicenter (35 clinical centres) double-blind, placebo-controlled, randomized, parallel-group clinical trial enrolled 363 patients. The mean age was 9.3±1.7 years. Children of both sexes aged between 7 and 12 years with a diagnosis of ADHD confirmed by DSM-V diagnostic criteria were included in the study. Patients with a total score of 22 or more on the Attention Deficit Hyperactivity Disorder-Rating Scale-V (ADHD-RS-V) were included in the study. After randomisation, patients in group 1 received Prospekta, 1 tablet twice daily; patients in group 2 received placebo according to the study drug regimen. The primary efficacy criterion was the proportion of patients with a 25% or greater reduction in the overall ADHD-RS-V scale score after 8 weeks of treatment. As additional criteria for efficacy assessment were assessed: change of ADHD-RS-V total score from baseline after 8 weeks of treatment; Clinical Global Impression Efficacy Index (CGI-EI) score after 8 weeks of treatment; side effects. RESULTS: The proportion of patients with a 25% or more reduction in the ADHD-RS-V scale score after 8 weeks of treatment was 55.9% in the Prospekta group, and 43.3% in the placebo group (p=0.0199). There was a reduction of ADHD symptoms in the Prospekta group as a mean ADHD-RS-V score decreased by 10.2±7.7 (in the placebo group by 8.1±7.9); the difference between the mean ADHD-RS-V score reduction during Prospekta and placebo treatment was 2.09±7.81 (p=0.0096). Mean CGI-EI scores calculated on the basis of physician scores were different in the Prospekta group compared to the placebo group at 6.9±3.2 versus 8.0±3.1 (p=0.0012), indicating greater clinical efficacy of the study drug. The frequency of adverse events (AEs) did not differ significantly between the groups. There were a total of 66 AEs in 46 patients, including 31 AEs in 23 (13.2%) Prospekta group participants and 35 AEs in 23 (12.2%) placebo group participants (p=0.87). No cases of serious AEs were reported during the study. Prospekta is compatible with drugs used in pediatric practice. Prospekta did not cause an exciting effect and did not adversely affect the sleep of patients. CONCLUSION: The drug Prospekta is an effective and safe treatment for ADHD in patients 7-12 years old.

[Glutamine as a component of nutritional and metabolic therapy for surgical patients in ICU]. / Glutamin kak komponent nutritivno-metabolicheskoi terapii patsientov khirurgicheskogo profilya v usloviyakh ORIT.

Glutamine is the most abundant amino acid in the human body that is involved in various metabolic processes. The development of hypermetabolic and hypercatabolic syndrome that accompanies critical conditions of ICU patients is associated with a decrease in the concentration of glutamine, especially in the blood plasma and muscles. This process may last for quite a long time and lead to a number of complications up to a fatal outcome. This review was aimed to analyze clinical studies conducted over the past 20 years that demonstrate the effect of intravenous infusion of glutamine dipeptide as part of balanced parenteral nutrition on the perioperative period: the severity of inflammatory response; the state of the intestinal mucosa; the incidence and severity of complications; mortality; the duration of stay in the ICU and hospital in general, etc. The analysis was performed using systematic reviews and meta-analyses based on randomized double-blind, placebo-controlled trials in different countries selected in the main databases (PubMed, EMBASE, Web of Science, The Cochrane Library, etc.). Most of the reports state that the inclusion of glutamine dipeptide in nutritional and metabolic therapy (NMT) in surgical patients reduces the frequency and severity of infectious complications and mortality, reduces the length of stay in ICU and in hospital in general, improves the biochemical parameters that reflect the condition of patients, and reduces the treatment costs. Thus, the conducted systematic reviews and meta-analyses confirm that the use of the parenteral form of glutamine dipeptide (Dipeptiven 20%) as part of balanced standard parenteral nutrition (PN) is a clinically and pharmacoeconomically justified strategy of NMT in surgical ICU patients.

[Predict of metabolic stability of xenobiotics by the PASS and GUSAR programs]. / Prognoz metabolicheskoi stabil'nosti ksenobiotikov programmami PASS i GUSAR.

Metabolic stability refers to the susceptibility of compounds to the biotransformation; it is characterized by such pharmacokinetic parameters as half-life (T1/2) and clearance (CL). Generally, these parameters are estimated by in vitro assays, which are based on cells or subcellular fractions (mainly liver microsomal enzymes) and serve as models of the processes occurring in living organisms. Data obtained from the experiments are used to build QSAR (Quantitative Structure-Activity Relationship) models. More than 8000 compounds with known CL and/or T1/2 values obtained in vitro using human liver microsomes were selected from the freely available ChEMBL v.27 database. GUSAR (General Unrestricted Structure-Activity Relationships) and PASS (Prediction of Activity Spectra for Substances) softwares were used to make quantitative and classification models. The quality of the models was evaluated using 5-fold cross-validation. Compounds were subdivided into "stable" and "unstable" by means of the following threshold parameters: T1/2 = 30 minutes, CL = 20 ml/min/kg. The accuracy of the models ranged from 0.5 (calculated in 5-fold CV on the test set for the half-life prediction quantitative model) to 0.96 (calculated in 5-fold CV on the test set for the clearance prediction classification model).

[Modeling of drug-drug interactions between omeprazole and erythromycin with cytochrome P450 3A4 in vitro assay]. / Modelirovanie mezhlekarstvennogo vzaimodeistviia omeprazola i éritromitsina s ispol'zovaniem tsitokhrom R450-zavisimoi sistemy in vitro.

In the present study the electrochemical system based on recombinant cytochrome P450 3A4 (CYP3A4) was used for the investigation of potential drug-drug interaction between medicinal preparations employed for Helicobacter pylori eradication therapy. Drug interactions were demonstrated in association of omeprazole as a proton pump inhibitor (PPI) and macrolide antibiotic erythromycin during cytochrome P450 3A4-mediated metabolism. It was shown that in the presence of omeprazole the rate of N-demethylase activity of CYP3A4 to erythromycin measured by means of product (formaldehyde) formation decreased. Mass-spectrometry analysis of omeprazole sulfone as a CYP3A4-mediated metabolite demonstrated the absence of erythromycin influence on CYP3A4-dependent omeprazole metabolism. This phenomenon may be explained by lower spectral dissociation constant of CYP3A4-omeprazole complex (Kd = 18±2 µM) than that of CYP3A4-erythromycin complex (Kd = 52 µM). Using the electrochemical model of electrochemically-driven drug metabolism it is possible to register CYP3A4-mediated catalytic conversion of certain drugs. In vitro experiments of potential CYP3A4-mediated drug-drug interactions are in accordance with in silico modeling with program PASS and PoSMNA descriptors in the case of omeprazole/erythromycin combinations.

[Surgical anatomy of the right portal vein]. / Khirurgicheskaia anatomiia vetvei vorotnoi veny pravoi doli pecheni.

OBJECTIVE: To study the features of surgical anatomy of intrahepatic segments of right portal vein. MATERIAL AND METHODS: The results of 260 histological examinations including sectional (n=60) and clinical (n=200) surveys were analyzed. Anatomical analysis implied assessment of organometric characteristics including liver weight, length, width and thickness of right and left lobes, division angles of portal vein, the number of branches, length and diameter of the vessels. Clinical examination was based on analysis of splenoportograms and X-ray direct portal venograms. Patients were divided into three groups according to their body type (dolichomorphic, mesomorphic, brachymorphic). RESULTS: Anatomical and clinical surveys confirmed the differences in metric characteristics of portal vascular system depending on the body type. There was medial angulation of the median fissure under 70-85º (78.0±3.4°) in dolichomorphic and mesomorphic patients. Right angle between the median fissure and lower liver surface was observed in brachymorphic subjects. Portal vein division into the branches of the first order to the right of the median fissure was found in 49 cases. Median or left-sided division was noted in other cases. In most cases (n=219), right portal vein dichotomously divided into the right paramedian and right lateral branches. Portal trifurcation was detected in 2.3% of cases, medial translocation of the right paramedian branch - in 1.1% of cases. CONCLUSION: Right liver lobe surgery may be associated with certain technical difficulties due to variable anatomy of the right portal vein. Anatomical and atypical liver resections should be preceded by preoperative identification of individual anatomical variations of the main liver vessels. Contrast-enhanced computed tomography is optimal method for this purpose.

PASS-based prediction of metabolites detection in biological systems.

Metabolite identification is an essential part of the drug discovery and development process. Experimental methods allow identifying metabolites and estimating their relative amount, but they require cost-intensive and time-consuming techniques. Computational methods for metabolite prediction are devoid of these shortcomings and may be applied at the early stage of drug discovery. In this study, we investigated the possibility of creating SAR models for the prediction of the qualitative metabolite yield ('major', 'minor', "trace" and "negligible") depending on species and biological experimental systems. In addition, we have created models for prediction of xenobiotic excretion depending on its administration route for different species. The prediction is based on an algorithm of naïve Bayes classifier implemented in PASS software. The average accuracy of prediction was 0.91 for qualitative metabolite yield prediction and 0.89 for prediction of xenobiotic excretion. The created models were included as a component of MetaTox web application, which allows predicting the xenobiotic metabolism pathways ( http://www.way2drug.com/mg ).

Drug-drug interaction prediction using PASS.

Simultaneous use of the drugs may lead to undesirable Drug-Drug Interactions (DDIs) in the human body. Many DDIs are associated with changes in drug metabolism that performed by Drug-Metabolizing Enzymes (DMEs). In this case, DDI manifests itself as a result of the effect of one drug on the biotransformation of other drug(s), its slowing down (in the case of inhibiting DME) or acceleration (in case of induction of DME), which leads to a change in the pharmacological effect of the drugs combination. We used OpeRational ClassificAtion (ORCA) system for categorizing DDIs. ORCA divides DDIs into five classes: contraindicated (class 1), provisionally contraindicated (class 2), conditional (class 3), minimal risk (class 4), no interaction (class 5). We collected a training set consisting of several thousands of drug pairs. Algorithm of PASS program was used for the first, second and third classes DDI prediction. Chemical descriptors called PoSMNA (Pairs of Substances Multilevel Neighbourhoods of Atoms) were developed and implemented in PASS software to describe in a machine-readable format drug substances pairs instead of the single molecules. The average accuracy of DDI class prediction is about 0.84. A freely available web resource for DDI prediction was developed (http://way2drug.com/ddi/).

[Xenobiotic toxicity prediction combined with xenobiotic metabolism prediction in the human body]. / Komp'iuternaia otsenka toksichnosti ksenobiotikov s uchetom ikh metabolizma v organizme cheloveka.

The majority of xenobiotics undergo a number of chemical reactions known as biotransformation in human body. The biological activity, toxicity, and other properties of the metabolites may significantly differ from those of the parent compound. Not only xenobiotic itself and its final metabolites produced in large quantities, but the intermediate and final metabolites that are formed in trace quantities, can cause undesirable effects. We have developed a freely available web resource MetaTox (http://www.way2drug.com/mg/) for integral assessment of xenobiotics toxicity taking into account their metabolism in the humans. The generation of the metabolite structures is based on the reaction fragments. The estimates of the probability of the reaction of a certain class and the probability of site of biotransformation are used at the generation of the xenobiotic metabolism pathways. The web resource MetaTox allows researchers to assess the metabolism of compounds in the humans and to obtain assessment of their acute, chronic toxicity, and adverse effects.

Strong long-range electron-phonon interaction as possible driving force for charge ordering in cuprates.

A model resulting in charge ordering (CO) similar to that observed in cuprate superconductors is under study. It includes strong long-range electron-phonon interaction (EPI) and high density of correlated carriers. Coexistence of large bipolarons and delocalized carriers is a feature of such system. We develop generalized variation method to calculate the bipolaron size (CO period) in the ground normal state of such system at various doping. The approach allows the revealing of a possible physical reason of strongly different doping behavior of the CO wave vector in different cuprates. Obtained doping dependences of the CO period and temperature of the CO decay demonstrate quantitative agreement with those observed in cuprates. Predicted in the suggested approach ratio of the CO wave vector to the wave vector of the high-energy anomaly (HEA) in ARPES spectrum is in consent with that in cuprates. Calculated resonant x-rays scattering on the CO emerging in the model is in good agreement with experiments on cuprates including the asymmetry of the CO peaks' cross-section. A gap arises in the spectrum of delocalized carriers near antinodal direction due to their scattering on the periodic potential created by autolocalized carriers, analogously to photon crystal effect.

Prediction of metabolites of epoxidation reaction in MetaTox.

Biotransformation is a process of the chemical modifications which may lead to the reactive metabolites, in particular the epoxides. Epoxide reactive metabolites may cause the toxic effects. The prediction of such metabolites is important for drug development and ecotoxicology studies. Epoxides are formed by some oxidation reactions, usually catalysed by cytochromes P450, and represent a large class of three-membered cyclic ethers. Identification of molecules, which may be epoxidized, and indication of the specific location of epoxide functional group (which is called SOE - site of epoxidation) are important for prediction of epoxide metabolites. Datasets from 355 molecules and 615 reactions were created for training and validation. The prediction of SOE is based on a combination of LMNA (Labelled Multilevel Neighbourhood of Atom) descriptors and Bayesian-like algorithm implemented in PASS software and MetaTox web-service. The average invariant accuracy of prediction (AUC) calculated in leave-one-out and 20-fold cross-validation procedures is 0.9. Prediction of epoxide formation based on the created SAR model is included as the component of MetaTox web-service ( http://www.way2drug.com/mg ).

[The Metabolic Optimized Fast Track Concept: preoperative preparation for abdominal surgery]. / Kontseptsiia 'Bystraia Metabolicheskaia Optimizatsiia' pri predoperatsionnoi podgotovke patsientov v abdominal'noi khirurgii.

In recent years the protocols of Enhanced Recovery After Surgery (E.R.A.S.) have been introduced into clinical practice and actively used. The goal of E.R.A.S. is to increase recovery, decrease complications and reduce length of stay after surgery through optimization of perioperative management. One of the key elements of E.R.A.S. is Metabolic Optimized Fast Track Concept (MOFA). It is aimed at the reduction of the period of preoperative fasting and at the activation of glucose transport inside the cell. It involves the administration of combined carbohydrate-protein-glutamine drinks which results into decreased insulin resistance in the early postoperative period. The implementation of MOFA within the structure of perioperative nutrition and metabolic support in abdominal surgery may actually be beneficial by reducing postoperative complications, length of hospital stay and mortality rate.

[Surgical treatment of a pregnant female with AVM hemorrhage]. / Khirurgicheskoe lechenie patsientki s krovoizliyaniem iz AVM vo vremya beremennosti.

Hemorrhages from arteriovenous malformations (AVMs) in pregnant females are rare, but they are known to lead to high maternal and infant mortality. There are no standards for AVM treatment in pregnant females. Many authors believe that AVM resection before delivery improves the prognosis for life and health of the mother and fetus. In this paper, we present a case of successful surgical treatment of a female patient with AVM hemorrhage at 20 weeks and address management issues of these patients.

[Rupture of a giant aneurysm of the accessory middle cerebral artery: a case report and a literature review]. / Razryv gigantskoi chastichno trombirovannoi anevrizmy dobavochnoi srednei mozgovoi arterii: sluchai iz praktiki i obzor literatury.

The accessory middle cerebral artery is a rare congenital vascular abnormality. The international literature has reported cases of accessory MCA aneurysms. In this article, we describe a case of rupture of a giant partially thrombosed aneurysm of the accessory MCA. This case is of great interest due to rarity of the pathology and associated diagnostic errors.

Tunable photonic elements at the surface of an optical fiber with piezoelectric core.

Tunable photonic elements at the surface of an optical fiber with piezoelectric core are proposed and analyzed theoretically. These elements are based on whispering gallery modes whose propagation along the fiber is fully controlled by nanoscale variation of the effective fiber radius, which can be tuned by means of a piezoelectric actuator embedded into the core. The developed theory allows one to express the introduced effective radius variation through the shape of the actuator and the voltage applied to it. In particular, the designs of a miniature tunable optical delay line and a miniature tunable dispersion compensator are presented. The potential application of the suggested model to the design of a miniature optical buffer is also discussed.

[Genome organization and life cycle of the hepatitis c virus].

The review summarizes the current data about the hepatitis C viral genome and polyprotein organization. The functional role of the structural and non-structural viral proteins including their interaction with cellular regulatory proteins and cell structural elements is discussed. Specific peculiarities of the life cycle of the hepatitis C virus important for the understanding of the viral hepatitis C pathogenesis are summarized.

[Frequency of diseases caused by group A streptococci among invasive infections of soft tissues and characteristics of the causative agent].

AIM: Determine frequency of diseases caused by group A streptococci (GAS) among invasive infections of soft tissues; identify emm-types of the isolated streptococci, determine the presence of bacteriophage integrases and toxin genes in their genomes. MATERIALS AND METHODS: 4750 case histories of patients with soft tissue infections of the purulent-surgical department of the 23rd City Clinical Hospital.of Moscow "Medsantrud" in 2008 - 2011 were analyzed. 46 strains of GAS isolated from patients with invasive streptococcus infection (ISI) were studied. GAS identification was carried out by latex-agglutination method. GAS emm-type was determined by molecular-genetic methods, as well as the presence of bacteriophage integrases int2, int3, int4, int5, int6, int7, int49, bacteriophage toxins speA, speI, sla, speC/J, speL, speH, speC, ssa and speB gene present on the chromosomal DNA. RESULTS: 132 cases (2.8%) were attributed to invasive infections. In 46 cases of invasive infections (35%) GAS were isolated. 22 different emm-types of invasive GAS strains were detected. Only speB gene among all the toxin genes (as well as the expression of the gene--SpeB toxin) was detected in all the strains, whereas sla and speI genes were not detected in any of the strains. Genes of the other toxins (ssa, speL, speC, speA, speH, speC/J) occurred in a number of strains. Genes of phage integrases were detected among all the strains however in varying combinations (from 1 to 4 genes). CONCLUSION: Invasive infections caused by GAS are more frequently spread than had been previously assumed and a high degree of genetic heterogeneity of invasive GAS strains was detected.

Enhanced interaction between a mechanical oscillator and two coupled resonant electrical circuits.

This paper reports result of calculation and experimental realization of an electromechanical system that consists of a high-Q mechanical oscillator parametrically coupled in the manner of a capacitive transducer with a radio frequency (RF) circuit, which is in turn inductively coupled with another RF circuit. The system operates in the resolved sideband regime when the mechanical oscillator's frequency is larger than the electrical circuits' bandwidths. Using two coupled RF circuits allowed one to enhance the interaction between them and the mechanical oscillator which is one of flexural vibrational modes of a free-edge circular silicon wafer. Such a coupled electromechanical system can be used as a high-sensitive capacitive vibration sensor.

Surface vibrational modes in disk-shaped resonators.

The natural frequencies and distributions of displacement components for the surface vibrational modes in thin isotropic elastic disks are calculated. In particular, the research is focused on even solutions for low-lying resonant vibrations with large angular wave numbers. Several families of modes are found which are interpreted as modified surface modes of an infinitely long cylinder and Lamb modes of a plate. The results of calculation are compared with the results of the experimental measurements of vibrational modes generated by means of resonant excitation in duraluminum disk with radius of ≈90 mm and thickness of 16 mm in the frequency range of 130-200 kHz. An excellent agreement between the calculated and measured frequencies is found. Measurements of the structure of the resonant peaks show splitting of some modes. About a half of the measured modes has splitting Δfsplit/fmode at the level of the order of 10(-5). The Q-factors of all modes measured in vacuum lie in the interval (2…3)×10(5). This value is typical for duraluminum mechanical resonators in the ultrasonic frequency range.

Computer evaluation of drug interactions with P-glycoprotein.

The (Q)SAR models for evaluating the structure-property relationships, fit for prediction of drug interactions with P-glycoprotein as inhibitors or substrates, were constructed using PASS and GUSAR software. The models were constructed and validated on the basis of information on the structure and characteristics of 256 and 94 compounds used as P-glycoprotein substrates and inhibitors, respectively. The initial samples were divided 80:20 into training and test samples. The best prediction accuracy for the test samples was 78% for P-glycoprotein substrate prediction (PASS) and 89% for inhibitor prediction (GUSAR).

[A method for differential identification of group C and G streptococci with PCR].

The paper describes a rapid method for PCR identification of Groups C and G streptococci (Streptococcus dysgalactiae subspecies equisimilis, Streptococcus constellatus, and Streptococcus anginosus) that cause human disease. Species-specific regions of the cpn60 gene encoding heat shock protein GroEL (HSP60) were chosen as markers for PCR diagnosis; three pairs of primers were constructed for these regions, each of which was peculiar to the specific type. The method was tested on a large collection of pathogenic streptococci of different serogroups isolated from man and animals; its specificity was shown to identify S. dysgalactiae subsp. equisimilis, S. constellatus, and S. anginosus. The proposed method has all benefits of PCR-based techniques, which enables it to be used for the purposes of molecular epidemiology.