International Journal of Risk & Safety in Medicine - Volume 27, issue s1

Article Type: Other

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S63-S63, 2015

Authors: Yarullina, D.R. | Damshkaln, L.G. | Bruslik, N.L. | Konovalova, O.A. | Ilinskaya, O.N. | Lozinsky, V.I.

Article Type: Abstract

Abstract: BACKGROUND: Probiotics are live microorganisms, generally either lactobacilli or bifidobacteria, which when administered in adequate amounts confer a health benefit to the host [1 ]. Due to the growing evidence of health benefits associated with their use, probiotics are of increasing interest and represent now a significant growth area in the functional foods industry [2 ]. However, to be effective, orally administered probiotics should survive preparation of dosage forms and passage through acidic environment of the gastrointestinal tract (GIT). Reaching the intestine, these microorganisms should be able to establish themselves, remain viable and perform their beneficial actions. In this context, …oral formulations have to protect probiotic bacteria from gastric acidity and delay their release in the small intestine in order to allow their complete release in the colon. OBJECTIVE: To evaluate effects of starch formulations of lactobacilli on their survival in gastric environment and probiotic properties. METHODS: Nineteen Lactobacillus strains belonging to the species L. fermentum (14 strains), L. plantarum (4 strains), and L. rhamnosus (1 strain), were isolated from dairy products and probiotics, and were used in this study. Lactobacilli were cultured in de Man, Rogosa, Sharpe (MRS) broth (Merck, Germany) under microaerobic conditions at 37°C. Amylolytic activity of lactobacilli, cultured for 3–5 days on MRS agar supplemented with 1% soluble potato starch (SPS), was determined with iodine reagent (0.01 M I2 -KI solution). Loading in starch was performed with L. plantarum 8PA3 bacteria (“Dry lactobacterin”, Perm, Russia), which were resuspended to the concentration 1010 cells/mL in 10 mL of 0.85% NaCl solution and added to 90 mL of 2.5% SPS solution. Resulting mixture was frozen at –18°C and then lyophilized (Martin Christ Alpha 1-2 LDplus, Germany). Atomic force microscopy (AFM) images of formulated L. plantarum 8PA3 cells were acquired in air by a Solver P47H atomic force microscope (NT-MDT, Moscow, Russia). Starch swelling and dissolution was studied in simulated colonic fluid (SCF), prepared according to [3 ] and in distilled water (pH = 6.0) as control. Amylase from Aspergillus oryzae (A8220, Sigma) was added to the solutions to study the influence of amylase. The formulation form was examined visually during 14 h incubation time. Fluorescence microscopy images were obtained with a Leica DM6000B (Germany) fluorescent microscope using Leica FW4000 software. L. plantarum 8PA3 loaded in SPS were placed either in HCl solution (pH 2), or in 2% oxgall bile solution, or in 0.85% NaCl solution. Viability was tested after 2, 4 and 6 h incubation at 37°C by plating diluted aliquots onto MRS agar with subsequent counting of bacterial colony forming units (CFU). In addition, viability was determined using LIVE/DEAD Bac Light bacterial viability kit L-7012 (Molecular Probes, Invitrogen) as described elsewhere [4 ]. Fluorescence in the stained samples was estimated with BD FACS Canto II (USA) flow cytometer or fluorescent microscope. Nitric oxide (NO) production was assessed with DAF-FM DA and DAA fluorescent dyes as described earlier [4 ]. Each experiment was performed in triplicate. RESULTS: In the present study we studied the probiotic composition comprising of SPS and bacteria L. plantarum 8PA3. We used AFM to confirm effective fixation of the cells to carbohydrate. The compositions were found to swell quickly (~5 min) in aqueous solutions either containing amylase, or not. Tested starch formulations disintegrated during the first 5-10 min of incubation in amylase solutions whereas in amylase-free probes dissolution was less intensive (after ~30 min). Amylolysis of starch excipients was less pronounced in aqueous amylase solution than in SCF, supplemented with amylase. None of 19 studied Lactobacillus strains hydrolyzed SPS when growing on MRS agar supplemented with it. The amount of viable L. plantarum 8PA3 cells formulated with SPS was high and did not change when stored for 6 months at 4°C. The bacterial viability tests also demonstrated that after 6 h treatment with 2% bile or HCl (pH 2) L. plantarum 8PA3 exhibited increased sensitivity (viability 14% and 0.4%, respectively). However, in similar conditions no significant differences were noticed between bacterial viability obtained for formulated with starch and non-formulated bacteria. Furthermore, we showed that loading into SPS had no effect on bacterial production of nitric oxide (NO) – a pluripotent regulatory molecule in human organism. CONCLUSIONS: Overall, the results strongly support that formulation with polymeric matrices on the basis of SPS represent an appealing technology of probiotics production. It provides slow release of bacteria in target environment and does not alter their viability and NO biosynthesis. However, SPS excipient does not preserve the bacteria from harsh conditions of upper GIT. Therefore, we conclude that for oral administration the composition should be loaded in acid-resistant capsules. Show more

Keywords: Probiotic, polymeric matrix, composition, soluble potato starch

DOI: 10.3233/JRS-150692

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S65-S66, 2015

Authors: Valeeva, I.Kh. | Titarenko, A.F. | Khaziakhmetova, V.N. | Ziganshina, L.E.

Article Type: Abstract

Abstract: BACKGROUND: It is believed that the anti-inflammatory activity of medicines is closely related to their antioxidant activity. However, in clinical practice rigorous evidence-based medicine approach fails to reveal important effects of antioxidants on patient important outcomes in inflammatory disorders, as has been shown by a number of Cochrane reviews [1–3 ]. OBJECTIVE: To evaluate anti-inflammatory and antioxidant effects of newly developed pharmacological agents: dimephosphone and its structural analogues ephorane and mephoprane, and xymedon, in comparison with prednisolone and etidronate in experimental animal model of adjuvant arthritis. METHODS: Experiments were conducted in 64 white mongrel rats of …both sexes weighing 180–200 g, which were divided into 8 groups 8 rats each (4 males and 4 females each), kept under standard vivarium conditions with certified feeding ration (kombikorm). The study was approved by the local ethics committee. We induced adjuvant arthritis by administration under the plantar aponeurosis of the left hind paw of 0.1 ml of Freund’s adjuvant (Sigma) in rats of 7 study groups. The groups were as follows: 1st group - intact animals (control); 2nd group – animals to whom the solvent (distilled water) was administered with intra-gastric tube in corresponding volume (control of the model); 3rd – 8th study groups, in which animals were administered with study agents each at a dose of 1 mmol/kg body weight: dimephosphone, ephorane, mephoprane, xymedon, etindronate and prednisolone. The intensity of the modeled arthritis was determined by measurements of paw volumes with plethysmometer (UgoBasile). We calculated the difference in rat paw volume before the administration (baseline) and after administration of Freund’s adjuvant at 3, 7, 11, 15, 20, 27, 31, 38, 41 days. The development of secondary arthritis was documented by the increase in volume of both hind and fore paws and tails. On the 41st day of the experiment the animals were sacrificed under light ether anesthesia and exsanguinated. The blood was used to determine the activity of catalase and peroxidase, the content of the total, reduced and oxidized glutathione, the level of ceruloplasmin, conjugated dienes of unsaturated fatty acids (DC), TBA-interacting products (MDA), and the total antioxidant activity of serum (AOA). The results were processed statistically using the Student’s t -test. RESULTS: The primary reaction to the Freund’s adjuvant in a form of swelling of the ankle joint of the left hind paw was observed at 24 hours after its injection. External clinical manifestations of the modeled disease were more pronounced on the third day: local inflammatory reaction (redness, swelling, ulceration) was seen in all the animals at the injection site with the increase of the paw volume. On the 11th day of the experiment 20% of the animals developed secondary arthritis. The study agents dimephosphone, ephorane, and prednisone exerted anti-inflammatory effect decreasing the volume of left hind paws by 45%, 46% и 27% respectively on the 40th day of experiment. Mephoprane did not affect the primary inflammatory response to the Freund’s adjuvant (rats’ left hind paws), however it reduced the volume of the contralateral right paw (secondary arthritis) by 90% on the 20th day of the experiement. This ant-inflammatory effect was accompanied by documented antioxidant activity in case of dimephosphone, ephorane, prednisolone, but not mephoprane. Dimephosphone reduced the levels of lipid peroxidation products in rats blood by 46% (DC) and by 25% (MDA). Ephorane also reduced the levels of lipid peroxidation products in the blood by 46% (DC) and by 25% (MDA), increasing the level of glutathione by nearly half, both the total and the reduced form. Prednisolone reduced the level of lipid peroxidation products in blood by 61% (DC), but not the TBA-interacting products. Mefopran did not affect the blood level of lipid peroxidation products. Xymedon and etidronate showed no anti-inflammatory effect. Xymedon demonstrated anti-oxidant properties, decreasing the blood levels of lipid peroxidation products, while etidronate seemed to behave in pro-oxidant mode, increasing the blood levels of lipid peroxidation products. CONCLUSIONS: The effects of studied agents on the intensity of inflammation and lipid peroxidation were inconsistent. The results of the study did not show a clear link between anti-inflammatory and anti-oxidant activity. Further research in potential anti-inflammatory activity of new drugs exhibiting antioxidant properties needs to be done before recommending their use in clinical practice. Show more

Keywords: Anti-inflammatory, anti-oxidant, rat paw oedema, arthritis

DOI: 10.3233/JRS-150693

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S67-S68, 2015

Authors: Zueva, I.V. | Semenov, V.E. | Mukhamedyarov, M.A. | Lushchekina, S.V. | Kharlamova, A.D. | Petukhova, E.O. | Mikhailov, A.S. | Podyachev, S.N. | Saifina, L.F. | Petrov, K.A. | Minnekhanova, O.A. | Zobov, V.V. | Nikolsky, E.E. | Masson, P. | Reznik, V.S.

Article Type: Abstract

Abstract: BACKGROUND: Alzheimer’s disease (AD) is the major age-related progressive neurodegenerative disorder. The brain of AD patients suffers from loss of cholinergic neurons and decreased number of synapses [1 ]. AD is caused by an imbalance between Aβ production and clearance, resulting in increased amount of Aβ in various forms [2 ]. Reduction of Aβ production and increasing clearance of Aβ pathogenic forms are key targets in the development of potential therapeutic agents for AD treatment. Unfortunately, only nosotropic approaches for treatment of AD are currently effective in humans. These approaches mainly focus on the inhibition of brain acetyl-cholinesterase (AChE) to …increase lifetime of cerebral acetylcholine [3 ]. It is important to emphasize that AChE itself promotes the formation of Aβ fibrils in vitro and Aβ plaques in the cerebral cortex of transgenic mouse models of AD [4 ]. This property of AChE results from interaction between Aβ and the peripheral anionic site of the enzyme (PAS) [5 ]. Dual binding site inhibitors of both catalytic active site (CAS) and PAS can simultaneously improve cognition and slow down the rate of Aβ-induced neural degeneration. Unfortunately, the assortment of AChE PAS ligands is still extremely limited. OBJECTIVE: To study putative advantages of AChE non-charged PAS inhibitors based on 6-methyluracil derivatives for the treatment of Alzheimer’s disease. METHODS: In vitro studies . Concentration of drug producing 50% of AChE/BuChE activity inhibition (IC50) was measured using the method of Ellman et al. [6 ]. Toxicological experiments were performed using IP injection of the different compounds in mice. LD50, dose (in mg/kg) causing lethal effects in 50% of animals was taken as a criterion of toxicity [7 ]. The ability of compound to block in vitro AChE-induced Aβ1–40 aggregation was studied using a thioflavin T (ThT) fluorescent probe [8 ]. In vivo biological assays . For in vivo blood–brain barrier permeation assay brains were removed 30 min after IP injection of LD50 dose of tested compound injection. The inhibitory potency was measured using the method of Ellman. Scopolamine and transgenic models of AD were used to evaluate the influence of compound 35 on spatial memory performance.Water solution of scopolamine was injected to mice (ip) 20 minutes before starting memory test during 14 days [9 ]. Mice were assigned to 7 groups, including 4 groups receiving injection (ip) of compound in different dosages, donepezil-treated mice (donepezil is conventionally used to treat Alzheimer’s disease), positive and negative control groups. Double transgenic (APP/PS1) mice expressing a chimeric mouse/human amyloid precursor protein and a mutant of human presenilin-1 [10 ] were assigned to 4 groups, including transgenic animals injected (ip) with compound 35 or donepezil solution, positive (transgenes injected with water) and negative (wild-type mice) controls. To evaluate spatial memory performance, mice were trained on a reward alternation task using a conventional T-maze [11 ]. The criterion for a mouse having learned the rewarded alternation task was 3 consecutive days of at least 5 correct responses out of the 6 free trials. For β-amyloid peptide load was evaluated quantitatively as a number and summary area of Thioflavine S fluorescent spots in cerebral cortex and hippocampal images using Image J program. Statistical analyses were performed using the Mann-Whitney test. RESULTS: We evaluated the acute toxicity of the most active compounds. The most potent AChE inhibitor compound 35 (IC50 (AChE) = 5 ± 0.5 nM) exhibited the lowest LD50 values (51 mg/kg) and inhibited brain AChE by more than 71 ± 1%. Compound 35 at 10 nM, exhibited a significant (35 ± 9%) inhibitory activity toward human AChE-induced Aβ aggregation. Scopolamine injection induced significant decrease in correct choice percentage in T-maze, as well as decrease in percentage of mice reaching criterion for learning the task by day 14. This memory deficit was relieved to some extent either by compound 35 (5 mg/kg) or donepezil (reference compound) treatment (0.75 mg/kg). Interestingly, higher doses of compound 35 (10 and 15 mg/kg) produced less therapeutic effect on spatial memory deficit. Group of APP/PS1 mice showed 3 times lower percentage of reaching behavioral criterion and lower percentage of correct choice in T-maze alternation task comparing to WT mice, whereas compound 35 (5 mg/kg) or Donepezil treatment effectively improved these parameters in APP/PS1 mice. Compound 35 treatment (5 mg/kg) during 14 days significantly reduced percentage of summary area and number of β-amyloid peptide (βAP) deposits visualized in sections of cerebral cortex, dentate gyrus, and hippocampal CA3 area in APP/PS1 mice. The most prominent reduction of βAP load by compound 35 treatment was found in CA3 area and cerebral cortex. Meanwhile, Donepezil treatment (1 mg/kg) during 14 days significantly reduced βAP load in cerebral cortex but not in dentate gyrus and CA3 area. CONCLUSIONS: Experiments showed that the most potent AChE inhibitor compound 35 (6-methyluracil derivative) permeated the blood-brain barrier, improved working memory in the APP/PS1 transgenic mice and significantly reduced the number and area of Aβ plaques in the brain. Thus, compound 35 is a promising candidate as a bi-functional inhibitor of AChE for treatment of AD. Show more

Keywords: Alzheimer’s disease, acetyl-cholinesterase inhibitors, methyluracil derivatives

DOI: 10.3233/JRS-150694

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S69-S71, 2015

Authors: Petrov, K.

Article Type: Abstract

Abstract: BACKGROUND: Acetylcholinesterase (AChE) inhibitors are widely used in medicine for pharmacological correction of cholinergic neurotransmission pathologies such as myasthenia gravis (MG) and Alzheimer’s disease [1, 2 ]. The efficacy of anti-AChE drugs is based on their ability to potentiate the effects of acetylcholine (ACh) due to a decrease in the rate of AChE-catalyzed hydrolysis of ACh. Crystallographic studies showed that the active site of AChE is located at the bottom of a deep gorge [3 ]. It was shown that, in addition to its catalytic center, AChE has other sites that are crucial for the proper functioning of the enzyme. …In particular, the so-called peripheral anionic site (PAS) located at the entrance of the active site gorge is responsible for: 1) allosteric modulation of the catalytic center; 2) enzyme inhibition at high substrate concentration; 3) and non-catalytic functions such as enhancement of cell adhesion and neurite outgrowth. OBJECTIVE: Especially interesting is the relationship between the PAS and pathological beta-amyloid deposition. This led to a new hypothesis for rational design of more effective anti-Alzheimer drugs [4 ]. METHODS: Concentration of drug producing 50% of AChE activity inhibition (IC50) was measured using the method of Ellman et al. [5 ]. Toxicological experiments were performed using IP injection of the different compounds in mice. LD50, dose (in mg/kg) causing lethal effects in 50% of animals was taken as a criterion of toxicity [6 ]. Molecular docking was performed with Autodock 4.2.6 software. RESULTS: We described previously a new class of selective mammalian AChE vs. butyrylcholinesterase (BChE) inhibitors based on alkylammonium derivatives of 6-methyluracil of acyclic topology [7 ]. In the present study, taking acyclic derivatives of 6-methyluracil as a model AChE inhibitor, we attempted to develop AChE inhibitors that specifically bind to the PAS with weak binding to the active site of AChE. We attempted to increase the size of AChE ligands to restrict specific binding to the PAS of AChE. To this aim we synthesized pyrimidinophanes bearing two o-nitrobenzylethyldialkylammonium heads. Almost all of synthesized pyrimidinophanes inhibited AChE in the nanomolar range. Based on molecular docking simulations, it was suggested that compounds bind AChE to the active center as well as to the PAS or only to the PAS. Thus, we found that introduction of the spacer, flexible or rigid, between [5-(o-nitrobenzylethylammonium)pentyl] units at N atoms of the 6-methyluracil moiety allows tuning the binding of 6-methyluracil derivatives with AChE. CONCLUSIONS: In conclusion, it can be stated that pyrimidinophanes are promising lead scaffold structures for further design of specific ligands for the PAS of AChE. Also AChE inhibitors with a 6-methyluracil moiety may be considered as potential drugs for the treatment of pathological muscle weakness syndromes. Show more

Keywords: Pyrimidinophanes, beta-amyloid, peripheral anionic site, acetylcholinesterase

DOI: 10.3233/JRS-150695

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S72-S73, 2015

Authors: Lushchekina, S. | Kots, E. | Kharlamova, A. | Petrov, K. | Masson, P.

Article Type: Abstract

Abstract: BACKGROUND: Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disorder characterized by fluctuating weakness of voluntary skeletal muscles. The cause of autoimmune response is unknown and only symptomatic therapies for MG are currently available. Pharmacological correction of synaptic failure underlying MG, involves partial inhibition acetyl- and butyrylcholinesterase. Effectiveness of cholinesterase inhibitors in the symptomatic treatment of MG is based on their ability to potentiate the effects of acetylcholine by decreasing the rate of its enzymatic hydrolysis at neuromuscular junctions. Several new inhibitors of AChE were tested in animal model of MG and may be considered as valuable candidates for …the treatment of pathological muscle weakness syndromes. In this study, we have investigated mechanisms of ChE inhibition by one of the most active 6-methyluracil derivatives (C547), as well as the possible benefits of using this compound for MG treatment compared to traditionally used pyridostigmine bromide. It was experimentally shown that C547 is a «pseudo-irreversible» slow-binding inhibitor of human AChE. Human BChE is reversibly inhibited by C547 with an affinity about 4 orders of magnitude lower than that of human AChE. Slow-binding inhibition of AChE leads to a lasting (over 24 hours) effect on the symptoms of muscle weakness in animal model of MG after a single administration of C547. OBJECTIVE: The aim of the present molecular modeling study was to reveal mechanism of AChE inhibition by C547 and elucidate its apparent «pseudo-irreversibility». METHODS: Two principle methods used in the present study were molecular docking and molecular dynamics (MD). Molecular docking was performed with Autodock 4.2.6 software, Lamarckian Genetic Algorithm to obtain structure of protein inhibitor complexes and Local Search for MD snapshots to compare relative binding affinity. For MD simulations NAMD 2.10 software with Charrm 36 force field was used, for the ligand C547 Charmm General Force Field was used, and missing parameters were obtained with quantum mechanical calculations. Unconstrained MD, steered MD (SMD) and free energy calculations with adaptive biasing force were performed. RESULTS: During unconstrained MD, C547 very rapidly binded to the peripheral anionic site (PAS) of AChE. To pass the bottleneck, application of the external force was required (SMD). Both SMD modelling and free energy calculation revealed that after crossing the AChE bottleneck, C547 falls into very favorable position. At the same time the rupture of interactions as well as overcoming the bottleneck gates in the course of pulling out procedure requires application of much higher force than during the pulling-in process. This difference between binding and dissociating processes explains apparent «pseudo-irreversibility» of the inhibitor. CONCLUSIONS: These findings are in good agreement with kinetics study showing that C-547 is a slow-binding inhibitor of type B, i.e. after rapid initial binding of inhibitor, the enzyme-inhibitor complex undergoes an isomerization step. Position obtained by SMD is in good agreement with X-ray data obtained by F. Nachon, IBS, France. Show more

Keywords: Molecular modeling, myasthenia gravis, slow-binding, inhibitor, acetylcholinesterase

DOI: 10.3233/JRS-150696

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S74-S75, 2015

Authors: Cong, H.H. | Khaziakhmetova, V.N. | Zigashina, L.E.

Article Type: Abstract

Abstract: BACKGROUND: Non-steroidal anti-inflammatory agents (NSAIDs), steroids and representatives of other pharmacological groups [1, 2 ] are widely used for pharmacological regulation of inflammation. However, their anti-inflammatory effects are accompanied by serious adverse reactions [3, 4 ]. There was a hope that newer NSAIDs, selective inhibitors of COX-2, would be safer, but their longer-term use appeared to cause an increased risk of heart attacks and stroke [5 ]. Carrageenan rat paw oedema model is traditionally used for search and development of new NSAIDs with assessment of effects after 3 to 5 hours after oedema induction [6, 7 ], neglecting longer-term effects …[8 ]. OBJECTIVE: To compare effects of traditional NSAIDs (indomethacin, naproxen) on the development, duration and intensity of carrageenan rat paw oedema. METHODS: Carrageenan paw oedema was induced in 18 rats by sub-plantar injection into the right hind paw of the animals of 0.1 ml of 1% aqueous gel of carrageenan-λ (22049 SIGMA λ-Carrageenan plant-mucopolysaccharide, Sigma-Aldrich). We assessed the intensity of the oedema development and its duration by measurements of rat paw volume using plethysmometer 37140 (UgoBasile, Italy). Measurements were made prior to induction of oedema (base-line volume) and at 1, 2, 3, 4, 5, 24, 48, 72, 96, 120, 144, 168 and 192 hours after sub-plantar carrageenan injection. Calculating the percentage of increase in paw volume assessed the intensity of the oedema. The base-line paw volume was taken for 100%. Animals were divided into 3 groups of 6 rats each; group 1: control (solvent); group 2: naproxen 15 mg/kg and group 3: indomethacin 10 mg/kg. These doses are known as ED50 (effective doses 50) on carrageenan rat paw oedema with single-dose NSAIDs administration [9 ]. To get the most accurate estimate of the intensity of the simulated by carrageenan inflammatory response and the potential effects of some NSAIDs with their longer-term use we calculated areas under the curve «increase in paw volume – time» using standard method of numerical integration - trapezoidal method. Statistical analysis was performed using Microsoft Office Excel 2007 with the calculation of arithmetic means M, their standard deviations (δ) and standard errors (m). We applied Student’s t -test and accepted as significant the differences with P values equal to or less than 0.05. RESULTS: The inflammatory reaction induced by carrageenan, developed in a form of swelling/oedema with an increase in the rat paw volume up to 55% of the baseline volume. The maximum volume of oedema was observed in the control group at 3 h after the injection of carrageenan, which is in accordance with the literature data on the development of carrageenan paw edema in rats [10, 11 ]. Naproxen at a dose of 15 mg/kg showed anti-inflammatory activity at 1, 2, 3, 4 and 5 hours after administration of carrageenan with suppression of oedema development by 59, 81, 73, 60 and 39% (p = 0.03; 0.001; 0.001; 0.001 and 0.01), respectively. There was no oedema inhibition by naproxen at later time-points. Indomethacin at a dose of 10 mg/kg showed anti-inflammatory effect at 2, 3, 4, and 5 hours after carrageenan oedema induction with inhibition of oedema development by 54, 54, 54 and 33% (p = 0.01, 0.004, 0.001 and 0.01) respectively. Again there was no oedema inhibition by indomethacin at the later time-points. When comparing the calculated areas under the curve «increase in paw volume – time» we found no differences between the values of control and study groups: naproxen (15 mg/kg) and indomethacin (10 mg/kg). We think that these values of areas under the curve «increase in paw volume – time» represent the total inflammatory reaction induced by carrageenan and need to be used for the assessment of future potential anti-inflammatory agents which should not only produce short-term symptomatic oedema suppression, but change the nature of the oedema response, potentially with alternative mechanisms of action. Our experimental findings are in accordance with the well-known lack of effects of NSAIDs on the outcomes of chronic inflammatory diseases [12 ]. This may be due to the fact that they suppress the development and symptoms of inflammation at the early stages, but the reaction to inflammatory stimuli develops fully over the longer period of time and takes its full course nonetheless. This proves that traditional modeling approaches to future potential anti-inflammatory agents development needs re-assessment. CONCLUSIONS: Single-dose administration of naproxen (15 mg/kg) or indomethacin (10 mg/kg) exerts decrease in rat paw oedema volume at no later than 5 hours after oedema induction by carrageenan. Evaluating anti-inflammatory activity by the areas under the curve «increase in paw volume – time» proves that a single-dose NSAID’s administration has no effect on the inflammatory response when evaluated not by single time-point index (at 3 or 5 hours), but by assessing the oedema development and duration over 192 hours (8 days). Show more

Keywords: Rat paw oedema, NSAIDs, timing of effects, anti-inflammatory

DOI: 10.3233/JRS-150697

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S76-S77, 2015

Authors: Vyshtakalyuk, A.B. | Nazarov, N.G. | Zobov, V.V. | Semenov, V.E. | Galyametdinova, I.V. | Tcherepnev, G.V. | Reznic, V.S.

Article Type: Abstract

Abstract: BACKGROUND: Research and development of effective hepatoprotective medicines is one of the priority areas of research in Russia. Literature data shows that active research and development of hepatoprotectors is carried out both in Russian and other countries [1–6 ]. Pirimidines are used as hepatoprotective medicines stimulating protein synthesis and reparation of hepatocytes in toxical and infectious liver disorders [7 ]. In our previous work ee have shown hepatoprotective properties of pyrimidine derivative, named Xymedon [8 ]. This research, funded by the Russian Science Foundation, is aimed at identifying the most effective hepatoprotectors among pirimidine derivatives. OBJECTIVE: To test …hepatoprotective properties of one of the new Xymedon (Xym) derivative - L-ascorbate 1-(2-hydroxyethyl)-4,6-dimethyl-1,2-dihydro-pirimidine-2-one (Asc-Xym) on the toxic liver damage model induce by carbon tetrachloride (CTC, CCl4 ). METHODS: The toxic liver damage in rats was modeled by subcutaneous injection of CTC (CCl4 ) in vegetable oil (mixed at 1:1 ratio) at a dose of 2 ml per kg. The experiments were carried out under two schemes: 1) oral administration of Xym or Asc-Xym preparations by gavage at the doses of 10 and 20 mg/kg followed by subcutaneous injection of CTC 1 hour after pyrimidine oral administration and continued for 3-4 days; - this was the design of preventive pyrimidine use, 2) liver damage modeling by CTC subcutaneous injections for 3 days followed by oral administration of Xym, Asc-Xym or Thiotriazolin (Thi) preparations at the doses of 20 mg/kg for 5 days; - this was the design of therapeutic scheme. The rats of control groups were injected with CTC according to the same schemes, but did not get any preparations. We looked at some biochemical parameters of blood serum: alanine aminotran-sferase (AlAT), aspartate aminotransferase (AsAT), their ratio (de Rytis coefficient), and the total protein level as the markers of toxic liver damage. We performed statistical data analysis by rank nonparametric Mann-Whitney U-criterion for comparison of two independent groups. We evaluated pathomorphologic characteristics of liver damage on the histological slices colored with hematoxylin and eosin. RESULTS: Carbon tetrachloride (CTC) caused profound changes in the studied biochemical parameters of rats’ blood serum. The AlAT activity level in the serum of control animals in the preventive scheme was 116,23 (the median) with the lower quartile and the upper quartile of 76,96 and 211,71 U/l respectively; the AsAT level was 230,08/201,49-290,03 U/l; this was the increase in comparison with the reference values. De Rytis coefficient was 1,76 /1,47-2,67. This was the decrease in comparison with the reference values of intact group (36,37/28,18-43,3 U/l; 132,95 /118,24-164,00 U/l and 4,26/3,03-5,23 respectively). The differences were statistically significant at P < 0,001. In the experimental groups the changes of the biochemical parameters with respect to the reference values were less marked than in Control. The AlAT level was 89,86/87,06-165,15; 103,23/38,19-270,87 U/l; 80,28/6,12-141,82 and 100,33/62,24-144,64 U/l in the groups of rats treated with Xym at the doses of 10 and 20 mg/kg or Asc-Xym at the doses of 10 and 20 mg/kg respectively. Similarly, in the same groups the AsAT level was 211,19/170,20-250,16; 193,61 /181,57-274,69 U/l; 190,91 /65,21-198,65 and 173,25/135,50-210,70 U/l respectively. The differences of the AsAT level were statistically significant at P < 0,05 in comparison with Control in the both groups treated with Asc-Xym. Nnearly 2 times increase of the AlAT level (67,60/1,22-94,60 U/l) (P = 0,00002) was shown in comparison with the reference values in the rats of Control group in the therapeutic scheme. However the AsAT level (163,80/130,1-178,8 U/l) was only slightly higher than reference values. De Rytis coefficient (2,07/1,78-3,48) was significantly lower than the reference values (P = 0,001). The total protein level (59,36/55,17-60,10 g/l) was lower than the reference values (65,06/62,06-68,98 g/l) by 8,4%. The differences of biochemical parameters as compared with the reference values in rats of experimental groups treated with Xym, Thi and Asc-Xym at the doses 20 mg/kg were less than those in the Control groups. They were: AlAT 52,49/44,64-62,30 and 61,42/53,20-96,66 U/l, AsAT 105,00/94,7-142,3 and 235,35/111,7-335,6 U/l, de Rytis coefficient 2,09/1,87-2,28 and 3,24/1,86-4,53, total protein 63,10/62,46-64,27 and 62,46/58,70-64,43 g/l respectively in the groups treated with Xym and Thi. The values of the studied biochemical parameters AlAT (39,04/32,46-44,24 U/l), AsAT (111,9/105,27-155 U/l), de Rytis coefficient (2,87/2,72-3,30), total protein (62,89/61,46-68,14 g/l) of the rats, treated with Asc-Xym, were the most close to the reference values in comparison with other experimental groups. The analysis of histological slices revealed large areas of steatosis and necrosis of hepatocytes in Control groups in both schemes. These were less pronounced in experimental groups than in Control groups and particularly in rats, treated with Asc-Xym. CONCLUSIONS: Hepatoprtotective properties of the new compound L-ascorbate 1-(2-hydroxyethyl)-4,6-dimethyl-1,2-dihydropirimidine-2-one were established. The hepatoprotective efficacy of the compound is higher than that of Xymedon and Thiotriazolin. Show more

Keywords: Rats, pyrimidine, liver damage, carbon tetrachloride, biochemical markers

DOI: 10.3233/JRS-150698

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S78-S79, 2015

Authors: Lushchekina, S. | Delacour, H. | Lockridge, O. | Masson, P.

Article Type: Abstract

Abstract: BACKGROUND: Prolonged apnoea following injection of ester-containing myoralaxants was first described in 1953. Because a large part of administered succinylcholine is shortly hydrolyzed by plasma butyrylcholinesterase (BChE) under normal conditions, prolonged apnoea was attributed to deficiency in BChE. It was found that BChE deficiency was due to genetic variations. Human BChE gene shows a large polyallelism. About 75 natural mutations of the BCHE gene have been documented so far [1 ]. Most of them cause alteration in BChE activity through point mutation effect on catalytic activity. Frame shifts and stop codons may also affect expression, or cause truncations in …the sequence. OBJECTIVE: Recently, two novel BChE “silent” variants, Val204Asp [2 ] and Ala34Val [3 ], causing prolonged neuromuscular block after administration of mivacurium, were discovered. Mutations were genetically and kinetically characterized. The aim of the current study was to understand how these mutations determine “silent” phenotype. METHODS: Molecular dynamics studies were carried out with NAMD 2.9 software at the Lomonosov supercomputer. Charmm 36 force field was used, periodical boundary conditions, 1 atm pressure, 298 K. 100 ns molecular dynamics runs were performed for the wild-type BChE and its mutants Val204Asp and Ala34Val. RESULTS: Unlike wild-type BChE, which retained its operative catalytic triad through the whole MD simulation, the catalytic triad of mutants was disrupted, making chemical step impossible. Val204Asp mutation leads to reorganization of hydrogen bonding network around the catalytic triad, which in turn increases the distance between catalytic residue main chains. Mutation Ala34Val, located on the protein surface, leads to increased fluctuations in the Ω-loop and subsequent disruption of the gorge structure, including disruption of the catalytic triad and formation of new hydrogen bonds involving catalytic center residues. CONCLUSIONS: Comparative study of the “silent” Ala328Asp mutant and the catalytically active mutant Ala328Cys shows that MD approach can discriminate between the differential effects of point mutations at a same position. Show more

Keywords: Genetic, polymorphism, butyrylcholinesterase, molecular modeling, allelozymes

DOI: 10.3233/JRS-150699

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S80-S81, 2015

Authors: Gabdrakhmanov, A.I. | Khayrullin, A.E. | Grishin, C.H. | Ziganshin, A.U.

Article Type: Abstract

Abstract: BACKGROUND: Extracellular purine compounds, adenosine triphosphate (ATP) and adenosine, are involved in regulation of many cell functions, engaging in rapid and long-term cellular processes. The nucleotides, including ATP, exert their extracellular effects by influencing membrane P2 receptors. ATP outside of the cell rapidly is metabolized by the ecto-enzyme system to produce adenosine, which acts on separate adenosine (P1) receptors. Since adenosine and ATP often are functional antagonists, ATP degradation not only limits its effect, but also brings new ligand with different, often opposing, properties. Great variety and widespread of P2 and adenosine receptors in the body emphasize the important physiological …and pathophysiological significance of these receptors, and make them very attractive as targets for potential drug action. The existence of several subtypes of P2 and adenosine receptors has been shown in the skeletal muscles. ATP as a co-transmitter is densely packed together with classical neurotransmitters in the presynaptic vesicles of vertebral motor units but until recently ATP was refused to have its own functional role there and was recognized only as a source of adenosine. However, on the eve of the third millennium there appeared data that ATP, released from the nerve ending and acting on presynaptic P2 receptors, suppresses subsequent quantum release of acetylcholine. The final product of its degradation, adenosine, performs a similar inhibitory effect acting on presynaptic adenosine receptors. Despite the fact that the mechanisms of presynaptic inhibitory action of ATP and other purines were studied earlier, the object of those studies was usually neuromuscular synapse of cold-blooded animals. The few studies, in which experiments were carried out on preparations of warm-blooded animals, described the basic effects of purines. These often were guided by the convenience of preparation of the synapses of the diaphragm. We think that those results cannot be considered as typical effects of ATP and other purines on skeletal muscles and could not be extrapolated to all warm-blooded animals. Furthermore the role of ATP and its derivatives in the accumulation of vertebrate muscular effort has not been investigated. It is known that in physiological conditions vertebrates may mobilize only up to a third of the maximum muscle force. Why the two-thirds of muscular strength are not used normally but may be used at stress, remains unknown. It is known that the body’s adaptive response to stress is a change in the activity of the endocrine system. The leading role in this is given to catechol amines and glucocorticoids, mobilized in significant quantities in blood under stress. We have found previously that incubation of frog sartorius muscle with hydrocortisone resulted in a decrease of contraction amplitude. However, when hydrocortisone was used in combination with ATP, its inhibitory effect on contractile responses disappeared. It is interesting that hydrocortisone had no effect on the inhibitory effect of adenosine. In the following experiments, assessing the effect of hydrocortisone on rat soleus muscle, it was established that hydrocortisone and purines had similar inhibitory effect. When ATP and hydrocortisone were given together the same oppression occurred. OBJECTIVE: To study the effects of ATP and adenosine on contraction parameters of rat skeletal muscle and assess the impact of the catechol amines on these processes. METHODS: Contractions of rat soleus muscles were recorded isometrically by mechanical sensor Linton FSG-01 (UK) according to standard procedures. The average of muscle parameters received within 30 seconds (30 responses) was treated as one result. Amplitude and time characteristics of the curve reductions were estimated. During all experiments standard Krebs solution flowed through the bath continuously to which agents were added at necessary concentrations. All experimental animals were maintained and prepared for dissection under the European Convention for the Protection of Vertebrate Animals used in scientific experiments. All agents used in the study were supplied by Sigma Chemical Company Ltd. (UK), Tocris Cookson and Research Biochemicals International (USA). RESULTS: The concentration of 100 μM for adenosine is close to saturation [1 ], and for its predecessor ATP this concentration is created after the passage of a pulse through the synapse [2 ]. We used this concentration of purines to study the mechanism of action of adenosine and ATP on neuromuscular synapse. The effect of adenosine was partially inhibited in the presence of 100 μM 8-SPT, an antagonist of adenosine receptors. The contraction force of "fast" and "slow" rat skeletal muscles was raised by half in the presence of norepinephrine. In the presence of norepinephrine adenosine exerted its effect fully, but ATP by half reduced its depressor effect on the contraction force of both muscles. CONCLUSIONS: 1. Norepinephrine increases half times of the reduction of “fast” and “slow” skeletal muscle. 2. In the presence of norepinephrine, inhibitory effect of adenosine on contraction force is maintained. 3. Inhibitory effect of ATP on contraction force of studied skeletal muscles becomes twice less pronounced in the presence of norepinephrine. We think that reduction of ATP depressive effect on the skeletal muscle by norepinephrine may be an adaptive response to acute stress. Show more

Keywords: Norepinephrine, effect of ATP, rat, skeletal muscle, neuromuscular synapse

DOI: 10.3233/JRS-150700

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S82-S83, 2015

Article Type: Other

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S85-S85, 2015

Authors: Egorova, S.N. | Akhmetova, T.

Article Type: Abstract

Abstract: BACKGROUND: The number of pharmacies, which produce drug formulations locally, has recently considerably reduced in Russia. Pharmacies mainly operate as retailers of industrially manufactured drugs. Pharmaceutical consultation of customers at pharmacies aimed at responsible self-medication is the most popular and accessible feature of pharmaceutical care. In Russia there is a significant list of medicines approved for sale in pharmacies on a non-prescription basis that is specified in the product label. In this regard, the role of pharmacists in public health in Russia increases. Pharmacist, working directly with population, is an important figure for the rational use of medicines. This type …of work requires high level of professional training and appropriate ethics. OBJECTIVE: To explore the current status of pharmaceutical counseling in Russia. METHODS: Situation analysis, surveys of pharmacists. RESULTS: Our experience in the system of postgraduate professional education, the results of the survey of pharmacists, and the long-term dialogue with pharmacists allowed us to identify several unresolved issues in the work of a pharmacist selling non-prescription drugs. Lack of differentiation in the functions of a pharmacist with a higher education and pharmaceutical technologist : In production/industrial pharmacy technicians are engaged in manufacturing of pharmaceutical formulations. However, due to the loss of production functions technologists had to move away from production laboratories of apothecaries to the sales area. Currently, the apothecary's assignment to receive prescriptions and dispense medications can be fulfilled by either a pharmacist or a pharmaceutical technician. It significantly discerns the pharmacy from the medical organization with clearly delineated functions of doctors and nurses. Russian regulations should consider the level of education required for high-quality pharmaceutical counseling. Contradiction between the pharmacist’s special functions and trade procedure with the lack of pharmaceutical counseling standards : Article 1.1 “Code of Ethics of the pharmaceutical worker of Russia” states: “The main task of the professional activity of the pharmaceutical worker - protection of human health ”, Article 1.3 states that a pharmaceutical worker must take professional decisions solely in the interests of a patient [1 ]. However, the pharmacy is a trade organization, thus as a retailer the pharmacy is directly interested in making profits and increasing sales of pharmaceutical products, including non-prescription medicines. Moreover, while the clinical medicine is monitored for unjustified prescribing and measures are being taken to prevent polypharmacy, for a pharmacist the growing sales of over-the-counter drugs, active promotion of dietary supplements, homeopathic medicines, medical devices, and, consequently, an increase of financial indicators (particularly “average purchase size”) – all are characteristics of success [2 ]. Rational use of over-the-counter medicines requires introduction of pharmaceutical counseling standards (pharmaceutical care) according to symptoms - major reasons to visit a pharmacy as part of responsible self-medication (cold, sore throat, headache, diarrhea, etc.). Standards of pharmaceutical counseling should be objective, reliable and up-to-date and contain recommendations for the rational use of over-the-counter drugs as well as indications requiring treatment to the doctor. Standardization of pharmaceutical counseling in terms of Evidence-based Pharmacy would enhance the efficiency, safety and cost-effectiveness of over-the-counter medicines. Currently, the lack of clinical component in the higher pharmaceutical education and the lack of approved standards of pharmaceutical counseling lead to the introduction of cross-selling technologies (which are broadly applied in other areas of trade, for example, the offer of a boot-polish during the sale of shoes) to the pharmaceutical practice [2 , 3 ]. However, drugs belong to a special group of products, proper selection of which requires special education, and the consumer is not always able to evaluate the quality of the recommendations. Marketing cross-selling recommendations are aimed at promotion of the over-the-counter medicines for customers buying prescription drugs. For example, business coaches recommend the pharmacists to make additional offers: with the purchase of physician-prescribed antibiotics - offer of vitamins, with prescribed nonsteroidal anti-inflammatory drugs – commercially available ointment with non-steroidal topical formulation (“to enhance the effect”) and others. These recommendations do not agree with evidence-based medicine and lead to inefficient use of over-the-counter drugs and unjustified financial expenses. CONCLUSIONS: Thus, to ensure the rational use of medicines permitted for free (non-prescription) dispensing at the pharmacies, pharmaceutical information needs standardization on the basis of evidence-based medicine as well as standardization of the pharmaceutical counseling service. The development of practical recommendations on the rational use of over-the counter medicines by doctors and pharmacists with further adoption at the state level, the recommendation of most secure, efficient and cost-effective over-the-counter medications during pharmaceutical counseling in pharmacies will contribute to the restoration and preservation of public health. Show more

Keywords: Pharmaceutical counseling, evidence-based medicine, profits, pharmacy, pharmacist

DOI: 10.3233/JRS-150701

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S87-S88, 2015

Authors: Verbitskaya, E.V.

Article Type: Abstract

Abstract: BACKGROUND: Meta-analysis is a powerful tool to identify Evidence Based medical technologies (interventions) for use in every day practice. Meta-analysis uses statistical approaches to combine results from multiple studies in an effort to increase power (over individual studies), improve estimates of the size of the effect and/or to resolve uncertainty when reports disagree. Meta-analysis is a quantitative, formal study design used to systematically assess previous research studies to derive conclusions from this research. Meta-analysis may provide more precise estimate of the effect of treatment or risk factor for a disease, or other outcomes, than any individual study contributing to the …pooled analysis. We have quite a substantial number of Russian medical publications, but not so many Meta-Analyses published in Russian. Russian publications are cited in English language papers not so often. A total of 90% of clinical studies included in published Meta-Analyses incorporate only English language papers. International studies or papers with Russian co-authors are published in English language. OBJECTIVE: The main question is: what is the problem with inclusion of Russian medical publications in Meta-Analysis? RESULTS: The main reasons for this are the following: 1) It is difficult to find Russian papers, difficult to work with them and to work with Russian journals: a. There are single Russian Biomedical Journals, which are translated into English and are included in databases (PubMed, Scopus and other), despite the fact that all of them have English language abstracts. b. The majority the meta-analyses authors use in their work different citation management software such as the Mendeley, Reference Manager, ProCite, EndNote, and others. These citation management systems allow scientists to organize their own literature databases with internet searches and have adds-on for the Office programs what makes process of literature citation very convenient. The Internet sites of the majority of International Journals have built-in tools for saving citations to reference manager software. The majority of articles in Russian journals cannot be captured by citation management systems: they do not have special coding of articles descriptors. c. Some journals still have PDF files of the whole journal issue without dividing it into articles and do not provide any descriptors, making manual time-consuming input of information the only possibility. Moreover the context search of the article content is unavailable for search engines. 2) The quality of research . This problem has been discussed for more than twenty years already. Still we have too many publications of poor quality of study design and statistical analysis. With the exception of pharmacological clinical tails, designed and supervised by international Pharma industry, many interventional studies, conducted in Russia, have methodological flaws inferring a high risk of bias: a. Absence of adequate control, b. No standard endpoints, duration of therapy and follow up, c. Absence of randomization and blinding, d. Low power of studies: sample sizes are calculated (if calculated at all) in such a way, that the main goal is to have as small sample size as possible. Very often statisticians have to solve the problem how to substantiate a small number of subjects, that sponsor could afford, instead of calculating the needed sample size to reach enough power. e. No standards of statistical analysis. f. Russian journals do not have standards for description and presentation of study results, in particular, results of statistical analysis (a reader even cannot see what is presented: standard deviation (SD) or standard error of the mean (SEM). We have a long standing experience in analysis of methodological and statistical quality of Russian biomedical publications and have found up to 80% publications with statistical and methodological errors and high risk of bias. In our practice, we had tried to perform two Meta-analyses for two local pharmaceutical products for prevention of stroke recurrence. For the first product, we did not found even two single Russian language studies suitable for the analysis (incomparable populations, different designs, endpoints, doses etc.). For the second product, only four studies had comparable populations and standard internationally approved scales for effectiveness analysis. However, the combinations of scales, the length of treatment and follow up differed widely, so that we could combine the results of only 2 or 3 studies for each end point. CONCLUSIONS: Russian researchers have to follow internationally recognised standards in study design, selection of endpoint, timelines and therapy regimens, data analysis and presentation of results. Russian journals need to develop consolidate rules for authors of clinical trials and epidemiological research of result reporting close to international standards. In this case the international Network EQUATOR (Enhancing the QUAlity and Transparency Of health Research http://www.equator-network.org/ ) is one to be taken into account. In addition, Russian Journals have to improve their online information for better interaction with search engines and citation managers. Show more

Keywords: Meta-analysis, evidence-based medicine, Russian publications, epidemiological research, clinical trials

DOI: 10.3233/JRS-150702

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S89-S90, 2015

Authors: Abakumova, T.R. | Safina, A.F. | Ziganshina, L.E.

Article Type: Abstract

Abstract: BACKGROUND: Clinical conferences are generally defined as scheduled events at which practicing physicians themselves present to their colleagues interesting clinical cases, share their new experiences and learn about the latest achievements of medical science and practice. The value of a clinical conference is thought to be in direct communication between physicians, in analysis of topical issues in a given specialty with the aim to improve the quality of care. Speakers based on their own observations and studies reveal the most urgent problems, analyze results and offer potential decisions to their colleagues interested in the same questions. The event format may …be different: workshops, highly specialized sections, round tables and seminars with participation of the leading specialists in a given field. These conferences are generally organised by the Ministries and Departments of Health, by leading research and/or educational institutions in the field, by recognised medical centres and other institutions. Recently pharmaceutical companies got actively involved in medical events, acting as sponsors of various scientific conferences and congresses, however threatening the mission of these events [1 ]. This brings up some uneasy questions: who are the medical conferences for? Who is in charge of setting the conference agenda? Do they contribute to evidence-based medicine; do they contribute to better health? Unfortunately, there is a trend to duplication or multiplication of conferences: various agencies and departments deliver the same conferences, presentations at which are often pre-arranged by pharmaceutical companies and do not have clear scientific novelty, while the conferences themselves have largely transformed into advertising of new pharmaceuticals or new technologies [2 ]. Pharmaceutical corporations sponsor invited speakers paying for their trips and paying honoraria, organising cocktail parties as part of medical activities. With the help of leading experts with impressive titles serving as speakers at the conferences, pharmaceutical companies are trying to be as close as possible to routine practice of prescribing of certain drugs, manipulating evidence, controlling scientific societies as well as the process of clinical guideline development and publication of research results [3 ]. The degree of expert involvement depends on their level of influence [4 ]. OBJECTIVE: We aimed to study how often regular medical practitioners attend these conferences; to analyse who were keynote speakers and where they were coming from; to identify which organizations were responsible for organisation of these conferences and for sending out invitations to these conferences and for disseminating information about them. METHODS:: We summarized all the invitations (printed on paper) received by one regular medical practitioner employed with the outpatient clinical of the city of Kazan for the period of two years (2012-2013). RESULTS: During the study period (2012-2013), a regular medical practitioner received 47 printed paper invitations to scientific conferences: 22 in 2012 and 25 in 2013. The conferences were not distributed evenly over the months of the years. November appeared to be the month with the highest density/number of medical conferences: 7 conferences in 2012 and 10 in 2013. If the distribution was even, then we could calculate the number per month dividing the number per year by 9 active months (excluding July, August and September). This resulted in 2.4 and 2.8 conferences per month. Among these studied conferences 4 were organized by public health agencies: invitation tickets were accompanied by the corresponding official order to organise a conference, issued by the Health Department. Noteworthy, that 2 of these conferences were held in conference rooms of the largest hotels of the city. Forty-one out of 47 medical conferences were sponsored by big pharma: either jointly with the major medical higher educational institutions of the city or plainly by pharmaceutical companies. Seventeen conferences were held during official working hours, in the first half of the day. Not only the logo of the pharmaceutical companies was printed on invitation tickets, but there was also an advert of the promoted pharmaceutical brand. Nine conference invitations contained invitation to dinner. In one of the invitations to a conference on neuroscience it was written: “dinner under the unforgettable music”. Two conference invitations contained invitation to a lunch. Programs of 20 conferences (which were included) listed guest lecturers, coming from the leading medical universities in Moscow and St. Petersburg. Opinion leaders’ involvement: some of the leading experts acted as speakers from 4 to 7 conferences a month in this sample conference invitations package of a regular polyclinic physician. CONCLUSIONS: In 2012-2013 health practitioners were invited to attend medical conferences regularly, at least 2 times a month, with November being the busiest month. The keynote speakers were the opinion leaders from the local medical educational institutions and visitors from Moscow and St. Petersburg; their involvement with the conferences was repetitive. Governmental institutions jointly with big pharma were responsible for organisation of these conferences and attracting audience. Limitations of these observations: Unfortunately, the information on printed-paper conference invitations was not complete because not all tickets have survived. From the interview with the physician we know that in addition to these printed on paper invitations there were many invitations and alerts sent out by e-mail, SMS messages and personal phone calls, making the regularity of these conferences much higher. The physician, who kindly provided this information to us, asked not to be named or thanked in any public presentation of the results of these analyses. Show more

Keywords: Conferences, opinion leaders, health practitioners, physicians, pharmaceutical companies

DOI: 10.3233/JRS-150703

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S91-S92, 2015

Authors: Nizamov, I.G. | Sadykova, T.I.

Article Type: Abstract

Abstract: BACKGROUND: In recent years, huge efforts to improve quality control process and efficiency of healthcare were put in advancing health systems in Russia. There are measurable and noteworthy achievements, there are unresolved issues. It’s impossible to manage the process of improving the quality and efficiency of care without high-quality training of respective troops. However, in the last decade a phrase about the poor quality of postgraduate medical education has been heard periodically in the speeches of the leaders at various levels. The source is unknown, but this information continues to be spread by word of mouth as a regular component …of speeches about health issues. Considering that the “poor quality” of postgraduate education has not been substantiated by solid evidence, this informational spam, of course, needs to be overcome. It is not only harmful to health system overall, it is harmful in particular for the process of formation of personnel reserve, but it also discredits the whole system of postgraduate education and a titanic work of thousands of teachers, who work as enthusiasts, most of them performing valuable research, teaching and organizational work. OBJECTIVE: To provide situation analysis in the field of postgraduate medical education. RESULTS: First of all, it begs the question - how and who measures the quality of education. What indicators in the evaluation process are key? As a rule, when assessing quality in any field, preference is given to the opinion of the consumer. Our direct customers are the heads of health organs and institutions who regularly undergo advanced training in the specialty “Public Health and Health Care” at sub-faculty. After the completion of each cycle of training and exams, each participant fills out a questionnaire, which points out the level of quality of pedagogical activity of the sub-faculty. The analysis of these questionnaires shows that the students generally give high assessment of the quality of pedagogical process. The health authorities of subjects of Russia that send the heads of their subordinate medical organizations to study public health and healthcare are satisfied with the work of sub-faculty, professorial teaching staff, they send thank-you letters to the educational organization. In this regard, natural questions related to the overall methodology for the assessment of the quality of education in the system of postgraduate training of doctors arise, which today is still very insufficiently developed. The quality of education in the system of continuous medical education of physicians can be assessed in the following levels with the help of quality indicators, which have to be developed appropriately for each particular level. In our opinion, the following levels should be included: 1) The level of the sub-faculty 2) The level of the faculty 3) The level of the medical organization 4) The level of the territorial health authority 5) The level of the subject of the federation. CONCLUSIONS: Multidimensional assessment of the results of evaluation in the mentioned levels will allow providing an integrated assessment system of quality of continuous medical education in the country. Show more

Keywords: Continuous medical education, quality control, assessments

DOI: 10.3233/JRS-150704

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S93-S94, 2015

Authors: Kamalbekova, G. | Kalieva, M.

Article Type: Abstract

Abstract: BACKGROUND: Understanding principles of evidence-based medicine is of vital importance for improving quality of care, promoting public health and health system development. Understanding principles of evidence-based medicine allows using the most powerful information source, which have ever existed in medicine. OBJECTIVE: To evaluate the effectiveness of teaching Evidence-Based Medicine, including long-term outcomes of training. METHODS: The study was conducted at the Medical University of Astana, where the Scientific and Educational Center of Evidence-Based Medicine was established in 2010 with the help of the corresponding project of the World Bank. The participants of the study were the …faculty trained in Evidence-Based Medicine at the workshop “Introduction to Evidence-Based Medicine” for the period of 2010–2015 years. There were a total of 16 workshops during the period, and 323 employees were trained. All participants were asked to complete our questionnaire two times: before the training - pre-training (to determine the initial level of a listener) and after the training – post-training (to determine the acquired level and get the feedback). Questionnaires were prepared in such a way, that the majority of questions before and after training were identical. Thus, it provided a clear picture of the effectiveness of training. Questions in the survey were open-ended so that the respondents had the opportunity to freely and fully express their views. The main part of the questionnaires included the following questions: “Do you understand what evidence-based medicine is”, “how do you understand what the study design means”, “what is randomization”, “how research is classified”, “do you know the steps of decision-making according to Evidence-Based Medicine, list them”, “what literature do you prefer to use when searching for information (print, electronic, etc.)”, “what resources on the Internet do you prefer to use”. RESULTS: Only 30–35% of respondents gave correct answers to the questions on understanding EBM, understanding study designs, randomization. There were no correct or complete answers to the question on study classification. Again, 35% of respondents provided correct answer to the question about the stages of decision-making process from the perspective of EBM, 65% - provided no answer. One fourth (25%) of the respondents preferred using printed literature. Only very few respondents indicated Cochrane Library, Medline (PubMed), Tripdatabasa as preferred Internet sources of information, with 40% indicating Google and 60% - other sources. The results of post-training survey showed that nearly 90% of the respondents gave correct answers to all the questions. With the aim to identify knowledge survival (the long-term training outcomes) we conducted the third survey in May 2014 in previously trained people at the seminar “Introduction to Evidence-Based Medicine”. The respondents were asked to answer 4 questions, and to assess previously obtained information on the basics of Evidence-Based Medicine on a 10-point scale. We found that 100% of the respondents answered «Yes» to the question: «Have you changed your behavior after the seminar?» To the question: «Have you encountered difficulties in implementing the principles of evidence-based medicine in the educational process?» 56% of the respondents answered that they had not encountered any difficulties. The other 44% faced the difficulties associated with implementation of Evidence-Based Medicine: lack of understanding by students, low knowledge survival rate among students, too many questions from the students, difficult disputes and discussions. To the question: «Have you encountered difficulties in implementing the principles of Evidence-Based Medicine in practical health-care?» only 37.5% of the respondents answered that they had not encountered difficulties. But the remaining 62.5% of the respondents faced the problems and difficulties in implementing the principles of evidence-based medicine in their practice. These were: failure in implementing, lack of understanding on the part of colleagues, commitment to traditional obsolete methods of treatment, discrepancy between some of the existing standards of diagnosis and treatment and principles of evidence-based medicine. To the question: «Are there any end products after listening to the seminar?» 67% of the respondents answered in affirmative. The end products were mainly marked by the publication of articles and abstracts, including international publications, and participation in the working group on the revision and development of clinical protocols. CONCLUSIONS: Barriers to implementation of Evidence-Based Medicine in education and practice are lack of funding to provide access to reliable sources of information, websites; outdated research methodology skills in medical education, lack of skills in critical evaluation of medical information; tradition of authoritarian relationships, use of past experience stencils; failure to comply with continuing education programs (“from training to professional development”). Knowledge of Evidence-Based Medicine, skills to perform searches for scientific data, to evaluate their validity and to transform scientific data into practical solutions are necessary for health workers in their daily activities. This culture needs to be rooted in modern medical education. Show more

Keywords: Evidence-based medicine, training, education, practice, survey, questionnaire

DOI: 10.3233/JRS-150705

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S95-S96, 2015

Authors: Sychev, D.A. | Malova, E.U.

Article Type: Abstract

Abstract: BACKGROUND: For improving quality, safety and efficiency of care, health systems perform a paradigm change towards personalized medicine, also referred to as genomic medicine. It uses combined knowledge (genomics, transcriptomics, proteomics, metabolomics) about a person to predict disease susceptibility, disease prognosis or treatment response and thereby to improve the person’s health. The last decade has witnessed a steady embrace of personalized medicine by senior government officials, industry leadership and health care providers [1 ]. On the 12th December of 2013 Russian President Vladimir Putin in his annual address to the Federal Assembly said: “The Ministry of Health and the Russian …Academy of Sciences must give priority to fundamental and applied research in medicine, including genomic studies” [2 ]. A year earlier, in 2012 the Ministry of Health of the Russian Federation, headed by Veronika Skvortsova established the strategy of personalized medicine development in Russia [3 ]. But still a lot of work is focused on using clinical research findings to aid the delivery of optimum clinical care to patients. Pharmacogenetic testing (using genetic information to guide drug therapy) is an actively developing field of personalized medicine and its current state indicates that it can be usefully introduced into clinical practice in the nearest future. In Russia pharmacogenetic testing is already used for personalizing prescription of certain drugs [4 ]. OBJECTIVE: To assess the extent of genetic testing use for improving use of medicines. METHODS: PubMed and E-Library searches for the period of 2004–2015. RESULTS: The number of publications retrieved in PubMed search for the term “pharmacogenetics” for 2004 year was 538 and was more than 15500 publications for 2015. 800 Russian-language publications in total were retrieved using a domestic scientific database E-Library search for the term “pharmacogenetics” for 2015 year. The sharp rise in the number of publications (including Russia) reflects growing interest not only among scientists, but also among practitioners. However evidence that is actually available on some key topics may not be of sufficiently high quality to support confident conclusions. As a rule, retrospective cohort studies, also known as historical cohort studies, are carried out. The number of randomized, prospective studies is not large, though in recent years, there has been an increase in their number. However, surrogate outcomes are commonly used in the mentioned studies as trial end points. The main reason for this is the lack of sponsorship. Quite often studies are not interesting for pharmaceutical companies and are carried out within the confines of the small grants. Nevertheless, systematic reviews and meta-analyses of some pharmacogenetic tests provide the high level of evidence (pharmacogenetic testing for clopidogrel, abacavir and antineoplastic drugs) so they appear even in clinical guidelines with the evidence level IIb. It is important to mention that for certain drugs FDA has already approved pharmacogenetic testing [5 ]. CONCLUSIONS: Evidence is often inconsistent. This leads to the fact that clinical use of pharmacogenetic testing seems to be most appropriate for the management of patients with high risk of adverse drug reactions. Show more

Keywords: Pharmacogenetics, evidence, personalized medicine

DOI: 10.3233/JRS-150706

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S97-S98, 2015

Authors: Faizullin, I. | Faizullina, E.

Article Type: Abstract

Abstract: BACKGROUND: Ankle sprain is a medical condition when ankle ligaments are totally or partially torn. The primary cause of ankle sprain is sharp movements like turning or rolling the foot [1 ]. The ankle sprain needs to be treated right after the trauma, because if not treated it could lead to decreased stability of the ankle joint and lead to chronic ankle instability, which is characterized by increased risk of the ankle sprain [2 ] . We suppose that rehabilitation after the ankle sprain could significantly increase the performance of sportsmen. OBJECTIVE: To investigate effects of balance exercise …training on instable ankle due to the previous ankle sprain injury. In addition, the secondary aim of this systematic review was to find the effectiveness of different balance training exercises on instable ankle in order to find better opportunities for rehabilitation of sportsmen. METHODS: The studies were selected from PubMed and Scopus using the library of the Friedrich-Alexander University of Erlangen-Nuremberg (further-UB FAU), we used full texts, and only texts in English were included in this review. The literature search was conducted at the end of December 2014. Texts included randomised controlled trials, which were published in the last 5 years (2009–2014). The literature was included in this review only if it was published in English and if the randomised controlled trial was conducted in the study and if the full text was available from UB FAU. The articles, which were found only in PubMed search, were excluded during Scopus search. PubMed search. First MeSH term was “Balance training for the ankle sprain” and 44 articles were found in PubMed. Then 29 articles were filtered by title and excluded from the study. Remaining 15 articles were assessed reading their abstracts, 6 of them were excluded and only 4 articles were left. The second MeSH term was “Balance training for ankle injury”. Four additional articles were found by initial search. Two of them were filtered by the title and 2 were excluded at the stage of reading abstracts. The third MeSH term was “Balance exercises for instable ankle”. One additional article was found by initial search and was excluded after reading the abstract. Scopus search. The same MeSH terms were used as in PubMed search. With the first MeSH term one article was found and filtered by the title. With the second MeSH term no results were found in the initial search and with the third term 2 articles were picked up by the initial search. One of these articles was filtered by the title. The other one was filtered after reading the abstract. Overall 8 articles were taken into consideration for conducting a systematic review. Nevertheless, three of them could not be downloaded for free even using UB FAU up to the 28th of December, 2014. Thus, five articles were taken for the systematic review. After reading all 5 articles, one article by Maraike Alice Wortmann and Carrie L. Docherty was excluded from the study because it was a systematic review per se and at the same time it was not mentioned neither in the article title, nor in the abstract that the current study was a systematic review [3 ]. Also the article by Borreani et al. 2014 [4 ] was excluded after reading the paragraph “Methods” as this was not an RCT but a descriptive study. Therefore, 3 articles were taken for conducting a systematic review. RESULTS: The first article by Janssen et al. 2011 [5 ] was a 3-way randomised controlled trial with 1 year follow-up. Participants aged from 12 to 70 years used this intervention. People with active participation in sports with a lateral ankle sprain during the last 2 months were eligible for inclusion in the study. Participants were divided into 3 groups. Group 1 undertook an 8 week neuromuscular training programme. Group 2 wore sports brace during their sport activities for the duration of 1 year, and group 3 was a control group and used the combination of neuromuscular training program and wore sports brace for 8 weeks. There were 122 participants in the neuromuscular training group, 126 in the brace group and 136 in combined group. The drawback of this intervention was that there was no control over the care provid. In the second study by Ben Moussa Zouita, A et al. 2013 [6 ] the objective was to investigate how the proprioceptive exercises effect the postural balance and isokinetic strength in athletes with ankle sprain. 16 participants were recruited in the study and divided into two groups. The experimental group consisted of 8 participants with unilateral ankle sprain symptoms. The control group included another 8 participants with bilateral non-injured ankles. The training programme included 24 sessions during 8 weeks, every session lasted between 20 and 30 minutes. Four prescribed exercises were used during the intervention: one exercise without any material, one exercise with a ball only, one exercise with a balance board only and one exercise with a ball and a balance board. As a result, after 8 weeks of proprioceptive rehabilitation a significant improvement in extensor and flexor strength of ankle at a speed of 60-deg/sec was registered. The third study by Emery, Meeuwisse 2010 [7 ] was aimed to examine the effectiveness of the neuromuscular prevention strategy in youth soccer players. The inclusion criteria were adolescents between 13 and 18 years of age. The exclusion criteria were injury within 6 weeks and the history of systemic disease in anamnesis (i.e. cerebral palsy, head injury). 82 soccer teams were invited to take part in the intervention. 12 trainers declined the invitation, other 10 teams declined participation. Overall 60 teams took part in the intervention programme. The teams were randomised by a club. 32 training group teams (n = 380 players) and 28 control group players (n = 364 players) took part in the intervention. The training programme included dynamic stretching exercises, agility, jumping and balance and eccentric strength. The control programme was a standardized warm-up including static, dynamic and aerobic components and home-based stretching programme using 16-inch diameter wobble board used for 15 minutes during exercises. The injury rate in the training group was 2.08 injuries/1000 player-hours, and in the control group 3.35 injuries/1000 player-hours. The neuromuscular training programme was protective in injuries of youth soccer players. CONCLUSIONS: Balance training is an effective training method for rehabilitation of instable ankle. Different approaches to balance training provide in general similar improvement for sprained ankle. Implications for future studies: More RCTs on chronic ankle instability are needed with large sample size and use of different intensities of exercises. It would be better for the UB FAU to provide access to articles so that students and researches could download articles for free from different electronic sources. Show more

Keywords: Ankle sprain, balance training, ankle injury, instable ankle

DOI: 10.3233/JRS-150707

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S99-S101, 2015

Authors: Mendelevich, V.D. | Zalmunin, K.Yu.

Article Type: Abstract

Abstract: BACKGROUND: For many years, clinical protocols for treatment of drug abuse patients and treatment standards in Russian Federation were not grounded on the principles of evidence-based medicine [1 ]. Recommendations for use of certain drugs were not accompanied by any indication of the level of credibility of the evidence supporting it. The appearance in 2014 of such indications in clinical recommendations can be considered a significant step forward for the science of addiction medicine [2 ]. OBJECTIVE: To compare Russian evidence and practice in addiction medicines with international standards. METHODS: Situation and literature analysis. …RESULTS: The analysis shows that in the wording of recommendations on the use of medicines, some were subject of serious methodological errors. For some drugs globally there is high quality evidence supporting effects of certain drugs globally, but this is not recognized in Russia. As a result, Russian standards of clinical care for the treatment of dependency syndrome are radically different to the standards of therapy, presented in the WHO recommendations. This is due both to the disregard of the meta-analyses presented in the Cochrane reviews and also to the specific bioethical preferences in drug treatment in Russia. It is known that there is no convincing data on the effectiveness and safety of antipsychotics in the treatment of alcohol dependence syndrome [3 ]. 13 randomized trials with a double blind placebo-controlled design involving 1593 patients assessing effects of amisulpride, aripiprazole, flupentixolum dekonoat, olanzapine, quetiapine, tiapride showed that antipsychotics do not result in abstinence, do not reduce abuse and do not stop craving in alcoholic patients: “Antipsychotics should not be used in patients with a primary diagnosis of dependence. Appointment of antipsychotics for the treatment of substance abuse disorders are contraindicated, since not only does it not improve the condition of patients, but it can even worsen the course of the disease, leading to a reduction in the duration and quality of the remission, and is fraught with serious side effects that threaten the health of patients .” SSRI antidepressants indirectly improve the results of treatment of comorbid alcoholism in depressed patients, without affecting alcohol dependence per se . Also, there is currently no convincing evidence of the efficacy of anticonvulsants in the treatment of dependence syndrome, particularly alcohol. Despite the fact that traditional psychotherapeutic interventions remain widespread in practice, and treatment of alcohol dependence syndrome showed high efficiency, there is no convincing evidence for long-term benefits as opposed to short-term benefits. The Cochrane Review with data based on 146 scientific studies involving 21,404 patients confirmed the effectiveness of opioid receptor agonists in treatment of opioid dependence. This therapy showed a statistically significant reduction in the use of illegal drugs, HIV transmission and risky sexual behavior, and was significantly more effective compared to the conventional maintenance therapy with opioid receptor antagonists. In countries, where law prohibits prescribing and use of opioid agonists for opioid dependence treatment, the drugs of choice are antagonists. A meta-analysis of thirteen randomized placebo-controlled trials of oral form of naltrexone (1158 subjects), did not show any advantages of this type of treatment both for management and prevention of relapse compared with placebo [4 ]. Special studies also showed no inclination to reduce the use of opiates in patients receiving naltrexone [5 ]. However, studies carried out in Russia, showed the best results for daily intake of naltrexone after detoxification, which increased the duration of remission [6 ]. It was noted that the effect is associated with higher levels of adherence and family support in the examined population. An overview based on controlled clinical studies on the use of antipsychotic drugs (neuroleptics) in patients dependent on opioids revealed no evidence of effectiveness of this approach. It was concluded that the use of antipsychotics is justified only in the presence of co-morbid psychiatric problems in patients [7 ]. In a recent meta-analytic review on the use of atypical antipsychotics for off-label indications (off-label), there was a lack of data to support the effectiveness of their use in substance abuse [8 , 9 ]. The effectiveness of anticonvulsants in the treatment of opioid dependence syndrome has not been proven. In connection with the above puzzling fact, for Russian standards of treatment (clinical guidelines) the level of credibility of the effectiveness of antipsychotics and antidepressants in treatment of substance abuse is assessed as A or B. This paradox raises the question of the methodology for determining the level of credibility of evidence. It should be noted that Russian recommendations for inclusion of certain drugs and therapies are based on sufficient consensus of experts rather than on the results of meta-analyses [2 ]. CONCLUSIONS: This fact casts doubt on credibility and validity of scientific recommendations. Thus, one may say that Russian addiction medicine is not based on evidence, which is, in our view, erroneous and may impair the quality of care. Show more

Keywords: Paradoxes, evidence-based medicine, addiction medicine

DOI: 10.3233/JRS-150708

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S102-S103, 2015

Authors: Nazarenko, G.I. | Kleymenova, E.B. | Payushik, S.A. | Otdelenov, V.A. | Sychev, D.A. | Yashina, L.P.

Article Type: Abstract

Abstract: BACKGROUND: Today medicine is facing a “knowledge crisis” in that explosively expanding medical knowledge encounters limited abilities to disseminate new practices [1 ]. Clinical practice guidelines (CPGs) are intended to promote high standards of care in specific areas of medicine by summarizing best clinical practice based on careful reviews of current research. However, doctors are often short of time to study these documents and check their updates, have little motivation for strict adherence to them. A systematic review of 11 studies reporting on 29 recommendations has found that median adherence to all recommendations was 34%, suggesting that potential benefits for …patients from health research may be lost [2 ]. Clinical decision support systems (CDSS) can serve as a knowledge translation tool, mediator between clinical guidelines and physicians by providing the right information to the right person at the right time. OBJECTIVE: To evaluate the effectiveness of implementation of international and national CPGs for venous thromboembolism (VTE) prevention with the help of CDSS in a general hospital. METHODS: A multifunctional CDSS based on national and international guidelines on the VTE prevention was developed and implemented in the Medical Center of the Bank of Russia (MC). The system has the following functionalities: 1) it supports the decision on the VTE prevention based on individual risk assessment of thrombosis (scales of Caprini, Rogers and Khorana, Padua Prediction Score, additional risk factors) and bleeding (IMPROVE scale for non-surgical patients, major bleeding scale for surgical patients and major orthopedic surgeries, hemorrhagic complications risk in cancer patients); 2) generates the summary containing the grade of recommendations and the level of evidence, personalized recommendations on regimen and duration of preventive antithrombotic therapy, dose correction according to creatinine clearance; 3) provides an audit form for and statistical analysis of VTE cases; 3) automatically generates a quality register for VTE prevention. CDSS was implemented in June 2014. We analyzed VTE cases identified by triggers (deep vein thrombosis diagnosed by Doppler ultrasound and pulmonary embolism at the chest CT) that occurred in 2014 before and after CDSS implementation, as well as in the first half of 2015. Patients with VTE diagnosed during the first 48 hours of hospitalization or receiving anticoagulants in therapeutic doses were excluded from the analysis. Chi-square test for linear trend and non-parametric methods of descriptive statistics were used for data analysis. RESULTS: CDSS utilization was regulated by a special hospital-wide policy; lectures were organized to educate doctors how to use the system. Although international recommendations require VTE risk assessment for all hospitalized patients (except those receiving anticoagulant in therapeutic doses), the doctors filled forms for only 306 patients during the first 6 months of CDSS functioning (14.1% of discharges with length of stay >48 hours during this period). In the first half of 2015 the coverage of VTE risk assessment with CDSS was 19% (n = 506). Correctness of filling out the forms was 78.4%, in the rest of cases doctors made mistakes in choosing patient's profile or when filling in risk scales. Doctors adhere to given recommendations in 85.4% of cases. Most often (47.5%) pharmacotherapy with low molecular weight heparin (LMWH), preventive doses, was recommended by the system, and in this category the adherence to recommended practice was the lowest (74.6%). Among patients who underwent pharmacoprophylaxis, in 21.1% cases the use of anticoagulants was inconsistent with clinical guidelines or drug package insert (typically inappropriate choice of LMWH prophylactic doses, delaying or reducing the duration of prophylaxis). The rate of hospital-acquired VTE significantly decreased after CDSS implementation and was 11.71, 8.28 and 4.84 per 1,000 hospitalizations in the first and second half of 2014 and in the first half of 2015, respectively (χ2 = 7.325, df = 1, p = 0.0068). The rate of postoperative VTE for the same period amounted to 8.76, 3.39 and 4.17 per 1,000 operations, respectively (χ2 = 7.266, df = 1, p = 0.007), reaching a level of the correspondent AHRQ safety indicator (4.99 per 1,000 operations) [3 ]. Deviations from clinical guidelines or anticoagulant package inserts were revealed in 74% of VTE cases; and more than 1/3 of deviations affected treatment outcomes. CONCLUSIONS: Coverage of hospitalized patients with documented VTE risk assessment gradually increased after the CDSS implementation, but remained at a low level (19% of eligible patients). Partly it may be attributed to the lack of CDSS integration in electronic health record or computerized physician order entry systems that would facilitate routine documentation of VTE and bleeding risks. However, the introduction of CDSS has allowed reducing significantly the rate of hospital-acquired VTE. This can be explained by drawing doctor’s attention to the VTE problem and by training effect of CDSS. After receiving appropriate recommendations doctors adhere to them, on average, in 85.4% of cases, although for LMWH pharmacoprophylaxis this level was lower (74.6%). Development of hospital-acquired VTE in most cases (74%) was accompanied by non-compliance with CPGs recommendations, emphasizing the importance of additional measures for better adherence to evidence-based clinical practices. Show more

Keywords: Decision support system, clinical practice guidelines, hospital-acquired, venous thromboembolism, prevention

DOI: 10.3233/JRS-150709

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S104-S105, 2015

Authors: Kamalov, M. | Dobrynin, V. | Balykina, J. | Kolbin, A. | Verbitskaya, E. | Kasimova, M.

Article Type: Abstract

Abstract: BACKGROUND: The actively developing approach in modern medicine is the approach focused on principles of evidence-based medicine. The assessment of quality and reliability of studies is needed. However, in some cases studies corresponding to the first level of evidence may contain errors in randomized control trials (RCTs). Solution of the problem is the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Studies both in the fields of medicine and information retrieval are conducted for developing search engines for the MEDLINE database [1 ]; combined techniques for summarization and information retrieval targeted to solving problems of finding the best medication …based on the levels of evidence are being developed [2 ]. OBJECTIVE: Based on the relevance and demand for studies both in the field of medicine and information retrieval, it was decided to start the development of a search engine for the MEDLINE database search on the basis of the Saint-Petersburg State University with the support of Pavlov First Saint-Petersburg State Medical University and Tashkent Institute of Postgraduate Medical Education. Novelty and value of the proposed system are characterized by the use of ranking method of relevant abstracts. It is suggested that the system will be able to perform ranking based on studies level of evidence and to apply GRADE criteria for system evaluation. METHODS: The assigned task falls within the domain of information retrieval and machine learning. Based on the results of implementation from previous work [3 ], in which the main goal was to cluster abstracts from MEDLINE database by subtypes of medical interventions, a set of algorithms for clustering in this study was selected: K-means, K-means ++, EM from the sklearn (http://scikit-learn.org ) and WEKA (http://www.cs.waikato.ac.nz/~ml/weka/ ) libraries, together with the methods of Latent Semantic Analysis (LSA) [4 ] choosing the first 210 facts and the model “bag of words” [5 ] to represent clustered documents. During the process of abstracts classification, few algorithms were tested including: Complement Naive Bayes [6 ], Sequential Minimal Optimization (SMO) [7 ] and non linear SVM from the WEKA library. RESULTS: The first step of this study was to markup abstracts of articles from the MEDLINE by containing and not containing a medical intervention. For this purpose, based on our previous work [8 ] a web-crawler was modified to perform the necessary markuping. The next step was to evaluate the clustering algorithms at the markup abstracts. As a result of clustering abstracts by two groups, when applying the LSA and choosing first 210 facts, the following results were obtained: 1) K-means: Purity = 0,5598, Normalized Entropy = 0.5994; 2) K-means ++: Purity = 0,6743, Normalized Entropy = 0.4996; 3) EM: Purity = 0,5443, Normalized Entropy = 0.6344. When applying the model “bag of words”: 1) K-means: Purity = 0,5134, Normalized Entropy = 0.6254; 2) K-means ++: Purity = 0,5645, Normalized Entropy = 0.5299; 3) EM: Purity = 0,5247, Normalized Entropy = 0.6345. Then, studies which contain medical intervention have been considered and classified by the subtypes of medical interventions. At the process of classification abstracts by subtypes of medical interventions, abstracts were presented as a "bag of words" model with the removal of stop words. The results: 1) Complement Naive Bayes: macro F-measure = 0.6934, micro F-measure = 0.7234; 2) Sequantial Minimal Optimization: macro F-measure = 0.6543, micro F-measure = 0.7042; 3) Non linear SVM: macro F-measure = 0.6835, micro F-measure = 0.7642. CONCLUSIONS: Based on the results of computational experiments, the best results of abstract clustering by containing and not containing medical intervention were obtained using the K-Means ++ algorithm together with LSA, choosing the first 210 facts. The quality of classification abstracts by subtypes of medical interventions value for existing ones [8 ] has been improved using non linear SVM algorithm, with “bag of words” model and the removal of stop words. The results of clustering obtained in this study will help in grouping abstracts by levels of evidence, using the classification by subtypes of medical interventions and it will be possible to extract information from the abstracts on specific types of interventions. Show more

Keywords: Data retrieval, computational experiments

DOI: 10.3233/JRS-150710

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S106-S107, 2015

Authors: Isakova, J.

Article Type: Abstract

Abstract: BACKGROUND: Rapid development of medicine requires regular update of clinical data evidence. This task accomplishment requires participation of numerous specialists in evidence-based medicine, who are proficient in various statistical methods and can work with big data analysis tools in biomedical sciences. This, in turn, requires significant time and other resources. Today, at the peak of IT development, cognitive systems in the field of medicine with special technologies of data collection and analysis, is the start of a new trend. OBJECTIVE: The development of cognitive IT system for drug prescription with the potential to analyze automatically the information about …drugs effectiveness and safety on the basis of clinical practice experience and scientific data according to evidence levels and patients’ personal characteristics. METHODS: The cognitive system was developed with the use of United Medical Knowledge Base (UMKB). UMKB is a semantic network of medical knowledge, which is structured according to the medical ontologies and the theory of fuzzy logic. UMKB is being filled simultaneously in all the areas of medicine. From one side it is filled by means of the linguistic module analyzing medical texts, from the second side - by academic institutions, from the third side – by the cognitive IT systems with the data from electronic health records (EHRs). Native language of UMKB is Russian. It is designed primarily for use in the Russian clinical practice. However the platform for filling knowledge is multilingual and supports any other languages. This means that the practice of world schools may also be integrated and used in UMKB. The peculiarity lies in the fact that UMKB is presented as a semantic network where biomedical knowledge are structured according to certain medical ontologies (special rules of information storage that 𠄼carries𠄽 data: phenomena, processes, simple and complex concepts in medicine, - in the form of interrelated objects). The keystone underlying UMKB is the model of medical knowledge representation, which is able to describe any area of medicine. With the help of this model one can accurately simulate risk factors, etiology, and pathogenesis of a disease (probability, time of development and the sequence of pathological signs at each stage of a disease). While describing pathological and compensatory mechanisms the database provides an opportunity to clarify a lot of conditions that affect this mechanism. It is also simple to simulate structural and functional features of the concept and its relationships (for example, compensatory mechanisms, reflexes, complex anatomical structures, all the features of variant anatomy and other characteristics), which form reactivity and resistance of the organism. All this is very important for cognitive IT systems concerning personalized and evidence-based medicine. When describing medical knowledge there are often situations of uncertainty, lack of sufficiently complete and accurate data on the subject area, poorly understood phenomena, conflicting theories or imprecise concepts. Semantic network of UMKB presents complex relationships among medical concepts characterized by the following features: type and direction of relationship, its weight and value, accuracy and personalization of the weight or value of relationship, date of actualization. Multifactorial influence on the weight or value of relationship, a lot of elementary and intermediate traits that influence weight, the moment of actualization are supported to formalize. United Medical Knowledge Base is a large-scale project, its main goal is to increase the quality and duration of life through personalized care based on evidence that can only be achieved by combining medical big data from various fields of biomedical sciences. RESULTS: On the basis of UMKB a prototype of the cognitive IT system PharmExpert with analytical potential was developed. PharmExpert is a clinical decision support system for drug prescribing, which is integrated into medical information system at health institutions and analyzes electronic health records (EHRs) in any format of the background mode, correcting drug therapy according to personal patient's profile and data about compatibility of the drugs. The system has a very important function - self-learning that will help it to absorb a huge mountain of medical data from routine clinical practice in the nearest future. Now it works on the basis of data from UMKB, handbooks in pharmacology, summaries of medical products characteristics (SmPCs), available reviews of scientific literature and clinical guidelines on drugs interactions and compatibility. In the short term, at the stage of clinical testing, PharmExpert memorizing all the cases of clinical experience and the reaction of the physicians (accepting or ignoring the recommendations of the system), will be able to realize self–learning function by rebuilding ties and remodeling knowledge of the semantic network according to clinical data and generating the best standards of drug therapy taking into account personal characteristics of the patient and levels of data evidence. Working in the background mode is one of the most important advantages of the system. The physician is not asked to enter any additional data beyond that the specialist enters into the EHR on an everyday basis. Now PharmExpert is installed in the medical information systems of the range of clinical centers in the Russian Federation. CONCLUSIONS: We developed a prototype of cognitive IT system for drug prescription with the potential to analyze automatically the information about drugs effectiveness and safety on the basis of clinical practice experience and scientific data according to evidence levels and patients’ personal characteristics. The system is based on the structured semantic network of medical knowledge from UMKB. Show more

Keywords: Cognitive IT-systems, big data, medicine, medical knowledge, semantic, network

DOI: 10.3233/JRS-150711

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S108-S109, 2015

Authors: Khakimov, N. | Khasanova, G. | Ershova, K. | Gibadullina, L. | Vetkina, T. | Lobisheva, G. | Chumakova, A.

Article Type: Abstract

Abstract: BACKGROUND: The relevance of the problem of colorectal cancer (CRC) is evident because of extremely high morbidity and mortality rates, associated with this disease. CRC is mostly diagnosed only at very advanced stages. The reduction of mortality can be achieved by the popularization of screening-methods for early identification of CRC and adenomatous polyps of the colon, which are proved to be precancerous condition. Fecal occult blood test is a well-known method of screening for CRC. The advantages of this method when compared, for example, with colonoscopy are its simplicity and cost-effectiveness. Two techniques are usually used for detection of occult …blood in the stool: Hemoccult (Guaiac) test and immunochemical test for hemoglobin. There is no consensus among researchers regarding the validity of these tests for the diagnosis of colorectal cancer. For example, J.S. Mandel (1996) notes 60% sensitivity of Guaiac-test for the detection of the early forms of colorectal cancer, while O.I. Kit (2014) suggets that it is not higher than 30%. There are also various opinions about specificity of these two tests. OBJECTIVE: To review the literature on the validity of the fecal occult blood tests for the diagnosis of CRC. METHODS: We looked for articles (electronic versions) available for free in the full-text versions, published from June 1, 1990 to December 31, 2014 in Russian or English. The following databases were used for search: E-LIBRARY; Cochrane; MEDLINE; EMBASE; Google search. Only original research papers were analyzed. Literature reviews or systematic reviews were not taken for analyses. Selection criteria: 1) use of Guaiac and/or immunochemical fecal occult blood test as screening-tests for the detection of colorectal cancer and/or colon polyps (1 cm or more in diameter) in people older than 45 years; 2) comparing of results with the results of colonoscopy (colonoscopy is counted by majority of the authors as a “gold standard” for the diagnosis of CRC and adenomatous polyps). RESULTS: Initial keyword search returned 803 000 results, of which 449 sources were selected. After reading the abstracts, 29 articles that met inclusion criteria were kept. 10 other articles were excluded after that because they did not contain enough data for extraction or did not contain a control group. At the final step 19 articles were used for meta-analysis. Forest plot and Rock curve, which were developed with inclusion of the data from all studies, showed heterogeneity of the data. Additional analyzes were performed in subgroups with different diagnoses and various tests. The sensitivity of the Guaiac test for the diagnosis of colorectal cancer varied from 0.13 to 1.00, and specificity - from 0.69 to 0.99. The sensitivity of the immunochemical test for the diagnosis of CRC ranged from 0.42 to 0.94 with specificity ranging from 0.40 to 1.00. The sensitivity of the Guaiac test for the diagnosis of the colon polyps was between 0.05 and 0.69, and its specificity - from 0.67 to 0.98. The sensitivity of the immunochemical test for the diagnosis of polyps was from 0.24 to 0.75, and its specificity - from 0.40 to 0.97. Bivariate analysis of the validity of Guaiac test and immunochemical method for the diagnosis of colorectal cancer showed better results for the immunochemical test compared to Guaiac test. The tests showed very similar results when used for the diagnosis of polyposis. Bivariate analysis, comparing the validity of tests for the diagnosis of colorectal cancer versus polyposis demonstrated better results for CRC. Multivariate analysis of the validity of the Guaiac and immunochemical tests for the diagnosis of colorectal cancer and polyps also showed better results for detection of colorectal cancer compared with the polyps for both tests. At the same time the highest validity for the diagnosis of CRC was demonstrated for immunochemical analysis. CONCLUSIONS: 1. The sensitivity of the Guaiac test for occult blood in stool is lower than its specificity. 2. Broad dispersion of the validity characteristics of the fecal occult blood tests was observed. 3. The validity of tests for occult blood was higher when they were used for detection of colorectal cancer than of colon polyposis. 4. The highest validity rate has been demonstrated for the immunochemical test when it was used for colon cancer screening. Show more

Keywords: Screening, colon cancer, occult blood

DOI: 10.3233/JRS-150712

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S110-S111, 2015

Authors: Yudina, E.V. | Ziganshina, L.E.

Article Type: Abstract

Abstract: BACKGROUND: Cochrane collaboration has made a huge contribution to the development of evidence-based medicine; Cochrane work is the international gold standard of independent, credible and reliable high-quality information in medicine. Over the past 20 years the Cochrane Collaboration helped transforming decision-making in health and reforming it significantly, saving lives and contributing to longevity [1 ]. Until recently, Cochrane evidence were available only in English, which represents a significant barrier to their wider use in non-English speaking countries. To provide access to evidence, obtained from Cochrane Reviews, for health professionals and general public (from non-English-speaking countries), bypassing language barriers, Cochrane collaboration …in 2014 initiated an international project of translating Plain language summaries of Cochrane Reviews into other languages [2 , 3 ]. Russian translations of Plain language summaries were started in May 2014 by the team from Kazan Federal University (Department of Basic and Clinical Pharmacology; 2014–2015 as an Affiliated Centre in Tatarstan of the Nordic Cochrane Centre, since August 2015 as Cochrane Russia, a Russian branch of Cochrane Nordic, Head - Liliya Eugenevna Ziganshina) on a voluntary basis. OBJECTIVE: To assess the quality of Russian translations of Cochrane Plain Language Summaries (PLS) and their potential impact on the Russian speaking community through user feedback with the overarching aim of furthering the translations project. METHODS: We conducted the continuous online survey via Google Docs. We invited respondents through the electronic Russian language discussion forum on Essential Medicines (E-lek), links to survey on the Russian Cochrane.org website, invitations to Cochrane contributors registered in Archie from potential Russian-speaking countries. We set up the survey in Russian and English. The respondents were asked to respond to the questionnaire regarding the relevance and potential impact of the Cochrane Russian translations project, topics of interest in the field of health and health care, the quality and clarity of translated content, the preferred style of presentation and suggestions to improve the quality of translations of Plain language summaries of Cochrane Reviews. RESULTS: Currently the team of translators includes volunteers from the staff, Masters and PhD students of the Department of Basic and Clinical Pharmacology of the Kazan Federal University, and Kazan Medical University, our colleagues from Kazan and other cities of Russia, from the Republic of Armenia and the USA. By September 20th 2015, 446 Plain language summaries of Cochrane Reviews were translated into Russian and published on the web-site http://www.cochrane.org/ru/evidence . Our project “Russian translations for Cochrane” has already covered a wide range of health priority areas with translations of Plain language summaries and abstracts of the most topical and priority Cochrane reviews. During the period from 03.03.2015 to 20.09.2015 we received 113 answers from our respondents (103 answers in Russian and 10 answers in English). These were representatives of the medical and pharmaceutical professions (60%), representatives of non-medical professions (17%), students/graduate students (16%), retirees (4%) and others categories of citizens among the respondents. Half of the respondents (50%) belonged to the age group of 36–60 years, followed by the group of 18–35 years (41%). According to the survey the vast majority of respondents consider that the Cochrane Russian translations project is needed for Russia and Russian speaking countries (94%; n = 106), it is needed for their work, studies, and life in general (91%; n = 103). Nobody answered “No” to the question: “Do you think that this project is needed for Russia and Russian-speaking countries?” Information from the Cochrane evidence can affect (change) individual practice and/or attitude to drugs or diagnostic procedures of 87% (n = 98) of respondents. Only two people answered negatively to this question. However, only one third of respondents would like to become volunteer members of the translations project. The Russian texts of translations of Cochrane summaries and their main message were completely understandable or mostly clear to the vast majority of respondents (92%; n = 104). Respondents, proficient in English (n = 61), answered that the Russian-language translations fully complied (43%; n = 26) or in general corresponded to (57%; n = 35) the original English text. The majority of respondents (85%, n = 96) rated the quality of the translated texts as excellent and good. “More than half of respondents (61%; n = 69) would prefer the translations to be adapted to the usual style of presentation in Russian. The respondents agreed that mistakes, or typos or both very few. Our respondents provided valuable suggestions for further improvement of the Russian translations project. We would like to present here some of these: “More translations needed”, “The ultimate goal... is to try to adapt the summaries to Russian language style as much as possible. This is a very challenging task, however and at present format the summaries are already great”, “Go great as you do!” “Move forward and be efficient!” “Distribute information about the project through social networks and different means of social media”, “Studying Cochrane Database should be included in the Russian medical school's curriculum at a much larger extent than it is included (if at all) now. It would be beneficial for high school students as well.” CONCLUSIONS: The survey provided positive feedback on the Russian translations project concerning the clarity and quality of Russian texts and overall satisfaction of the readers. It confirmed the importance and relevance of the Russian translations project for Russian speaking audience, representing various professions and age groups. The survey results with detailed feedback contribute to further improvement of the Russian translations project. Limitations: Selective and subjective evaluation of translations by the respondents, difficulties with clear criteria for the objective evaluation. Further quality improvement of original PLS texts would contribute to higher translation quality. Acknowledgments: We would like to thank Juliane Reed, Coordinator of the Cochrane Translations Project, Professor Peter C Gøtzsche, Director of the Cochrane Nordic, co-founder of the Cochrane Collaboration, Cochrane leadership and the global Cochrane network together with the leadership of the Kazan Federal University for continuous encouragement, spirit and support. Show more

Keywords: Cochrane, russian translations, plain language summaries

DOI: 10.3233/JRS-150713

Citation: International Journal of Risk & Safety in Medicine, vol. 27, no. s1, pp. S112-S113, 2015