Hepatitis C virus (HCV) infection causes viral hepatitis leading to hepatocellular carcinoma. Despite the clinical use of direct-acting antivirals (DAAs) still there is treatment failure in 5-10% cases. Therefore, it is crucial to develop new antivirals against HCV. In this endeavor, we developed the "Anti-HCV" platform using machine learning and quantitative structure-activity relationship (QSAR) approaches to predict repurposed drugs targeting HCV non-structural (NS) proteins. We retrieved experimentally validated small molecules from the ChEMBL database with bioactivity (IC50/EC50) against HCV NS3 (454), NS3/4A (495), NS5A (494) and NS5B (1671) proteins. These unique compounds were divided into training/testing and independent validation datasets. Relevant molecular descriptors and fingerprints were selected using a recursive feature elimination algorithm. Different machine learning techniques viz. support vector machine, k-nearest neighbour, artificial neural network, and random forest were used to develop the predictive models. We achieved Pearson's correlation coefficients from 0.80 to 0.92 during 10-fold cross validation and similar performance on independent datasets using the best developed models. The robustness and reliability of developed predictive models were also supported by applicability domain, chemical diversity and decoy datasets analyses. The "Anti-HCV" predictive models were used to identify potential repurposing drugs. Representative candidates were further validated by molecular docking which displayed high binding affinities. Hence, this study identified promising repurposed drugs viz. naftifine, butalbital (NS3), vinorelbine, epicriptine (NS3/4A), pipecuronium, trimethaphan (NS5A), olodaterol and vemurafenib (NS5B) etc. targeting HCV NS proteins. These potential repurposed drugs may prove useful in antiviral drug development against HCV.

Bitter taste receptors (TAS2R) are expressed in many non-sensor tissues including skeletal muscles but their function remains unexplored. The aim of this study is to investigate the role of TAS2R in rat abdominal skeletal muscles contractions using denatonium, a TAS2R agonist. Low concentration of denatonium (0.01 mmol/l) caused a significant decrease of amplitudes of the electrical field stimulation (EFS)-induced contractions in abdominal skeletal muscles preparations in vitro. This inhibitory effect was significantly reduced when the preparations were pre-incubated with gentamicin (0.02 mmol/l) used as a non-specific inhibitor of IP3 formation or with BaCl(2) (0.03 mmol/l) applied to block the inward-rectifier potassium current. All experiments were performed in the presence of pipecuronium in order to block the nerve stimulation of the contractions. The data obtained suggest that denatonium decreases the force of rat abdominal muscles contractions mainly via activation of TAS2R, phosphatidylinositol 4,5-biphosphate and its downstream signal metabolites.

The paper is devoted to the study of the effectiveness of multimodal low-opioid anesthesia during coronary bypass grafting (CABG) surgery under artificial blood circulation. The study included 36 patients aged 69,5±6.2 years, who were performed CABG. All patients were operated under general anesthesia. The average duration of anesthesia was 257,4±19,1 min. Induction included propofol (1,52±0.05 mg/kg), fentanyl (1-1.5 μg/kg), pipecuronium bromide (0.1 mg/kg). Maintenance of Maintaining anesthesia: Sevoflurane (1.5-2MAC). Аnesthesia: ketamine (0.5 mg/kg), lidocaine 1 mg/kg bolus, with the establishment of continuous infusion (1.5-2 mg/kg/h). The average dose of fentanyl, which was used for the entire period of anesthesiology support was 1,09±0.03 μg/kg/h (358,3±27,1 μg for the duration of surgery). As a result of the carried-out researches it was established, that multimodal low-opioid anesthesia, provides an adequate analgesic effect, and allows to refuse from intraoperative application of high doses of narcotic analgesics in the performance of highly traumatic operations, which is confirmed by the lack of hemodynamic and endocrine-metabolic shifts in its use.

Despite long-standing availability of an effective vaccine, tetanus remains a significant problem in many countries. Outcome depends on access to mechanical ventilation and intensive care facilities and in settings where these are limited, mortality remains high. Administration of tetanus antitoxin by the intramuscular route is recommended treatment for tetanus, but as the tetanus toxin acts within the central nervous system, it has been suggested that intrathecal administration of antitoxin may be beneficial. Previous studies have indicated benefit, but with the exception of one small trial no blinded studies have been performed. The objective of this study is to establish whether the addition of intrathecal tetanus antitoxin reduces the need for mechanical ventilation in patients with tetanus. Secondary objectives: to determine whether the addition of intrathecal tetanus antitoxin reduces autonomic nervous system dysfunction and length of hospital/ intensive care unit stay; whether the addition of intrathecal tetanus antitoxin in the treatment of tetanus is safe and cost-effective; to provide data to inform recommendation of human rather than equine antitoxin. This study will enroll adult patients (≥16 years old) with tetanus admitted to the Hospital for Tropical Diseases, Ho Chi Minh City. The study is a 2x2 factorial blinded randomized controlled trial. Eligible patients will be randomized in a 1:1:1:1 manner to the four treatment arms (intrathecal treatment and human intramuscular treatment, intrathecal treatment and equine intramuscular treatment, sham procedure and human intramuscular treatment, sham procedure and equine intramuscular treatment). Primary outcome measure will be requirement for mechanical ventilation. Secondary outcome measures: duration of hospital/ intensive care unit stay, duration of mechanical ventilation, in-hospital and 240-day mortality and disability, new antibiotic prescription, incidence of ventilator associated pneumonia and autonomic nervous system dysfunction, total dose of benzodiazepines and pipecuronium, and incidence of adverse events. Trial registration: ClinicalTrials.gov NCT02999815 Registration date: 21 December 2016.

Applying patient friendly and cost-efficient medications in healthcare will be a real challenge in the 21st century. Sugammadex is a selective, yet expensive agent used for the post-surgical reversal of neuromuscular block since 2008. A wide library of cyclodextrin-based follow-ups, having potentially similar affinity towards target aminosteroid type neuromuscular blocking agents has been established. Almost 20 compounds were assessed with respect to in vitro affinity against three commonly applied drugs. Based on the capillary electrophoretic screening, carboxymethylated and sulfobutylated gamma-cyclodextrin derivatives have the potential to be promising lead molecules for their affinity towards pipecuronium was identical or even superior to Sugammadex. Carboxymethylated gamma-cyclodextrin showed efficient and complete reversal of the pipecuronium induced neuromuscular block in an ex vivo rat diaphragm experiment.

Impact of a durable action of myorelaxant pipecuronium bromide on intraabdominal pressure (IAP) in rats in experimentally simulated acute peritonitis was studied. In the rats in purulent pancreatitis, іnduced by L-аrginin, IAP was in 4,5 times high (p < 0.001), than in intact laboratory animals. Pipecuronium bromide have lowered IAP by 33.4%, witnessing efficacy of application of myorelaxants in treatment of intraabdominal hypertension in purulent pancreatitis.

Acute respiratory distress syndrome (ARDS) is severe medical condition occurring in critically ill patients and with mortality of 33-52 % is one of the leading causes of death in critically ill patients. To better understand pathophysiology of ARDS and to verify novel therapeutical approaches a reliable animal model is needed. Therefore we have developed modified lavage model of ARDS in the pig. After premedication (ketamine and midazolam) 35 healthy pigs were anesthetized (propofol, midazolam, morphin, pipecuronium) and orotracheally intubated and ventilated. Primary ARDS was induced by repeated cycles of lung lavage with a detergent Triton X100 diluted in saline (0.03 %) heated to 37 °C preceded by pre-oxygenation with 100 % O(2). Single cycle included two subsequent lavages followed by detergent suction. Each cycle was followed by hemodynamic and ventilation stabilization for approx. 15 min, with eventual administration of vasopressors according to an arterial blood pressure. The lavage procedure was repeated until the paO(2)/FiO(2) index after stabilization remained below 100 at PEEP 5 cm H(2)O. In 33 pigs we have achieved the desired degree of severe ARDS (PaO(2)/FiO(2)<100). Typical number of lavages was 2-3 (min. 1, max. 5). Hemodynamic tolerance and the need for vasopressors were strongly individual. In remaining two animals an unmanageable hypotension developed. For other subjects the experimental ARDS stability was good and allowed reliable measurement for more than 10 h. The present model of the ARDS is clinically relevant and thus it is suitable for further research of the pathophysiology and management of this serious medical condition.

Diabetes mellitus, especially type 2 diabetes, remains the dominant metabolic disease worldwide, with an expected increase in prevalence of over 50% in the next 20 years. Our knowledge about the pathophysiology of type 2 diabetes continues to be incomplete, with unmet medical need for new therapies. The characterization of the fibroblast growth factor (FGF) family and the discovery of endocrine FGFs provided new information on the mechanisms of regulation and homeostasis of carbohydrate metabolism. More specifically, FGF19 and FGF21 signaling pathways have been linked to different glucose metabolic processes, including hepatic glucose synthesis, glycogen synthesis, glucose uptake, and insulin sensitivity, among others, and these molecules have been further related to the pathophysiology of diabetes mellitus. In-depth comprehension of these growth factors may bring to light new potential therapeutic targets for the treatment of diabetes mellitus.

Phenols are uremic toxins of intestinal origin formed by bacteria during protein metabolism. Of these molecules, p-cresol is the most studied and has been associated with renal function impairment and vascular damage. Bisphenol A (BPA) is a molecule with structural similarity with phenols found in plastic food and beverage containers as well as in some dialyzers. BPA is considered an environmental toxicant based on animal and cell culture studies. Japanese authorities recently banned BPA use in baby bottles based on observational association studies in newborns. BPA is excreted in urine and uremic patients present higher serum levels, but there is insufficient evidence to set cut-off levels or to link BPA to any harmful effect in CKD. However, the renal elimination and potential exposure during dialysis warrant the monitoring of BPA exposure and the design of observational studies in which the potential health risks of BPA for end-stage renal disease patients are evaluated.

The rationale for cost-effectiveness of modern muscle relaxants (MR) administration in general anesthesia was evaluated. New MRs are more expensive than traditionally used pipecuronium and succinylcholine. However, the old MRs are often required as a block reversion with anticholinesterase medicines at the end of surgery, the longer artificial lung ventilation and observation in patients during recovery in intensive care unit. It was found that the district military hospital had done an annual average of about 900 general anesthesia assisted with artificial ventilation and muscle relaxation. About 2% of all anesthesias accrue to short-term anesthesia, the 27% to medium-term and 71% to long-term. 81% of the medium-term anesthesia accrue small hospitals. According to cost/effectiveness the most optimal muscle relaxants administration scheme for short-term (up to 30 min) anesthesia was mivacurium, for the operation of medium duration (30-120 min)--rocuronium, for long-term (120 min)--pipecuronium. An electronic form of annual report, which allows to obtain the necessary data for calculation of annual muscle relaxants demand and costs both in hospital and in the whole of the armed forces quickly, was developed.

The paper analyzes the incidence of residual neuromuscular blockade (NMB) after pipecuronium and rocuronium administration in 124 neurosurgical patients. We analyzed neuromuscular conductance with TOF-Watch SX Residual NMB incidence after neuromuscular blocking agents administration in neurosurgical patients is 87.7%. Use of pipecuronium accompanied by a greater incidence and duration of residual NMB in comparison with rocuronium. Sugammadex administration is effective method of residual NMB reversal and can restore NMC in 3-5 minutes.

A comparative analysis of gas, the metabolic rate, pressor, resistive and volumetric characteristics of pulmonary blood flow, central and intracardiac hemodynamics in patients undergoing thoracic surgery was conducted. 2 methods of anesthesia maintenance: on the basis of ketamine - fentanyl - pipecuronium and propofol - fentanyl - pipecuronim were compared. Invasive monitoring system PiCCOplus for the behaviour of the transpulmonary thermodilution (TT) in combination with VoLEF for the pulmonary thermodilution (PT) the change of ventilation mode ALV - OLV - ALV was used. OLV lasted for more than 1.5 hours.

Transsphenoidal pituitary surgery is usually accompanied by severe hemodynamic stress response which is hardly treated with fentanyl. The main goal of the study is to compare anesthetic methods for endonasal endoscopic transsphenoidal pituitary adenomectomy and single out the most effective way of reducing or preventing the stress reaction. 65 patients underwent endonasal endoscopic transsphenoidal pituitary adenomectomy. In all the patients general an- esthesia was induced with propofol. Analgesia was provided by phetanyl boluses. The patients were divided into three groups. In the first group of patients TIVA with propofol-TCI was used. In the second group of patients anesthesia was maintained by N20 plus sevoflurane. The third group of patients received an additional bilateral endoscopic mucosal 2% lidocain 5 ml infiltration of the pterygopalatine nerve branches zone. Pipecuronium was used for neuromuscular blockade. The simultaneous HR, ABP and metabolism increase were qualified as stress response. In the first and second groups of patients the maximum stress response was recorded on the stage of mucosal coagulation and on the opening of the blades of bivalve nasal speculum. No major difference in stress response severity was noted in these groups. In the third group stress response was significantly lower. According of the results of the study bilateral endoscopic mucosal lidocaine infiltration of the pterygopalatine nerve branches zone for anesthetic management of endonasal endoscopic transsphenoidal pituitary adenomectomy can be recommended.

The study enrolled 30 patients aged 2 to 18 years, who had been operated on at the Prof A. L. Polenov Russian Neurosurgical Institute in 2008-2009. The patients had undergone total intravenous anesthesia with the opioid analgesic fentanyl (3.5 microg/kg x hr), the central alpha 2-adrenoblocker clofelin (1.2 microg/kg x hr), recofol (3 mg/kg x hr) under myorelaxation (arduan, esmeron) and artificial ventilation. Assessment of a neuroendocrine response and postoperative analgesia levels by the physiological and self-appraisal scales showed the high efficacy of pre-emptive analgesia using paracetamol in the complex of multicomponent anesthesia using the central alpha 2-adrenoblocker clofelin.

Severe tetanus is characterised by muscle spasms and autonomic dysfunction. We recently reported the results of a randomised placebo controlled trial of magnesium sulphate infusions for the treatment of severe tetanus which showed magnesium was associated with improved muscle spasm and cardiovascular control. We hypothesised that magnesium controlled autonomic dysfunction by reducing catecholamine release and thus urinary excretion. Urinary adrenaline and noradrenaline concentrations were measured during the first 24 h of therapy in 180 adults with severe tetanus randomised to treatment with magnesium (n = 92) or placebo (n = 88). Magnesium therapy was associated with lower urinary adrenaline excretion and higher urinary noradrenaline excretion. High urinary adrenaline concentrations were associated with documented autonomic dysfunction. Patients given magnesium had significantly less autonomic dysfunction, required less cardiovascular stabilising drugs, and had lower urinary concentrations of adrenaline. These findings suggest adrenaline is important in the pathophysiology of severe tetanus and magnesium controls autonomic dysfunction by reducing adrenaline release.

A sensitive and selective HPLC method with coulometric electrode array detection for the determination of pipecuronium bromide and its four impurities has been developed. The coulometric electrode array detection at increasing potentials from +300 to +900mV of the porous graphite electrode versus the palladium reference electrode was used. The limit of detection and quantitation for pipecuronium bromide was 8 and 25ngml(-1), respectively. This elaborate method for the simultaneous analysis of pipecuronium bromide and its impurities proved to be fast, precise, accurate, sensitive, and could be applied to analysis in substances and in pharmaceutical preparations.