Department of Hygiene, Faculty of Medicine, University of Banja Luka, Banja Luka, the Republic of Srpska, Bosnia and Herzegovina. Department of Hygiene, Public Health Institute of Republic of Srpska, Banja Luka, the Republic of Srpska, Bosnia and Herzegovina. Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Banja Luka, Banja Luka, the Republic of Srpska, Bosnia and Herzegovina. Institute for Medicinal Plant Research "Dr Josif Pančić", Belgrade, Serbia. Institute of Hygiene and Medical Ecology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.

Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, Banja Luka, the Republic of Srpska, Bosnia and Herzegovina. Public Health Institute of the Republic of Srpska, Banja Luka, the Republic of Srpska, Bosnia and Herzegovina. Agency for Certification, Accreditation and Healthcare Quality Improvement of the Republic of Srpska (ASKVA), Banja Luka, the Republic of Srpska, Bosnia and Herzegovina.

Abstract Prophylactic antidotes are needed primarily in the case of soman poisoning, since its complex with acetylcholinesterase (AChE) ages very quickly and becomes resistant to the posttherapeutic administration of AChE reactivators. Among the many compounds tried as prophylactic antidotes, reversible AChE inhibitors (physostigmine, pyridostigmine, galantamine and huperzine A), noncompetitive antagonists of NMDA/AMPA receptors for excitatory amino acid glutamine (memantine, dizocilpine, procyclidine, ketamine), transdermal patches with a combination of physostigmine and procyclidine or patches with asoxime and stoichiometric and catalytic scavengers of nerve agents gave best results. Postexposure treatment of nerve agent intoxication consists of a triple regimen: anticholinergics, AChE reactivators, and anticonvulsants. Antimuscarinics, mainly atropine, but also more liposoluble scopolamine, oximes pralidoxime (2-PAM, P2S), trimedoxime (TMB-4), obidoxime LuH-6, asoxime (HI-6), HLo-7 and, most recently, K-oximes and benzodiazepines, diazepam, midazolam, and clonazepam, are discussed. Special attention is paid to glutamate receptor antagonists, memantine, ketamine, and procyclidine, as anticonvulsants that prevent the perpetuation of seizures following poisoning with nerve agents.

Abstract Carboxylesterases (CarbE) represent an important factor in studying the new antidotes against G-agents, tabun, sarin, and especially soman. Its isoenzymes exist in many mammalian tissues, but the most important is blood, as it is a medium for transportation of nerve agents to the target organs, such as the central nervous system and respiratory muscles. Rodent species used extensively in such research contain high plasma CarbE activity (mice, rats) or medium level (guinea pigs). At the same time, a low level of plasma CarbE activity was found in marmosets and there was practically no such activity in the plasma of rhesus monkeys and humans. In order to obtain results that would be easily extrapolated to humans, either nonhuman primates with naturally minimal plasma CarbE activity or rodents pretreated with CarbE inhibitors (TOCP, CBDP) should be utilized. In such animals, the LD50 of nerve agents is very similar, as is the efficacy of the prophylactic/postexposure antidotes. CarbEs are also potential stoichiometric scavengers of nerve agents and can be used intravenously to bind organophosphorus compound molecules.

Abstract Pomegranate peel contains high levels of various phytochemicals. We evaluated the effects of pomegranate peel extract (PoPEx) consumption on plasma lipid profile, fatty acids (FA) level and blood pressure (BP) in patients with diabetes mellitus type 2 (DMT2). Thirty-seven subjects were recruited in this double blind, placebo controlled randomized trial. The study group (n = 19) received over 8 week’s capsules containing PoPEx twice a daily, while the placebo group received placebo. Treatment with PoPEx induced a significant lowering of both systolic and diastolic BP. The plasma levels of triglycerides, low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio (LDL-C/HDL-C), and HbA1c were significantly decreased, while the level of HDL-C was significantly increased, compared with placebo intake. Moreover, the PoPEX treatment significantly improved the plasma lipids fatty acids content. It is concluded that consumption of PoPEx in DMT2 subject had favourable effects on some metabolic parameters, BP, lipid profile and plasma lipid FA composition.

Endotoxemia is associated by dysregulated apoptosis of immune and non-immune cells. We investigated whether simvastatin has anti-apoptotic effects, and induces hepatocytes and lymphocytes survival signaling in endotoxin-induced liver and spleen injuries. Wistar rats were divided into the groups pretreated with simvastatin (20 or 40 mg/kg, orally) prior to a non-lethal dose of lipopolysaccharide (LPS), the LPS group, and the control. The severity of tissue inflammatory injuries was expressed as hepatic damage scores (HDS) and spleen damage scores (SDS), respectively. The apoptotic cell was detected by TUNEL (Terminal deoxynucleotidyl transferase dUTP Nick End Labeling) and immunohistochemical staining (expression of cleaved caspase-3, and anti-apoptotic Bcl-xL, survivin and NF-κB/p65). Simvastatin dose-dependently abolished HDS and SDS induced by LPS (p < 0.01), respectively. Simvastatin 40 mg/kg significantly decreased apoptotic index and caspase-3 cleavage in hepatocytes and lymphocytes (p < 0.01 vs. LPS group, respectively), while Bcl-XL markedly increased accordingly with simvastatin doses. In the simvastatin, groups were determined markedly increased cytoplasmic expression of survivin associated with nuclear positivity of NF-κB, in both hepatocytes and lymphocytes (p < 0.01 vs. LPS group). Cell-protective effects of simvastatin against LPS seemed to be mediated by up-regulation of survivin, which leads to reduced caspase-3 activation and inhibition of hepatocytes and lymphocytes apoptosis.

BACKGROUND Carbamates physostigmine and pyridostigmine have been used as a pretreatment against poisoning with nerve agents in order to reversibly inhibit and thus protect from irreversible inhibition a portion of acetylcholinesterase (AChE) in brain and respiratory muscles that is crucial for survival. Memantine, an adamantine derivative, has emerged as a promising alternative to carbamates, since it prevented the fasciculations and skeletal muscle necrosis induced by carbamates and organophosphates, including nerve agents. AIM This experimental study was undertaken in order to investigate and compare the protective and behavioural effects of memantine and standard carbamates physostigmine and pyridostigmine in rats poisoned with soman and treated with atropine, oxime HI-6 and diazepam. Another goal was to elucidate the mechanisms of the antidotal effect of memantine and its potential synergism with standard antidotes against nerve agents. MATERIALS AND METHODS Male Wistar rats were used throughout the experiments. In dose-finding experiments memantine was administered at dose interval 0-72 mg/kg sc 60 min before sc injection of soman. In time-finding experiments memantine was injected 18 mg/kg sc 0-1440 min before soman. Standard treatment antidotes - atropine 10 mg/kg, HI-6 50 mg/kg and diazepam 2.5 mg/kg - were administered im within 15 s post-exposure. Soman 0.75 LD50 was used to study its inhibitions of neuromuscular transmission on the phrenic nerve-diaphragm preparation in situ and of tissue AChE activity. Behavioural effects of the prophylactic antidotes were investigated by means of the rotarod test. Based on these data therapeutic index and therapeutic width was calculated for all three prophylactic agents. RESULTS Memantine pretreatment (18 mg/kg sc) produced in rats poisoned with soman significantly better protective ratios (PRs) than the two carbamates - 1.25 when administered alone and 2.3 when combined with atropine pretreatment and 6.33 and 7.23 with atropine/HI-6 and atropine/HI-6/diazepam post-exposure therapy, respectively. The highest PR of 10.11 obtained in Atr/HI-6-treated rats was achieved after pretreatment with memantine 36 mg/kg. This additional protection lasted for 8 h. All three prophylactic regimens antagonised the soman-induced neuromuscular blockade, but the effect of memantine was fastest. Pretreatment with memantine assured higher AChE activity in brain and diaphragm than in unpretreated rats (46% vs 28% and 68% vs. 38%, respectively). All three prophylactic regimens affected the rotarod performance in rats, but the effect of memantine was relatively strongest. Memantine and pyridostigmine had lowest and highest therapeutic index and therapeutic width, respectively. CONCLUSIONS Although memantine assures better and longer-lasting protection against soman poisoning in rats than the two carbamates, its small therapeutic index and narrow therapeutic width seriously limit its potential as a pretreatment agent. Despite its behavioural effects, memantine seems to be beneficial antidote when administered after soman, along with atropine/HI-6/diazepam therapy. Mechanism of the antidotal effect of memantine against soman poisoning appears to be a combination of AChE-protecting and NMDA receptor-blocking action.

Background/Aim. Drug utilisation monitoring could identify drug-related problems and hence improve the awareness of irrational drug use. The objective of this study was to analyse the drug utilisation patterns in a rehabilitation hospital over the period 2011?2016. Methods. The Anatomic Therapeutic Chemical classification/Defined Daily Dose (ATC/DDD) methodology was used to monitor the drug utilisation expressed as a number of DDD per 100 patient-days (HPD). The values of DDDs were obtained from the World Health Organisation (WHO) Collaborating Centre for Drug Statistics Methodology. Utilisation trends were analysed by means of the Compound Aggregate Growth Rate (CAGR), which is defined as an average annual change rate of some value during the period of interest. Results. The number of patient-days increased during the six years period; the CAGR being1.8% annually. At the same time, the total number of dispensed DDDs as well as the number of DDD/HPD decreased with the CAGR of -2.0% and -3.7% respectively. The average drug cost per patient-day varied from BAM 1.38 in 2013 to 0.95 in 2016; the CAGR being -1.8%. The most utilised drugs belonged to the ATC groups C, A, B, M and N and they contributed to an average of 77% of all drugs used each year. On the top of the list of most utilised drugs were: hydroxocobalamin, thioctic acid, enalapril, diclofenac, amlodipine, acetylsalicylic acid, pantoprazole, paracetamol and bromazepam. Conclusions. The overall drug utilisation in the hospital was modest and almost equal in 2016 compared to 2011. Besides the leading consumption of vitamin B12 and thioctic acid, this study points out some interesting prescribing patterns, such as predominant use of diclofenac over ibuprofen, and overuse of proton pump inhibitors. There is a need for educative interventions among physicians in order to improve their prescribing practice.

Background: The purpose of this study was to assess the antiviral efficacy and safety of the direct-acting antivirals (DAAs) in therapy of chronic hepatitis C virus (HCV) infection. Methods: This real-life multi-centric study was performed at the Clinic for Infectious Diseases, University Clinical Centre of the Republic of Srpska, Banja Luka and it included a total of 89 patients. All patients received the adequate doses of ombitasvir (OBV)/ paritaprevir (PTV)/ritonavir (RTV) + dasabuvir (DSV) plus ribavirin (RBV). RBV was given to all patients except to those with HCV sub-genotype 1b. DSV was not administered to patients infected with HCV genotype 4. For the majority of patients the treatment duration was 12 weeks. For ten patients with liver cirrhosis the duration of treatment was 24 weeks. Viraemia was assessed at three points in time: at baseline, 12 or 24 weeks after the beginning of treatment (end of treatment response ETR), and 12 weeks after the end of treatment (sustained viral response SVR). Results: Complete ETR after 12 weeks of treatment was achieved in 79 patients, while in 10 high-risk patients it was achieved after 24 weeks of treatment. Full SVR was recorded in 88 patients 12 weeks after the end of treatment. This therapy was well tolerated and mild adverse effects were recorded in only 10 patients. Conclusion: Treatment of patients with chronic HCV infection with OBV/PTV/ RTV+ DSV + RBV resulted in excellent antiviral activity and mild adverse events.

Background/Aim. The era of direct-acting antiviral (DAA) regimen in the treatment of chronic hepatitis C virus (HCV) started in 2011. The aim of this study was to assess the antiviral efficacy and safety of DAA regimen, ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) + dasabuvir (DSV) + ribavirin (RBV), in patients with chronic HCV infection, genotype 1. Methods. The real-life data were collected. The study was multicentric and included seven infectious diseases and hepatology departments in Serbia. A total of 21 patients were enrolled in the OBV/PTV/r + DSV + RBV early access program, 20 of which were previously treated with pegylated interferon + RBV, while 1 was treatment-naive. All patients received the adequate doses of these antiviral drugs. RBV was not given to the patients with HCV genotype 1b infection according to the therapeutic protocol. For the majority of patient, the treatment duration lasted for 12 weeks. For the patients with liver cirrhosis, who were infected with HCV genotype 1a, the duration of treatment was 24 weeks. Viremia was assessed at four points in time: at baseline, 4 weeks after the treatment beginning (rapid viral response, RVR), 12 or 24 weeks after the treatment beginning (end of treatment response ? ETR) and 12 weeks after the end of treatment (sustained viral response ? SVR). SVR, as a confirmation of the absence of HCV was considered as endpoint of successful treatment. Results. Complete RVR, ETR and SVR were achieved in 64.71%, 85.71% and 95.24% of the patients, respectively. Only 3 patients had mild adverse effects which did not required dose reduction. Conclusion. The treatment of the patients with a chronic HCV infection with OBV/PTV/r + DSV + RBV resulted in excellent antiviral activity and tolerability.

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