Background: It is considered that acute lung injury (ALI) is an uncontrolled inflammation, mainly attributed to the release of inflammatory mediators and extensive apoptosis. Aim: As simvastatin exerts antiinflammatory properties by regulating cellular signaling pathways, we explored its effects on ALI development and apoptotosis of immune and epithelial cells in endotoxic shock. Methods: Male Wistar rats were intraperitoneally injected with 0.25 of the medial lethal dose of endotoxin (lipopolysaccharide, LPS). Simvastatin was given orally (10, 20, 40 mg/kg, per group) as a five-day pre-treatment prior to a single dose of LPS, and 48 afterwards the animals were sacrificed. Lung tissue inflammatory damage was assessed by histopathological examination (haematoxylin-eosin staining), and expressed as a tissue damaged score (TDS). Apoptosis was analysed by TUNEL (DNA fragmentation assay) and expressed as an apoptotic index (AI), and immunohistochemically by detection of cleaved caspase-3, Bcl-XL, inhibitor of apoptosis, survivin as well as expression of nuclear factor (NF)- κB signalling pathway. Results: TDSs showed that simvastatin ameliorated ALI induced by LPS in dose-dependent manner (simvastatin 20 mg/kg and 40 mg/kg vs LPS, 2.0±0.59 and 1.33±0.48 vs 3.35 ±0.42, p<0.01, respectively). LPS induced significant apoptosis (AI 43.8%±11.3), and increased expression of cleaved caspase-3

Abstract Respiratory failure is the predominant cause of death in humans and animals poisoned with anticholinesterases. Organophosphorus and carbamate anticholinesterases inhibit acetylcholinesterase irreversibly and reversibly, respectively. Some of them contain a quaternary atom that makes them lipophobic, limiting their action at the periphery, i.e. outside the central nervous system. They impair respiratory function primarily by inducing a desensitization block of nicotinic receptors in the neuromuscular synapse. Lipophilic anticholinesterases inhibit the acetylcholinesterase both in the brain and in other tissues, including respiratory muscles. Their doses needed for cessation of central respiratory drive are significantly less than doses needed for paralysis of the neuromuscular transmission. Antagonist of muscarinic receptors atropine blocks both the central and peripheral muscarinic receptors and effectively antagonizes the central respiratory depression produced by anticholinesterases. To manage the peripheral nicotinic receptor hyperstimulation phenomena, oximes as acetylcholinesterase reactivators are used. Addition of diazepam is useful for treatment of seizures, since they are cholinergic only in their initial phase and can contribute to the occurrence of central respiratory depression. Possible involvement of central nicotinic receptors as well as the other neurotransmitter systems – glutamatergic, opioidergic – necessitates further research of additional antidotes.

The influence of naloxone on respiration impaired by the highly toxic organophosphate nerve agent soman in anaesthetized rats was investigated. Soman, administered in a dose that was ineffective in blocking the electrically induced contractions of the phrenic nerve‐diaphragm preparation in situ, induced a complete block of the spontaneous respiratory movements of the diaphragm, indicating the domination of central over the peripheral effects. Naloxone dose‐dependently antagonized the soman‐induced respiratory blockade. Atropine, at a dose that was per se ineffective in counteracting soman‐induced respiratory depression, potentiated the protective effects of naloxone and completely restored respiration. Naloxone remained completely ineffective in antagonizing respiratory depression induced by the muscarinic receptor agonist the oxotremorine. It is assumed that naloxone antagonizes soman‐induced respiratory inhibition by blocking endogenous opioidergic respiratory control pathways that are independent of the stimulation of muscarinic receptors.

ABSTRACT The prescribing of medicines is a fundamental component of care for the elderly; however, there is increasing concern with polypharmacy and its impact on morbidity, mortality and costs. As a result, long-term prescription-medicine use and the prevalence of polypharmacy in the elderly in the Republic of Srpska were analyzed. The findings were subsequently used to suggest potential future measures. A retrospective study of all elderly patients during 2005–2010 stratified by age group (three groups), sex and long-term medicine use was performed. Polypharmacy (five or more medicines) increased from 1.4% of the elderly taking medicines long-term to 3.6% by 2010, with 53.6% of elderly taking two or more medicines long-term. The most prevalent diseases were cardiovascular diseases and diabetes. Most prescriptions were in accordance with recent guidelines; however, there was a concern with appreciable prescribing of digoxin and aminophylline. Whilst polypharmacy rates are low in the Republic, the increasing rate is a concern. Further studies are planned.

BACKGROUND/AIM Prescription of drugs is a fundamental care component of the elderly. Elderly patients often take multiple drugs, and it is known that polypharmacy may lead to drug interactions and adverse events. The aim of this study was to analyze the long-term drug use and the prevalence of polypharmacy among the elderly population in the Republic of Srpska, Bosnia and Herzegovina. METHODS; A retrospective study of outpatient drug use in 2005 and 2010 was conducted, analyzing prescriptions for patients aged ≥ 65 years reimbursed by the Health Insurance Fund. The study population was stratified by gender and age. Long-term drug use was defined as continuous drug dispensing for a whole year or at least two thirds of the year. Polypharmacy was defined as the use of 5 or more different reimbursed drugs. RESULTS Of all insured people aged ≥ 65 years, long-term drug use was identified in 10% (2005) and in 19% (2010), of whom 62% were women. Two to four different drugs were used by almost 49% (2005) and 54% (2010) of the elderly patients. The polypharmacy prevalence increased from 1.4% (2005) to 3.6% (2010); it increased in all the age groups of both genders. The largest increase was observed in the age group 65-74 years. Polypharmacy prevalence increase was higher in women. The most commonly used drugs were those for to treatment of cardiovascular diseases, in particular drugs for hypertension and cardiac treatment. CONCLUSION The study findings point out to the increase of elderly population with a long-term drug use. Over a half of elderly patients use 2-4 different drugs on the long-term basis. The polypharmacy prevalence was low. It increased in the period of 5 years in both genders. The increase was more prominent in women of all the age groups. The use of multiple drugs and polypharmacy increased with ageing.

Objective. Hip arthroplasty is one of the most common operations in elderly population. Pre- and postoperative risks increase their postoperative morbidity and mortality. One of the most important factors, which is included in the perioperative risks, is pain. Control of postoperative pain diminishes the incidence and severity of complications afterwards. Methods. We compared three different techniques of pain control in 30patients scheduled for elective hip arthroplasty: 1) pharmacological - morphine 5 or 10 mg iv q6h, depending on body weight, paracetamol 1 g i.v q6h (MP), 2) nerve block: femoral nerve block, single shot (FNB) and 3) fascia iliaca compartment nerve block (FICNB). Measurement of pain intensity was performed with numerical pain scale (NPS). Systolic blood pressure and consumption of additional analgesics on demand were monitored, as well as the duration of nerve blocks. Results. Both nerve blocks produced significantly lower pain scores than the purely pharmacological approach (MP 5.4+0.6 vs. FNB 2.8+1.6 and FICNB 2.9+1.2 after the first postoperative hour). Consequently, the first group required more additional morphine and paracetamol after the first hour compared to FNB and FICNB groups. Morphine was significantly more frequently added in the MP group (3.4+0.4 mg/kg IV) than in the FNB (2.1+0.5 mg/kg i.v.) and FICNB (2.5+0.4 mg/kg i.v.). Maximal duration of analgesia was 5 hours in MP group compared to 9 and 8 hours after FNB and FlCNB, respectively. Conclusion. Postoperative analgesia with blocks enables better pain control, better cardiovascular stability and less adverse effect than the classical morphine-based analgesia.

Background: Metabolic capacity of gut microflora is huge and this “microb” organ can be considered as second biggest metabolic organ in body. The potential for an antibiotic to influence gut microflora is related to its spectrum of activity, pharmacokinetics, dosage and length of administration. In terms of pharmacokinetics, the rate of intestinal absorption plays a fundamental role. Apart from basic physiological functions, bile acids and their analogues are recognized as transport promoters for other substances, in potentiating their action. The aim of this study was to demonstrate potential protective effect of monoketocholic bile acid on rat intestinal microflora from oral ampicillin. Materials, Methods & Results: Eighteen Wistar rats were divided into three groups (n = 6). The experimental protocol was approved by Ethics Committee on Animal Use of the University Novi Sad. All animals received 10 mL/kg of body weight of drugs solutions per os by oral intubations. The animals have been treated twice daily for three days, with saline, ampicillin 500 mg/kg and ampicillin 500 mg/kg + monoketocholic bile acid (MKH) 4 mg/kg. The fecal pellets were collected twice, before and after the treatment was completed. Within 2 h of collection, samples of whole pellets were processed microbiologically. Weighed portions of feces were suspended 1:10 in sterile 0.9% NaCl and further diluted with same solutions up to 1: 10 13 . The number of colony forming units (CFU) was determined by direct counting. Only the plates containing 30 to 300 CFU were considered as valid. The ampicillin treated group, showed significant reduction of CFU number compared to value before treatment under aerobic (P = 0.019) and anaerobic (P = 0.00) conditions. Concomitant use of ampicillin and MKH did not show statisticaly significant reduction ( P > 0.05) of CFU number compared to value before treatment in both cultivation conditions. There is significant reduction of CFU number ( P = 0.02) only in group treated with ampicillin comparing to control group under the aerobic condition. Statistical analysis was performed by single test ANOVA and Kruskal- Wallis test with Monte Carlo exact test to test significant differences in CFU reduction between groups. Paired two-tailed t-test was performed on the log-transformed data of the CFU/g fecal sample to test for significant differences between counts before and after treatments inside the group. Discussion: Oral antibiotic applications can change the composition of normal gut microflora. Modification of normal mi croflora can change metabolism of many compounds. Longer local retention of ampicillin in the gut, due to poor absorption of antibiotic has led to a significant reduction in the number of intestinal microorganisms. Although the fecal flora does not exactly represent the gut flora, comparison of number of CFU from feces specimen before and after antibiotic treatment indirectly reflects the effect of the antibiotic on the bacteria in the gut. Co-administration of ampicillin and MKH, due to promoting effect of bile acid on to absorption of ampicillin, led to less disruption of CFU than in ampicillin group. Based on these results, it is concluded that concomitant use of ampicillin and MKH, could be useful for reducing the harmful effects of ampicillin on the intestinal flora . These results are consistent with the results obtained in pharmacokinetics study with the same substances.

Research on the renin-angiotensin system (RAS) has contributed significantly to advances in understanding cardiovascular and renal homeostasis and to the treatment of cardiovascular diseases. This review offers a brief history of the RAS with an overview of its major components and their functions, as well as blockers of the RAS, their clinical usage and current research that targets various components of the RAS. Because angiotensin-converting enzyme (ACE) metabolizes two biologically active peptides, one in the kallikrein-kinin system (KKS) and one in the RAS, it is the essential connection between the two systems. ACE releases very powerful hypertensive agent, angiotensin II and also inactivates strong hypotensive peptide, bradykinin. Inhibition of ACE thus has a dual effect, resulting in decreased angiotensin II and increased bradykinin. We described the KKS as well.

INTRODUCTION Hyperkalemia secondary to beta-adrenergic receptor blockade occurs in 1-5% of patients and is likely to develop with non-cardio-selective beta-blockers. CASE REPORT We have described hyperkalemia in a patient with angina pectoris receiving propranolol, clinically manifested as weakness, tightness behind the sternum and numbness in the limbs. Laboratory tests showed hyperkalemia (6.6 mmol/L), peaked T wave and a corrected QT interval of 510 ms. After discontinuation of propranolol, decline in potassium level, normalisation of electrocardiographic changes and clinical improvement were achieved. Causal relationship of drug related hyperkalemia has been confirmed as probable/likely according to Naranjo Adverse Drug Reaction Probability Score of 7 and the World Health Organization Uppsala Monitoring Centre Probability Scale. CONCLUSION Hyperkalemia can be unpredictable and life-threatening complication of propranolol or a non-selective adrenergic beta blocker treatment, and requires timely identification of cause and implementation of therapeutic measures.

Introduction. Information on antibiotic utilization in the Republic of Srpska is limited. The aim of this study was to analyze antibiotic utilization in the community from 2007 to 2011 and to compare this data with antibiotic use in other European countries. Materials and Methods. We did a population-based study to analyze systemic antibiotic utilization by an outpatient population using Anatomical Therapeutic Chemical/Defi ned Daily Dose methodology. The results were expressed as the defi ned daily dose (DDD) per 1000 inhabitants per day. The data were obtained from the annual reports of the Agency for Drugs and Medical Devices of the Republic of Srpska and Public Health Institute. Results. Outpatient use of systemic antibiotics ranged between 21.51 DDD in the year with the highest use (2010) and 17.01 DDD in the year with the lowest use (2011). Penicillins were the most frequently prescribed antibiotic group, and amoxicillin was the most frequently prescribed drug. Cefalexin was the most frequently prescribed cephalosporin. Increased use of a second-generation cephalosporin, cefuroxime constituted almost a third of cefalexin consumption in 2011. Second-generation quinolones, mostly ciprofl oxacine, accounted for about 70% of total quinolones consumption, with rising third-generation drugs also in proportion to the increasing use. Erythromycine was the most frequently used macrolide, followed by long-acting azithomycin. Conclusion. Outpatient use of systemic antibiotics in the Republic of Srpska, at about 19 DDD, does not exceed that in Europe. As in other European countries, a shift between generations of drugs was noted for antibiotic use. Additional studies, including monitoring of seasonal variation impact on antibiotic use, are needed.

Background: Multiple reforms have been introduced in the Republic of Srpska to enhance prescribing efficiency. Objectives: First, assess their influence on utilization and expenditure on proton-pump inhibitors, statins and renin–angiotensin inhibitor drugs. Second, assess whether the Republic can obtain low prices for generics. Third, suggest additional reforms that could be introduced. Methods: Observational study of all ambulatory care patients between 2003 and 2010. Defined daily doses (DDDs) and DDDs per 1000 inhabitants per day used for measuring changes in utilization. Reimbursed expenditure used as health insurance perspective. Results: Increasing utilization in all three classes. Utilization of angiotensin-receptor blockers principally limited by prescribing restrictions. Reimbursed expenditure/DDD in all three classes decreased by up to 82% in 2010 versus 2004, appreciably improving prescribing efficiency for the statins. Increased utilization of esomeprazole at higher reimbursed expenditure/DDD, and similarly angiotensin-converting enzyme-inhibitor combinations at higher expenditure versus single drugs, limited the ability to fully capitalise on these reductions. Conclusion: Multiple measures helped lower expenditure/ DDD, providing hope to countries with small populations. Additional measures are planned to further improve prescribing efficiency in the Republic of Srpska.

In this article the neurotoxic disorders appearing in patients poisoned with organophosphorus pesticides (OPs) are reviewed. OPs cause four important neurotoxic effects in humans: the cholinergic syndrome, the intermediate syndrome, organophosphate-induced delayed polyneuropathy and chronic organophosphateinduced neuropsychiatric disorder. Compared to the cholinergic syndrome, that causes millions of cases of poisoning with fatality of more than 15% each year, other disorders involve much smaller number of patients. This article is focused on neurotoxic disorders appearing after acute and chronic exposure to OPs with emphasis on clinical presentation, molecular mechanisms and possibilities of medical treatment.

Great scientifi c discoveries rarely originate from small and poor countries, especially if they are frequently engulfed in wars, like it was the case with Serbia, and other parts of the former Yugoslavia. Despite the odds, quite a few well educated, curious, wise, and brave minds have made signifi cant contributions under such circumstances. For example, the achievements of Laza K. Lazarević (18511891), Milutin Milankovic (1879-1958), Ivan Djaja (18841957), Pavao Stern (1913-1976), and several other Yugoslav researchers clearly show that some scientists are able to make great discoveries under limited resources. 1 Nikola Tesla (1856-1943), and two Nobel laureates of Yugoslav origin, Leopold Ruzicka (1887-1976) and Vladimir Prelog (1906-1998), are only mentioned here because their major scientifi c contributions had been mostly conducted in the USA and Switzerland.