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Academic medicine encompasses education, research and clinical practice, and plays a crucial role in advancing medical science and training physicians. However, the field faces a crisis, with fewer graduates pursuing academic careers.

Background: Among many genes which have been analyzed to understand obesity and related metabolic traits among children and adolescents, not many studies are conducted on LGALS3 gene, especially in population of children. A positive correlation of circulating galectin 3 serum levels with impaired blood glucose, high blood pressure and higher values of serum lipids and was found in general population. The aim was to investigate possible association of rs4644 with body mass index, glycaemia, and lipid profile in Serbian adolescents. Methods: The study included 72 boys and 79 girls, 14-15 years of age. Among boys 51 (67.1%) had normal values of BMI, 11 (14.5%) were overweight, and 14 (18.4%) were obese. Among girls, 53 (63.9%) had normal BMI, 16 (19.3%) were overweight, and 14 (16.9%) were obese. Diabetes type 1 or 2, genetic syndromes, generalized inflammation, cardiovascular and malignant diseases were criteria for exclusion. Genotyping was performed by Real time PCR. Results: Girls carriers of CC genotype had statistically higher mean values of BMI, and triglycerides in comparison to the girls carriers of CA+AA genotypes, p=0.041, and p=0.045, respectively. The higher frequency of obese was found among group of girls who were carriers of CC genotype, p=0.049. No statistically significant association was observed among other analyzed parameters in neither examined groups. Results: Our research indicates that there is an association between the CC genotype of rs4644 polymorphism with obesity and higher triglycerides level in the group of female adolescents.

Background: In last 2 decades, there have been substantial changes in the utilization patterns of antihypertensive medicines following new clinical trials and the introduction of new treatment guidelines. The aim of this study was to analyze utilization and prescribing patterns regarding antihypertensive medicines in the Republic of Srpska, Bosnia and Herzegovina during an 11-years follow-up according to national and European treatment guidelines. Methods: In this retrospective, observational study, medicine utilization data were analyzed between 2009-2019 period using the ATC/DDD methodology and expressed as the number of DDD/1,000 inhabitants/day (DID/TID). The medicine utilization 90% (DU90%) method was used for determine the quality of prescribing. Results: During the observed period, the use of antihypertensive medicines increased more than 3-times (125.97 DDD/TID in 2009 vs 414.95 DDD/TID in 2019), corresponding to a rise in the prevalence of hypertensive patients from 91.7/1,000 to 186.3/1,000 in the same period. This was mainly driven by increased use of angiotensin converting enzyme inhibitors with 241.69%, beta blockers with 146.87%, calcium channel blockers with 251.55%, and diuretics with 178.95%. Angiotensin receptor blockers were the fastest growing group of antihypertensive medicines in this period and their utilization increased nearly 40 times. Conclusions: The overall antihypertensive medicines utilization was largely influenced by national and ESH/ESC guidelines and strongly corresponded to the positive medicine list of the national health insurance fund. Antihypertensive medicines utilization is comparable with medicine utilization trends in other countries.

Background/Aim: The placenta is an extraembryonic organ necessary for foetal development. Due to its availability and high content of stem cells and growth factors, placenta tissue has found its application in regenerative medicine. The aim of this paper was to determine whether the age of the pregnant woman or the gestational age affects the morphology of the term placenta and whether placentas of advanced maternal age are suitable for application in regenerative medicine. Methods: In this research 30 placentas of healthy pregnant women, aged from 18 to 42 years and from 36 up to 41 weeks of gestational age were used for analyses. Tissue samples were stained with standard haematoxylin and eosin staining and immunohistochemical staining with anti-CD34 antibody. The parameters of volume density of chorionic villi, intervillous spaces and fibrinoids, as well as the thickness of the placental barrier were determined. Results: The volume densities of chorionic villi and fibrinoids were higher in placentas of advanced maternal age, as well as in placentas of gestational age from 38 to 41 weeks of gestation, while the volume of intervillous spaces was lower in these groups. With increased maternal and gestation age, the placental membrane thickens. Conclusion: When sampling placentas for regenerative medicine purposes, only the placentas from pregnant women younger than 35 years of age and whose gestational age are not exceeding 38 weeks should be selected. [ABSTRACT FROM AUTHOR]

Background/Objectives: The importance of fixed-dose combinations (FDCs) for the treatment of hypertension is well established. However, from a stability perspective, FDCs present a challenge since the degradation of one active pharmaceutical ingredient (API) can be affected by the presence of another API. The aim of this study was to compare the degradation behaviors and evaluate the degradation kinetics of three antihypertensive drugs, perindopril tert-butylamine (PER), amlodipine besylate (AML), and indapamide (IND). Methods: The degradation processes were studied using the previously developed reverse phase high-performance liquid chromatographic (RP-HPLC) method after exposing each drug individually, as well as the combinations of two/three drugs, to different stress factors, such as light, oxidation, acidic, basic, or neutral pH values at different temperatures. Results: The results show that PER is most unstable under basic conditions and that AML displays a negative, while IND displays a positive effect, on PER stability when combined. AML is most affected by basic conditions and oxidation, and its stability is affected by both drugs positively; IND undergoes extreme photolysis, which is positively affected by AML but negatively by PER. Conclusions: Great care must be taken when formulating FDCs with these three drugs, as well as solutions or oral suspensions adjusted for geriatric or pediatric populations, since the stability of all three drugs is greatly affected by pH conditions, as well as light or oxidation factors and their interactions. [ABSTRACT FROM AUTHOR]

Background/Aim: Hypomagnesaemia is one of the most detected electrolyte abnormalities in diabetics. Modulation of numerous cardiovascular pathophysiological processes is a potential goal for anti-diabetic therapy. Magnesium supplementation prevents subclinical tissue magnesium deficiency, thus delaying the onset of metabolic imbalance in diabetes, but long-term effects of magnesium supplementation in chronic diabetes and numerous pathophysiological processes remain unknown. Aim of this study was to determine the effects of subchronic intake of magnesium hydrocarbonate-rich mineral water on cardiometabolic markers and electrolytes in rats with streptozotocin-induced diabetes. Methods: A total of 28 Wistar, male rats, body weight 160 g at start, were divided into four groups of 7 each: two controls, group that drank tap water and received a single ip injection of saline (0.9 % NaCl) (TW-C), group that drank mineral water rich in magnesium hydrocarbonate and received a single ip injection of saline (0.9 % NaCl) (MW-C); and two experimental groups with streptozotocin-induced diabetes, group that drank tap water and received a single ip injection of streptozotocin (100 mg/kg) in saline (0.9 % NaCl, 1 mL) (TW-DM), group that drank mineral water rich in magnesium hydrocarbonate and received a single ip injection of streptozotocin (100 mg/kg) in saline (0.9 % NaCl, 1 mL) (MW-DM). Results: Regarding the biochemical parameters, a decrease was observed in the MW-C group for vitamin B12 and proteins, while triglycerides were higher compared to the TW-C group. By comparing the haemostatic biomarkers between TW-C and MW-C groups, a statistically significant decrease was found for fibrinogen, while the electrolyte analysis showed an increase in phosphates for the MW-C group. Biochemical value comparison between TW-DM and MWDM groups showed that magnesium hydrocarbonate usage in diabetic rats did not significantly reduce glycaemia although the average glycaemic values were lower in the group treated with magnesium hydrocarbonate. Regarding the electrolyte values, a statistically significant decrease was observed for sodium, potassium and phosphate in the MW-DM group. The MW-DM group also showed a significant increase in iron value compared to TW-DM group. Conclusion: Subchronic intake of magnesium hydrocarbonate-rich mineral water, as a form of magnesium supplementation, did not cause a significant improvement in glycaemia or normalisation of diabetes-induced dyslipidaemia. This study showed the reduction of fibrinogen value, thus indicating the possibility of usage of this form of magnesium supplementation in different pro-thrombogenic conditions.

Background/Aim: Sulphur mineral water is widely used in the treatment of musculoskeletal diseases. Hydrogen sulphide is an important regulator of bone metabolism and its application in the treatment of osteoporosis is intensively researched. The aim of this study was to analyse biochemical and histological effects of H2S containing mineral water of "Mlječanica" spring on ovariectomy-induced experimental osteoporosis in rats. Methods: In this experiment a 14-week-old Wistar female rats were used. The animals undergone bilateral ovariectomy (OVX groups) as an experimental model for oestrogen-deficient osteoporosis. After six weeks, animals were divided into control and the experimental group. Rats from the experimental group treated with H2S (SW group) containing mineral water ad libitum during five weeks. Biochemical parameters for monitoring sulphur water effects were concentration in serum of osteocalcin, alkaline phosphatase, calcium and phosphorus. Histological analyses of the left tibia coloured with haematoxylin-eosin were carried out. Results: Regarding the biochemical parameters, a statistically significant increase was observed in the OVX group for osteocalcin, alkaline phosphatase calcium and phosphorus compared to the sham-operated (CNT) group (p < 0.01). In SW + OVX, alkaline phosphatase was statistically significantly decreased (p < 0.01) and serum osteocalcin and phosphorus increased (p < 0.01). Calcium values were increased without significance. In the OVX + SW group, histological analyses showed numerous osteoblasts along the trabecular endosteum and the growth of young chondrocytes in the central bone zone and their migration to the peripheral parts. Conclusion: Drinking the H2S containing "Mlječanica" mineral water has led to decreased alkaline phosphatase, increased osteocalcin and phosphorus concentration in serum and stimulated the bone reparation in osteoporotic rats.

Background/Aim: Optimal intake of magnesium minerals is essential in maintaining the coordinated physiological functions of cells, tissues and organs. The importance of this element is reflected in the fact that it is the fourth most abundant cation in the human body, participating as a cofactor in more than three hundred enzymatic reactions. Its presence is necessary for the proper functioning of a number of vital functions, such as glycaemic control, the work of the heart and the vascular system and it can potentially play a role in the regulation of body weight. Aim of this study was to investigate the effects of subchronic intake of magnesium hydrocarbonate-rich water on changes in body weight, organ weight and cardiovascular variables in rats with streptozotocin-induced diabetes. Methods: Wistar rats (n = 28) were divided into 4 groups: two control groups, on tap water (TW-C, n = 7) and magnesium hydrocarbonate-rich water (MW-C, n = 7); and two experimental groups with streptozotocin-induced diabetes, on tap water (TW-DM, n = 7) and magnesium hydrocarbonate-rich water (MW-DM, n = 7). The values of body weight, organ weight and cardiovascular parameters were compared after 6 weeks between control groups of rats on subchronic treatment with tap water (TW-C) and magnesium hydrocarbonate-rich water (MW-C) and between groups with streptozotocin-induced diabetes on tap water (TW-DM) and with magnesium hydrocarbonate-rich water (MW-DM). Results: By comparing the values of cardiovascular parameters between groups, significant (p < 0.05) positive effects of magnesium hydrocarbonate-rich water were registered on the values of systolic and pulse blood pressure in diabetic rats fed with magnesium hydrocarbonate-rich water (MW-DM) compared to those fed with tap water (TW-DM). In contrast, no significant effect of magnesium hydrocarbonate on changes in body weight and organ weight was observed. Conclusion: Based on the results, the beneficial effects of magnesium hydrocarbonate-rich water in the regulation of blood pressure can be clearly observed. Potential effects on other cardiovascular variables and body weight and organ weight should be further investigated.

Background/Aim: Type 2 diabetes is a common comorbidity in patients with knee osteoarthritis. Bearing in mind that obesity and insulin resistance are risk factors for the development of knee osteoarthritis, physical therapy and balneotherapy containing hydrogen sulphide (H2S) has a positive effect on the functional and metabolic status of these patients. This work was aimed to investigate the effect of sulphate-sulphide-rich mineral baths containing H2S on the level of serum glucose in patients with knee osteoarthritis. Methods: An open prospective randomised clinical trial included patients suffering from stage I and II of the knee osteoarthritis. Patients were divided into two groups of 40 subjects each: control group and experimental group. All subjects underwent inpatient physical treatment consisting of kinesitherapy and transcutaneous electrical nerve stimulation (TENS) 6 days a week. Patients from experimental group, in addition to all the mentioned treatments, also took sulphate-sulphide mineral water baths once a day for 30 minutes for 7 days, unlike the patients from control group who took tap water baths, according to the same schedule. The level of serum glucose was monitored in all patients on admission, after discharge and 6 months after the treatment. The Student t-test was used for statistical data processing and p < 0.05 was considered as statistically significant. Results: Study included 80 patients of both sexes, with an average age of 67.00 ± 5.75 years. All patients had elevated serum glucose values on admission. The initial levels of glycaemia in the control and experimental groups were not significantly different (6.99 ± 1.95 and 7.88 ± 1.90 mmol/L, respectively). At discharge, patients who performed balneotherapy had a statistically significant decrease in serum glucose values compared to patients from the control group (by 1.84 vs 0.26 mmol/L, p < 0.001). This effect did not persist six months after the end of the treatment (p > 0.05). Conclusion: The application of balneotherapy with sulphate-sulphide mineral baths containing H2S as a potent gas transmitter significantly reduces serum glucose levels in patients with knee osteoarthritis.

The enzymes of the cytochrome P450 superfamily play a critical role in phase I drug metabolism. Among them, CYP2C9 and CYP2C19 are clinically important, as they can mediate severe toxicity, therapy failure, and increased susceptibility to cancer and other diseases caused by chemicals. The aim of this study was to determine the prevalence of pharmacologically most important allelic variants of the CYP2C9 and CYP2C19 genes in the general population of the Republic of Srpska (Bosnia and Herzegovina) and to compare them with other populations. For this purpose we determined the genotype profile and allele frequency of 216 randomly selected healthy volunteers using real-time polymerase chain reaction (RT-PCR). The prevalence of the CYP2C9 *2 and *3 alleles was 13.6 and 7.4 %, respectively. Based on these frequencies, of the 216 participants four (1.86 %) were predicted to be poor metabolisers, 78 (36.11 %) intermediate, and the remaining 134 (62.03 %) normal metabolisers. Based on the prevalence of CYP2C19 *2 and *17 variants – 16.2 and 20.4 %, respectively – nine (4.17 %) were predicted to be poor, 57 (26.39 %) rapid, and nine (4.17 %) ultra-rapid metabolisers. We found no significant differences in allele frequencies in our population and populations from other European countries. These findings suggest that genetically determined phenotypes of CYP2C9 and CYP2C19 should be taken into consideration to minimise individual risk and improve benefits of drug therapy in the Republic of Srpska.

Patients suffering from cholelithiasis have an increased risk of developing cardiovascular complications, particularly ischemic myocardial disease. Ursodeoxycholic acid (UDCA), already used in clinical practice for the treatment of cholelithiasis and related conditions, has proven antioxidative, anti-inflammatory, and cytoprotective effects. Therefore, the aim of this study was to investigate the cardioprotective effect of UDCA pre-treatment on isoprenaline-induced myocardial injury in rats. Male Wistar albino rats were randomized into four groups. Animals were pre-treated for 10 days with propylene glycol + saline on days 9 and 10 (control), 10 days with propylene glycol + isoprenaline on days 9 and 10 (I group), 10 days with UDCA + saline on days 9 and 10 (UDCA group), and 10 days with UDCA + isoprenaline on days 9 and 10 (UDCA + I group). UDCA pre-treatment significantly reduced values of high-sensitivity troponin I (hsTnI) and aspartate aminotransferase (AST) cardiac markers (p < 0.001 and p < 0.01, respectively). The value of thiobarbituric acid reactive substances (TBARS) was also decreased in the UDCA + I group compared to the I group (p < 0.001). UDCA also significantly increased glutathione (GSH) levels, while showing a tendency to increase levels of superoxide dismutase (SOD) and catalase (CAT). The level of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression, a key regulatory gene of inflammation, was diminished when UDCA was administered. A reduction of cardiac damage was also observed in the UDCA pre-treated group. In conclusion, UDCA pre-treatment showed a cardioprotective effect on isoprenaline-induced myocardial injury in rats, primarily by reducing oxidative stress and inflammation. [ABSTRACT FROM AUTHOR]

Background/Aim: The prevention of cardiovascular risk factors and cardiovascular disease management contributes to the cardiovascular mortality reduction. The effects of these activities have been measured by quality indicators. The aim of this study was to determine the effects of family medicine team training workshop and implementation of clinical guidelines on the cardiovascular risk factors and diseases management in primary health care in the Republic of Srpska/Bosnia and Herzegovina. Methods: The "CardioVascular Risk Assessment and Management" study included a sample of 373 teams from 41 primary health care centres trained to provide adequate services and to compare the quality of cardiovascular risk management before and after the training workshop and implementation of clinical guidelines. The comparison was based on nine project defined performance indicators related to hypertension, type 2 diabetes mellitus, hyperlipidaemia, tobacco smoking and obesity. Results: Significant improvements were observed in six indicators after the training workshop and implementation of guidelines. Target values for blood pressure and HbA1c were achieved in over 80 % of patients (82.12 ± 15.81 vs 84.49 ± 12.71 and 84.49 ± 12.71 vs 85.49 ± 24.55; before and after the training workshop, respectively), while the target values for LDL cholesterol were achieved in 54.98 % ± 20.33 before and 57.64 % ± 16.66 after the training workshop. The number of teams that had less than 20 % of recorded data significantly decreased after the training workshop and guidelines implementation, and adequate recording of all indicators was improved. Conclusion: The training workshop of family medicine teams and implementation of clinical guidelines resulted in significant quality improvement of cardiovascular diseases management in primary health care.

Introduction: Oganophosphorus compounds (OP) bind to acetylcholinesterase (AChE) and inactivate it. In the synaptic cleft, undestroyed and accumulated acetylcholine produce the acute cholinergic effects. The aim of this study was to determine the frequency, speed of onset and intensity of certain signs of paraoxon poisoning depending on dose and outcome of poisoning. Methods: The study was conducted in adult Wistar rats. The median lethal dose (LD50) of paraoxon as well as protective ratio (PR) of atropine (10 mg/kg intramuscularly) was determined. Clinical signs of poisoning were observed: fasciculations, tremor, seizures, ataxia, piloerection, lacrimation, exophthalmos, bizzare/stereotypic behaviour and dyspnoea. The time from paraoxon injection to the first appearance of the sign of poisoning was recorded as well as the intensity of poisoning with evaluation at 10 time intervals throughout the 4 h observational period. Results: The LD50 of paraoxon was 0.33 mg/kg (subcutaneously) and PR of atropine was 2.73. Dose-dependent, piloerection occurred more often (p = 0.009) and at higher intensity (p = 0.016) at higher doses. Fasciculations, tremor, seizures and ataxia occurred significantly earlier at higher doses of paraoxon (p = 0.015, 0.002, 0.021 and 0.016, respectively), as well as the intensity of seizure, tremor and fasciculation. Piloerection (p = 0.002) and seizures occurred more frequently (p = 0.009) in non-survivors. Fasciculations, tremor, seizures and ataxia occurred significantly earlier and at higher intensity in non-survivors (p < 0.001, for all parameters), as well as dyspnoea (p = 0.009 and p = 0.048). In atropine-protected rats, nicotinic effects persevered, so they were the prognostic parameter of the severity of the poisoning. Conclusion: Seizures and fasciculations followed by tremor were strong prognostic parameters of the probability of lethal outcome of paraoxon poisoning. Also, the mentioned poisoning signs were with their intensity and speed of occurrence in a clear positive correlation with the administered dose of paraoxon. Even at high doses of paraoxon, atropine blocked the muscarinic (but not nicotinic) effects and somewhat mitigated the CNS toxic effects.

Background/Aim: There have been different experimental conditions for in vitro studies on human umbilical arteries (HUA) in tissue bath system. This diversity was mainly reflected in variables such as stretching tension, incubation period and initial constriction challenging with potassium (KCl). The aim of the study was to establish optimal experimental conditions which will provide better responsiveness of HUA preparations, as well as to examine the impact of 24 h cold storage on viability and responsiveness of HUA to KCl and serotonin. Methods: The KCl-induced constrictions at different stretching tensions (0.5 g, 1.0 g, 2.0 g, 4.0 g), incubation times (30 min, 60 min, 120 min), and after multiple initial constriction challenging were compared. Dose response curves for serotonin were obtained under different conditions (1.0 g and 60 min vs. 2.0 g and 120 min). The influence of 24 h cold storage on KCland serotonininduced vasoconstriction of HUA preparations was examined as well. Results: The strongest constrictions induced by serotonin or KCl were obtained when preparations were adjusted at 2.0 g and incubated for 120 min. The KCl-induced constrictions observed after 120 min were statistically higher (p < 0.05) when preparations were challenged three times (30 min, 60 min, 120 min), compared to those challenged only once. The preparations that were stored at 4 ⁰C for 24 h showed significantly stronger serotonin-induced constrictions (p < 0.01). The cold storage had no influence on KCl-induced constriction. Conclusion: For performing in vitro studies on HUA preparations in tissue bath, we propose stretching tension of 2.0 g, incubation period of 120 min and multiple initial constriction challenging with KCl as optimal experimental condition. We also showed that HUA preparations retained functional viability even after 24 h of cold storage.

Background/Aim: Polyphenol compounds obtained from pomegranate have beneficial pharmacological activities in the treatment of diabetes mellitus type 2 (DMT2). Most of DMT2 patients are overweight or obese and obesity by itself is very much related to insulin resistance and abnormalities in insulin secretion. This clinical study aimed to evaluate the pomegranate peel extract (PoPEx) activity on anthropometric parameters and body composition of overweight patients with DMT2. Methods: Sixty patients with DMT2 on continuous metformin therapy were involved in this double-blind, placebo-controlled, randomised clinical trial. Patients from the study group (n=30) were treated with capsules containing PoPEx (250 mg) twice a day for 8-week period, while those ones from the placebo group (n=30) received placebo capsules for the same period. Anthropometric characteristics (body weight, waist circumference, fat mass percentage, visceral fat level) were measured at the beginning and at the end of the study. Results: Eight-week treatment with PoPEx resulted in significant changes in BMI (mean value ± standard deviation: 0.18 ± 0.30 kg/m2 ) and body mass (0.48 ± 0.93 kg). The intake of PoPEx produced a significant decrease in waist circumference (z = -4.613, p < 0.001, r = 0.60) indicating a large effect size using Cohen's d-test, and a non-significant decrease in the level of visceral fat. The results showed a non-significant reduction in fat mass percentage in PoPEx group (-0.58 ± 2.21 %, p = 0.159) compared with the placebo group (0.14 ± 1.24 %, p = 0.546). Conclusion: The eight-week supplementation with PoPEx had a beneficial effect on anthropometry and body composition of overweight diabetic patients.

Background: Clinical pathways are important tools to achieve better quality of care and to reduce the costs for healthcare system. The total hip replacement (THR) is among the most expensive procedures in health system and the number of these operations has greatly increased in the past decade in the Republic of Srpska. Aim: The aim of the present study was to determine how the implementation of a clinical pathway for THR can influence the length of stay and postoperative complications in hospitals in the Republic of Srpska. Methods: This prospective and comparative study was performed on 2,485 patients who underwent the THR over a 3-year-period in 2012 (prior to the introduction of the clinical pathways, baseline), in 2013 (first evaluation period) and in 2014 (second evaluation period), one and two years after its implementation, respectively. The study was conducted in 10 hospitals in the Republic of Srpska, where the effects of the clinical pathways on length of stay and postoperative complications after THR were measured. Results: The introduction of THR clinical pathways significantly decreased the length of stay in hospital from 14.53 ± 7.03 days measured at baseline, to 12.79 ± 4.81 days and 11.19 ± 4.11 days at first and second evaluation period, respectively. At the same time, the number of early postoperative complications such as death and venous thromboembolism significantly decreased in both groups, while the number of dislocations, as parameter of late complications, decreased just after the second evaluation period. For all other complications, such as revision procedures, infections and periprosthetic fracture, there were no statistical differences after the implementation of clinical pathways. Conclusion: The introduction of clinical pathways was successful in reducing the length of stay in hospitals as well as the postoperative complications after THR.

Considering the escalating global prevalence and the huge therapeutic demand for the treatment of hypertension, there is a persistent need to identify novel target sites for vasodilator action. This study aimed to investigate the role of TRPA1 channels in carvacrol-induced vasodilation and to design novel compounds based on carvacrol structure with improved activities. In an isolated tissue bath experiment, it was shown that 1 µM of the selective TRPA1 antagonist A967079 significantly (p < 0.001) reduced vasodilation induced by 3 mM of carvacrol. A reliable 3D-QSAR model with good statistical parameters was created (R2 = 0.83; Q2 = 0.59 and R p r e d 2 = 0.84) using 29 TRPA1 agonists. Obtained results from this model were used for the design of novel TRPA1 activators, and to predict their activity against TRPA1. Predicted pEC50 activities of these molecules range between 4.996 to 5.235 compared to experimental pEC50 of 4.77 for carvacrol. Molecular docking studies showed that designed molecules interact with similar amino acid residues of the TRPA1 channel as carvacrol, with eight compounds showing lower binding energies. In conclusion, carvacrol-induced vasodilation is partly mediated by the activation of TRPA1 channels. Combining different in silico approaches pointed out that the molecule D27 (2-[2-(hydroxymethyl)-4-methylphenyl]acetamide) is the best candidate for further synthesis and experimental evaluation in in vitro conditions. [ABSTRACT FROM AUTHOR]

Background and Objectives: The aim of this study was to determine the role of physicians in the intensive intervention and education regarding the smoking cessation of patients undergoing elective surgery under general anaesthesia. Materials and Methods: A randomised prospective study was conducted in family physicians' clinics in which smokers of both sexes, aged 21–65 years, without cognitive impairments, and who were not addicted to psychoactive substances voluntarily participated. Four weeks preoperatively, 120 smokers were randomised into two equal groups; the intervention group (IG) underwent an intervention for the purpose of smoking cessation and the control group (CG) underwent no intervention. Biochemical tests were performed in order to determine the smoking status of the participants in the phase of randomisation, one week preoperatively, as well as 40, 120, and 180 days and 12 months postoperatively. The examinees of the IG talked to the physician five times and received 140 telephone messages, leaflets, and motivational letters along with the pharmacotherapy, while the participants in the CG received little or no advice on smoking cessation. Results: The results of this study confirmed a significant influence of the intervention and education on the smoking abstinence in the IG compared to the CG (p < 0.001). The smokers in the IG had 7.31 (95% CI: 2.32–23.04) times greater odds of abstinence upon the 12-month follow-up than the smokers in the CG. The smokers in the IG who did not stop smoking had a lower degree of dependence and smoked fewer cigarettes (p < 0.0001) compared to those in the CG, as well as a multiple times higher prevalence of short- and long-term abstinence. Conclusions: It can be concluded that the intensive intervention and education can motivate patients preparing for elective surgery to stop smoking in the short- and long term. [ABSTRACT FROM AUTHOR]

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.

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.

Many non-native English speakers, especially those whose mother language has no articles (like Slavic languages) make mistakes when they speak or write English. This may sound rather rough to English-speaking listeners or readers. To improve their command of the language and the usage of articles, individuals for whom English is a second language should review the usage of articles from time to time. We prepared a short text on this subject and also included exercises from the medical publications.

Hypotensive influences of benzodiazepines and other GABAA receptor ligands, recognized in clinical practice, seem to stem from the existence of "vascular" GABAA receptors in peripheral blood vessels, besides any mechanisms in the central and peripheral nervous systems. We aimed to further elucidate the vasodilatatory effects of ligands acting through GABAA receptors. Using immunohistochemistry, the rat aortic smooth muscle layer was found to express GABAA γ2 and α1-5 subunit proteins. To confirm the role of "vascular" GABAA receptors, we investigated the vascular effects of standard benzodiazepines, midazolam, and flumazenil, as well as the novel compound MP-III-058. Using two-electrode voltage clamp electrophysiology and radioligand binding assays, MP-III-058 was found to have modest binding but substantial functional selectivity for α5β3γ2 over other αxβ3γ2 GABAA receptors. Tissue bath assays revealed comparable vasodilatory effects of MP-III-058 and midazolam, both of which at 100 µmol/L concentrations had efficacy similar to prazosin. Flumazenil exhibited weak vasoactivity per se, but significantly prevented the relaxant effects of midazolam and MP-III-058. These studies indicate the existence of functional GABAA receptors in the rat aorta, where ligands exert vasodilatory effects by positive modulation of the benzodiazepine binding site, suggesting the potential for further quest for leads with optimized pharmacokinetic properties as prospective adjuvant vasodilators. [ABSTRACT FROM AUTHOR]