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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.

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.

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.

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.

This editorial presents the analysis of volumes 50 (2019) and 51 (2020) of Scripta Medica. Original articles made 53 % of 80 articles published in these two volumes. Article rejection rate was 38 %. Mean duration of period until reaching the first decision on an article was 20 days, while mean time until reaching the final decision was 31 days. Mean time needed for accepting the revised manuscript was 3 days, reflecting a significant decrease from 5 days in 2019 to 2 days in 2020. Mean time needed for reaching a decision to reject an article was 7 days. Coverage of the journal included both basic and clinical research and a considerable space was devoted to articles on COVID-19. Further efforts will be made in order to reach a more international recognition of the journal.

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/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: 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. 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/Aim. The values of the Böhler’s angle (BA) are relevant parameters for diagnosis, management and prognosis of the calcaneal fracture and the outcome. Range of normal values of Böhler’s angle (BA) in adults varies depending on the examined population, age, gender or ethnicity. The aim of this study was to determine the range of normal values of the Böhler’s angle in the central part of Serbia. Methods. The lateral foot radiographs of 225 subjects (111 males and 114 females) without calcaneal fractures, divided into 6 age groups were observed to determine the normal values of the Böhler’s angle by using the IMPAX 6.5.2.114 Enterprise software. Obtained values for Böhler’s angle were compared among gender and groups using appropriate statistical tests. Results. The mean of Böhler’s angle in observed population was 34.06°, ranging from 25.1° to 49.5° and was higher in males than in females included in our study. Gender difference was statistically significant. The distribution of the mean BA across the age groups showed tendency of decreasing with age and the highest BA was found in the youngest group. Conclusion. The findings presented in this paper confirmed the existence of wide range of BA values as well as its gender and age differences.

The article is written by the current Editor-in-Chief of the scientific journal Scripta Medica (Banja Luka) on the occasion of publishing the final issue of the fiftieth volume of the journal. Founded in 1966, the Scripta Medica (Banja Luka) started as a local journal of the Banja Luka Medical Centre, its General Hospital, later belonging to the Association of Medical Doctors of the Bosnian Krajina region and the Republic of Srpska and the Faculty of Medicine, University of Banja Luka. Its eight editors were: Professor Andrija Mikeš (1966-1968), Dr Dragomir Todorović (1969-1971), Assistant Professor Zvonimir Klepac (1972-1974), Professor Branko Pikula (1975-1990), Professor Bogdan Žigić (1995-2009), Professor Rajko Igić (2010-2013), Professor Predrag Grubor (2014-2018) and Professor Miloš P Stojiljković (since 6 August 2018). It used to appear twice a year or quarterly. The Scripta Medica (Banja Luka) has a peer-review process and tends to reach a status of well-established scientific journal.

This editorial is written on the occasion of the 25th anniversary of the infamous sarin and VX terrorist attacks in Japan, in order to increase the awareness of the potential terrorist use of nerve agents and to urge the preparedness to cope with its consequences. Nerve agents are extremely toxic organophosphorus acetylcholinesterase inhibitors, divided in three known groups: G-, Vand A-agents. G-agents tabun, sarin and soman were synthesised in Nazi Germany (1938-1944), V-agents including VX by the British in the 1950s and A-agents or Novichok agents between 1971 and 1993 in the Soviet Union. The use or alleged use of tabun and sarin was mentioned in connection with the Iraq-Iran war (1980-1988) and the Syrian conflict in 2013 and 2017. Sarin and VX were used for terrorist purposes by the Japanese religious sect AUM Shinrikyo in 1994 and 1995. The assassination of Kim Jong NAM with VX took place in Kuala Lumpur, Malesia in 2017, while the 2018 Salisbury and Amesbury poisonings in the UK were ascribed to the so-called Novichok agent A234. Milder cases of poisoning with nerve agents is accompanied by predominantly muscarinic symptomatology and more massive intoxications with mainly nicotinic and central symptoms. Treatment consists of use of atropine, oximes and anticonvulsants.

In Issues 1 and 2 the scientific biomedical journal Scripta Medica devoted a total of six articles to the aetiological, epidemiological and clinical aspects of serious acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease caused by this virus - coronavirus disease 2019 (COVID-19). The present Issue 2 also contains an obituary on the occasion of demise of Professor Folke Sjöqvist, one of the founding fathers of clinical pharmacology as a discipline and several other articles from the fields of quality assurance in healthcare, experimental and clinical medicine.

Introduction/Aim. In acute organophosphate poisoning the issue of special concern is the appearance of muscle fasciculations and convulsions that cannot be adequately antagonised by the use of atropine and oxime therapy. The aim of this study was to examine atidotal effect of obidoxime or HI-6 combinations with memantine in mice poisoned with soman, dichlorvos or heptenophos. Methods. Male Albino mice were pretreated intravenously (iv) with increasing doses of oximes and/or memantine (10 mg/kg) at various times before poisoning with 1.3 LD-50 of soman, dichlorvos or heptenophos, in order to determine the median effective dose and the efficacy half-time. In a separate experiment, cerebral extravasation of Evans blue dye (40 mg/kg iv) was examined after application of memantine (10 mg/kg iv), midazolam (2.5 mg/kg intraperitonealy - ip) and ketamine (20 mg/kg ip) 5 minutes before soman (1 LD-50 subcutaneously - sc). Results. Coadministration of memantine induced a significant decrease in median effective dose in null time of both HI-6 (7.96 vs 1.79 mmoL/kg in soman poisoning) and obidoxime (16.80 vs 2.75 mmoL/kg in dichlorvos poisoning; 21.56 vs 6.63 mmoL/kg in heptenophos poisoning). Memantine and midazolam succeded to counteract the soman-induced proconvulsive activity. Conclusion. Memantine potentiated the antidotal effect of HI-6 against a lethal dose of soman, as well as the ability of obidoxime to antagonize the toxic effects of dichlorvos and heptenophos probably partly due to its anticonvulsive properties.

T-2 mycotoxin, secondary metabolite of Fusarium fungi, is one of the most potent cytotoxic representatives of trichothecene mycotoxin type A. After ingestion, T-2 toxin affects actively dividing cells and irreversible post-mitotic cells. In our experiments, the best protective effects were produced by dexametasone (PI = 3.37) and different methylprednisolone formulations (PI = 2.43-2.64). Significant protective efficacy was shown by nimesulide (PI = 1.44) and N-acethyilcistein (PI = 1.29), but their values were higher in a combination with methylprednisolone (PI = 2.16-2.34). Radioprotector amifostine (WR-2721) expressed good protective effects (PI = 1.26) or/and different absorbent formulations, such as: activated charcoal (PI = 1.13) and various Min-a-zel® powder compounds, which are a well known zeolite clinoptilolite absorbents. Among the five zeolite regimens investigated, only Min-a-zel Plus® showed a significant protective effect (PI = 1.77). In summary, the steroidal anti-inflammatory drugs could be recommended as a regimen of choice for treatment of acute T-2 toxicosis while nonsteroidal anti-inflammatory compounds, different absorbent formulations and their combinations with antioxidants or radioprotectors could be important for the treatment of subacute and chronic T-2 toxin poisonings.

Ritodrine is the only medicament approved by FDA in the USA as well as in our country for prevention of the threatening preterm labor. Its adverse effects upon the respiratory and cardiovascular systems, including pulmonary edema and myocardial ischemia, occur more frequently during the intravenous therapy than during the oral maintenance therapy. The aim of this report was to present a patient with cardiovascular adverse effects of ritodrine, who had her pregnancy terminated by an urgent cesarean section under general anesthesia. In the course of operation, the patient had two cardiac arrest (total of 70 min). Resuscitation was performed by direct and indirect heart massage. The patient's condition was stabilized during the next six hours. The patient was transferred to the coronary unit, where the treatment was continued for 30-days period, after which the patient was released home as completely recovered.

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.