Acutely applied melatonin prevents CCl4-induced testicular lesions in rats: the involvement of the oxidative capacity and arginine metabolism

Abstract Carbon tetrachloride (CCl4) represents an organic chemical that causes reactive oxygen species derived organ disturbances including male infertility. Melatonin (MLT) is a neurohormone with strong antioxidant capacity, involved in numerous physiological processes. In this study we evaluated the capability of MLT, administered in a single dose of 50 mg/kg, to preserve the testicular tissue function after an acute administration of CCl4 to rats. The disturbance in testicular tissue and the effects of MLT after CCl4 exposure were estimated using biochemical parameters that enabled us to determine the tissue (anti)oxidant status and the intensity of arginine/nitric oxide metabolism. Also, the serum levels of testosterone and the histopathological analysis of tissue gave us a better insight into the occurring changes. A significant diminution in tissue antioxidant defences, arginase activity and serum testosterone levels, followed by the increased production of nitric oxide and extensive lipid and protein oxidative damage, was observed in the CCl4-treated group. The application of MLT after the CCl4 caused changes, clearly visible at both biochemical and histological level, which could be interpreted mainly as a consequence of general antioxidant system stimulation and a radical scavenger. On the other hand, the application of MLT exerted a limited action on the nitric oxide signalling pathway.

Contemporary surgical management of drug-resistant focal epilepsy.

Introduction: Seizures, which could not be controlled by drug therapy, have profound negative influence on the quality of life of the affected person. If with clear locus of origin and accompanied by loss of consciousness, drug-resistant epilepsy could be treated by surgery.Areas covered: The aim of this article was to review current status of epilepsy surgery through description of the most important operative methods and narrative comparison of their benefits and harms. In total 1154 articles were retrieved from MEDLINE, SCOPUS, EBSCO, and SCINDEKS databases, and 78 included in the review. The review included systematic reviews, meta-analyses, clinical trials, observational studies on humans, case series, and case reports.Expert opinion: Sophisticated diagnostic methods nowadays offer much more precise localization of epileptogenic focus and detailed planning of a surgical procedure which will make minimal damage of neural pathways and structures essential for movements, speech, cognition, and emotions. Advent of perioperative care, and improved diagnostics and surgical techniques resulted with significant drop in rates of postoperative complications, long-term neurological deficit, and mortality in the last decade, while seizure freedom rate and quality of life increased.

Cost-utility of tafenoquine vs. primaquine for the radical cure (prevention of relapse) of Plasmodium vivax malaria.

The aim of this study was to compare cost-utility of tafenoquine (TQ) and primaquine (PQ) for a radical cure (prevention of relapse) of Plasmodium vivax (PV) malaria in Serbia using A five-state, 1-month cycle Markov model. The perspective of Republic Health Insurance Fund was chosen, and the time horizon was 10 years. The model results were obtained after Monte Carlo microsimulation of a sample with 1000 virtual patients. After base case analysis PQ was dominated by TQ, as the net monetary benefit was positive (20,713.84 ± 7,167.46 RSD (99% CI) (174.95 ± 60.54 €)) and incremental cost-effectiveness ratio was below the willingness-to-pay line of 1 Serbian gross national product per capita per quality-adjusted life year gained. Multiple one-way sensitivity analysis and probabilistic sensitivity analysis confirmed the results of the base case simulation. In conclusion, TQ was cost-effective in comparison to PQ for radical cure of PV malaria in socio-economic settings of a South-Eastern European country.

Design and development of novel therapeutics for brucellosis treatment based on carbonic anhydrase inhibition.

Carbonic anhydrase is a metalloprotein, an enzyme with strong inhibition in antibacterial treatment. This study presents QSAR modeling for a series of 41 chemical compounds, 40 sulfonamides and one sulfamate, including 13 clinically tested drugs as carbonic anhydrase inhibitors based on the Monte Carlo optimization with molecular descriptors based on the SMILES notation and local invariants of the molecular graph, and field 3D based methods. Conformation independent QSAR models were developed for three random splits and a 3D QSAR model for one random split into the training and test sets. The statistical quality of the developed models, including robustness and predictability, was tested using various statistical approaches and the results that were obtained were very good. An excellent correlation between the results from the conformation independent and the 3D QSAR model was obtained. A novel statistical metric known as the index of ideality of correlation was used for the final assessment of the model, and the obtained results were good. Molecular fragments responsible for the increases and decreases of a studied activity were defined and further used for the computer-aided design of new compounds as potential carbonic anhydrase inhibitors. Molecular docking was applied for the final assessment of the developed QSAR model and designed inhibitors, and an excellent correlation between the results from QSAR modeling and molecular docking studies was obtained.Communicated by Ramaswamy H. Sarma.

Population Pharmacokinetic Analysis of Bisoprolol in Patients With Acute Coronary Syndrome.

To date, many questions about the extent and cause of pharmacokinetic (PK) variability of even the most widely studied and prescribed ß1-adrenergic receptor blockers, such as metoprolol and bisoprolol, remain unanswered. Given that there are still no published population pharmacokinetic (PopPK) analyses of bisoprolol in routinely treated patients with acute coronary syndrome (ACS), the aim of this study was to determine its PK variability in 71 Serbian patients with ACS. PopPK analysis was conducted using a nonlinear mixed-effects model (NONMEM), version 7.3.0 (Icon Development Solutions). In each patient, the same formulation of bisoprolol was administered once or twice daily at a total daily dose of 0.625-7.5 mg. We separately assessed the effects of 31 covariates on the PKs of bisoprolol, and our results indicated that only 2 covariates could have possible influence on the variability of the clearance of bisoprolol: the mean daily dose of the drug and smoking habits of patients. These findings suggest that possible autoinduction of drug metabolism by higher total daily doses and induction of cytochrome P450 isoform 3A4 (CYP3A4) by cigarette smoke in liver could be the potential causes of increased total clearance of bisoprolol in patients with ACS.

The effects of physical training on cardiovascular parameters, lipid disorders and endothelial function.

BACKGROUND/AIM: [corrected] Regular physical activity is widely accepted as factor that reduces all-cause mortality and improves a number of health outcomes. The aim of this study was to investigate the effects of aerobic exercise training on cardiovascular parameters, lipid profile and endothelial function in patients with stable coronary artery disease (CAD). METHODS: The study included seventy patients with stable CAD. All the patients were divided into two groups: the group I--33 patients with CAD and with regular aerobic physical training during cardiovascular rehabilitation program phase II for 3 weeks in our rehabilitation center and 3 weeks after that in their home setting, and the group II (control)--37 patients with CAD and sedentary lifestyle. Exercise training consisted of continual aerobic exercise for 45 minutes on a treadmill, room bicycle or walking, three times a week. We determined lipid and cardiovascular parameters and nitric oxide (NO) concentration at the beginning and after a six-week of training. RESULTS: There were no significant differences in body weight, waist circumference and waist/hip ratio at the start and at the end of physical training program. Physical training significantly reduced body mass index after six weeks compared to the initial and control values. Physical training significantly reduced systolic and diastolic blood pressure and heart rate after a six-week training period (p < 0.05). Heart rate was significantly lower after a training period as compared to the control (p < 0.05). A significant reduction of triglyceride and increased high density lipoprotein cholesterol (HDL-C) concentration after cardiovascular rehabilitation were registered (p < 0.05). The concentration of triglycerides was significantly lower while NO and HDL-C were higher after six weeks in the exercise training group (p < 0.05). CONCLUSION: Dynamic training can improve blood pressure in patients with moderate to severe hypertension and reduce the need for medication. Exercise programs induced favorable adaptations on lipoproteins profile, cardiovascular parameters and endothelial function which are clinically desirable in primary and secondary prevention of CAD.

Aerobic capacity as an indicator in different kinds of sports.

Physical capacity of athletes is an important element of success in sports achievements. Aerobic capacity has been accepted as its major component. Maximal oxygen uptake (VO2max) has been regarded by majority of authors as the best indicator of aerobic capacity of an organism, and at the same time, the best indicator of an athlete's physical capacity. The aim of the investigation was to analyze the aerobic capacity as an indicator of physical capacity of athletes, differences in their aerobic capacity with regard to the kind of sport they are practicing, as well as the differences obtained when compared to physically inactive subjects. The investigation included the determination of absolute and relative VO2max in the total of 66 male examinees. The examinees were divided into two groups of active athletes (football players (n=22) and volleyball players (n=18) of different profiles, while the third group of non-athletes served as control group. Maximal oxygen uptake was determined by performing the Astrand 6 minute cycle test. Peak values of VO2 max were recorded in the group of football players (4,25+/-0,27 l/min), and they were statistically significantly higher (p<0,001) compared to other examined groups. In the group of volleyball players the oxygen uptake was 3,95+/-0,18 l/min, while statistically significantly lower values were reported in the group of non-athletes compared to the groups of athletes (p<0,01). A similar ratio of VO2 max values was also shown by the analysis of values expressed in relative units. Our results showed that peak values of VO2 max were obtained in football players, and that football as a sport requires higher degree of endurance compared to volleyball. Having considered the morphological and functional changes which are the consequence of the training process, it can be concluded that VO2 max values are statistically significantly higher in the groups of athletes compared to the group of non-athletes.

Dynamic response of blood vessel in acute renal failure.

In this study we postulated that during acute renal failure induced by gentamicin the transient or dynamic response of blood vessels could be affected, and that antioxidants can prevent the changes in dynamic responses of blood vessels. The new approach to ex vivo blood vessel experiments in which not only the end points of vessels response within the time interval is considered, but also dynamics of this response, was used in this paper. Our results confirm the alteration in dynamic response of blood vessels during the change of pressure in gentamicin-treated animals. The beneficial effects of vitamin C administration to gentamicin-treated animals are also confirmed through: lower level of blood urea and creatinine and higher level of potassium. The pressure dynamic responses of isolated blood vessels show a faster pressure change in gentamicin-treated animals (8.07 +/- 1.7 s vs. 5.64 +/- 0.18 s). Vitamin C administration induced slowdown of pressure change back to the control values. The pressure dynamic properties, quantitatively defined by comparative pressure dynamic and total pressure dynamic, confirm the alteration in dynamic response of blood vessels during the change of pressure in gentamicin-treated animals and beneficial effects of vitamin C administration.

Pentoxifylline ameliorates glomerular basement membrane ultrastructural changes caused by gentamicin administration in rats.

Gentamicin is commonly used for the treatment of severe gram negative bacterial infections but inevitably cause renal failure during prolonged use. The aim of our study was to emphasize protective effects of pentoxifylline on glomerular basement membrane (GBM) alterations induced by gentamicin in rats. Experiments were done on 40 male Wistar rats divided in three experimental groups. GM-group was treated daily with gentamicin in dose of 100 mg/kg during 8 days. PTX-group was treated daily with pentoxifylline in dose of 45 mg/kg and the same dose of gentamicin as in GM-group during 8 days. The control group received 1 ml/day saline intraperitoneally. Morphometric parameter measured during the analysis was glomerular basement membrane thickness. In GM-group of animals glomeruli were enlarged and GMB was diffusely and unequally thickened with neutrophil cells infiltration. In proximal tubules epithelial cells, vacuolization of cytoplasm with coagulation-type necrosis were observed. In PTX-group of animals glomeruli were somewhat enlarged and GBM was thickened only in some segments. Coagulation-type necrosis was not found. Blood urea and serum creatinine concentration in GM-group were significantly elevated in comparison with PTX-group while potassium level was decreased. Our results suggest that PTX has protective effects on GBM and proximal tubules in GM-treated rats.

Effects of physical exercise on inflammatory parameters and risk for repeated acute coronary syndrome in patients with ischemic heart disease.

BACKGROUND/AIM: Inflammation is an important factor in the pathogenesis of atherosclerosis, and several markers of inflammation have been associated with an increased risk of cardiovascular events. Physical activity may lower the risk for coronary heart disease (CHD) by mitigating inflammation. The aim of this study was to investigate the effects of aerobic physical exercise on systemic inflammatory response in patients with stable coronary disease participating in a cardiovascular rehabilitation exercise program. METHODS: Male (n=29) and female (n=23) patients with stable coronary heart disease were enrolled in this study. All the patients were divided into two groups: the group with regular aerobic physical training during cardiovascular rehabilitation program phase II for 3 weeks in our rehabilitation center and 3 weeks after that in their home setting, and sedentary lifestyle group. There were no significant differences in gender distribution among the analysed groups. Student's t-test showed no significant differences in average age, waist circumference (OS) and waist/hip ratio (WHR). RESULTS: The degree of obesity was measured by BMI and there was a significant improvement in BMI in the patients who undertook 6-week physical training compared to the controls (p<0.05). Physical training during 6-week appeared not to have any effects on leukocite count and ICAM-1 levels compared to controls. Exercise induced reduction in plasma CRP levels by 23.72% (p<0.001) and reduction in plasma VCAM-1 levels by 10.23%, (p<0.05). CONCLUSION: Moderate aerobic exercise resulted in a significant reduction of inflammatory state by decreasing CRP and VCAM-1 levels with significant obesity reduction but without visceral obesity reduction. The obtained results indicate that regular physical activity is clinically desirable in primary and secondary prevention of coronary heart disases.

Protective effects of pentoxifylline treatment on gentamicin-induced nephrotoxicity in rats.

Gentamicin (GM) is a widely used antibiotic against serious and life-threatening infections, but its usefulness is limited by the development of nephrotoxicity. Thus, the present study was undertaken to determine if pentoxifylline could protect the kidney in this experimental model. Thirty male Wistar rats were used. The animals were divided into three groups, each with 10 animals. The GM group of animals was treated daily with gentamicin in a dose of 100 mg/kg for eight days. The GMP group of animals was treated daily with pentoxifylline in a dose of 45 mg/kg and the same dose of gentamicin as the GM group for eight days. The control group received 1 mL/day saline intraperitoneally. For histological analysis, 5 microm-thick sections were stained with hematoxylin and eosin (HE), periodic acid Schiff (PAS), and Jones methenamine silver. The morphometric parameters included were glomerular area, major and minor axis, perimeter, diameter, roundness, and mean optical density. Biochemical analyses were used to determine concentrations of blood urea, serum creatinine, sodium, and potassium. In the GM group of rats, glomerular basement membrane was diffusely and unequally thickened with polymorphonuclear leukocyte infiltration, and coagulation-type necrosis and vacuolization of cytoplasm of proximal tubules epithelial cells were observed. In the GMP group of rats, glomeruli were slightly enlarged with thickened basement membrane in some segments but without coagulation-type necrosis of proximal tubules epithelial cells. Blood urea and serum creatinine concentration in the GM group were significantly elevated in comparison with the GMP group, while the potassium level was decreased. The present study indicated that pentoxifylline could provide a marked protective effect against gentamicin-induced acute renal failure, most likely mediated by vascular decongestion.

[Gender difference in hipolipemic and anti-inflammatory effects of statins in diabetics with coronary artery disease].

BACKGROUND/AIM: Statins produce hipolipemic and pleotropic effects on markers of inflammation with stabilization of atheromatous plaque. The aim of this paper was to examine gender difference in hipolipemic and antiinflammatory effects of statins in patients with diabetes mellitus (DM) type 2 with coronary artery disease (CAD). METHODS: Sixty dyslipidemic patients with DM type 2 were analyzed. Lifestyle modification and hipolipemic diet were applied in all patients divided into two groups: 30 patients with statins therapy (20 mg of simvastatin or equivalent dose of some other statins, during 3 months) and 30 patients without statins therapy. Estimation of obesity, quality of glicoregulation, and determination of inflammatory parameters: C-reactive protein (CRP), fibrinogen, total and differential leukocyte count, intracellular adhesive molecules (ICAM-1), vascular adhesive molecule-(VCAM-1) and lipid profile (total cholesterol--TC, LDL-C, HDL-C, triglicerides--TG) were done. RESULTS: Women with DM type 2 were more obese and had significant disturbances in lipid profiles, glicoregulation and inflammatory markers compared to men. Statins therapy significantly improved all lipid parameters and quality of glicoregulation in women, while there were only significant reduction of LDL-C and nonHDL-C in males. There were more significant reductions of inflammatory markers in women as compared to men with statins therapy. In the group without statins there was not such significant reduction. Concentration of ICAM-1 was the lowest in men on statins therapy, while there were no significant variability of VCAM-1 values between groups and genders. CONCLUSION: Women with DM type 2 and CAD have more prominent lipoprotein disorders and impaired glicoregulation with expression of enhanced proinflammatory state which could not be seen in men. Statins therapy exerts more favorable effects in women leading to stabilization of lipoprotein profiles, improvement of glicoregulation and reduction of inflammatory markers. More superior antiinflammatory effects of statins therapy in men were registered only in significant ICAM-1 reduction.

[Physiological aspects of altitude training and the use of altitude simulators].

Altitude training in various forms is widely practiced by athletes and coaches in an attempt to improve sea level endurance. Training at high altitude may improve performance at sea level through altitude acclimatisation, which improves oxygen transport and/or utilisation, or through hypoxia, which intensifies the training stimulus. This basic physiological aspect allows three training modalities: live high and train high (classic high-altitude training), live low and train high (training through hypoxia), and live high and train low (the new trend). In an effort to reduce the financial and logistical challenges of travelling to high-altitude training sites, scientists and manufactures have developed artificial high-altitude environments, which simulate the hypoxic conditions of moderate altitude (2000-3000 meters). Endurance athletes from many sports have recently started using nitrogen environments, or hypoxic rooms and tents as part of their altitude training programmes. The results of controlled studies on these modalities of high-altitude training, their practical approach, and ethics are summarised.

[Hepatoprotective effects of silymarin in androgenic-anabolic steroid-induced liver damage]. / Hepatoprotektivno delovanje silimarina kod ostecenja jetre izazvanog androgenim-anabolikim steroidom.

INTRODUCTION: The use and abuse of anabolic-androgenic steroids (AAS) commonly induces liver damage. MATERIAL AND METHODS: The study included 40 male Wistar rats, divided into 4 groups of 10 rats each. Animals in the first experimental group (M), were subjected to progressive systematic forced swimming test, 5 days a week, during 8 weeks. Animals in this group were treated with AAS methandienone, 2 mg/kg BW/day, per os, before swimming, 5 d/w for 8 weeks. After swimming, animals were given three times more food than the laboratory animals of the same age and kind. Animals in the second group (M+S), were subjected to progressive forced swimming test, 5 d/w 8 weeks. Animals in this group were treated with methandienone equally as the experimental group M and received the same amount of food. Apart from that, they received silymarin 20 mg/kg BW/day. Animals in the third group (K), represented the control group, which was neither subjected to swimming test, nor treated with methandienone or silymarin. Animals in this group received the same amount of food as animals in groups M and M+S. Animals in the fourth group (C), also represented a control. This group was not exercised nor treated, and animals received a standard amount of food for laboratory animals of this kind and age. Quantitative analysis of obtained hemataxylin-eosin, periodic acid shift and enzymohistochemical preparations was processed using Digital Image Analysis System: Microimage 3.0. RESULTS: It was established that processes in the nuclei of animals in groups M and K were significantly more intensive (p<0.001) in relation to groups M+S and C. The investigation of glycogen showed significantly higher density in the cells of groups M and M+S in comparison to groups K and C. Also, there was a significant difference between groups M+S and M. Density of enzyme activity of glutamate dehydrogenase in hepatocytes of animals in the group M+S was significantly higher in relation to the remaining three groups. A statistically significant difference was not found in enzyme activity of succinate dehydrogenase and lactate dehydrogenase. DISCUSSION: In cell nuclei of animals in the experimental group M, in the absence of silymarin effect, methandienone causes damages which induce regenerative processes and in this way increase high intensity activity. Silymarin significantly increases the glycogen density in hepatocytes. Increased activities of GDH are attributed to cell vitality. CONCLUSION: The present results show hepatoprotective effects of silymarin in androgenic-anabolic steroid induced liver damage.