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The interaction of aqueous solutions of stevioside and bile acids with cardioactive drugs was studied in rats by registering changes in their electrocardiograms (ECG). Wistar rats of both sexes received daily doses of 20 mg/kg (i.p.) of an aqueous solution of stevioside or physiological solution (controls), then were narcotized with urethane and connected to the ECG apparatus for the first recording. The jugular vein was prepared and connected to an infusion pump to administer one of the drugs: adrenaline (0.1 mg/ml), verapamil (2.5 mg/ml) or metoprolol (1 mg/ml) to rats in both groups, while recording their ECGs. In the second part of the study, the animals were treated in the same way but instead of the stevioside solution received a single dose of 4 mg/kg of monoketocholic acid methyl ester (ME) or sodium salt of the same bile acid (MKHNa), 30 minutes before cardioactive drug infusion. The infusion rate of cardioactive drugs was 0.2 ml/min, except for verapamil (0.1 ml/min). The events observed on ECG recordings were the first myocardial reaction to drug infusion, the second longer-lasting reaction (observed as more extended extrasystoles, decrease in intensity of the QRS complex, or changes in heart rate frequency), and toxicity effect. In the control animals, adrenaline induced a decrease in heart rate frequency at a dose of 0.094 mg/kg, while with stevioside-pretreated rats this effect appeared significantly earlier (at a dose of 0.018 mg/kg). No toxic effect of adrenaline was observed, either in control or stevioside-pretreated group. Bile acids caused no changes in myocardial reaction to adrenaline. Only in the group of animals that received MKHNa, a significant decrease in the QRS complex was observed. Finally, the infusion of stevioside to intact animals at doses of 45 and 55 mg/kg caused no significant changes in the ECG patterns. The myocardial reaction to metoprolol remained unchanged in rats of all groups when compared with controls except for a mild decrease in heart rate frequency. Stevioside induced/produced a significant increase in myocardial sensitivity to verapamil, but no toxic effect was observed in any of the cases. A similar conclusion also holds for the interaction with MKHNa, whereas ME caused an increase in the toxicity of verapamil.

The discovery of agents which induce regeneration of pancreatic beta cells and insulin secretory potential would be useful to develop new therapeutic approaches to treat diabetes. We investigated effects of mushroom Coprinus comatus on regeneration Langerhans islets after alloxan treatment. In this study, on immunohistochemically stained histological preparations (insulin and glucagon) was apply morphometric analysis of of rat pancreatic tissue to examined: a) the degree of regenerative characteristics of islets of Langerhans in alloxan induced diabetes, b) the impact of mushroom Coprinus comatus on pancreatic tissue and c) the impact of the mushroom Coprinus comatus regenerator properties Langerhans islets after administration of alloxan. Suspension of mushroom Coprinus comatus was applied in three time periods (7, 21, and 42 days) at three different doses of 0.835, 1.67, and 3.34 g/kg. Morphometric parameters were used: the volume density of endocrine and exocrine part of islets per pancreatic tissue; the mean corrected islet diameter , the numerical density of alpha and beta cell per islet profile, the number of alpha and beta cell type per islet, the corrected mean nuclear diameter, and corrected mean nuclear volume. The results showed that the application of alloxan confirmed so far above the selective destruction of beta cells with a relative degree of regeneration that occurred in animals sacrificed after 4, 5, 7, 21 and 42 days after application of alloxan. In the experimental group of animals that received only the mushroom Coprinus comatus, the application dose of 1.67 g/kg is observed to increase in alpha and beta cells, while the other groups showed no significant difference compared with the control group. In rats which after inducing diabetes with alloxan and then applied preparation mushroom Coprinus comatus can be observed much greater regeneration of islets compared to pure alloxan induced group. Morphometric analysis revealed a proliferation of alpha cells and a significant increase in beta cell mass. In addition to clearly immunopositive cells were observed and transitional cell forms between alpha and beta cells, indicating the occurrence of the process of transdifferentiation of one cell into another form. Therefore, regeneration of islets covered the two processes, one is the proliferation of alpha cell population and the second is the appearance of new beta cells for which assume that the resulting direct conversion of alpha cells. Stimulating effect of mushroom Coprinus comatus on the regeneration of the islets of Langerhans gives us precious, so far no published data on the impact of these mushrooms in vivo in living systems.

Commercial preparations of Cordyceps sinensis, Ganoderma lucidum and Coprinus comatus mushroom marketed as healthy food supplements in Serbia were analyzed by atomic absorption spectrometry with a graphite furnace (GFAAS) for their element content. Antioxidant activity potential and total phenolics of the same mushrooms were determined. The element content of mushroom samples was in the range of 0.130-0.360 mg kg(-1) for lead (Pb)

Background/Aim. Stevioside is a glycoside that supposedly possesses a number of pharmacodynamic effects such as anti-infective, hypoglycemic, along with the beneficial influence on the cardiovascular system. The aim of this study was to determine the effect of rats pretreatment with aqueous solution of stevioside on pharmacological actions of adrenaline, metoprolol and verapamil. Methods. Rats were administered (intraperitoneally 200 mg/kg/day) stevioside as aqueous solution or physiological saline in the course of 5 days, then anaesthetized with urethane and the first ECG recording was made. The prepared jugular vein was connected to an infusion pump with adrenaline (0.1 mg/mL), verapamil (2.5 mg/mL) or metoprolol (1 mg/mL). Control animals, pretreated with saline, in addition to the mentioned drugs, were also infused with the solution of stevioside (200 mg/mL) in the course of recording ECG. Results. The infusion of stevioside produced no significant changes in ECG, even at a dose exceeding 1,600 mg/kg. In the control group, a dose of adrenaline of 0.07 ± 0.02 mg/kg decreased the heart rate, whereas in the steviosidepretreated rats this occurred at a significantly higher dose (0.13 ± 0.03 mg/kg). In stevioside-pretreated rats, the amount of verapamil needed to produce the decrease in heart rate was significantly lower compared to the control. The pretreatment with stevioside caused no significant changes in the parameters registered on ECG during infusion of metoprolol. Conclusion. The results suggest that pretreatment with stevioside may change the effect of adrenaline and verapamile on the heart rate. [Projekat Ministarstva nauke Republike Srbije, br. 41012]

Background Natural antioxidant products are increasingly being used to treat various pathological liver conditions considering the role of oxidative stress in their pathogenesis. Rosemary essential oil has already being used as a preservative in food industry due to its antioxidant and antimicrobial activities, but it was shown to possess additional health benefits. The aim of our study was to evaluate the protective effect of rosemary essential oil on carbon tetrachloride - induced liver injury in rats and to explore whether its mechanism of action is associated with modulation of hepatic oxidative status. Methods Chemical composition of isolated rosemary essential oil was determined by gas chromatography and mass spectrometry. Antioxidant activity was determined in vitro using DPPH assay. Activities of enzyme markers of hepatocellular damage in serum and antioxidant enzymes in the liver homogenates were measured using the kinetic spectrophotometric methods. Results In this research, we identified 29 chemical compounds of the studied rosemary essential oil, and the main constituents were 1,8-cineole (43.77%), camphor (12.53%), and α-pinene (11.51%). Investigated essential oil was found to exert hepatoprotective effects in the doses of 5 mg/kg and 10 mg/kg by diminishing AST and ALT activities up to 2-fold in serum of rats with carbon tetrachloride - induced acute liver damage. Rosemary essential oil prevented carbon tetrachloride - induced increase of lipid peroxidation in liver homogenates. Furthermore, pre-treatment with studied essential oil during 7 days significantly reversed the activities of antioxidant enzymes catalase, peroxidase, glutathione peroxidase and glutathione reductase in liver homogenates, especially in the dose of 10 mg/kg. Conclusions Our results demonstrate that rosemary essential oil, beside exhibiting free radical scavenging activity determined by DPPH assay, mediates its hepatoprotective effects also through activation of physiological defense mechanisms.

Influence of two newly synthesized bile acids derivates, namely sodium salt of monoketocholic acid MKH-Na and methyl ester of monoketocholic acid MKH-Me on tramadol (12.5 mg/kg oral and intramuscular) analgesic effect was examined in this research. Analgesic effect was measured by antinociceptive hot plate method. Interaction was estimated by detection of changes in analgesic effect of tramadol combined with bile acids (subcutaneous administration of 4 mg/kg 20 min before tramadol) compared to analgesic effect of the same dose of tramadol given alone. Hydrosoluble sodium salt of monoketocholic acid did not show interaction with tramadol, regardless of the route of administration of tramadol. However, methyl ester of monoketocholic acid increased the analgesic effect of tramadol when it was given intramuscularly. After oral administration of tramadol, methyl ester of monoketocholic acid decreased the analgesic effect of tramadol. According to the time point when interaction reached statistically significant difference, it can be presumed that after intramuscular administration of tramadol, methyl ester of monoketocholic acid increases tramadol absorption and transport to brain and in that way increases its analgesic effect. The analgesic effect of tramadol after oral administration was decreased, which could be explained by the induction of tramadol metabolism in the liver, but should be examined in more details.

Purpose The aim of this study was to measure the consumption of serum lipid reducing drugs in Serbia from 2004 to 2008, to compare this data with that from Scandinavian countries, and to compare the consumption of lipid lowering drugs and the rate of mortality from cardiovascular diseases in these countries. Methods A population-based study was undertaken to analyse lipid lowering drug consumption using the Anatomical Therapeutic Chemical/Defined Daily Dose methodology. Cause-specific mortality rates were obtained from the WHOSIS annual report for the year 2009. Results In 2008, a total of 1207.44 DDD/1000 inh/day of all drugs, was used in Serbia, of which 38.89% belonged to drugs for cardiovascular diseases. While in Scandinavian countries 17.03–24.80% of drugs for cardiovascular diseases belonged to lipid-lowering drugs, in Serbia it was substantially lower (3%). In 2004 in Serbia, 1.50 DDD/1000 inh/day of statins were used. In 2008, this value was 14.24 DDD/1000 inh/day. In every investigated country, simvastatin made up more than 50% of the consumption of statins. After simvastatin, the next most frequently used statin was atorvastatin, with 5.52, 11.00, 11.17 and 24.82 DDD/1000 inh/day, in Serbia, Denmark, Finland and Norway, respectively. In 2004 Serbia has the highest mortality rate for cardiovascular diseases among investigated countries with 762/100.000 inhabitants and Norway has the lowest rate with 158/100.000 inhabitants. Conclusion The use of lipid lowering drugs is 6–8 times lower in Serbia than in Scandinavian countries but there is an evident rise in lipid lowering drugs consumption in Serbia during years. Copyright © 2010 John Wiley & Sons, Ltd.

In this study the effects of an aqueous suspension of a commercial preparation of the mushroom Coprinus comatus on oxidative stress induced in rats by alloxane and carbon tetrachloride was examined. The effects were estimated from changes in the biochemical parameters (xanthine oxidase, glutathione peroxidase and catalase activity, reduced glutathione content, and extent of lipid peroxidation) of liver homogenate as well as histological changes in the liver of the rats treated with alloxane and carbon tetrachloride. Two screening doses of alloxane sufficient to induce diabetes in rats did not have any significant effect on the examined biochemical parameters of liver homogenate or on the cytoarchitectonics of liver cross-sections. Treatment with carbon tetrachloride resulted in a significant increase in the intensity of lipid peroxidation and peroxydasis activity, as well as with decrease in catalase activity. Certain changes in liver cross sections were detected, such is lymphocyte infiltration of dilated sinusoid capillaries. Administration of Coprinus comatus suspension thus showed antioxidative potential, evidenced by an increase of antioxidative status of liver homogenate and prevention of histological changes in liver cross sections.

Background The increasing presence of both methicillin-resistant isolates of Staphylococcus aureus (MRSA), and lately vancomycin-resistant Staphylococcus aureus (VRSA), requires pursuit of new antibiotics. This is achieved in several ways: by modification of existing antibiotics, by synthesis of new antibiotics or by empirical screening of, so far, unexamined compounds. Consumption of fresh or processed berries (raspberry, blackberry, strawberry, currant, cranberry and other berries) is considered exceptionally beneficial due to the potent antioxidant and antibacterial activity of their phenolic compounds. Having in mind high percentage of highly resistant bacterial strains of Staphylococcus aureus and antibacterial potency of red raspberries' phenolic compounds, the goal of study was to investigate interactive effect of red raspberries' concentrate and antibiotics on Staphylococcus aureus [1-4].

Role of BeNzodiazepiNeS iN CaRdiaC SafeTy of low MeThadoNe doSeS iN paTieNTS duRiNg MeThadoNe MaiNTeNaNCe TReaTMeNT S. Petkovic ; V. Mijatovic ; I. Samojlik; S. Vukmirovic ; A. Dickov; and T. Popov Faculty of Medicine, University of Novi Sad, Vojvodina, Serbia; and Institute of Cardiovascular Diseases Vojvodina, Sremska Kamenica, Serbia Introduction: Despite the fact that most of health care professionals are aware of possible respiratory depressant effect of methadone and benzodiazepines coadministration, recently published data reveal that ventricular arrhythmia and cardiac arrest are currently the most frequent adverse event attributed to methadone and benzodiazepine comedication. The aim of this study is to assess cardiac safety of low methadone doses used concomitantely with benzodiazepines in opiate addicts in methadone maintenance treatment (MMT). Material and Methods: A clinical trial in which participated 30 opiate addicts at the start of MMT was performed. ECG (to calculate corrected QT (QTc) interval) and blood sampling (to determine methadone and diazepam concentrations ) were performed in all study participants at 3 time points (before the introduction of MMT, after 1 and 6 mo of MMT). Methadone and diazepam concentrations in serum were determined by using liquid chromatography-mass spectrometry (LC-MS). Results: The length of QTc interval before the introduction of MMT was 411.87 ± 27.22 ms, after 1 month of MMT 425.20 ± 17.71 ms and after 6 months of MMT 423.50 ± 14.72 ms. The mean methadone concentration at observed time points was 176.77 ± 118.56 ng/ mL and 342.86 ± 181.54 ng/mL, respectively, while the mean diazepam concentration was 560.74 ± 436.72 ng/mL and 1045.32 ± 932.72 ng/mL, respectively. There was a statistically significant increase in the length of QTc interval after 1 and 6 months of MMT in comparison to the value before the application of MMT. A statistically significant correlation between the concentration of methadone and QTc interval length after 1 and 6 months of MMT was observed and it remained statistically significant if concentration of diazepam was included. Conclusions: Further studies could clarify the possible role of benzodiazepines in the increasing cardiotoxicity of methadone in opiate addicts in MMT. Acknowledgement: The Ministry of Education and Science of the Republic of Serbia (grant numbered 41012) supported this research work.

e30 Volume 35 Number 8S Conclusion: LHA tends to accept EU requirements as much as it could match local regulation, but local regulation differs significantly from EU. As a consequence, LSU makes additional efforts and communications with LHA and Company, to fulfill each requirement in its own way. The differences could be overcome with harmonization of local regulation with EU and if LHA receive access to EudraVigilance database. Disclosure of Interest: None declared.

Background Serbia is one of the leading countries in the world with respect to mortality from cardiovascular diseases. Drugs that reduce serum lipids belong to the group of drugs that can significantly lower complications of cardiovascular diseases and their utilization in Serbia deserves special attention. The aim of this study was to measure the consumption of serum lipid reducing drugs in Serbia from 2004 to 2010, to compare these data with those from Scandinavian countries, and to compare the consumption of lipid-lowering drugs and the rate of mortality from cardiovascular diseases in these countries.

Background Silymarin, an extract of Silybum marianum seeds, possesses a broad spectrum of action: antifibrotic, antiinflammatory, lipid peroxidation-inhibiting and free radical-scavenging effects. It is a complex of five major compounds, and silibinin is the most biologically active component of the complex. The aim of this study was to investigate, evaluate and confirm the potential antioxidative effects of silymarin rich in silibinin.

Featured Application Biomedical sector, sports sector-applications in the detection of drug concentrations in sweat samples. This work presents a new multilayered microfluidic platform, manufactured using a rapid and cost-effective xurography technique, for the detection of drug concentrations in sweat. Textile fabrics made of cotton and polyester were used as a component of the platform, and they were positioned in the middle of the microfluidic device. In order to obtain a highly conductive textile, the fabrics were in situ coated with different amounts of polyaniline and titanium dioxide nanocomposite. This portable microfluidic platform comprises at least three layers of optically transparent and flexible PVC foils which were stacked one on top of the other. Electrical contacts were provided from the edge of the textile material when a microfluidic variable resistor was actually created. The platform was tested in plain artificial sweat and in artificial sweat with a dissolved cytostatic test drug, cyclophosphamide, of different concentrations. The proposed microfluidic device decreased in resistance when the sweat was applied. In addition, it could successfully detect different concentrations of cytostatic medication in the sweat, which could make it a very useful tool for simple, reliable, and fast diagnostics.