Nebojša Stilinović

The Protective Effects of Silymarin against Doxorubicin-Induced Cardiotoxicity and Hepatotoxicity in Rats

Silymarin 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 cardioprotective and hepatoprotective effects of administration of silymarin, rich in silibinin, at a dose of 60 mg/kg orally for a time-span of 12 days on doxorubicin induced toxicity in male Wistar rats. The in vivo model was used to explore whether silymarin could prevent damage of liver and heart tissue induced by doxorubicin administered every other day at dose of 1.66 mg/kg intraperitoneally for twelve days. In the study the change of body weight, ECG changes, biochemical parameters of oxidative stress, serum activity of alanine and aspartate transaminase, lactate dehydrogenase, creatine kinase and histological preparations of heart and liver samples of treated animals were examined. According to physiological, pharmacological, microscopic and biochemical results, we confirmed that at the examined dose, silymarin exhibits a protective influence on the heart and liver tissue against toxicity induced by doxorubicin.

Anti-oxidative activity of an aqueous suspension of commercial preparation of the mushroom Coprinus comatus.

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.

Consumption of serum lipid-reducing drugs in Serbia compared with Scandinavian countries: a population-based study, 2004–2008

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.

The outpatient utilization of non-steroidal anti-inflammatory drugs in South Bačka District, Serbia.

Objective To evaluate the utilization of non-steroidal anti-inflammatory drugs (NSAIDs) in South Bačka District (SBD), Serbia. Setting State-owned and private pharmacies in SBD, a northern district of Serbia, with 605,720 inhabitants (according to the 2008 census). Method Data on the number of packages, size of packages, and retail price of NSAIDs (Anatomical Therapeutic Chemical (ATC) group M01A) from 1 January to 31 March 2008 were obtained from all state-owned and private pharmacies in SBD. This included NSAIDs bought without prescription and those issued by prescription (on the Health Insurance Companies List for Reimbursement). The number of defined daily doses/1000 inhabitants/day (DDD/1000 inh/day) was calculated. Within the DU90% (drug utilization 90%) segment, the proportion of high-, medium- and low-risk NSAIDs with respect to the risk of gastrointestinal (GI) bleeding was determined. Price/DDD was also calculated. Main outcome measure Consumption of drugs expressed as DDD/1000 inh/day. Results The total consumption of NSAIDs over a 3-month period was 48.31 DDD/1000 inh/day. Only four drugs were within DU90%: diclofenac, ibuprofen, nimesulide and meloxicam (62.14, 19.87, 5.77, and 5.73% of total NSAID consumption, respectively). All dispensed NSAIDs within the DU90% segment except nimesulide (which was exclusively purchased without prescription) were nearly equally purchased without prescription and issued by prescription. The average price per DDD within the DU90% segment was 0.17 Euro/DDD, whereas it was 0.30 Euro/DDD for NSAIDs beyond the DU90% segment. The pattern of use of NSAIDs according to their GI risk showed that medium-risk diclofenac accounted for 66.45%, whereas low-risk ibuprofen was estimated to be 21.25% within the DU90% segment. Conclusion Factors other than evidence-based medicine (such as poor health education in the past that led to long-lasting consequences on the cultural behaviour of the general population as well as on the prescribing habits of physicians) have a dominating impact on the use of NSAIDs in SBD. Targeted education from independent sources in the prescribing, dispensing and use of drugs is required to improve the quality of prescription and use of NSAIDs in Serbia.

Pharmacodynamic Action of a Commercial Preparation of the Mushroom Coprinus comatus in Rats

The pharmacodynamic effect of a 7‐day oral treatment with a suspension of Coprinus comatus at doses of 0.835 and 1.670 g/kg in rats was studied. Changes in body weight, bile secretion and hypoglycaemic action were examined together with antipyretic activity and paw oedema tests. Such treatments resulted in a significantly lower increase in the body weight of tested animals (15.73 ± 8.36 g/rat in the untreated group, 8.44 ± 8.23 g/rat (p < 0.05) and 3.18 ± 7.93 g/rat (p < 0.05), for C. comatus 0.835 and 1.67 g/kg, respectively). Hypoglycaemic action was evident only in the glucose load test (6.79 ± 0.61 to 9.70 ± 1.16 (p < 0.05) in the untreated group and 6.47 ± 0.35 to 7.27 ± 0.76 for C. comatus 1.67 g/kg). Histological examination of pancreas cross‐sections suggested certain protective functions of the mushroom suspension in alloxan poisoning. In the antipyretic test, a significantly lower increase in body temperature was observed in the mushroom‐pretreated rats. In the paw oedema test, no decrease in oedema induced by formalin injection was observed following treatment with C. comatus. Copyright

Interaction between different extracts of Hypericum perforatum L. from Serbia and pentobarbital, diazepam and paracetamol.

Herb-drug interactions are an important safety concern and this study was conducted regarding the interaction between the natural top-selling antidepressant remedy Hypericum perforatum (Hypericaceae) and conventional drugs. This study examined the influence of acute pretreatment with different extracts of Hypericum perforatum from Serbia on pentobarbital-induced sleeping time, impairment of motor coordination caused by diazepam and paracetamol pharmacokinetics in mice. Ethanolic extract, aqueous extract, infusion, tablet and capsule of Hypericum perforatum were used in this experiment. The profile of Hypericum perforatum extracts as well as paracetamol plasma concentration was determined using RP-HPLC analysis. By quantitative HPLC analysis of active principles, it has been proven that Hypericum perforatum ethanolic extract has the largest content of naphtodianthrones: hypericin (57.77 µg/mL) and pseudohypericin (155.38 µg/mL). Pretreatment with ethanolic extract of Hypericum perforatum potentiated the hypnotic effect of pentobarbital and impairment of motor coordination caused by diazepam to the greatest extent and also increased paracetamol plasma concentration in comparison to the control group. These results were in correlation with naphtodianthrone concentrations. The obtained results have shown a considerable influence of Hypericum perforatum on pentobarbital and diazepam pharmacodynamics and paracetamol pharmacokinetics.

Insight into anti-diabetic effect of low dose of stevioside

Diabetes mellitus is a chronic disease characterized by abnormal carbohydrate, lipid and protein metabolism due to a lack of insulin or reduced target cell sensitivity to insulin. Stevia rebaudiana is an important source of biochemically active substances with proven anti-diabetic effect. The aim of this study was to determine anti-diabetic effects of the low dose of stevioside in NMRI Haan mice. Aqueous stevioside solution (20mg/kg body weight) was administered by oral route of administration. Anti-diabetic effect of stevioside was estimated by oral glucose tolerance test, adrenaline test after a 10day stevioside treatment, and alloxan induced hyperglycaemia in mice (two experimental groups, 10day stevioside treatment before and after alloxan administration). Aqueous stevioside solution prevented significant increase in glycaemia in oral glucose tolerance test (9.22±1.13 to 9.85±1.32mmol/l, P<0.05), and not in adrenaline test. Significant difference in glycaemia was detected in mice pre-treated with saline and stevioside in alloxan induced hyperglycaemia (saline 23.32±2.14, stevioside 14.70±4.95mmol/l, P<0.05). In mice pre-treated with stevioside, smallest β cells loss was found compared to other alloxan treated groups. Preserved normal cytoarchitectonic arrangement in islets was detected. Based on the given results we presume there exist a potential therapeutic use of low dose stevioside in diabetes.

Pharmacokinetic Herb-Drug Interaction between Essential Oil of Aniseed (Pimpinella anisum L., Apiaceae) and Acetaminophen and Caffeine: A Potential Risk for Clinical Practice.

Aniseed (Pimpinella anisum L., Apiaceae) and its essential oil (EO) have been widely used. Because there are some data about the impact of aniseed EO on drug effects, this survey aimed to assess the potential of pharmacokinetic herb–drug interaction between aniseed EO and acetaminophen and caffeine in mice. The chemical analysis (gas chromatography–mass spectrometry) of aniseed EO has confirmed trans‐anethole (87.96%) as the main component. The pharmacokinetic studies of intraperitoneally (i.p.) and orally applied acetaminophen (200 mg/kg) and caffeine (20 mg/kg) were performed in mice after 5 days of oral treatment with human equivalent dose of aniseed EO (0.3 mg/kg/day). The analysis of pharmacokinetic data showed that in the group treated by aniseed EO, the significant decrease in the peak plasma concentration of acetaminophen after oral application (p = 0.024) was revealed when compared with control group and the reduction of systemic exposure to the drug after oral application (74 ± 32% vs. 85 ± 35% in the control) was noted. The bioavailability of orally applied caffeine was also significantly decreased (p = 0.022) after the EO treatment in comparison with the control (57 ± 24% vs. 101 ± 29%). Therefore, the compromised therapeutic efficacy of acetaminophen and caffeine during the usage of aniseed EO preparations should be considered. Copyright

The Effect of Aminophylline on Quinidine Passage into the Central Nervous System of Rats

Background and Objective: There is significant interest in mutual influence of substances during their passage into the central nervous system (CNS). Quinidine is a drug which can achieve significant concentration in CNS and cause side effects and aminophylline is a drug with possibility to change distribution of drugs in CNS. Thus the aim of this work was to study the effect of aminophylline on the transition of quinidine through the bloodbrain barrier into the central nervous system. Material and Methods: The experiments were carried out on Wistar rats, which received quinidine in the form of the retrograde intra-arterial bolus injection into the right axillary vein. The control group of animals received subcutaneously physiological solution 30 min before the intra-arterial quinidine application, whereas the test group animals also received subcutaneously aminophylline 30 min before quinidine application. The rats were sacrificed by decapitation in specified time intervals in order to determine quinidine concentration in different parts of CNS. Results: There were no significant changes in serum quinidine levels by comparing the results of experimental group with those of the control group of animals. In all parts of CNS aminophylline pre-treatment caused significant decrease in CNS quinidine concentration. Conclusion: The results suggest that co-administration of aminophylline and quinidine, decreases quinidine concentrations in the CNS of rats.

Influence of Bile Salts as Excipients in Ranitidine, Aminophylline and Phenobarbital Tablets on Dissolution Rate

Aim: The aim of this study is to investigate the influence of bile salts, sodium cholate, sodium 12-ketocholate and sodium dehydrocholate, as excipients in ranitidine, aminophylline and phenobarbital tablets on dissolution rate. Methods: Four groups of tablets (control without bile salts and three investigational groups containing different bile salts) were prepared for three different drug substances: ranitidine, aminophylline and phenobarbital. Dissolution rate was measured. Results: Dissolution rate is increased significantly in all investigational groups comparing to the control group in all three drug substances. Discussion: Presented results are very favourable and encouraging in case of dissolution enhancing and should be further investigated, especially in drug substances that are classified in class II and IV as per Biopharmaceutical Classification System (BCS) classification. Conclusion: Bile acid salts are very promising excipients, proven to act as surfactants and as lubricants. Running title: Bile salts as excipients in ranitidine, aminophylline and phenobarbital tablets.