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High concentrations of pesticides and toxic metal pollutants in the environment, often present in surface waters in nature, can accumulate in wild animals and are a significant public health concern. Serbia is a moderately developed, south European country in transition, with a long tradition in agriculture, particularly in the northern part, Vojvodina. Our study aimed to assess the presence of pesticides and to measure concentrations of toxic metals in the district of Backi Petrovac, Vojvodina. Water samples were analyzed from canals, ditches, fish from the canals and wild animals caught in the Backi Petrovac district. We identified nine pesticides in water samples. Of all detected pesticides, one was a hormonal disruptor. There were no pesticides in animals, fish and organs in a concentration above the limit of detection (LOD) in observed periods. The concentrations of toxic metals detected in superficial water (Cd, Pb, Hg, As, Mn, Cu) were below the permitted limits, as well as the concentrations of Cd, Pb, Hg, As and Mn in the whole bodies of fish. Concentrations in kidneys and livers of wild animals (rabbit and roe deer) were below the permitted limits, with the exception of cadmium, whose concentrations in some animal samples were above the permitted limit. Based on the obtained results, we concluded that in the developed agricultural region unencumbered by heavy industry, pollution by pesticides and heavy metals can be controlled.

This journal is © The Royal Society of Chemistry. This study was designed to define total protein, phenol and flavonoid content as well as LC-MS/MS phenolic profile related to antioxidant and antidiabetic activity of ethanolic (EtOH) and water extracts of G. pfeifferi and G. resinaceum. G. resinaceum water extract possessed the highest ability to scavenge DPPH and O2-, while the EtOH extract of the same species showed better activity on NO related to other extracts. The highest level of bioactive compounds was determined generally in EtOH extracts. Antidiabetic action was evaluated by the oral glucose tolerance test (OGTT) and histological examination of pancreas and liver in normoglycemic and alloxan-induced diabetic animals. Histological examination of pancreatic tissue demonstrated that G. pfeifferi extracts have protective effects. To conclude, analysed extracts could be considered as a promising candidate for further research with the aim to promote antidiabetic activity, which is for the first time reported for G. pfeifferi.

This article presents a compact, low-cost, robust, and flexible test platform for determining the concentration of drugs in fluids. This device is based on a PVC foil card containing copper conductive foils in which disposable paper test strips are inserted. The paper test strips are overlaid with deposition of multiwalled carbon nanotubes (MWCNTs) acting as a sensing layer. When a paper test strip is inserted into the test card, the conductive path between two copper lines is established. A drop of test fluid on the sensing MWCNT layer changes the conductivity in a concentration-dependent manner, enabling calculation of the drug concentration after measurement of the electrical resistance at the copper terminals. An equivalent electrical circuit was also proposed to model the response of the fabricated sensor. It was shown that model parameters are dependent on the concentration of the cytostatic drug methotrexate. Additionally, the fabricated sensor demonstrated the ability to differentiate the same concentration of methotrexate and cyclophosphamide. The complete readout electronics and polynomial transfer function for calculating drug concentrations were also developed and are presented.

Gut microbiota and bile acids possess the ability to modify absorption and pharmacokinetic profile of numerous drugs. Since the variability of gliclazide response in patients cannot be explained only by genetic factors, the influence of gut microbiota and bile acids should be considered. The aim of this study was to determine the effects of probiotic bacteria and bile acids on the gliclazide permeability. The permeability of gliclazide with and without probiotic bacteria and bile acids (cholic acid, CA and deoxycholic acid, DCA) was tested using in vitro PAMPA model, at three different pH values (5.8, 6.5 and 7.4). Concentrations of gliclazide were determined by HPLC analysis. The interactions of gliclazide and bile acids were also investigated by molecular mechanics calculations (MM2). Probiotic bacteria significantly increased the permeability of gliclazide across the PAMPA membrane at all observed pH values while the total amount of gliclazide during incubation with bacteria was significantly reduced at pH 7.4, which could be a consequence of partial metabolism of the drug by enzymes of probiotic bacteria. Bile acids decreased the permeability of gliclazide through PAMPA membrane, with more pronounced effects of DCA, by forming more stable complexes with gliclazide. Given that probiotic bacteria and bile acids are naturally present in the gut and that each individual has a specific bacterial fingerprint, future research should extend the explanation of their effect on the gliclazide bioavailability and therapy individualization in in vivo conditions.

This study investigated the chemical and nutritional profile and antioxidative properties of cultivated Coprinus comatus. Proximate analysis revealed that C. comatus is rich in carbohydrates, dietary fibres and proteins, and could also be a valuable source of phenolics. Additionally, fat content is low, consisting mainly of polyunsaturated and omega-3 fatty acids. Furthermore, the safety profile of C. comatus is satisfactory, with all elements of toxicological importance within the proposed limits. Oral treatment with C. comatus for 42 days improved the antioxidant capabilities and ameliorated carbon tetrachloride-induced liver damage in rats, marked by decreased serum aminotransferase levels and lipid peroxidation intensity. Glutathione concentrations increased in a dose-dependent manner. Histological morphometric and immunohistochemical analysis confirmed antioxidative and hepatoprotective potential. These findings imply that cultivated C. comatus could be considered a nutraceutical, having beneficial nutrient and therapeutic properties.

Gliclazide is a drug commonly used in type 2 diabetes mellitus. Recently, gliclazide has shown desirable pharmacological effects such as immunoregulatory and anti-clotting effects, which suggests potential applications in type 1 diabetes mellitus (T1DM). Gliclazide has variable absorption after oral administration, and thus using targeted-delivery techniques, such as microencapsulation, may optimise gliclazide absorption and potential applications in T1DM. Bile acids such as cholic acid have shown microcapsule-stabilising and controlled-release effects, and thus their incorporation into gliclazide microcapsules may further optimise gliclazide release, absorption and antidiabetic effects. Accordingly, this study aimed to examine the hypoglycaemic effects of gliclazide microcapsules with and without cholic acid, in a rat model of T1DM. Thirty-five alloxan-induced T1DM rats were randomly divided into five equal groups and gavaged a single dose of empty microcapsules, gliclazide, gliclazide microcapsules, gliclazide-cholic acid or gliclazide-cholic acid microcapsules. Blood samples were collected over 10 h post-dose and analysed for blood glucose and gliclazide serum concentrations. Gliclazide microcapsules exerted a hypoglycaemic effect in the diabetic rats, and cholic acid incorporation diminished the hypoglycaemic effects, which suggests the lack of synergistic effects between gliclazide and cholic acid. In addition, neither microencapsulation nor cholic acid incorporation optimised gliclazide absorption which suggests that hypoglycaemic effects of gliclazide are independent of its absorption and serum concentrations. This also suggests that hypoglycaemic effects of gliclazide may be associated with gut-metabolic activation rather than gut-targeted delivery and systemic absorption. Gliclazide microcapsules exerted hypoglycaemic effects in T1DM rats independent of insulin and thus may have potentials in treatment of T1DM.

Background/Aim: Gliclazide is one of the most commonly prescribed oral anti-hyperglycaemic therapies in type 2 diabetes mellitus (T2D). Recently reported additional beneficial pharmacological properties of gliclazide, including immunomodulatory and anticoagulant activities, suggested its potential application in treatment of type 1 diabetes mellitus (T1D). However, following oral administration, gliclazide was shown to have poor and variable absorption directing research into development of novel pharmaceutical delivery systems of gliclazide suitable for T1D. Since bile acids have previously demonstrated stabilising and controlled-release effects on microcapsules, their use for preparation of microcapsules of gliclazide may lead to improvements in gliclazide release, absorption and antidiabetic effects. This investigation was aimed to evaluate drug absorption profiles and hypoglycaemic effects of alginate-based microcapsules of gliclazide, prepared together with or without cholic acid, in healthy rats. Methods: Thirty healthy Wistar rats with confirmed normal glucose blood concentration were allocated into five groups and administered with a single dose of either vehicle microcapsules, gliclazide in suspension, gliclazide microcapsules, gliclazide in suspension together with cholic acid or microencapsulated gliclazide in combination with cholic acid. Following respective gliclazide dose, blood was sampled over next 10 hours and blood glucose levels and gliclazide serum concentrations were measured. Results: This analysis demonstrated altered effects of different gliclazide formulations in healthy rats with the highest gliclazide absorption mirrored by the most profound hypoglycaemic effect being achieved after its oral administration as a suspension (p

Introduction: Inter-individual differences in gut microflora composition may affect drug metabolism and overall therapeutic response. Gliclazide is a drug characterized by large inter-individual differences in therapeutic response; however, the causes of these differences are not fully explained and may be the outcome of microbial biotransformation. Recently, great attention has been paid to studies on bile acid (BA) interactions with gut microflora and the role of BAs in the modification of drug transport through biological membranes. The Aim: Considering the assumption of gliclazide-probiotic-BAs interactions, the aim of the study was to investigate the transport and biotransformation of gliclazide in probiotic bacteria, as well as the effects of deoxycholic acid (DCA) on gliclazide transport into bacterial cells. Materials and Methods: Probiotics were incubated with gliclazide with or without DCA for 24 h at 37°C. The intracellular and extracellular concentrations of gliclazide were determined at seven time points by high-performance liquid chromatography. Gliclazide biotransformation by the enzymatic activity of probiotic bacteria was examined using appropriate software packages. Results: During the 24 h incubation with probiotic bacteria, significantly lower extracellular concentrations of gliclazide were observed at all time points compared to controls, while in the group with DCA, the decrease in concentration was noticed only at 24 h. The total concentration of gliclazide throughout the whole period was significantly lower compared to control. Proposed pathways of gliclazide biotransformation by probiotic bacteria involve reactions of hydrolysis and hydroxylation. Conclusion: Based on the results obtained, it can be concluded that there are interactions of gliclazide-probiotics-DCA, at both the level of active and passive transport into the cells, and at the level of drug biotransformation by enzymatic activity of probiotic bacteria. The effect of these interactions on the final therapeutic response of gliclazide should be further studied and confirmed in in vivo conditions.

Introduction The aim of our study was to compare the level of the most common organophosphate metabolite, dimethyl phosphate, in urine of women giving birth to both boys with cryptorchidism (study group), and healthy boys (control group), as well as to compare the level of dimethyl phosphate in our population with the results obtained in other populations. Material and methods After the ethical approval we included thirty women in both study and control groups. All newborns were born between 38 and 42weeks' gestation. Urine samples were taken on 3rd postpartal day. Gas chromatography with flame photometric detection was used to analyze dimethyl phosphate in urine following the method of Wu et al. Statistical analysis was done using Mann–Whitney test to compare the results in the two groups. Results Geometric mean of dimethyl phosphate in the study group was 7.18±8.26μg/L and the creatinine-corrected level was 5.63±5.95μg/L, and in the control group, the values are 7.98±6.75μg/L and 6.15±7.01μg/L, respectively. There was not a statistically significant difference in levels of dimethyl phosphate between these two groups ( p =0.72786). Dimethyl phosphate levels obtained in similar studies are: 14.4μg/L in Israel, 3.7μg/L in Palestine, 10.3μg/L in Jerusalem, 1.60μg/L in Caribbean islands and 2.60μg/L in Canada. Conclusions Pregnant women in our country are exposed to organophosphate pesticides, but a correlation between the exposure to organophosphate pesticides and cryptorchidism was not found. Level of evidence I. Type of study : Prognostic study, prospective study.

This study investigated the chemical and nutritional profile and antioxidative properties of cultivated Coprinus comatus . Proximate analysis revealed that C. comatus is rich in carbohydrates, dietary fibres and proteins, and could also be a valuable source of phenolics. Additionally, fat content is low, consisting mainly of polyunsaturated and omega-3 fatty acids. Furthermore, the safety profile of C. comatus is satisfactory, with all elements of toxicological importance within the proposed limits. Oral treatment with C. comatus for 42 days improved the antioxidant capabilities and ameliorated carbon tetrachloride-induced liver damage in rats, marked by decreased serum aminotransferase levels and lipid peroxidation intensity. Glutathione concentrations increased in a dose-dependent manner. Histological morphometric and immunohistochemical analysis confirmed antioxidative and hepatoprotective potential. These findings imply that cultivated C. comatus could be considered a nutraceutical, having beneficial nutrient and therapeutic properties.

Binary polymeric amorphous carvedilol solid dispersions were prepared using solvent method by varying solvent type, polymer type and carvedilol to polymer ratio in order to assess the influence of these factors and maximize carvedilol dissolution rate. Low and high molecular weight polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer were used as polymeric carriers in carvedilol to polymer ratios 1:1, 1:2 or 1:4, while absolute ethanol or acetone were used as solvents. Hard gelatin capsules were prepared with carvedilol solid dispersion and lactose monohydrate, mannitol or microcrystalline cellulose. FTIR and PXRD were used to detect carvedilol crystallinity and identify carvedilol-polymer interactions and carvedilol polymorphs. These techniques confirmed carvedilol transition to amorphous state and suggested that hydrogen bonds were formed between carvedilol and polymer molecules. Carvedilol dissolution rate was significantly higher from solid dispersions with higher carvedilol to polymer ratio and solid dispersions prepared using the solvent in which the polymer was more soluble. Solid dispersion with polyvinylpyrrolidone-vinyl acetate copolymer in 1:4 ratio in absolute ethanol displayed the highest carvedilol dissolution rate with 91.78% carvedilol dissolved in the first 30 min. Capsules prepared with the selected solid dispersion and microcrystalline cellulose as diluent displayed the highest carvedilol dissolution rate, with 93.43% carvedilol dissolved within the first 30 min. Carvedilol bioavailability was significantly increased by formulating solid dispersions, while the analysis of serum biochemical parameters excluded damage on liver and kidney function and the lipid profile of animals exposed to investigated drug delivery system.

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.

Many forms of breast carcinoma are hormone-dependent and therefore development of novel aromatase inhibitors is of particular interest. Since brain metastases are frequent in patients with advanced breast carcinoma, one of the goals of modern drug development is the discovery of drugs with specific pharmacokinetic profile. High performance thin layer chromatography (HPTLC) is often used to determine lipophilicity of the molecules based on their retention constant. As a predictive analysis, multiple linear regression method was performed to connect pharmacokinetic-dependent parameters with independent physicochemical properties such are: RM0 , TPSA and Mw of fourteen D-ring modified oestrone derivatives. Additionally, docking studies were performed. Conducted correlation analysis indicates excellent dependence between experimental RM parameter values and calculated values of pharmacokinetic parameters. Results show sufficient intestinal absorption of all the investigated molecules as well as moderate volumes of distribution and strong affinity for binding to plasma proteins. Crossing blood-brain barrier is predicted to be successful for 11 compounds. The created quantitative structure activity relationship model represents an excellent predictive tool and enables determination of pharmacokinetic properties of examined compounds. Docking analysis defined molecules I3 and II3 to be the best candidates; however, compound II3 violates the Lipinski rule. It has been concluded that molecules with hydroxyl group at C-3 more effectively pass through blood-brain barrier while structures with benzyloxy groups have stronger interactions with CYP1A19. Molecules II2 , II4 , II6 , and II7 are regarded as most suitable candidates for further investigation considering their good pharmacokinetic and docking characteristics. Copyright © 2017 John Wiley & Sons, Ltd.

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.

Background/Aim. It is known that bile acids improve the absorption, bioavailability and pharmacodynamic characteristics of some drugs. Morphine analgesia is produced by activation of opioid receptors within the central nervous system (CNS) at both spinal and supraspinal levels. Since a morphine molecule contains 3 polar groups and therefore hard to transfer through the blood-brain barrier, the aim of the study was to examine the potential influence of bile acids derivates, namely sodium salt of monoketocholic acid (MKH-Na) and methyl ester of monoketocholic acid (MKH-Me), on analgesic effect of morphine. Methods. White male mice of NMRI-Haan strain, with body weight of 20-24 g, were used in this study. The analgesic effect of morphine (administered by subcutaneous and intramuscular route in a dose of 2 mg/kg), with and without pretreatment with MKH-Na (4 mg/kg) and MKH-Me (4 mg/kg) was estimated by the hot plate method. Results. Administration of MKH-Me prior to subcutaneous administration of morphine increased the morphine analgesic effect but the increase was not statistically significant. At the same time administration of MKH-Na did not affect morphine analgesic effect. The analgesic effect of morphine increased when administered intramuscularly 20 min after MKH-Me administration. When compared with the group of animals treated only with morphine, a statistically significant increase in analgesic effect was detected 10, 30, 40 and 50 min after morphine administration (p < 0.05). Pretreatment with MKH-Na did not affect morphine analgesic effect. Conclusion. According to the results of this study it can be presumed that after intramuscular morphine administration methyl ester of monoketocholic acid increases morphine transport into the central nervous system and consequently the analgesic effect, as well. Further research on bile acids-morphine interaction both in vitro and in vivo is necessary to completely elucidate the mechanism of this interaction and increase in the morphine analgesic effect. [Projekat Ministarstva nauke Republike Srbije, br. 41012: Interactions of xenobiotics and the impact on biomedical system i br. 172050: Development and application of advanced chromatographic and spectroscopic techniques in analysing xenobiotics and the mechanisms of their decomposition in biotic and abiotic samples]

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.

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

Aims The current treatment of Alzheimer's disease is purely symptomatic. Scientists are looking for new treatment options which could alter the course of the disease and improve the quality of life in patients with Alzheimer's disease. In this paper 14 novel s-triazine molecules have been evaluated for their lipophilicity. In addition docking study was carried out to evaluate acetylcholinesterase activity of these compounds. Main methods Lipophilicity was evaluated by RP HPTLC using 5 different mobile phases and obtained results were used in calculations of pharmacokinetic parameters - logBB, Ka and Pej. Multiple linear regression analysis was refined, taking account of molecular polarity (total polar surface area, TPSA) and molecular weight (Mw) descriptors. Appropriate QSAR models were developed. Docking studies were carried out using the Vina docking. Key findings Five out of fourteen compounds evaluated [5-10] are selected as the most promising compounds with satisfactory pharmacokinetic properties and good docking scores. Significance Compound 10 possesses the best combination of favourable pharmacokinetic characteristics (brain penetration, intestinal absorption) and capacity for acetylcholinesterase inhibition. Consequently this molecule should be further evaluated for potential therapeutic use in Alzheimer's disease.

Purpose Information on ADME properties of examined bile acids and their oxo derivatives are scarce, although the interest for bile acids and their use in nanochemistry and macromolecular chemistry is increasing. The purpose of this research was to evaluate the lipophilicity, a crucial physicochemical parameter for describing ADME properties of selected bile acids and their oxo derivatives, and to compare two approaches: experimentally determined hydrophobicity parameters and calculated log P values. Methods Commercially available bile acids - deoxycholic, chenodeoxycholic, hyodeoxycholic and ursodeoxycholic acid were used to synthesize oxo derivatives. Lipophilicity was evaluated in two solvent systems: toluene/ethanol and toluene/butanol. Retention parameters were acquired by normal-phase TLC. The correlations between calculated log P values obtained using five different software and experimentally determined hydrophobicity parameters ( R M 0 (tol/eth) , R M 0 (tol/but) , b (tol/eth) and b (tol/but) ) were examined. Results Correlation analysis confirmed significant dependence between experimental R M 0 values and software calculated parameters. Results suggest satisfactory intestinal absorption after oral administration for all of the examined compounds as well as low volumes of distribution, and high affinity for binding with plasma proteins. Penetration through blood-brain barrier and skin is not satisfactory. All of the examined compounds show high affinity for binding with G-protein coupled receptors and consequently inhibition of ionic channels. Results also suggest possible binding with nuclear receptors. Conclusions Established lipophilicity testing model of studied compounds showed excellent predictive ability and might represent significant tool in development of relations between chromatographic behavior and ADME properties. Compounds 3α-hydroxy-7,12-dioxo-5β-cholanoic and 12α-hydroxy-3,7-dioxo-5β-cholanoic acid might be the most suitable candidates for further development studies (satisfactory pharmacokinetic properties and lowest haemolytic potential) followed by 3α-hydroxy-12-oxo-5β-cholanoic acid and 3α-hydroxy-7-oxo-5β-cholanoic acid (slightly higher haemolytic potential, but better ligand properties).

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.

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.

Matricaria recutita L. (Asteraceae) is one of the most ancient medical herbs, although the therapeutic uses and health benefits of chamomile are based largely on tradition. The present study aimed to investigate the effects of chamomile extract on the intestinal motility. Due to the fact that preparation techniques could significantly alter the glucoside content in the chamomile, we also explored the possible differences in the effects on gastrointestinal motility between native and fermented chamomile extract. Thirty minutes after the administration of saline or chamomile ligulate flower extracts, all animals were orally administered charcoal meal by gavage (0.6 ml emulsion–0.4 g Carbo medicinalis and 0.2 g Gummi arabicum in 10 ml of olive oil). Animals were sacrificed by cervical dislocation 30 min after charcoal meal administration. Intestinal motility was estimated according to the distance between Carbo medicinalis and pylorus in centimeters. Both native and fermented extract decreased intestinal motility compared to control. Native chamomile extract (5 mg/kg) and fermented chamomile extract (2.5 mg/kg) significantly decreased intestinal motility compared to control group (NE5=27.41±2.79, P

Introduction: Distribution coefficient (D) is useful parameter for evaluating drugs permeability properties across biological membranes, which are of importance for drugs bioavailability. Given that bile acids are intensively studied as drug permeation-modifying and -solubilizing agents, the aim of this study was to estimate the influence of sodium salts of cholic (CA), deoxycholic (DCA) and 12-monoketocholic acids (MKC) on distribution coefficient of simvastatin (SV) (lactone [SVL] and acid form [SVA]) which is a highly lipophilic compound with extremely low water solubility and bioavailability.Methods: LogD values of SVA and SVL with or without bile salts were measured by liquid-liquid extraction in n-octanol/buffer systems at pH 5 and 7.4. SV concentrations in aqueous phase were determined by HPLC-DAD. Chem3D Ultra program was applied for computation of physico-chemical properties of analyzed compounds and their complexes.Results: Statistically significant decrease in both SVA and SVL logD was observed for all three studied bile salts at both selected pH. MKC exerted the most pronounced effect in the case of SVA while there were no statistically significant differences between observed bile salts for SVL. The calculated physico-chemical properties of analyzed compounds and their complexes supported experimental results.Conclusions: Our data indicate that the addition of bile salts into the n-octanol/buffer system decreases the values of SV distribution coefficient at both studied pH values. This may be the result of the formation of hydrophilic complexes increasing the solubility of SV that could consequently impact the pharmacokinetic parameters of SV and the final drug response in patients.

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.

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.

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].

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.