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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 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.

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.

Background/Aim. Hypertension is one of the leading causes of cardiovascular morbidity and mortality and more than a half of all health insurance expenditures for reimbursed medicines are allocated to antihypertensive drugs in Serbia. The aim of this study was to identify the antihypertensive drug utilization patterns among hypertensive outpatients in the city of Novi Sad, Serbia, determine the adherence to clinical guidelines and address the economic aspects of current prescribing practices. Methods. This retrospective observational study was conducted in Novi Sad over a period of six months. The data on the number of packages, size of packages, and retail price of antihypertensives issued on prescription in outpatients with the diagnosis of essential arterial hypertension was collected from all state-owned pharmacies in Novi Sad. Drug consumption was analyzed using the Anatomical Therapeutic Chemical (ATC)/defined daily dose (DDD) methodology. Results. Total consumption of antihypertensives issued on prescription over 6 month period in the city of Novi sad, Serbia was 283,48 DDD per 1,000 inhabitans per day (DID). Angiotensin converting enzyme inhibitors (ACEi) were most commonly prescribed drugs, and were used 3 times more often than calcium channel blockers and 5 times more than betablockers. The consumption of diuretics and angiotensin receptor antagonists was low within all groups of outpatients. Both national and international guidelines state superiority and effectiveness of diuretics in treatment of hypertension in the elderly, but their consumption was unreasonable low despite the fact that over 70% of all antihypertensive drugs in the city of Novi Sad were dispensed in people aged > 60. The use of more expensive ACEi was observed, despite the guidelines deeming all the drugs of these class equally effective in treatment of hypertension. Conclusion. Large differences in utilization of different groups of antihypertensive agents were noted in this study. Underutilization of valuable, efficacious, and cost-effective thiazide diuretics and over use of expensive ACE inhibitors is unjustifiable. There is a potential for large savings with switching to low-price ACEi, modeling the practice of Scandinavian countries. [Projekat Ministarstva nauke Republike Srbije, br. III 41012]

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]

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.

This review describes the most recent data on the eff ects of endocrine disrupting compounds on reproductive tract development, as well as controversies in the fi eld. One of the most frequent conditions aff ected by endocrine disrupting compounds is cryptorchidism. Recent reports regarding the cause of this disorder continue to increase our understanding of this common and important problem. Endocrine disruptors are defi ned as exogenous substances with the ability to disrupt normal endocrine homeostasis and reproduction, and they include xenoestrogens, synthetic and natural hormones, phyto- and mycoestrogens, and other substances aff ecting endocrine signaling. Human exposure to endocrine disrupting chemicals is widespread. Epidemiological studies suggest associations between prenatal exposure to endocrine disrupting chemicals and numerous malformations of androgen dependent tissues. Animal models and epidemiological evidence link exposure to androgen disrupting chemicals with cryptorchidism, reduced sperm cell counts, increasing infertility, and testicular and prostate cancers. Since male sexual diff erentiation is androgen dependent, it is highly susceptible to endocrine disruptors. Whether the level of exposure contributes to the increasing prevalence of cryptorchidism is an ongoing debate. Further, there appears to be increased sensitivity to these agents during critical developmental periods when male diff erentiation is at its peak. Diff erences in the interpretation of the available studies underlie the disparate conclusions of scientifi c and regulatory body panels on the potential toxicological eff ects of endocrine disrupting chemicals at the current levels of human exposure. This review will highlight the evidence for endocrine disrupting chemicals that act through interference with the androgen receptor and lead to cryptorchidism., Ovaj pregledni članak donosi najnovije podatke o učincima endokrinih disruptora na razvoj reprodukcijskog sustava, kao i o proturječjima u ovom području. Kriptorhizam je jedno od najčešćih stanja na koja utječu endokrini disruptori. Novija izvješća o uzroku ovoga poremećaja sve više doprinose razumijevanju ovoga čestog i važnog problema. Endokrini disruptori defi niraju se kao egzogene tvari sposobne prekinuti normalnu endokrinu homeostazu i reprodukciju, a obuhvaćaju ksenoestrogene, sintetske i prirodne hormone, fi to- i mikoestrogene te druge tvari koje utječu na endokrine signale. Ljudi su uvelike izloženi takvim kemikalijama. Epidemiološke studije ukazuju na udruženost prenatalne izloženosti endokrinim disruptorima i brojnih malformacija tkiva ovisnih o androgenima. Životinjski modeli i epidemiološki dokazi povezuju izloženost androgenim disruptorima s kriptorhizmom, smanjenim brojem spermija, povećanjem neplodnosti te s rakom testisa i prostate. Muška seksualna diferencijacija ovisna je o androgenima, a time i veoma osjetljiva na endokrine disruptore. I dalje traju rasprave o tome doprinosi li razina izloženosti rastućoj učestalosti kriptorhizma. Nadalje, izgleda da je osjetljivost na ova sredstva povećana tijekom kritičnih razvojnih razdoblja obilježenih vršnom diferencijacijom kod muškog spola. Razlike u tumačenju dostupnih studija obilježavaju neujednačene zaključke znanstvenih i regulatornih panela o potencijalnim toksikološkim učincima endokrinih disruptora uz današnju razinu izloženosti ljudi. Ovaj pregledni rad pokazuje dokaze za endokrine disruptore koji djeluju kroz interferenciju s androgenim receptorima i dovode do kriptorhizma.

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.

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 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.