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Introduction: Cardiovascular diseases are the leading cause of death both in Serbia and in the rest of the world. It has been shown that as many as 80% of them are preventable. Control of serum lipid levels is one of the most important tasks of cardiovascular diseases prevention. Aim: The aim of the study was to analyze the use of serum lipid-modifying drugs in Serbia, Norway and Finland in the period 2015-2017. Methods: Data on drugs use during 2015, 2016 and 2017 were taken from the official websites of national drug regulatory authorities: the Serbian Medicines and Medical Devices Agency, the Norwegian Institute of Public Health and the Finnish Medicines Agency. Use was expressed as DDD/1000 inhabitants/day according to the Anatomical Therapeutic Chemical classification. Results: The share of drugs used for treatment of cardiovascular diseases in total drugs use was the largest in all three countries during the observed period. The use of lipidmodifying agents was 3-4 times lower in Serbia than in Norway or Finland. Of all lipidmodifying drugs, statins are most commonly prescribed in all three countries. Atorvastatin and rosuvastatin are the most widely used in Serbia, and simvastatin and atorvastatin in Norway and Finland. Conclusions: Use of lipid-modifying drugs in Serbia is lower than in Norway and Finland, but it is constantly increasing. This use in Serbia still represents the smallest share of all drugs for the treatment of cardiovascular diseases.

Introduction: Community-acquired pneumonia is one of the most common diseases in infancy but most of these diseases have relatively simple course. We are presenting a case of child who developed lung abscess as a complication of pneumonia. Case Report: The goal of our case report is to point out that lung abscess is a relatively rare entity whose development is not always typical, sudden and acute, but also hidden, inconspicuous and perfidious. Although clinical picture and laboratory findings indicated that the pneumonia was cured, a single control CT scan showed that there was inflammation (hotspot) in the organism. Discussion: Lung abscess is a rare state which is developed as a complication only at 1% of pneumonias. Complications are rare and depend on the previous immunological status of the child and the presence of comorbidity. The duration of antibiotic therapy depends on the clinical and radiographic response of the patient. The chosen antibiotics have to cover a wide specter of Gram-positive and Gram-negative bacteria. Conclusions: The key role in making a diagnosis played radiological methods which were crucial in monitoring the evolution of the change itself, from its creation to regression. The triple antibiotic therapy with meropenem, vancomycin and metronidazole enabled an (excellent) recovery outcome.

Graphical abstract, Resveratrol was recognized as the major factor responsible for the beneficial properties of red wine. Several resveratrol-based dietary supplements are available, but their efficacy has not been sufficiently tested. This study was designed to examine the effect of resveratrol supplementation, using a commercially available product, on the metabolic status of experimental animals with induced hyperlipidemia or type 2 diabetes mellitus (T2DM). Hyperlipidemia was induced by feeding the rats a standard pellet diet supplemented with cholesterol. T2DM was induced by adding 10% fructose to drinking water and streptozotocin. Treatment with resveratrol-based supplement improved glycemic control in diabetic animals and significantly decreased serum low-density-lipoprotein (LDL) and triglyceride levels, concurrently increasing the high-density-lipoprotein (HDL) levels in animals with hyperlipidemia. Resveratrol-treated animals had improved tolerance to glucose loading. Supplementation did not induce alterations in parameters of liver and renal function. Findings indicate that commercial resveratrol supplement improves metabolic control in rats with induced hyperlipidemia and T2DM.

Introduction: In addition to the active pharmaceutical ingredient (API), excipients and the pharmaceutical dosage form can also affect the overall effect of pharmacotherapy. Knowledge about these effects is not important only from the aspect of drug efficacy, but also from the aspect of pharmacovigilance. Materials and Methods: This paper presents secondary academic study results. Data on the dosage form and content of excipients were taken from SmPC documents on the official website of Medicines and Medical Devices Agency of Serbia. The presence of excipients with known effect (EKE) and their labeling was considered in accordance with the national and European regulations regarding this area. Results: We analyzed a total of 50 medicines for topical administration that are registered in Serbia. These all contained corticosteroids as API. Thirty-five (70 %) of them had one or more EKE. Creams had the highest number of different EKE per drug (3.25). Five out of seven identified EKE have the preservative function in formulations, which could be avoided by extemporaneous drug production. The labeling of these compounds was in accordance with the regulations in most drugs. Conclusions: The cause of an adverse drug reaction should be considered in a wider context and all the drug ingredients should be taken into account. In case of topical corticosteroids, over two third of drugs have the potential to cause adverse drug reactions that are non-API-related.

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

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. 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]

Introduction: Anaphylactic reaction is a most serious allergy where the symptoms may occur shortly after contact with an allergen and can get worse quickly. Therefore, timely and appropriate treatment is of crucial importance. Methods: In this article, we draw on evidence from publications on the subject of anaphylaxis treatment that we got by searching Google Scholar and PubMed databases. Used articles included: systematic reviews, case reports and randomised controlled trials. We also used World Allergy Organization guidelines for the management and the assessment of anaphylaxis. A literature search with the keywords 'anaphylaxis treatment', 'anaphylactic shock', and 'allergy' identified a number of potentially eligible studies, of which 42 satisfied our eligibility criteria and were therefore included in this review. Topic: There was evidence regarding the optimum route, dose and site of adrenaline administration ,with the latest recommendations indicating the intramuscular route (i.m.) in the mid-outer thigh as the optimum treatment. We found studies suggesting the purpose of applying H1 and H2 antihistamines, systemic glucocorticosteroids, calcium and methylxantines to manage anaphylactic shock, recommended doses and mode of administration. With regard to treatment, we focused on acute rather than on long-term management. Further, we have taken into consideration the mechanisms, common triggers and clinical manifestations of anaphylaxis. Conclusion: Adrenaline represents the first choice drug and it is necessary to be applied as soon as possible. However, there is a controversy regarding the application of the other specified medications in this life-threatening condition.

Treatment of advanced soft tissue sarcoma usually includes dacarbazine (DTIC), an alkylating agent that methylates DNA and is active during all phases of the cell cycle. Common side effects of DTIC include nausea, vomiting, impaired liver and kidney function, myelosuppression, and pneumonia. There are no accounts, however, of histological and hematological changes caused by DTIC. We investigated acute hematological and morphological changes in different organs and in tumors that were caused by a single dose of DTIC. Adult Syrian golden hamsters were inoculated with a suspension of tumorigenic baby hamster kidney (BHK) cells by subcutaneous injection. On day 14 after inoculation, doses of 1.4, 1.6, 1.8 or 2.0 g/m(2) DTIC were injected intraperitoneally into the hamsters. Hamsters in the control group were injected with physiological saline in the same way. Seven days after drug or saline injection the animals were sacrificed and samples of blood, heart, kidney, liver, lungs, spleen, small intestine and tumor were excised, processed and analyzed. Mitoses were counted using an ocular extension with engraved frame. Anemia, thrombocytopenia and leukocytosis were found in the control group of hamsters with fibrosarcoma, whereas animals with fibrosarcoma treated with DTIC developed anemia, thrombocytopenia and leukopenia. Severe pneumonia and moderate hepatitis were detected in all DTIC treated groups. Effects of DTIC on tumor cells included rounding and enlargement of nuclei and rarefaction of chromatin. The number of mitoses was reduced with increasing doses of DTIC. Hepatitis, myelosuppression, pneumonia, and dose-related inhibition of tumor cell proliferation were observed after a single dose of DTIC.

Major problem for diabetic patients represents damage of blood vessels and the oxidative stress of the brain cells due to increased concentration of free radicals and poor nutrition of brain cells. Gliclazide has antioxidative properties and poor blood brain barrier (BBB) penetration. Bile acids are known for their hypoglycemic effect and as promoters of drug penetration across biological membranes. Accordingly, the aim of this study is to investigate whether the bile acid (deoxycholic acid) can change the permeation of gliclazide, through the blood brain barrier of a rat model type-1 diabetes. Twenty-four male Wistar rats were randomly allocated to four groups, of which, two were given alloxan intraperitoneally (100 mg/kg) to induce diabetes. One diabetic group and one healthy group were given a bolus gliclazide intra-arterially (20 mg/kg), while the other two groups apart from gliclazide got deoxycholic acid (4 mg/kg) subcutaneously. Blood samples were collected 30, 60, 150, and 240 seconds after dose, brain tissues were immediately excised and blood glucose and gliclazide concentrations were measured. Penetration of gliclazide in groups without deoxycholic acid pretreatment was increased in diabetic animals compared to healthy animals. Also in both, the healthy and diabetic animals, deoxycholic acid increased the permeation of gliclazide through that in BBB.

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 the last years there appeared many articles about the adverse influence of non-steroidal anti-inflammatory drugs on the liver and heart. This study is concerned with the influence of the duration of treatment with diclofenac and ketoprofen on the macroscopic and microscopic changes in the liver, lungs, heart, and kidneys in rats. Experiments were carried out on mature Wistar strain rats. Animals of test groups received diclofenac and ketoprofen in a dose of 8 mg/kg/day (equivalent to the therapeutic dose for man) during 7 per os (p.o.) or 28 days intraperitoneally (i.p.), whereas controls received physiological solution p.o. A high morbidity was observed in the animals receiving diclofenac p.o. and somewhat lower in those treated with ketoprofen. On the other hand, the rats got through the 28-day i.p. treatment with both drugs mainly without significant complications. Macroscopic examinations revealed some changes in treated rats: distension of the stomach, ascites, fibrin deposits on the internal organs, lung effusion and the changes in color and structure of the liver. These changes were more frequent in the group of rats receiving diclofenac for the 7 days compared with those that received ketoprofen for the same time. It may be thought that the high mortality and macroscopic changes in the internal organs of experimental animals are a consequence of the microscopic changes in the liver and its lowered function.

e142 Volume 37 Number 8S aspects of development of topical treatments for AD were not specifically addressed. Conclusions: There is little information available to guide the development of topical dermatological products for the treatment of AD and psoriasis. Because recommendations are disperse, and lacking for some development aspects, a systematic approach to create specific guidance to development in AD and P may be useful.

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.

2013 e83 PP208—Deoxycholic AciD As A MoDifier of the BlooD BrAin BArrier PerMeAtion in rAt M. Lalic-Popovic; S. Golocorbin-Kon; V. Vasovic; B. Milijasevic; and M. Mikov Department of Pharmacy, Faculty of Medicine, Novi Sad, Serbia; Faculty of Pharmacy, University of Montenegro, Podgorica, Montenegro; and Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, Novi Sad, Serbia Introduction: Major problem for diabetic patients represents damage of blood vessels and the oxidative stress of the brain cells due to increased concentration of free radicals and poor nutrition of brain cells. Gliclazide has antioxidative properties and poor blood brain barrier (BBB) penetration. Bile acids are known for their hypoglycemic effect and as prooters of drug penetration across biological membranes. Aim: The aim of this study is to investigate whether the bile acid (deoxycholic acid) can change the permeation of gliclazide, through the blood brain barrier of a rat model type-1 diabetes. Patients (or Materials) and Methods: Twenty-four male Wistar rats were randomly allocated to 4 groups, of which 2 were given alloxan intraperitoneally (100 mg/kg) to induce diabetes. One diabetic group and 1 healthy group were given a bolus gliclazide intra-arterially (20 mg/kg), while the other 2 groups apart from gliclazide got deoxycholic acid (4 mg/kg) subcutaneously. Blood samples were collected 30, 60, 150, and 240 seconds after dose, brain tissues were immediately excised, and blood glucose and gliclazide concentrations were measured. Results: Penetration of gliclazide in groups without deoxycholic acid pretreatment was increased in diabetic animals compared with healthy animals. Also in both, healthy and diabetic animals, deoxycholic acid increased the permeation of gliclazide through that in BBB. Deoxycholic acid pretreatment also changed the pattern of blood glucose level increase after gliclazide application in diabetic as well as in healthy animals. Conclusion: Deoxycholic acid promotes gliclazide penetration across BBB in diabetic and in healthy animals. In addition, deoxycholic acid alters some pharmacokinetic properties of gliclazide in both healthy and diabetic rats. Thus, deoxycholic acid should be more investigated in the treatment of diabetes mellitus and as permeation promoter of lipophilic molecules through BBB as well as other biological membranes. Financial Source: This work has been supported by Ministry of Science and Technology development of Serbia N041012.

Background Cardiovascular diseases are the most frequent cause of morbidity and mortality in many countries. That explains why medications for the treatment of cardiovascular diseases are the group of drugs with the largest consumption, and ACE inhibitors take a large part in this consumption. The aim of this study was to analyze the consumption of ACE inhibitors in Serbia in 2010 compared with Norway, a country with a developed pharmacotherapeutic practice.

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.

PP217—CORRELATION BETWEEN IN VITRO TESTS FOR BLOOD BRAIN BARRIER PENETRATION WITH IN VIVO GLICLAZIDE PENETRATION M. Lalic-Popovic; V. Vasovic; H. Al-Salami; S. Golocorbin-Kon; B. Milijasevic; and M. Mikov Department of Pharmacy; Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, Novi Sad, Serbia; School of Pharmacy, Curtin University, Perth, WA, Australia; and Faculty of Pharmacy, University of Montenegro, Podgorica, Montenegro Introduction: Nowdays, great effort is put into development of effective in vitro model for prediction of blood brain barrier (BBB) penetration of drugs. Recent investigation showed that gliclazide has protective effect on the brain of diabetic rat, but it has low BBB permeability that could be increased. Aim: The aim of this study was to investigate whether in vitro models of gliclazide distribution in systems n-octanol/water and cyclohexane/ water are good in vitro models for the prediction of its penetration as well as for the prediction of influence of dexycholic acid (DCA) influence on penetration. Patients (or Materials) and Methods: Distribution coefficient (logD) was determined using a ...Flask shake “method. Partition profile was determined over physiological pH range (from pH 1.2 HCl solution, pH 4.5 acetate buffer, pH 6.8 and 7.4 phosphate buffer, and pH 7 distilled water) for 5 combinations of n-octanol or cyclohexane with aquase gliclazide solution (10 μg/mL) of different pH and with or without the addition of DCA (0.5 mM) into n-octanol or cyclohexane phase. The analyses were done in triplicate for each pair of organic solvent/ water. Concentrations of gliclazide were determined using high-performance liquid chromatography. Values of logD at pH 7.4 were compared with literature date of gliclazide BBB penetration and influence of DCA on it penetration. Results: Higher partition into organic layer was found in system n-octanol/water than cyclohexane/water. Also DCA increased partition of gliclazide in system cyclohexane/water but not in system n-octanol/ water. Value of logD at pH 7.4 without DCA in organic layer in system n-octanol/water was 0.34 (0.05) and in system cyclohexane/water was –0.74 (0.11). Value of logD at pH 7.4 with DCA in organic layer in system n-octanol/water was 0.54 (0.07) and in system cyclohexane/water was 0.18 (0.01). Thus, partition of gliclazide in system cyclohexane/water better correlate with in vivo data where penetration of gliclazide was increased with DCA pretreatement, but in diabetic animals, penetration was increased in group with and without DCA pretreatment what this in vitro system could not predict. Conclusion: Investigated system cyclohexane/water predicted poor gliclazide BBB penetration and the influence of DA on gliclazide penetration but system n-octanol/water failed to do so. However, more substances are need to claim that system cyclohexane/water successfully could predict drugs BBB penetration. Funding Source: This work has been supported by Ministry of Science and Technology development of Serbia N041012.