To accomplish therapeutic goal it is necessary to adjust the dose of medication to be right for every single patient. This procedure of dose adjustment is individualized dose regimen. First of all, pharmacokinetic aspects should be revised, including parameters such as resorption, distribution, metabolism and secretion of drug. For these purposes, the authors developed and clinically assessed the modified Bayesian method supported by original basic computer program. The aim of research was to compare frequency of adverse events in cases of individualized and empiric dose regimens of amitriptyline in the treatment of major depressive episode. Sixty subjects (32- 65 years old), with major depressive disorder (International Classification of Disease, 10th revision), were randomly assigned and single- blinded to take individualized (experimental group, n=30) or empiric (control group, n=30) doses of amitriptyline for 8 weeks. CGI scale and originally designed questionnaire were used for adverse events assessment. In experimental group, 69 complaints on nine different types of adverse effects were recorded during eight-week treatment period. Severe adverse events, such as confusion or arrhythmia, were not registered in this subgroup. In control group, 111 complaints on twelve different types of adverse effects were recorded. Most common were anticholinergic effects, but during the third and fourth week from baseline, some severe adverse events were observed: tremor (16%), fatigue (16%), in one of the subjects confusion occurred and arrhythmia in another. Analyzing of the results according to CGI scale for adverse events showed that, during the treatment period, adverse events were less frequent in experimental group. This was particularly obvious in the first four weeks of treatment, when statistically significant difference (p<0.05) was observed.

The mortality rate from cardiovascular diseases is high in Serbia. Analysis of antihypertensive drugs utilization is the basis for assessment of cardiovascular pharmacotherapy appropriateness. The aim of this study was to analyze the trend in antihypertensive drugs utilization among outpatients in Niš region, South Serbia compared to some Nordic countries (Norvay, Sweden) and Australia as well as to analyze trends in educational and drug promotion activities directed to primary healthcare workers within the same region. Using the ATC/DDD methodology, we analyzed the utilization of antihypertensive drugs dispensed on prescription in the Nis region over the 2003–2007 period. The study was retrospective, based on data obtained from Central City Pharmacy Nis. Educational and drug promotion activities were noted from the records of Medical Faculty, University of Nis, and from the records of local branches of pharmaceutical companies active in Serbia. Wilcoxon’s test was used in order to calculate the statistical significance of difference. A significant increase of 79.8% (153.8/ 276.6 DDD/inhabitants/day) in antihypertensive drug consumption was observed in the same period. This analysis showed there were substantial increases in the use of diuretics (134.7%), ACE inhibitors (79.5%) and calcium channel blockers (116.1%), especially amlodipin (241.2%). During the observed period, annual numbers of educational activities and of pharmaceutical sales representatives employed within the region increased for almost one fourth. This analysis pointed to a significant increase in the use of antihypertensive drugs in the Nis region, which was matched with increase in educational and drug promotion activities within the region, so that in 2006–2007 total consumption was approximate to some referential countries (Norvay, Sweden).

INTRODUCTION The aim of our study was to develop and use a population pharmacokinetic model for assessment of individual valproate clearance in children and young adults suffering from epilepsy. MATERIAL AND METHODS The analysis was performed using 52 steady-state concentrations of valproate collected from 26 epileptic patients during the routine clinical practice in our hospital. The mean values of age and total body weight were 19.92 years and 57.12 kg, respectively. NONMEM software with ADVAN 1 subroutine was used for model building and assessing the influence of different covariates. A validation set of 20 epileptic patients (one blood sample per a patient) was used to estimate predicted performances of the pharmacokinetic model. RESULTS The typical mean value of the clearance of valproate estimated by the base model in our population was 0.3 77 I/h. Out of five considered covariates (total body weight, age, total daily dose, gender and polytherapy) only the age of the patients was a significant determinant of the clearance of valproate. The final regression model for the clearance of valproate was as following: CL (l/h) = 0.223 + 0.00819 * AGE CONCLUSION: The derived pharmacokinetical model describes the clearance of valproate in relation to patient's age in the observed population. it will help to improve the seizure control in young patients with epilepsy in Serbian population.

Multiple sclerosis (MS) is chronic inflammatory and demyelinating disease with either a progressive (10%–15%) or relapsing-remitting (85%–90%) course. The pathological hallmarks of MS are lesions of both white and grey matter in the central nervous system. The onset of the disease is usually around 30 years of age. The patients experience an acute focal neurologic dysfunction which is not characteristic, followed by partial or complete recovery. Acute episodes of neurologic dysfunction with diverse signs and symptoms will then recur throughout the life of a patient, with periods of partial or complete remission and clinical stability in between. Currently, there are several therapeutic options for MS with disease-modifying properties. Immunomodulatory therapy with interferon beta-1b (IFN-β1b) or -1a, glatiramer and natalizumab shows similar efficacy; in a resistant or intolerant patient, the most recently approved therapeutic option is mitoxantrone. IFN-β1b in patients with MS binds to specific receptors on surface of immune cells, changing the expression of several genes and leading to a decrease in quantity of cell-associated adhesion molecules, inhibition of major histocompatibility complex class II expression and reduction in inflammatory cells migration into the central nervous system. After 2 years of treatment, IFN-β1b reduces the risk of development of clinically defined MS from 45% (with placebo) to 28% (with IFN-β1b). It also reduces relapses for 34% (1.31 exacerbations annually with placebo and 0.9 with higher dose of IFN-β1b) and makes 31% more patients relapse-free. In secondary-progressive disease annual rate of progression is 3% lower with IFN-β1b. In recommended doses IFN-β1b causes the following frequent adverse effects: injection site reactions (redness, discoloration, inflammation, pain, necrosis and non-specific reactions), insomnia, influenza-like syndrome, asthenia, headache, myalgia, hypoesthesia, nausea, paresthesia, myasthenia, chills and depression. Efficacy of IFN-β1b in relapsing-remitting MS is higher than that of IFN-β1a, and similar to the efficacy of glatiramer acetate. These facts promote IFN-β1b as one of the most important drugs in the spectrum of immunological therapies for this debilitating disease.

The purpose of this study was to investigate the effects of endothelins (ET) 1, 2 and 3 on isolated isthmic segments of the human oviduct at the luteal phase of menstrual cycle. Fallopian tubes were taken from 21 patients and the isthmic segments were mounted in an organ bath longitudinally. Tension of the isolated preparations was recorded with an isometric transducer. ET-1 and ET-2 triggered concentration-dependent tonic contractions of the isolated isthmic segment and inhibited rhythmic activity, while ET-3 caused no effect. Furthermore, the selective ET(A) antagonist BQ-123 and the selective ET(B) antagonist BQ-788 inhibited the ET-1 effects on both tone and spontaneous rhythmic contractions. These results suggested that during the luteal phase of the menstrual cycle, both ET(A) and ET(B) receptors participate in contractile effects of endothelins on isthmic segment of fallopian tubes, probably regulating the length of time the oocyte remains in the oviduct ampulla.

A combined test performed at the 12th week of gestation enables us to classify the pregnancy as high risk (risk higher than 1:300) or low risk (risk lower than 1:300) for congenital foetal anomalies, with great accuracy of 85 - 90%. According to the available data, the frequency of false positive results is estimated at around 5%. The objective of the study was to examine possible correlation between the serum marker values and amniocentesis results in prenatal diagnostics of congenital foetal anomalies. The study included 745 pregnant women monitored by the Genetic Counselling Service of the Clinic of Gynaecology and Obstetrics of the Clinics Centre Kragujevac. The subjects were included in the study under condition that CRL (embryonic crown-rump length) was from 45 to 84 mm and that the gestational age was at 11-13+6 weeks. Free beta HCG and PAPP-A were determined from venous blood using commercial DPS-USA tests. Tests were based on the analytic principle of the immuno-chemiluminescence technique and were performed by application of the automatic Immulite 2000 analyzer by DPC-USA. The foetal nuchal translucency thickness (NT) and CRL were measured by Colour Doppler. The chromosome identification was performed after a certain number of cell divisions by stopping the cell division in metaphase of mitosis when the chromosomes were the most distinguishable. The foetal karyotype was prepared using G bands. In the total sample of pregnant women (n=745), there were six cases of pathological foetal karyotype. A statistical paradox in the frequency of congenital foetal anomalies in favour of younger population was noticed. A high coefficient of Spearman's rank correlation suggests great importance of the combined test in the detection of congenital foetal anomalies (p<0,05). A high consistency was also proved for components of biochemical screening and ultrasonographic markers. The combined test, as a method of prenatal screening in the first trimester of pregnancy, if used at 11 - 13+6 weeks' gestation and for CRL of 45-84 mm, has a great importance in the detection of congenital foetal anomalies.

Background. Pentoxyphylline is a methylxanthine derivative used in the treatment of peripheral vascular diseases. One eff ect of pentoxyphylline action is the vasodilatation of blood vessels. In this study, the eff ect of increasing concentrations of pentoxyphylline on contractility of isolated rat uteri was examined. Methods. Uteri were isolated from virgin Wistar rats (180–220 g) and suspended in an isolated organ bath chamber containing De Jalon’s solution and aerated with 95% O2 and 5% CO2. Th e temperature was maintained at 37oC. Isometric contractions were recorded using an isometric force transducer (Ugo Basile). Th e preload of the preparation was about 1 g. Uteri were allowed to contract spontaneously or in the presence of Ca2+ (6 mM) and were treated with pentoxyphylline. Results. Pentoxyphylline caused concentration-dependent inhibition of spontaneous rhythmic uterine activity and uterine activity induced by calcium. We showed that the inhibitory eff ect of pentoxyphylline depends on the type of muscle contraction activation, and that it is signifi cantly stronger in spontaneous contractions induced by calcium Ca2+. As opposed to methylene blue, L-arginine and glibenclamide did not antagonise the relaxing eff ect of pentoxyphylline on the isolated rat uterus. Conclusion. Our results suggest that the signaling pathway by which pentoxyphylline causes relaxation of uterine muscle cells does not involve NO because the presence of Larginine did not aff ect the action of the drug; however, it may depend on an NO-independent cGMP signaling pathway because the presence of methylene blue signifi cantly antagonised the eff ect of pentoxyphylline. Th ese results indicate that pentoxyphylline could be a potential tocolytic drug.

In spite of a variety of established therapeutic approaches to the treatment of acne vulgaris, up to 12.7% of patients cannot be cured using these methods. To overcome the limitations of established therapies, botanicals and natural mineral preparations are also used to treat acne. Th e aim of our study was to investigate the effi cacy of topical preparations of peloid and medicinal plants from Montenegro in an acne therapy regimen. Th e study design was a retrospective cohort study, with two cohorts defi ned by the type of topical preparation used: one cohort (n = 70) was comprised of the patients treated with Peloderm (a topical preparation containing both peloid and medicinal plants’ extracts), and another cohort (n = 70) of the patients was treated with Antiacne (a topical preparation with only medicinal plants’ extracts). Patients in both cohorts were treated for 18 months. In both treatment groups, the FDA acne severity score improved gradually throughout the study visits. However, fi nal FDA acne severity score (after 18 months of topical treatment) was signifi cantly (T = 7.556, df = 1, p = 0.000) lower in the Peloderm group (1.0 ± 0.0) than in the Anitiacne group (1.8 ± 0.9). Both topical preparations of peloid and selected medicinal plants from Montenegro, in ratios observed in this study, are effi cacious and safe options for topical treatment of acne, with the peloid preparation demonstrating somewhat greater potency.

BACKGROUND/AIM Recurrent vulvovaginal candidiasis is relatively frequent condition, and may have serious health consequences, like chronic vulvovaginal pain syndrome. The aim of our study was to determine possible risk factors for recurrent vulvovaginal candidiasis in non-pregnant females within the reproductive age. METHODS The design of our study was of a case-control type. Case and control patients were selected from the gynecological patients at six primary care facilities in Serbia and in Montenegro. The data on the patients' health condition, concomitant therapy and diseases were taken from their records, and the data on habits were obtained by unstructured interview. For potential risk factors crude odds ratios were calculated, and then adjusted by logistic regression. RESULTS A total of fifty-one patients had four or more episodes of vulvovaginal candidiasis during the last year (cases), and 132 patients with one to three episodes of vulvovaginal candidiasis were sampled as controls, matched by age. The only two significant associations were found between recurrent vulvovaginal candidiasis and continual wearing of panty liners during the last year (Odds ratio - OR adjusted: 3.97; confidence interval--CI: 1.57-10.02;p = 0.004), and between recurrent vulvovaginal candidiasis and predominant use of vaginal tampons during menstruation in the last year (OR adjusted: 4.25; CI: 1.11-16.27;p = 0.035). The synergistic effect was observed for the concurrent continual wearing of panty liners during the last year and self-medication with antimycotics. CONCLUSIONS Local factors, like wearing of panty liners or use of tampons during menstruation, may promote recurrence of vulvovaginal candidiasis, especially in patients who practice self-medication with antimycotics.

The aim of our study was to find drug‐associated changes in serum levels of major electrolytes using clinical‐event monitoring method.

During the recent 4th European Summer School in Clinical Pharmacology and Therapeutics in Vrsac (2006, September 16–20), organized by the European Association of Clinical Pharmacology and Therapeutics (EACPT) and the Clinical Pharmacology Section (CPS) of the Serbian Pharmacological Society (SPS), as well as the International Federation of Associations of Pharmaceutical Physicians and the Serbian Association of Pharmaceutical Physicians it was obvious that the status of clinical pharmacology still varies widely from country to country in Europe 1, . Namely, in spite of many initiatives, its development in many countries is too slow. The aim of this review was to present the development and the state of the art of clinical pharmacology in Serbia.