Effects of intestinal flora on pharmacokinetics and pharmacodynamics of drugs.

Gut microbiota is known as unique collection of microorganisms (including bacteria, archaea, eukaryotes and viruses) that exist in a complex environment of the gut. Recently, this has become one of the most popular areas of research in medicine because this plays not only an important role in disease development, but gut microbiota also influences drug pharmacokinetics. These alterations in drug pharmacokinetic pathways and drug concentration in plasma and blood often lead to an increase in the incidence of toxicological events in patients. This review aims to present current knowledge of the most commonly used drugs in clinical practice and their dynamic interplay with the host's gut microbiota as well as the mechanisms underlying these metabolic processes and the consequent effect on their therapeutic efficacy and safety. These new findings set a foundation for the development of personalized treatments specific to each metabolism, maximizing drugs' therapeutic effects and minimizing the side effects because they are one of the major limiting factors in treating patients.

SCHOOL CHILDREN EXPOSURE TO LOW INDOOR AIR QUALITY IN CLASSROOMS DURING COVID-19 PANDEMIC: RESULTS OF A PILOT STUDY.

BACKGROUND: Indoor air quality (IAQ) in classrooms affects children's health and academic perfor-mance. The aim of this pilot study was to determine IAQ in elementary schools different in their inter-nal and external characteristics, in settings of COVID-19 epidemics. METHODS: IAQ parameters: fine particulate matter (PM2,5) mass concentration, CO2 concentration, tempera-ture and relative humidity were measured in parallel in four elementary schools/classrooms during October (non-heating season) and four months (including holiday in January) of heating season. IAQ parameters were measured in settings of anti-epidemic restrictions (≤13 students in classroom, frequent ventilation). RESULTS: During October, except in one school, PM2,5 concentrations were below the upper recommended value (25 µg/m³), but started rising in all schools in the heating season. The highest concentrations of PM2,5 were registered in two schools with closed or shortly opened windows. CO2 concentrations were mostly in the recommended range (up to 1000ppm) except in the school with constantly closed windows and in three schools in February when concentrations were higher. Except in one, the same school, and in January, both temperature and relative humidity were out of the recommended range (24,0-27,0°C in non-heating; 20,0-24,0°C in heating season; and 45-55%), with temperature mainly above and relative humidity mainly below it in three schools. The largest deviation in temperature and relative humidity were registered in urban schools. Registered differ-ences may be explained by different internal and external characteristics. CONCLUSION: Despite anti-epidemic restrictions, most of the measured IAQ parameters were out of the recom-mended values in heating season. In addition, further deterioration of IAQ could be expected if all students had been presented in the classroom. Finally, to assure a healthy school environment in heating season, further optimisation of both indoor and outdoor conditions is needed in both pandemic and non-pandemic settings.

Unveiling drug induced nephrotoxicity using novel biomarkers and cutting-edge preventive strategies.

Drug-induced nephrotoxicity is still a significant obstacle in pharmacotherapy of various diseases and it accounts for around 25 % of serious side-effects reported after drug administration. Furthermore, some groups of drugs such as nonsteroidal anti-inflammatory drugs, antibiotics, antiviral drugs, antifungal drugs, immunosuppressants, and chemotherapeutic drugs have the "preference" for damaging the kidney and are often referred to as the kidney's "silent killer". Clinically, the onset of acute kidney injury associated with drug administration is registered in approximately 20 % of patients and many of them develop chronic kidney disease vulnerability. However, current knowledge about the mechanisms underlying this dangerous phenomenon is still insufficient with many unknowns. Hence, the valuable use of these drugs in clinical practice is significantly limited. The main aim of this study is to draw attention to commonly prescribed nephrotoxic drugs by clinicians or drugs bought over the counter. In addition, the complex relationship between immunological, vascular and inflammatory events that promote kidney damage is discussed. The practical use of this knowledge could be implemented in the engineering of novel biomarkers for early detection of drug-associated kidney damage such as Kidney Injury Molecule (KIM-1), lipocalin associated with neutrophil gelatinase (NGAL) and various microRNAs. In addition, the utilization of artificial intelligence (AI) for the development of computer algorithms that could detect kidney damage at an early stage should be further explored. Therefore, this comprehensive review provides a new outlook on drug nephrotoxicity that opens the door for further clinical research of novel potential drugs or natural products for the prevention of drug-induced nephrotoxicity and accessible education.

Curcumin and its combination with a reduced dose of rosuvastatin: A promising therapy for chronic kidney disease and associated dyslipidemia in rat animal models.

The objective of this study was to confirm the effects of curcumin and to investigate the effects of its combination with a reduced dose of rosuvastatin in an adenine-induced model of chronic kidney disease (CKD) and associated dyslipidemia in rats. Renal function and morphology, as well as lipid status, were assessed using laboratory parameters and histopathological analysis. Male Wistar rats (n=36) randomly divided into six groups, were treated for 24 days: normal control (standard diet), CKD control (adenine diet, 0.75% w/w adenine-supplemented diet), curcumin (100 mg/kg/day + adenine diet), rosuvastatin minimal therapeutic dose (MTD) (5 mg/day + adenine diet), rosuvastatin reduced dose (RD, 25% of rosuvastatin MTD + adenine diet), and rosuvastatin RD + curcumin (25% of rosuvastatin MTD + curcumin 100 mg/kg/day + adenine diet) group. While rosuvastatin alone showed only antilipemic action, both curcumin alone and its combination with a reduced dose of rosuvastatin showed better renal protection with lower serum creatinine levels and milder renal morphological alterations, as well as better antilipemic action with lower levels of triglycerides, very low-density lipoprotein (VLDL), and low-density lipoprotein (LDL) cholesterols compared with the levels in CKD control rats. Treatment with curcumin alone also resulted in a significantly higher estimated glomerular filtration rate, lower uric acid levels, and higher high-density lipoprotein (HDL) cholesterol, while the combined therapy additionally resulted in higher serum albumin levels, lower total cholesterol, and both atherogenic and coronary risk indexes compared with CKD control rats. The results of this study confirmed the beneficial effects of curcumin alone and provided new evidence for the beneficial effects of its combination with a reduced dose of rosuvastatin in rats with CKD and associated dyslipidemia.

Are We Scared of Clinical Trials if Not Sufficiently Informed and Educated?

Purpose: Educational interventions have already been shown to positively affect awareness of clinical trials (CTs) among medical students. We aimed to explore basic knowledge and attitudes about CTs among medical students in terms of educational interventions that should be reflected in their further involvement in performing CTs and their role in raising awareness about CTs. Methods: This cross-sectional, self-report anonymous online survey involved undergraduate medical students of the Medical Faculty University of Sarajevo enrolled in classes held within the Department of Pharmacology and Toxicology in the academic year 2015-2016. To include all accessible subjects for better representation of the whole population, consecutive sampling was applied. Results: Among 142 students who completed questionnaire, 50% of them expressed partial or full agreement with the questionnaire statement that they were satisfied with the available information on CTs. Only 38% said they would participate in a CT, 21% would not, while 41% were not sure. Positive correlations were detected for composite subscale scores of agreement with questionnaire statements conveying the student's knowledge about ethical and legal aspects of CTs and their perception about reliability/integrity and impact of CTs on medical practice. Conclusion: Students have knowledge of the basic design and ethical aspects of CTs. Positive attitudes toward the impact of CTs on medical practice were shown in students of higher years of study, where educational intervention of additional knowledge of CTs was inserted and those students expressed better knowledge of CTs. However, no significant impact was detected between knowledge and willingness to participate in CTs, irrespective of years of study, reflecting the third of students that would participate in CTs. Changes in medical curricula led to the change in students' knowledge and attitudes regarding CTs as well as their involvement in CTs.

Effects of topically applied diclofenac and ketoprofen on prostaglandin E2 and Stat3 sera levels and body temperature in two different acute inflammation models in rats.

INTRODUCTION: Cytokines exert biological function through signal transducer and activator of transcription factors. Prostaglandins have function as promotors, where play a key role in generation of the inflammatory response and as ones that solve inflammatory process.Non-steroidal anti-inflammatory drugs, inhibit prostaglandin synthesis but the existence of additional mechanisms is present. Thus, we aimed to explore effects of topically applied NSAIDs on the levels of PGE2 and Stat3 in the setting of two in vivo induced acute inflammation models. METHODS: Male Wistar rats were randomized into five equal groups: 4 treated and a control group. Diclofenac or ketoprofen patches were applied in two different doses, i.e. equivalent to human therapeutic dose, and three times higher dose. Three hours later either model of inflammation (with 20% yeast, or with 1% carrageenan) was induced.Blood samples were taken 3 hours after and concentration levels of PGE 2 and Stat3 were determined using ELISA. Body temperature was measured at 0. 1st, 3rd and 5th hour after inflammation induction and presented in Celsius degrees. Shapiro-Wilk, Leven's, Welch's One-Way ANOVA, Kruskal-Wallis test and adjustment by Bonferroni correction were applied. RESULTS: In both inflammation models, no differences in the mean values of PGE 2 between control, low and high dose groups treated by either diclofenac or ketoprofen were found. In yeast inflammation, the mean value of Stat3 was significantly higher in both dose ketoprofen groups compared to control group. After ketoprofen application, no significant differences in body temperature between groups at hour 0 and 5 in either model of inflammation induced, while at 1st hour after carrageenan inflammation, significant differences were found with significantly higher values in low dose ketoprofen group compared to control group. In yeast application, significant differences in body temperature were found at hour 3 after inducing inflammation and post hoc pairwise comparison test revealed significant higher values in low dose ketoprofen group compared to control. CONCLUSION: Elevated Stat3 values post ketoprofen application in yeast model of induced inflammation were detected. Further investigation of cytokine microenvironment as well as the mechanisms of ketoprofen influence on inflammation are needed.

Outpatient management of oral anticoagulation therapy in patients with nonvalvular atrial fibrillation.

Due to heightened risk for thromboembolic complications, nonvalvular atrial fibrillation (NVAF) presents an absolute indication for long-term oral anticoagulation therapy. This was an observational, analytical, randomised, one-year clinical study, conducted in the Blood Transfusion Institute Sarajevo, Bosnia & Herzegovina. The aim of this study was to present the oral anticoagulation treatment in terms of International normalised ratio (INR) monitoring and warfarin/acenocoumarol dose titration in 117 patients with NVAF. INR values, the doses of warfarin and acenocoumarol, as well as the tendency and adequacy of their changes were monitored. Percentages of the therapeutic INR values were 51,77% and 53,62%, subtherapeutic 42,84% and 35,86%, and supratherapeutic 5,39% and 10,53% for the warfarin and acenocoumarol treatment, respectively. The average total weekly doses (TWD) which most frequently achieved the therapeutic INR values were 27,89+/-12,34 mg and 20,44+/-9,94 mg, for warfarin and acenocoumarol, respectively. The dose changes with the INR values 1,7 or lower/3,3 or higher were omitted in 13,46% and 15,63%, and with the INR values 1,8-3,2 were noted in 8,62% and 13,48% of all the check-up visits in the warfarin and acenocoumarol group, respectively. The annual dose changes were noted in 24,65% and 31,41%, and the daily dose changes in 74,43% and 73,36% of all the check-up visits of warfarin and acenocoumarol group, respectively. We can conclude that the management of the oral anticoagulation treatment in our country is in accordance with the relevant recommendations, but with the present tendency toward underdosing and unnecessary frequent dose changing.

Neuroenhancing Substances Use, Exam Anxiety and Academic Performance in Bosnian-Herzegovinian First-Year University Students.

OBJECTIVE: The aim of this study was to assess the relationship between the use of neuroenhancing substances, exam anxiety and academic performance among first-year Bosnian-Herzegovinian (BH) university students. METHODS: In a cross-sectional study, an ad hoc questionnaire was delivered to a sample of BH first-year university students. The following data were collected: socio-demographic features, consumption of neuroenchancing substances, the Westside Test Anxiety Scale (WTAS) and academic performance. RESULTS: A total of 214 students were included. Consumption of lifestyle substances, coffee, energy drinks, nicotine, alcohol, and marijuana, for the purpose of neuroenhancement increased during the week before the exams. OTC cognitive enhancer use was reported by 31.0%, and of benzodiazepines by 1.5% of students. No psycostimulants were used. A high to extremely high exam WTAS score was reported in 38.3% students. The exam WTAS score was positively correlated with consumption of coffee (rho=0.31; P<0.001), energy drinks (rho=0.18; P=0.009), and nicotine (rho=0.22; P=0.001), and negatively correlated with last exam grade (rho=-0.33; P<0.001). The exam WTAS score was a significant independent predictor (OR=0.55; 95% CI 0.31 to 0.97, P=0.039) for self-assessed academic performance. Self-assessed academic performance was positively correlated with last exam grade (rho=0.15; P=0.043). CONCLUSIONS: Although first-year BH university students do not seem to use either prescription or illicit psycostimulants, the consumption of nicotine, alcohol, and marijuana is worrying. However, the consumption of these neuroenhancing substances seems not to be related to better self-assessed academic performance. Finally, exam anxiety seems to be a significant problem among BH first-year university students.

Role of inhaled corticosteroids in the exacerbation rate of moderate chronic obstructive pulmonary disease.

Aim To analyse frequency of chronic obstructive pulmonary disease (COPD) exacerbation in patients on therapy with inhaled corticosteroids (ICS) and relevant factors that influence the rate of COPD exacerbations in a subgroup of moderate illness, like FEV1, comorbidities and other concomitant therapy. Methods The study included patients with moderate COPD with at least 10 pack-years history of smoking and accompanying cardiovascular comorbidity. Demographic data, frequency of exacerbations and information about proscribed treatments - ICS alone or in combination with long acting beta agonist (LABA), were collected from medical records for the previous 12 months from the index date. Results Data were collected for 210 patients (170 males) with the mean age 65.63±8.66 years, 72 of which were treated with a fixed combination of long acting beta blocker (LABA) and ICS. Significantly more frequent exacerbations were detected in patients using ICS p<0.0001) and having higher Modified British Medical Research Council (mMRC) score p=0.004). No statistically significant difference was registered related to ratio of FEV1 /FVC (p=0.121) or a number of cardiovascular comorbidities per patient (p=0.969). CONCLUSIONS: Our results present a small contribution to the current scientific discussion about the use of ICS in COPD treatment. Further prospective studies are needed to confirm the impact of ICS on the frequency of COPD exacerbations.

Metformin use associated with lower risk of cancer in patients with diabetes mellitus type 2.

Aim In order to increase the database related to the antineoplastic potential of metformin, association between the use of metformin and risk of cancer occurence in patients with diabetes mellitus type 2 (DM2) was investigated. Methods In this cross-sectional study, medical records of patients with DM2 were reviewed for cancer occurence. Data on age, body mass index (BMI), alcohol and nicotine consumption, glucose and HbA1c levels, duration of DM2, medication used in the treatment of DM2 and cancer occurence were collected and analyzed. Unpaired Student's t-test or Mann-Whitney U test were used for comparisons between treatment groups, and logistic regression to asses how well our set of predictor variables predicts occurence of carcinoma. P-value less than 0.05 was considered statistically significant. Results The mean age of 234 included patients was 66.8±11.5 years, and DM2 duration was 7± 6.49 years. Mean glucose value was 8.51±4.17mmol/L, and HbA1c 7.74±1.53. Metformin therapy was prescribed in 190 (81%) patients. Cancer was diagnosed in 16 (6.8%) patients: prostate cancer in eight (3.4%), breast cancer in four (1.7%), rectal cancer in two (0.9%) and cancer of the uterus and cervix in one patient. Age, duration of DM2 and BMI did not contribute significantly to the model, while metformin use was shown to be a significant independent predictor (OR=0.049; 95% CI=0.013-0.181; p=0.001). Conclusion Our findings support the hypothesis that the use of metformin compared to the use of other oral antidiabetic drugs is associated with a lower risk of cancer in patients with DM2.

Metformin use associated with protective effects for ocular complications in patients with type 2 diabetes - observational study.

OBJECTIVE: The aim was to study the association of the use of an oral antihyperglycemic agent metformin with the presence of ocular complications in patients with type 2 diabetes (T2D). METHODS: Medical records were reviewed for 234 patients with diagnosed T2D. 81.2% (n=190) patients were using metformin and 18.8% (n=44) using other oral antihyperglycemic agents. Plasma glucose concentration, glycated haemoglobin, and the presence of ocular complications in patients treated with metformin were compared to those in patients treated with other oral antihyperglycemic agents. RESULTS: Ocular complications occurred in 65 patients (27.8%). Patients treated with metformin had fewer ocular complications compared to patients treated with other oral antihyperglycemic agents (χ2=19.985; p<0.0001). After adjustment for gender, age, duration of T2D, serum concentration of cholesterol, smoking, body mass index and presence of other diseases, treatment with metformin decreased the odds of both glaucoma (OR=0.14, 95% CI: 0.03-0.57, p=0.006) and diabetic retinopathy (OR=0.33, 95% CI: 0.14-0.82, p=0.017) compared with other oral antihyperglycemic agents. CONCLUSION: Our results suggest that metformin may have a protective effect on ocular complications, especially glaucoma, in patients with T2D. The effects of metformin either regarding prevention of ocular complications or ocular complications already developed in patients with T2D, should be further investigated.

Topical treatment of standardised burns with herbal remedies in model rats.

Experimental studies of burns require the use of different animal models. The aim of this work was to establish experimental model of thermal injuries and to evaluate the effects of topical agents on healing of the burn wounds. Forty female Wistar rats were randomly classified in 4 groups and isolated for 2 weeks before the onset of experiment. Animals were primarily anaesthetized with pentobarbital-sodium and then shaved (skin area of their back with diameters 5 cm x 5 cm). A round metal stamp with contact area of 5 cm2 and total weight of 100 g was heated up to 80 degrees C and then applied without additional pressure on the depilated skin of the back for 14 seconds. This procedure produced a standardized burn wound. Induced burn wounds were immediately drowned in the 4 degrees C- water for 3 s in order to maintain microcirculation. After the inducement of thermal injures, all rats were treated with 1% silver sulfadiazine cream, herbal topical preparations or were not treated at all. Burn wounds were treated twice a day until the healing completion. The result of treatment application was a significant reduction of burn wound diameters. Herbal topical preparations expressed positive therapeutic effects on the parameters of burn wounds. The efficiency of silver sulfadiazine cream in burn wound healing was significantly more expressed in comparison to healing process in control group of animals (p < or = 0,001). We conclude that herbal topical preparations efficiently caused the completion of burn wound healing process without scar formation.

Models of treatment with antipsychotics of the schizophrenic patients.

The aim of this study were to determine which antipsychotic are currently in use, to establish which doses are administrated to patients, to find out is there a practice of proscribing simultaneously more then one antipsychotic drug, to determine whether antipsychotic are proscribed in divided doses, to establish whether there is, besides antipsychotics, treatment with other medicaments (co-administration), especially with antiparkinsonics. The research (study) is epidemiological-clinical prospective, descriptive and analytical and it was conducted at University hospitals in Sarajevo, Tuzla and Mostar. Criteria for inclusion, non-inclusion and exclusion from the study were precisely defined as a mean for formation of sample. Based on this hypothesis were established, zero and alterative. According to zero hypothesis in the treatment of schizophrenia at University hospitals in FBiH new antipsychotic drugs are in use, small doses are proscribed (up to 20 mg), not more then one antipsychotic drug is used simultaneously, antipsychotics are administrated once a day and alongside with antipsychotics other medicaments are not co-administrated, especially antiparkinsons. The results of our study are showing that majority of patients are treated with classical antipsychotics. Minority of patients is treated with atypical neuroleptics like olanzapine, which is proscribed only in Sarajevo. Use of risperidone and ziprasidone is registered also only in Sarajevo, but only small number of patients is treated with these drugs. Most frequent antipsychotics were promazine and haloperidol. The range between minimal and maximal daily dose of promazine was from 50 to 450 mg/daily, and for haloperidol from 1 to 75 mg/daily. Above-mentioned drugs were administrated in an average from two to three times a day. Alongside with antipsychotics, other drugs were used. Most frequent was the use of biperidine in oral and parenteral formulation, as well as nitrazepam and diazepam. The importance of this study is following: data are useful for the current mental health care reform in FBiH, results will point out place and position of FBiH in contemporary world trends in the treatment of schizophrenia, they will contribute to rational use of antipsychotic therapy, they will point out possible ways in reduction of side effects, often dangerous adverse effects of antipsychotics, and they will give contribution to faster rehabilitation of schizophrenics with the reduction of financial means for the treatment of patients with schizophrenia.

In vitro Antiproliferative activity of Melissa officinalis L. (Lamiaceae) leaves essential oil / Actividad antiproliferativa in vitro de aceite esencial de hojas de Melissa officinalis L (Lamiaceae)

In the present study, we investigated the antiproliferative activity of essential oil from leaves of Melissa officinalis L. grown in Southern Bosnia and Herzegovina. In vitro evaluation of antiproliferative activity of the M. officinalis essential oil was carried out on three human tumor cell lines: MCF-7, NCI-H460 and MOLT-4 by MTT assay. M. officinalis essential oil was characterized by high percentage of monoterpenes (77,5%), followed by the sesquiterpene fraction (14,5%) and aliphatic compounds (2,2%). The main constituents of the essential oil of M. officinalis are citral (47,2%), caryophyllene oxide (10,2%), citronellal (5,4%), geraniol (6,6%), geranyl acetate (4,1%) and ß- caryophyllene (3,8%). The essential oil showed significant antiproliferative activity against three cancer cell lines, MOLT-4, MCF-7, and NCI-H460 cells, with GI50 values of <5, 6±2 and 31±17 µg/mL, respectively. The results revealed that M. officinalis L. essential oil has a potential as anticancer therapeutic agent.

En el presente estudio, investigamos la actividad antiproliferativa del aceite esencial de las hojas de Melissa officinalis L. cultivadas en el sur de Bosnia y Herzegovina. La evaluación in vitro de la actividad antiproliferativa del aceite esencial de M. officinalis se llevó a cabo en tres líneas celulares de tumores humanos: MCF-7, NCI-H460 y MOLT-4 utilizando el ensayo de MTT. El aceite esencial de M. officinalis se caracterizó por un alto porcentaje de monoterpenos (77,5%), seguido de la fracción sesquiterpénica (14,5%) y compuestos alifáticos (2,2%). Los principales constituyentes del aceite esencial de M. officinalis fueron citral (47,2%), óxido de cariofileno (10,2%), citronelal (5,4%), geraniol (6,6%), acetato de geranilo (4, 1%), y ß-cariofileno (3,8%). El aceite esencial mostró una actividad antiproliferativa significativa contra las líneas celulares de cáncer MOLT-4, MCF-7 y NCI-H460, con valores GI50 de <5, 6±2 y 31±17 µg/mL, respectivamente. Los resultados revelaron que el aceite esencial de M. officinalis L. tiene potencial como agente terapéutico contra el cáncer.

Better stability of acenocoumarol compared to warfarin treatment in one-year observational, clinical study in patients with nonvalvular atrial fibrillation.

AIM: To evaluate differences in the treatment quality between often used oral anticoagulants, warfarin and acenocoumarol in patients with nonvalvular atrial fibrillation (NVAF). METHODS: This was an observational, comparative, one-year clinical study, conducted in the Blood Transfusion Institute of Sarajevo, Bosnia & Herzegovina. All patients who were using warfarin/ acenocoumarol and monitored were eligible. Patients who met inclusion criteria (the age of 40-80, diagnosed NVAF, CHADS index score > or = 2, the planned long-term treatment) were includes in two parallel groups of 60 patients, composed according to the warfarin/acenocoumarol treatment as well as the gender and age. Routinely measured International normalised ratio (INR) values were the basic parameter for individual quality and stability assessment. RESULTS: All average, monthly INR values were in therapeutic range (2.0-3.0) in both therapeutic groups. There were no significant differences either in the number of therapeutic INR values per patient (50.53 +/- 23.72% vs. 51.74 +/- 26.68%, P = 0.795) or in individual quality of treatment: > 50% therapeutic INR values (60.0% vs. 64.9%, P = 0.721) and > 75% therapeutic INR values (18.3% vs. 22.8%, P = 0.714) in the warfarin and acenocoumarol group, respectively. Significantly better stability was determined for acenocoumarol as compared with warfarin treatment in terms of a longer period of the total observed time during which therapeutic INR values were stable (37.6% vs. 35.7%, P = 0.0002). CONCLUSION: Both drugs have shown similar quality of individual anticoagulation control, but acenocoumarol have shown significantly better anticoagulation stability with therapeutic INR values covering significantly longer time of treatment.

Occupational exposure of workers at gas station to inorganic lead.

Exposure to the lead is public health problem and threat to environment with proven harmful impact on human, including industrial workers and general population. Harmful impacts of exposition to nervous, endocrine, hematological, cardiovascular, immune and reproductive system to the lead are well known. This article addresses the results of retrospective research carried out with attendants at gas station and those who are professionally exposed to inorganic lead (n=73; n=81), during the course of two periodic reviews performed in 2003 and 2008. All subjects underwent physical examination, ECG, were measured blood pressure and laboratory tests encompassing basic hematological parameters, including measuring of blood lead level (BLL), as bioindicators of exposure and biomarkers of toxic impact of the lead, by the means of determining concentration of 6-aminolevulinic acid in urine (ALA).Valued obtained included (arithmetic mean +/- standard deviation): for BLL 42.5 +/- 26.2 microg/L(-1), for ALA 35.2 +/- 10.6 micromol/L(-1). Quoted values are within normal values for general population. Correlation test established positive correlation between BLL and hematological parameters, number of erythrocytes, concentration of hemoglobin and MCV, and the same correlation ratio was established between BLL and years of age, years of service and exposition years of service as well as BLL and GGT. There was not established correlation between ALA and observed hematological parameters, BLL and systole pressure. Data from our research indicate unification between professional exposure to lead and duration of exposure and increase of concentration of BLL, which are far bellow marginalvalue, but do exceed average values of BLL for people of industrial countries with possible generation of harmful impact of lead. Likewise, the results suggest the increase of overall lead load in the body does not have to be necessarily only the result of professional exposure, but of the intake through other channels as well.

[Subacute toxicity study of combination of adrenocorticotropine 1-13 and met-enkephalin]. / Studija subakutne toksicnosti kombinacije adrenokortikotropnog hormona 1-13 i metenkefalina.

PURPOSE: Combination FAR4 consists from two peptide components: met-enkephalin and alpha adrenocorticotropine 1-13 (ACTH 1-13) named before as alpha-melanocyte-stimulating hormone-like (alpha-MSH-like). Met-enkephalin and alpha-MSH exhibited cytoprotective effects individually and statistically significant additive effect was registered when both peptides were applied in combination on the model of ethanol induced gastric lesions in rats. We performed subacute toxicity study with subcutaneous application. WORK METHOD: Wistar rats were randomized in 3 test groups (treatments) consisted of 10 male and to female rats and one control group consisted of 20 male and 20 female rats. One daily dose was applied 3 days a week. Three dose ranges as multiplication of expected maximal human therapeutic dose (10 mg of met-enkephalin and 2 mg of alpha-ACTH 1-13) were estimated: equivalent dose, dose that was 5 times higher and 10 times higher dose. Animals were treated during 4 weeks with 10-days long observation period without the treatment after. After the planned scarification at the end of study, necropsy with histopathology examination was performed. RESULTS: No lethality, toxic signs or histopathological changes were observed during the subacute toxicity testing. Variation of laboratory animals body mass was observed through six terms of body mass deternimation. Increase in body mass was noted in all test and control groups. Statistical analysis with Kruskal Wallis single variance test showed statisticaly significant difference in the number of respirations between the groups of ma-. les for the first measurement (p = 0.040332) and second measurement (p = 0.016852), but multiple comparation with control group showed statisticaly significant difference. Afterthe planned scarification at the end of the study, necropsy did not reveal changes in macroscopic structure of organs and tissues. Histopathology examination was performed on the samples of liver, kidneys, lungs, heart, brain, spleen and thymus and no pathological changes were noted, while microscopic structure of tissues was perserved. The changes regarding postmortem organ mass as percentual ratio towards total group mass were not noted nor for males, nor for females. DISCUSSION: Study was conducted following the rules of the Guide for the Care and Use of Laboratory Animals made by the U.S. National Institutes of Health. Methodologicaly our study complys with rutine design of thistipe of studies. Subacute toxicity studies usually last for fourweeks and the way of test substance application to laboratory animals should comply to future way of application in human use. In our study no lethality was registered and low toxicity

Basiliximab, mechanism of action and pharmacological properties.

Basiliximab is a chimeric anti-intcrleukin-2 receptor monoclonal antibody. Basiliximab is a glycoprotein produced by recombinant technology. It is used to prevent white blood cells from acute renal transplantation rejection. It specifically binds to and blocks the alpha chain of interleukin-2 receptors (IL-2R alpha), also known as CD25 antigen, on the surface of activated T-lymphocytes. Due to its monoclonal nature it provides safer and more predictable therapeutic, that is, immunosuppressive response of the polyclonal antibodies. The most common adverse effects in adult patients are constipation, infections, pain, nausea, peripheral oedema, hypertension, anaemia, headache, hyperkalacmia, hypercholesterolemia, increase in serum creatinine, and hypophosphataemia.

[Genotoxicity evaluation of paracetamol applying Allium test]. / Ispitivanje genotoksicnosti paracetamola primjenom Allium testa.

Paracetamol genotoxic potential was evaluated among different concentrations, applying Allium test on Allium cepa. Total number of roots, number of dark roots, the length of the longest root, the average root, and the shortest root were determined. Statistically significant differences among total number of roots (p > 0.05) was observed at concentrations of 50 microg/ml and 100 microg/ml, and highly statistically significant differences at concentrations of 5 microg/ml and 25 microg/ml, while at the highest concentration (400 microg/ml) was observed statistically significant higher number of roots in comparation to all other concentrations of paracetamol and control group. The results of research suggest the concentrations of 5 microg/ml, 25 microg/ml and 400 microg/ml for further evaluation of paracetamol mutagenic potential.

Frequency and characteristics of side effects associated with antidepressant drugs.

Depression is among the most common of chronic health problems. WHO report predicts that depression will be the leading cause of disability in the industrial world by the year 2020. To be successful, treatment for the patients suffering from depression must be continued until complete recovery, but most patients do not stay on their antidepressant medication long enough. One of the most frequent reasons for break down is appearance of unpleasant side effects. In this study we followed up dynamics of the characteristic side effects of antidepressant therapy, with the major goal to assess their frequency and characteristics. The sample was all female patients taking antidepressant drugs in the Department of Psychiatry of Clinical Centre of University in Sarajevo. The treatment with antidepressants was efficient in most of the patients. A major advantage of SSRI over TCA was less pronounced side effects. The most intensive side effects of TCA (amitriptyline) were dry mouth, tremor and tachycardia while the most frequent side effects included blurred vision, tachycardia, dry mouth, tremor and sedation. Side effects of SSRI (fluoxetine/fluvoxamine) were mild, and the most frequent were nausea, tachycardia, swelling, dry mouth.