The aim of our study was to estimate clearance of bisoprolol and reveal the factors that could influence its pharmacokinetic (PK) variability in hypertensive patients on hemodialysis, using the population PK analysis. Parameters associated with plasma concentration of bisoprolol at steady state were analyzed in 63 patients (mean age 62.12 years, mean total weight 69.63 kg) who were hypertensive and on hemodialysis due to severe renal failure using non-linear mixed-effect modeling with ADVAN1 subroutine. The final regression model for the clearance of the drug included only creatinine clearance (CLcr) out of 12 tested covariates. The equation that describes CL of bisoprolol is the following: CL (l/h) = 0.12 + 6.33 * CLcr. These findings suggest that the routine measuring of serum creatinine level may be used to facilitate administration of bisoprolol in patients on hemodialysis.

BACKGROUND Knowledge about adverse effects of medications is an important part of proper medication use and prerequisite for good treatment adherence. OBJECTIVE The aim of our study was to construct, develop, and test a new questionnaire for the measurement of patients' knowledge about adverse drug reactions of angiotensin-converting enzyme (ACE) inhibitors. METHODS The 8-item questionnaire was constructed to measure adverse reactions to ACE inhibitors. The questions were closed, with 7 offered answers, in the form of a Likert scale. It was tested for psychometric properties on patients who visited their general practitioners at state-owned health facilities in 5 Serbian cities: Belgrade, Kragujevac, Banja Luka, Gracanica, and Despotovac. RESULTS The questionnaire was tested on 259 patients from general practice, taking an ACE inhibitor for more than 3 months. Experience with at least 1 adverse effect of ACE inhibitor was reported in 64 patients (24.7%), only 94 patients (36.3%) previously received any form of information about at least 1 adverse effect of ACE inhibitors from health workers, and only 42% expressed knowledge of any adverse events. The patients who were informed knew about the following adverse events as phrased in the official patient information leaflets: severe dizziness or light-headedness (44%); cough (37%); swelling of the hands, face, lips, or tongue (32%); indigestion (22%); headache (51%); and difficulty in breathing (15%). The questionnaire showed satisfactory internal consistency, with Cronbach α of 0.767, and individual scores correlated with general education of the patients. Factorial analysis revealed 2 domains (subscales): the first one with 5 questions is directed to adverse effects the patients may physically experience directly, whereas the second with 3 questions measures knowledge about adverse effects that could be experienced only indirectly, through conditions caused by the adverse effects. CONCLUSIONS The questionnaire about knowledge of ACE inhibitors' adverse effects is a reliable and probably valid instrument for measuring patients' knowledge about adverse effects of ACE inhibitors.

CORRESPONDENT IVANA STAŠEVIĆ KARLIČIĆ Clinic for psychiatric disorders “Dr Laza Lazarević”, Belgrade, Serbia ivanastasevic73@gmail.com doi:10.5937/pramed1604101S

Neuroleptic malignant syndrome (NMS) is a life-threatening, often fatal idiosyncratic reaction to neuroleptic or other drug therapies that antagonise the central dopaminergic neurotransmission. The clinical presentation of NMS is very heterogeneous. The lack of specific levels of symptom severity in currently used diagnostic criteria dims the diagnosis of NMS. Therefore differential diagnosis is of priority, because NMS is a diagnosis of exclusion. The aim of this paper is to present a complex clinical picture in a patient that after a differential diagnostic exclusion of other medical conditions and intoxications is diagnosed as NMS. Case reports such as these help raise awareness of this clinical issue.

BACKGROUND Targeted light sedation is recommended because it shortens the time of mechanical ventilation and the length of stay in an intensive care unit (ICU). However, there is no validated scale for sedation and agitation in ICU in the Serbian speaking area. The aim of the current study was to validate, verify the reliability and enable the application of the Richmond Agitation and Sedation Scale (RASS) in the Serbian speaking area. METHODS In this prospective cohort study, RASS was applied to 301 adult patients hospitalized in surgical ICUs by two different research team members. We tested RASS for inter-rater reliability by the correlation between them. The scale was validated by comparison to Glasgow Coma Scale (GCS) scores which was applied by the third investigator. Interrater agreement was measured using weighted kappa (k) and for correlation Spearman's test was used. RESULTS The inter-rater reliability of the scale was high (k ˃0.7). The degree of correlation between the RASS and the GCS during all five days of observation was high (˃0.7 for both investigators, the fifth day). In all the cases, Spearman's correlation coefficient was highly significant (p ˂0.01). CONCLUSIONS The Serbian translation of the RASS is a reliable and valid instrument for the assessment of the levels of sedation and agitation with patients in ICU. Hippokratia 2016, 20(1): 50-54.

BACKGROUND/AIM Benign prostatic hyperplasia (BPH) is one of the most common disease among males aging 50 years and more. The rise of the prevalence of BPH is related to aging, and since duration of life time period has the tendency of rising the prevalence of BPH will rise as costs of BPH treatment will and its influence on health economic budget. Dutasteride is a new drug similar to finasteride, inhibits enzyme testosterone 5-alpha reductase, diminish symptoms of BPH, reduce risk of the complications and increases quality of life in patients with BPH. But, the use of dutasteride is limited by its high costs. The aim of this study was to compare cost effectiveness of dutasteride and finasteride from the perspective of a purchaser of health care service (Republic Institute for Health Insuranse, Montenegro). METHODS We constructed a Markov model to compare cost effectivenss of dutasteride and finasteride using data from the available pharmacoeconomic literature and data about socioeconomic sphere actual in Montenegro. A time horizon was estimated to be 20 years, with the duration of 1 year per one cycle. The discount rate was 3%. We performed Monte Carlo simulation for virtual cohort of 1,000 patients with BPH. RESULTS The total costs for one year treatment of BPH with dutasteride were estimated to be 6,458.00 € which was higher comparing with finasteride which were 6,088.56 €. The gain in quality adjusted life years (QALY) were higher with dutasteride (11.97 QALY) than with finasteride (11.19 QALY). The results of our study indicate that treating BPH with dutasteride comparing to finasteride is a cost effective option since the value of incremental cost-effectiveness ratio (ICER) is 1,245.68 €/QALY which is below estimated threshold (1,350.00 € per one gained year of life). CONCLUSION Dutasteride is a cost effective option for treating BPH comparing to finasteride. The results of this study provide new information for health care decision makers about treatment of BPH in socioeconomic environment which is actual both in Montenegro and other countries with a recent history of socioeconomic transition.

Objective. Postoperative headache can be one of the complications that occur after waking the patient from general anesthesia. The aim of this study was to evaluate the prevalence of postoperative headaches after general anesthesia, in our conditions. Methods. Our study was designed as a comparative, open, non-randomized clinical study, carried out in a routine clinical practice. It was conducted at the departments of thoracic, abdominal, vascular, orthopedic surgery and gynecology, in the Clinical Center in Kragujevac. The study involved patients who signed the informed consent before the study and who were operated at these departments and underwent general anesthesia during the time frame from 01/03/2016 to 01/04/2016. Results. The results of this study showed that the frequency of postoperative headache after general anesthesia was 9%. Patients rated intensity of these headaches on a visual analogue scale. The mean value of this scale of the study participants was 0.33±1.3. It was found that alcohol consumption is an important factor associated with the development of postoperative headache after general anesthesia (p=0.035). Conclusion. Assessing frequency of postoperative headache after general anesthesia is significant both for patients and for doctors, because it puts the emphasis on the headache as a postoperative complication. Therefore, it is necessary to pay attention at this type of headache and affect the reduction of its frequency and improve the quality of life of patients after waking up from general anesthesia.

Introduction Healthcare-acquired urinary tract infections (HAUTI) make up to 40% of all healthcareacquired infections and contribute significantly to hospital morbidity, mortality, and overall cost of treatment. Objective The aim of our study was to investigate possible risk factors for development of HAUTI caused by multi-drug resistant pathogens. Methods The prospective case-control study in a large tertiary-care hospital was conducted during a five-year period. The cases were patients with HAUTI caused by multi-drug resistant (MDR) pathogens, and the controls were patients with HAUTI caused by non-MDR pathogens. Results There were 562 (62.6%) patients with MDR isolates and 336 (37.4%) patients with non-MDR isolates in the study. There were four significant predictors of HAUTI caused by MDR pathogens: hospitalization before insertion of urinary catheter for more than eight days (ORadjusted = 2.763; 95% CI = 1.352–5.647; p = 0.005), hospitalization for more than 15 days (ORadjusted = 2.144; 95% CI = 1.547–2.970; p < 0.001), previous stay in another department (intensive care units, other wards or hospitals) (ORadjusted = 2.147; 95% CI = 1.585–2.908; p < 0.001), and cancer of various localizations (ORadjusted = 2.313; 95% CI = 1.255–4.262; p = 0.007). Conclusion Early removal of urinary catheter and reduction of time spent in a hospital or in an ICU could contribute to a decrease in the rate of HAUTI caused by MDR pathogens.

Polymorphonuclear neutrophils make about 60-70% of all leucocytes in adults. Neutropenia is defined by neutrophil count below 1.5 h 109/l. It could be classified as mild, moderate and severe, based on the following absolute neutrophil count: 1-1.5 h 109/l, 0.5-1 h 109/l, and < 0.5 h 109/l. Incidence of drug-induced neutropenia is 3-10 cases per million. Drug-induced neutropenia emerges suddenly, and develops a few hours to 1-2 days after administration of the offending drug. There are several mechanisms of neutropenia induced by non-cytotoxic drugs: (1) drug binding to neutrophil membrane, formation of hapten and induction of immune response which destroys neutrophil; (2) induction of neutrophil apoptosis; (3) formation of immune complexes; (4) induction of autoantibodies and complement activation with destruction of neutrophils; (5) dose-dependent inhibition of granulopoesis; and (6) direct toxic effect on myeloid precursors. Treatment of patients with drug-induced neutropenia consists of the offending drug discontinuation, maintenance of strict hygiene and administration of granulocyte-colony stimulating factors in the case of severe neutropenia.

Background/Aims: One of the most common polymorphisms of ABCB1 gene, a synonymous mutation C3435T (rs1045642), is associated with increased in vivo activity. The main goal of this study was to determine the association of C3435T polymorphism with clopidogrel and 2-oxo-clopidogrel concentrations in plasma. Methods: The patients were recruited upon acute myocardial infarction diagnosis. They were all tested for ABCB1 C3435T polymorphism. In plasma, drawn 1 h after the drug administration, concentrations of clopidogrel and 2-oxo-clopidogrel were measured using UHPLC-DAD-MS analysis. Results: Due to differences in the maintenance doses, we have calculated the dose-adjusted concentrations of clopidogrel (0.2 ng/ml/mg (0.1-0.4)) and 2-oxo-clopidogrel (2.1 ng/ml/mg (0.5-4.6)). Patients carrying at least one C allele achieved significantly higher serum concentration of clopidogrel (p < 0.001), as well as dose-adjusted clopidogrel (p < 0.001) and 2-oxo-clopidogrel concentrations (p < 0.05). Conclusion: The ABCB1 3435CC genotype is associated with increased clopidogrel and 2-oxo-clopidogrel dose-adjusted concentrations. Therefore, the ABCB1 C3435T genotyping should be one of the parameters taken into account when deciding about the dosing regimen of clopidogrel.

The group A streptococcus (GAS) tonsillopharyngitis is a very common disease in children’s age. Inappropriate use of antibiotics is frequently encountered, both for treatment purposes and for eradication of the causative agents. The aim of our study was to discover reasons and causes for inappropriate use of antibiotics in children. We have used the triangulation approach to the problem which was studied by the analysis of interviews, observation of patient-cases and by the review of medical records. We discovered that prescribers had very different attitudes towards curing GAS tonsillopharyngitis as well as towards curing GAS carriage. The physicians were under the pressure to prescribe antibiotics and the parents were prone to administer antibiotics to children by themselves. Such behavior could be partially explained by the lack of funds for laboratory analyses. Moreover, the patients were still allowed to buy antibiotics without prescriptions. General culture of using antibiotics should be increased to a higher level among both health workers and parents in order to change some irrational behavior when managing patients who have been cured from streptococcal tonsillopharyngitis. Acta Medica Medianae 2015;54(4):46-51.

Summary The aim of this study was to analyze the reasons why the guidelines for post-splenectomy vaccination are not being followed. Considering that vaccination reduces the risk of overwhelming post-splenectomy infection, it is important to determine the reasons for inadequate vaccination after splenectomy. Our research was a qualitative study based on interviews with six surgeons, one general practitioner and three patients who underwent splenectomy, and on the review of patient’s medical charts and discharge summaries. This study has shown that health care team and patients lack sufficient knowledge about postsplenectomy vaccination. In addition, the study has shown that splenectomy registers, medical bracelets and up-to-date vaccination cards still have not become part of our current practice. Our study has shown that patient education and health care team education is crucial to follow the guidelines for post-splenectomy vaccination, which is similar to most other reports. In order to increase the level of post-splenectomy vaccination, we need to upgrade the education of health care teams and patients. Moreover, we need to start using splenectomy registers, medical bracelets and up-to-date vaccination cards. Sažetak Cilj ove studije bio je da se analiziraju razlozi zbog kojih se ne prate vodiči za postsplenektomijsku vakcinaciju. Imajuću u vidu da vakcinacija smanjuje rizik od ozbiljnih postsplenektomijskih sepsi, važno je da se odrede razlozi za neadekvatne vakcinacije nakon splenektomije. Naša studija je kvalitativna, bazirana na intervjuima sa šestoro hirurga, jednim lekarom opšte prakse i tri pacijenta koji su bili podvrgnuti splenektomiji, kao i na uvidima u kartone i otpusne liste bolesnika. Ustanovljeno je da zdravstveni tim i bolesnici imaju nedovoljno znanja o postsplenektomijskoj vakcinaciji. Takođe, ustanovljeno je da splenektomijski registri, medicinske narukvice, kao i karton vakcinacije i dalje nisu deo naše prakse. Naša studija je pokazala da je obrazovanje bolesnika, kao i medicinskog tima, krucijalno da bi se pratili vodiči za postsplenektomijsku vakcinaciju, što je u skladu sa rezultatima drugih studija. Kako bi se povećao stepen primene postsplenektomijske vakcinacije, neophodno je poboljšati edukaciju medicinskog tima i bolesnika, kao što je neophodno početi sa korišćenjem splenektomijskih registara, medicinskih narukvica i kartona vakcinacije.