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AbstractAcute, subacute and chronic neurotoxicity have been observed after the administration of high-dose and/or intrathecal methotrexate (MTX). Acute toxicity is usually transient without permanent damage. Subacute and chronic toxicity are associated with changes in the brain and/or the spinal cord which may be progressive and even lead to coma and death in severe cases. It is believed that MTX can induce direct toxic effects to the CNS by damaging the neuronal tissue. Moreover, MTX interferes with the metabolic pathways of folates, excitatory amino acids, homocysteine, S-adenosylmethionine/S-adenosylhomocysteine, adenosine and biopterins, inducing biochemical alterations which have been associated with neurotoxic symptoms. It has been suggested that acute toxicity is partly mediated by adenosine, whereas homocysteine, S-adenosylmethionine/S-adenosylhomocysteine, excitatory amino acids and biopterins may play an important role in the development of subacute and chronic toxicity. A better understanding of the pathogenesis of MTX neurotoxicity would offer the possibility of developing new therapeutic strategies for its treatment or prevention.Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The study aimed to estimate lidocaine (LID) pharmacokinetic parameter values in patients with impaired liver function, level of correlation between the pharmacokinetic parameters and Child-Pugh class and change in pharmacokinetic parameters after liver tumor resection compared to the preoperative value., Methods: Patients with impaired liver function were subject to the LID test 1 day prior to, 3 and 7 days after the intervention. LID was administered in single i.v. dose of 1 mg/kg. Blood samples were collected at 15, 30 and 90 minutes after drug administration. Non-compartmental analysis was applied for calculating the pharmacokinetic parameters., Results: The study included 17 patients with the diagnosis of cirrhosis and 41 patients with liver tumor. In both groups of patients, the values of the coefficients of correlation show the best correlation between clearance (CL) and Child-Pugh score (-0.693, p<0.005) over other pharmacokinetic parameters. The results indicate worsening hepatic function on 3rd day after operation in comparison to the values of LID CL prior to operation (mean LID CL for patients with Child-Pugh class A are 25.91 L/h, 41.59 L/h, respectively; while for B class are 16.89 L/h, 22.65 L/h, respectively). On day 7th, the values of LID CL (mean value for patients with Child-Pugh class A and B are 40.98 L/h and 21.46 L/h, respectively) are increased in comparison to 3rd day after., Conclusions: LID pharmacokinetic parameters consequently changed according to the severity of liver impairment, assessed by Child-Pugh score. Values of LID CL and volume of distribution (Vd) coupled with standard biochemical parameters may be used for preoperative assessment of liver function and monitoring of its postoperative recovery., Competing Interests: All the authors declare that they have no conflict of interest in this work.Conflict of Interest: The authors stated that they have no conflicts of interest regarding the publication of this article., (2023 Marija Jovanović, Milena Kovačević, Sandra Vezmar-Kovačević, Ivan Palibrk, Jasna Bjelanović, Branislava Miljković, Katarina Vučićević, published by CEON/CEES.)

Background: Data on drug-induced liver injury (DILI) caused by newer antiseizure medications (ASMs) in the elderly are scarce and mainly come from literature case reports. We analyzed Individual Case Safety Reports (ICSRs) of DILI in elderly patients treated with newer ASMs reported to VigiBase., Research Design and Methods: Empirica™ Signal software was used to retrieve ICSRs reported to VigiBase up to 31 December 2021 and to calculate Empirical Bayesian Geometric Mean and corresponding 90% confidence intervals (EB05, EB95) for each drug-event pair. EB05 > 2, N  > 0 was considered a signal. Analysis by age subgroups and gender was performed to assess the influence of these factors on ICSR characteristics and identified signals., Results: There were 1399 ICSRs reporting 1947 events of hepatotoxicity. 56.97% of the reports were reported in females, 67.05% were serious, and 3.36% resulted in death. For one or more events of hepatotoxicity, signals were detected for lamotrigine, levetiracetam, oxcarbazepine, topiramate, and zonisamide. Age- and gender-biased reporting frequency was identified for topiramate-induced hyperammonemia, with disproportionally higher reporting frequency in ≥75-year-old male patients., Conclusions: The results of our study indicate differences among newer ASMs in their potential to cause DILI in the elderly. Further studies are needed to confirm the associations identified in this study.

The COVID-19 pandemic exerted a profound impact on health systems worldwide. Moreover, significant concerns were raised in terms of middle- and long-term consequences of postponing care in non-COVID patients. The primary aim of the study was to describe the remote pharmaceutical care service (telepharmacy) during the COVID-19 pandemic in the Republic of Srpska (RS), Bosnia and Herzegovina. The secondary aim was to identify service users' needs and concerns and to describe community pharmacists' interventions. Ten community pharmacists were appointed by the Pharmaceutical Society of the RS to deliver telepharmacy services. After obtaining users' verbal permission, pharmacists documented issues discussed with them. The prospective data collection included the period from April 13 to May 21, 2020. Descriptive and statistical analysis was performed using IBM SPSS Statistics software (ver. 22). A total of 71 service users' charts were analyzed. Telepharmacy users were on average 61.31 ± 13.27 years of age, with almost equal gender distribution. Patients with chronic or acute/subacute conditions were predominant with a share of 84.5%. Chronic diseases were the main reason for searching pharmacists' consultation (74.6%), 7% had a complaint about worsening of a chronic condition, 9.9% reported only acute/subacute conditions as ambulatory conditions, whereas 15.5% asked information about coronavirus or COVID-19. The vast majority of patients' and users' needs were addressed by a pharmacist during counseling and only 15.5% of the patients required immediate referral to a doctor for refill/prescribing purposes. Remote pharmaceutical care service (telepharmacy) is deemed a convenient model in the RS during the COVID-19 pandemic. Patients and users presented with explicit and specific needs and concerns, both COVID- and non-COVID-related, which should not be neglected. Community pharmacists showed a high level of resilience and ability in addressing patients' needs., (© 2021 John Wiley & Sons Ltd.)

Aims: The aim of this study was to analyse potential drug-drug interactions (pDDIs) and their potential adverse drug reactions (ADRs) among hypertensive patients. Moreover, we investigated the possibility of reducing pDDIs with different treatment choices., Methods: This was a cross-sectional study including all outpatients with hypertension and two or more medications, treated in a university hospital in Serbia. Lexicomp Interact (Lexi-Comp, Inc., Hudson, OH) was used for identification of pDDIs and potential ADRs. Treatment choices were explored according to patient characteristics, treatment guidelines and the interacting potential of drugs. Data were analysed using descriptive analysis and multiple logistic regression., Results: A total of 350 patients were included in this study, with average age (77 [36-98] years and 6.1 [2.5]) medications. The majority of patients (86.0%) had at least one clinically significant pDDI, and the average was 3.78 (3.90) (range 1-25). Suggestions for treatment change aimed mainly at eliminating drug duplications, reducing the use of thiazide diuretics, sulfonylureas, alpha-lipoic acid and pentoxifylline and increasing the use of calcium-channel blockers, when appropriate. pDDIs would have decreased to 2.10 (2.52), P <.001, yet male gender, ≥6 medications, cardiovascular diseases, diabetes, benign prostatic hyperplasia, would be predictive of two or more pDDIs. The main potential adverse outcomes of pDDIs were hypotension, renal failure, hypoglycaemia, bradycardia and lactic acidosis., Conclusion: Careful choice of drugs can reduce but not eliminate pDDIs and their potential ADRs in hypertensive patients. Close monitoring for hypotension, renal failure, hypoglycaemia, bradycardia and lactic acidosis is necessary., (© 2021 British Pharmacological Society.)

Background: Clostridioides difficile infection (CDI) is one of the most common healthcare-associated (HA) infections. Cancer patients, particularly haemato-oncological patients, have an increased risk for CDI due to more risk factors compared with non-cancer patients. The aim of this study was to investigate differences in outcomes associated with HA CDI in patients with solid and haematological malignancies compared with patients with no underlying malignant disease in a tertiary healthcare centre in Serbia., Methods: A prospective cohort study was conducted including adult patients diagnosed with an initial episode of HA CDI. Their demographic and clinical characteristics associated with risk factors for CDI were documented. Outcomes such as all-cause 30-day mortality, cure of infection, diarrhoea relaps and recurrence of disease were followed. Patients were assigned to cancer and non-cancer groups. Within the cancer group, patients were divided into the solid tumour subgroup and haematological malignancy subgroup., Results: During a 7-year period, HA CDI was observed in 28 (5.1%) patients with haematological malignancy, 101 (18.3%) patients with solid tumours and 424 (76.7%) non-cancer patients. Older age (OR 1.04, 95% CI 1.02 to 1.07, p<0.001), admission to the intensive care unit (ICU) (OR 2.61, 95% CI 1.37 to 4.95, p=0.003), mechanical ventilation (OR 5.19, 95% CI 2.78 to 9.71, p<0.001) and use of antibiotics prior to CDI (OR 1.04, 95% CI 1.02 to 1.06, p=0.02) were associated with increased mortality. Compared with patients with solid tumours, patients with haematological malignancy were younger (65 vs 57 years, p=0.015), did not require ICU admission (25.0% vs 0%) or mechanical ventilation (8.9% vs 0%) and were treated longer with antibiotics prior to CDI (14 vs 24 days, p=0.002)., Conclusions: Patients with haematological malignancy were exposed to different risk factors for CDI associated with mortality compared with patients with solid tumours and non-cancer patients. Older age, ICU stay and mechanical ventilation, but not presence or type of cancer, predicted the all-cause 30-day mortality., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Previous investigations suggest the use of extract from the roots of Pelargonium sidoides (EPs 7630) for the therapy of uncomplicated rhinosinusitis. The aim of this prospective study was to compare the effects of herbal drug EPs 7630 and antibiotic roxithromycin on chemokine production in nasal mucosa and clinical parameters in patients with uncomplicated acute bacterial rhinosinusitis (ABRS)., Methods: Seventy-eight ABRS patients were divided into 26 patients receiving EPs 7630 tablets, 3 × 20 mg/day per os (group 1), 26 patients receiving roxithromycin tablets, 2 × 150 mg/day per os (group 2), both for 10 days, and 26 patients who received no therapy (Control group). We measured chemokine levels in nasal secretions by flow cytometry and assessed clinical parameters on day 0 and day 10 of investigation., Results: EPs 7630 increased concentrations of MCP-1 ( P = .001) and IP-10 ( P = .049) and decreased levels of MIP-1α ( P  < .001), ENA-78 ( P  < .001), and IL-8 ( P  < .001). Roxithromycin increased levels of IP-10 ( P = .049) and decreased levels of MCP-1 ( P  < .001), MIP-1α ( P  < .016), ENA-78 ( P  < .001), and IL-8 ( P  < .001). Comparison of the non-treated patients' group with groups 1 and 2 revealed significant improvement of all clinical parameters in treated patients ( P  < .001), but therapy with roxithromycin resulted in better improvement in nasal symptoms and endoscopic findings than therapy with EPs 7630., Conclusion: Our results suggest the presence of similar modulatory effects of both therapies on production of chemokines that regulate the function of neutrophils and monocytes in nasal mucosa. Roxithromycin shows better clinical efficacy than EPs 7630 in patients with uncomplicated ABRS., Level of Evidence: 1b., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC. on behalf of The Triological Society.)

Introduction : Clostridioides difficile ( C. difficile ) infection (CDI) is one of the most common healthcare-associated (HA) infections in contemporary medicine. The risk factors (RFs) for HA CDI in medical and surgical patients are poorly investigated in countries with a limited resource healthcare system. Therefore, the aim of the study was to investigate differences in patients' characteristics, factors related to healthcare and outcomes associated with HA CDI in surgical and medical patients in tertiary healthcare centre in Serbia. Materials and Methods : A prospective cohort study was conducted including adult patients diagnosed with initial episode of HA CDI, first recurrence of disease, readmission to hospital, while deaths within 30 days of CDI diagnosis and in-hospital mortality were also recorded. Patients hospitalized for any non-surgical illness, who developed initial HA CDI were assigned to medical group, whereas those who developed initial HA CDI after surgical procedures were in surgical group. The data on patients' characteristics and factors related to healthcare were collected, too. Results : During 7-year period, from 553 patients undergoing in-hospital treatment and diagnosed with CDI, 268 (48.5%) and 285 (51.5%) were surgical and medical patients, respectively. Age ≥ 65 years, use of proton pump inhibitors, chemotherapy and fluoroquinolones were positively associated with being in medical group, whereas admission to intensive care unit and use of second- and third-generation cephalosporins were positively associated with being in surgical group. Conclusions : Based on obtained results, including significant differences in 30-day mortality and in-hospital mortality, it can be concluded that medical patient were more endangered with HA CDI than surgical ones.

Objective: Previous investigations suggest the use of extract from the roots of Pelargonium sidoides (EPs 7630) for improvement of the symptoms of uncomplicated upper airway inflammations, due to its antimicrobial and immunomodulatory actions. The aim of this investigation was to evaluate the effects of EPs 7630 on chemokine production in nasal mucosa and clinical parameters of patients with acute postviral rhinosinusitis (APRS)., Methods: Twenty-six ( n  = 26) APRS patients and 25 ( n  = 25) control subjects were included in this prospective study. We measured the concentrations of thirteen chemokines in nasal secretions of APRS patients and controls by flow cytometry. The patients with APRS were treated by EPs 7630 20 mg oral tablets, three times daily for 10 days. We compared the chemokine levels in nasal secretions, nasal symptoms and endoscopic findings in patients, before and after therapy., Results: We found higher Total Symptom Score (TSS) and higher concentrations of MCP-1, MIP-1α, MIP-1β, MIP-3α, ENA-78 and IL-8 in nasal secretions of APRS patients than in controls. After therapy by EPs 7630, we found significant improvement in all symptoms and endoscopic findings of APRS. The concentrations of MCP-1, IP-10 and MIP-1β were significantly increased and levels of MIP-1α, ENA-78, GROα and IL-8 significantly decreased in nasal fluid samples after therapy. No adverse effects were reported during the treatment., Conclusion: Our results suggest the presence of modulatory effects of EPs 7630 on production of chemokines regulating the function of neutrophils and monocytes in the site of inflammation of the nasal mucosa in patients with APRS., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: The progression of the nonalcoholic fatty liver disease to nonalcoholic steatohepatitis (NASH) is multifactorial, and there is still a lack of approved medications for its treatment. The study aimed to evaluate the impact of combined treatment with Pentoxifylline and Metformin on biochemical parameters in patients with Nash. Setting: Outpatient hepatology clinic., Methods: A prospective trial was conducted. The first cohort included patients with biopsy-proven Nash, while the second cohort consisted of patients with biopsy-confirmed NAFLD. Blood tests were checked at baseline and every three months. Pentoxifylline at a dosage of 400 mg t.i.d. and Metformin at the dosage of 500 mg t.i.d. were introduced for six months in Nash group. The impact of the treatment was assessed based on biochemical results after combined treatment with low-cost medications., Results: All 33 Nash patients completed 24 weeks of treatment. We observed significant improvement (p<0.05) of median values after treatment for the following parameters: serum uric acid levels decreased by 51.0 mmol/L, calcium decreased for 0.27 mmoL/L, magnesium showed an increase of 0.11 mmoL/L. Insulin resistance improved as a reduction of HOMA - IR by 1.3 was detected. A significant decrease of median in liver enzymes, alanine aminotransferase, aspartate aminotransferase and gamma-glutamyltransferase by 24.0 U/L, 9.1 U/L, 10.8 U/L respectively, was noted., Conclusions: Pentoxifylline and Metformin may provide possible treatment option in Nash. Some new potential benefit of the therapy in improving liver function whilst decreasing cardiovascular risk was perceived., Competing Interests: Conflict of Interest: The authors stated that they have no conflicts of interest regarding the publication of this article., (2020 Milica Ćulafić, Sandra Vezmar-Kovačević, Violeta Dopsaj, Branislav Oluić, Nemanja Bidžić, Branislava Miljković, Đorđe Ćulafić, published by CEON/CEES.)

Background Drug-drug interactions represent one of the causes of adverse therapy outcomes through deteriorated efficacy or safety. However, the true extent of harm related to drug-drug interactions is not well established due to a lack of recognition and understanding. Objective The aim of this study was to investigate the association of potential drug-drug interactions with patients variables recorded at admission. Setting A cross-sectional correlation study was performed on the Cardiology ward of the University Clinical Hospital Center in Belgrade, Serbia. Method Data were retrospectively obtained from medical records and LexiInteract was used as the screening tool for potential drug-drug interactions. Main outcome measure Clinical and laboratory parameters recorded at the patients admission. Results A total of 351 patient records entered the analysis, with the mean age of 70 ± 10 years. The prevalence of potentially relevant drug-drug interactions was 61% (N = 213). After controlling for patient characteristics, nine potential drug-drug interactions were significantly associated with laboratory values outside the range and five potential drug-drug interactions with inadequate clinical parameter values. Potential drug-drug interactions were associated with abnormalities in blood count, metabolic parameters, electrolyte imbalance and renal function parameters. Association with inadequate control of systolic, diastolic blood pressure, as well as heart rhythm was also shown. Conclusion Drug-drug interactions were associated with patients clinical and laboratory findings. Our findings may assist in the identification of patients with increased likelihood of suboptimal therapy outcomes. Generating evidence through post-marketing drug-drug interactions research would lead to improvement in clinical decision-support systems, increased effectiveness and utilization in everyday clinical practice.

Objective: Cardiovascular disease (CVD) drugs have been frequently implicated in adverse drug reaction (ADR)-related hospitalizations. Drug-drug interactions (DDIs) are common preventable cause of ADRs, but the impact of DDIs in the CVD population has not been investigated. Hence, the primary aim of the study was to identify DDIs associated with ADRs in CVD patients at hospital admission. The second aim was to develop a simple tool to identify high-risk patients for DDI-related adverse events. Methods: An observational study was conducted on the Cardiology Ward of University Clinical Hospital Center. Data were obtained from medical charts. A clinical panel identified DDIs implicated in ADRs, using LexiInteract database and Drug Interaction Probability Scale. Statistics were performed using PASW 22 (SPSS Inc.). Results: DDIs contributed to hospital admission with a total prevalence of 9.69%. DDI-related ADRs affected mainly cardiac function (heart rate or rhythm, 41.07%); bleeding and effect on blood pressure were equally distributed (17.86%). Non-cardiovascular ADRs were found in 23.21% of DDIs. After admission, 73% of the identified DDIs led to changes in prescription. Prediction ability of calculated DDI adverse event probability scores was rated as good (AUC = 0.80, p  < .001). Conclusions: CVD patients are highly exposed to adverse DDIs; about one in ten patients hospitalized with CVD might have a DDI contributing to the hospitalization. Given the high prevalence of CVD, DDI-related harm might be a significant burden worldwide. Identification of patients with high DDI adverse event risk might ease the recognition of DDI-related harm and improve the use of electronic databases in clinical practice.

Background and objectives: Data suggests that nearly 30% of the general population have steatosis and up to 5% of this population develops nonalcoholic steatohepatitis (NASH). Liver biopsy is still considered to be the gold standard for the diagnosis of NASH. Great effort is being made toward the identification of sensitive diagnostic tests that do not involve invasive procedures to address a common concern in patients with the nonalcoholic fatty liver disease-whether they have NASH or simple steatosis. We aimed to investigate the independent predictors and develop a non-invasive, easy-to-perform, low-cost set of parameters that may be used in clinical practice to differentiate simple steatosis from NASH. Methods: А cross-sectional study of nonalcoholic fatty liver disease (NAFLD) patients divided into two groups: group I-simple steatosis (SS) and group II-biopsy-proven NASH. Strict inclusion criteria and stepwise analysis allowed the evaluation of a vast number of measured/estimated parameters. Results: One hundred and eleven patients were included-82 with simple steatosis and 29 with biopsy-proven NASH. The probability of NASH was the highest when homeostatic model assessment of insulin resistance (HOMA-IR) was above 2.5, uric acid above 380 µmol/L, ferritin above 100 µg/L and ALT above 45 U/L. An acronym of using first letters was created and named the HUFA index. This combined model resulted in an area under the receiver operator characteristic curve (AUROC) of 0.94, provided sensitivity, specificity, positive predictive value and a negative predictive value for NASH of 70.3%, 95.1%, 83.1% and 90.0%, respectively. Conclusion : We suggest a simple non-invasive predictive index HUFA that encompasses four easily available parameters (HOMA-IR, uric acid, ferritin and ALT) to identify patients with NASH, which may reduce the need for a liver biopsy on a routine basis in patients with NAFLD.

Introduction: Healthcare-associated infections (HAIs) and irrational use of antibiotics in healthcare settings are major global public health concerns. Surveillance of HAIs in intensive care units (ICU), surgical-site infections (SSIs), and Clostridium difficile infections (CDIs), together with implementation of antibiotic stewardship, are cornerstones of hospital infection prevention programs. The aim of this study was to evaluate antibiotic consumption, especially of broad spectrum antibiotics, in relation to HAI incidence density (ID)., Methodology: The study was conducted from 2011 to 2016 in a tertiary hospital, the Military Medical Academy (MMA), in Belgrade, Serbia. Through regular hospital surveillance we identified all patients with a new HAI. Data on consumption of antibacterials for systemic use were expressed as defined daily dose per 100 bed days (DDD/100 BD)., Results: The highest incidence density (ID) of HAI was observed among patients in surgical ICUs (47.2 per 1000 patient-days), while the highest incidence rate among SSI was 3.7%. Moreover, the highest ID of CDI in medical patients was 6.2 per 10,000 patient-days, while in surgical patients it was 4.3 per 10,000 patient-days. The most frequently used antibiotics were cephalosporins, aminoglycosides and carbapenems (16.0 ± 2.3, 4.8 ± 0.7, 4.3 ± 0.7 DDD/100 BD, respectively). There was no significant correlation between consumption of any groups of antibiotics and ID of CDI in medical and surgical patients., Conclusion: The multidisciplinary healthcare team would have crucial importance in the implementation of the antibiotic stewardship program in order to decrease unnecessary exposures of patients treated in healthcare settings., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2018 Aneta Perić, Viktorija Dragojević-Simić, Bojana Milenković, Sandra Vezmar Kovačević, Vesna Šuljagić.)

Background and Aim: Adverse effects are common in children treated with antiepileptic medications and may affect parental beliefs about treatment. The aim of the study was to investigate the relationship between adverse effects and parental beliefs about antiepileptic drugs used for the treatment of their children. Methods: The study was performed at the University Children's Hospital, Belgrade, Serbia from 2013⁻2015. Parents of children treated with valproic acid, carbamazepine or lamotrigine, were eligible. They were asked to fill in the Beliefs about Medications Questionnaire (BMQ) and The Liverpool Adverse Events Profile (LAEP). Results: Parents of 127 children (average age 9.88 ± 4.16 years) of whom 111 had epilepsy (67 generalized, 44 focal) and 16 with febrile seizures participated in the study. Nervousness and/or agitation, weight gain, restlessness, headache, difficulty in concentrating, feeling of aggression and upset stomach were most frequent adverse effects, reported in 37% of the population. BMQ-specific necessity scores significantly correlated with parental education; parents with elementary school showed lower scores than those with higher education. The presence of difficulty in concentrating of their child was associated with higher BMQ concern scores (20.73 ± 4.25 vs. 18.99 ± 3.60, p = 0.043) as well as necessity scores (18.42 ± 3.31 vs. 16.40 ± 2.73, p = 0.017). Higher scores of BMQ-general overuse were reported in the presence of a headache (8.79 ± 2.81 vs. 7.64 ± 2.72, p = 0.027). Conclusions: The main finding of our study is that parental beliefs about antiepileptic drugs were associated with the presence of adverse effects. Understanding this relationship could allow physicians and pharmacists to structure better educational programs for parents of children treated with antiepileptic drugs. Education should be more focused towards understanding the adverse effects of antiepileptics which could alleviate parental concerns and strengthen their beliefs about the necessity of medication use in their children.

Aim: To determine the general population willingness to pay for cognitive pharmacist service in community pharmacy, describe the behavior of participants regarding health care issues, and evaluate correlation between participants' sociodemographic characteristics or attitudes and their willingness to pay., Methods: A questionnaire-based survey was conducted among general population visiting community pharmacies. The participants were asked about receiving cognitive pharmacist services to identify and resolve potential medication therapy problems after the initiation of a new medicine to optimize health outcomes of the patients. A univariate and multivariate analysis were used to analyze associations between different variables and willingness to pay for pharmacy service., Results: Of 444 respondents, 167 (38%) reported that they were willing to pay for a medication management service provided in the community pharmacy. Univariate analysis showed significant association between the willingness to pay for pharmacist-provided service and respondents' socio-demographic factors, health-related characteristics, and behavior, dilemmas, or need for certain pharmacist-provided service. The logistic regression model was statistically significant (χ2=4.599, P<0.001)., Conclusions: The respondents expressed their willingness to pay for cognitive pharmacist services, which has not been fully recognized within the health care system. In future, pharmacists should focus on practical implementation of the service and models of funding.

Aim: The aim was to describe the type and prevalence of potentially relevant drug-drug interactions (pDDIs) in a population of patients admitted for cardiovascular diseases (CVD), and management strategies for reducing the occurrence of pDDIs., Methods: A retrospective cross-sectional study was performed on Cardiology ward of University Clinical Hospital Center in Belgrade, Serbia. A total of 527 patients, with more than one prescription during hospital stay, were enrolled in this study. Data were obtained from medical records. LexiInteract was used as the screening tool., Results: At least one potentially relevant pDDI was identified in 83.9% of patients. Occurrence was significantly more prevalent in patients with higher number of drugs, multimorbidity, longer length of stay, arrhythmia, heart failure, infectious and respiratory disease. About 13% of pDDIs exposures were accompanied with concurrent renal or liver disease, as an additional risk for DDI manifestation. Among CVD, patients with a history of myocardial infarction possessed the highest additional risk. The most common potential clinical outcome was the effect on cardiovascular system 48.5%, renal function and/or potassium 22.3%, bleeding 9.5%, impaired glucose control 6.8% and digoxin toxicity 4.6%. Main management strategies to avoid X or D class included using paracetamol instead of NSAID or alternative NSAID (38%), alternative antibiotic or antifungal (20.4%), H 2 receptor antagonist instead of PPI (8.3%), avoiding therapeutic duplication (7.3%), and alternative HMG-CoA reductase inhibitor (7%). Heart rate, blood pressure, electrolytes/potassium and blood glucose could have been employed in monitoring for potential consequence of 72.2% C class pDDIs., Conclusions: Use of drug interaction screening tools can be beneficial risk mitigation strategy for potentially relevant pDDIs in CVD patients. DDI screening software could be linked to the patient's laboratory results or clinical data regarding renal or liver function, as an approach to reinforce DDIs alert quality., (© 2017 John Wiley & Sons Ltd.)

Background In the last 30 years, activities of hospital pharmacists have gone through significant changes. Pharmacists are increasingly involved in patient care. Objectives To explore drug-related and logistic problems, interventions, and their outcomes during routine everyday work of hospital pharmacists. Setting Institute for physical medicine and rehabilitation, Banja Luka, Bosnia and Herzegovina. Methods In the period of January 2013-October 2015 a prospective observational study was performed. Medical doctors, nurses, therapists, and patients addressed pharmacists, face-to-face or by telephone, with drug-related problems (DRPs) and/or logistic issues. Main outcome measure Type of DRP or logistic issue, intervention, outcome, initiator and time spent for solving the problem were documented for each consultation. Results Out of 1515 interventions, 48.8% were aimed at solving DRPs. The most common DRPs were the recommendation of a drug or dose and need for additional information about drugs. Drug price and supply were the most prevalent logistic issues. DRPs were more frequently initiated by medical doctors and required more time to solve the problem compared to logistic issues (Mann-Whitney U test, p ≤ 0.001, respectively). The acceptance rate of interventions to solve DRPs (83.7%) was lower compared to logistic issues (95.2%; p ≤ 0.001). Conclusions Hospital pharmacists were faced with an approximately equal number of DRPs and logistic issues during their routine everyday work. The overall acceptance rate of pharmacists' interventions was high, and the results of our study indicate that there is a need for more involvement of hospital pharmacists in Bosnia and Herzegovina in clinical activities. Impact on practice.

Objectives: The aim of the study was to determine the rate of Potentially Inappropriate Medicines (PIM) and Potential Prescription Omissions (PPO) according to Screening Tool of Older Person's potentially inappropriate Prescriptions/Screening Tool to Alert doctors to the Right Treatment (STOPP/START) criteria., Study Design: A cross-sectional survey in community pharmacy., Method: A prospective cross-sectional study was performed, during March-May 2012, in five community pharmacies. Patients aged ≥65 years, who collected one or more prescribed medications, were asked to participate in the study, and an interview was scheduled. Patients were asked to provide their complete medical and biochemical record from their general practitioner., Results: 509 patients, mean age 74.8±6.5 years, 57.4% female, participated in the study. 164 PIM were identified in 139 patients (27.3%). The most common were: long-term use of long-acting benzodiazepines (20.7%), use of non-steroidal antiinflammatory drugs (NSAID) in patients with moderate-severe hypertension (20.1%), use of theophylline as monotherapy for chronic obstructive pulmonary disease (COPD, 15.9%) and use of aspirin without appropriate indication (15.2%). Patients with more than four prescpritions had a higher risk for PIM (OR 2.85, 95% CI 1.97-4.14, p<0.001). There were 439 PPO, identified in 257, (50.5%) patients. Predictors for PPO were older age, presence of diabetes, myocardial infarction, osteoporosis, stroke, COPD and/or angina pectoris., Conclusion: STOPP/START criteria may be useful in identifying inappropriate prescribing and improving the current prescribing practices. Pharmacists should focus more on patients with more than four medications and/or patients with gout or pain accompanied with arterial hypertension because those patient may be at higher risk of PIM. Additionlly, patients older than 74 years with diabetes, osteoporosis, myocardial infarction, stroke, angina pectoris and/or COPD may have an increased risk of PPO.

Background: Drug use in pregnancy is often reason of concern for mothers and their physicians. However, only few studies investigated predictors of drug use in pregnancy., Objectives: To examine maternal characteristics as predictors of medication use in the 6 months before pregnancy and during the first 6 months of pregnancy. To examine whether prescription and over-the-counter (OTC) medication use in the 6 months before pregnancy had an impact on medication use in pregnancy., Setting: Six maternity care units and five community pharmacies., Method: Data were collected using a specially designed self-reported questionnaire during the period March 2009-March 2010. Logistic regression was used to identify factors associated with medication use., Main Outcome Measure: Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were used as association measures., Results: A total of 236 women were included in the analysis. After controlling for maternal characteristics, parity of more than one was associated with lower prescription medication use in pregnancy (aOR 0.46; 95% CI 0.22-0.93), higher household income with higher OTC medication use before pregnancy (aOR 3.13; 95% CI 1.22-8.00), and miscarriage with higher C and D Food and Drug Administration (FDA) risk category medication use in pregnancy (aOR 3.65; 95% CI 1.30-10.25). Prescription medication use before pregnancy was associated with higher prescription medication use in pregnancy (aOR 2.49; 95% CI 1.12-5.52), OTC medication use before pregnancy with higher OTC medication use in pregnancy (aOR 35.95; 95% CI 7.95-162.49), and C and D FDA risk category medication use before pregnancy with the same category medication use in pregnancy (aOR 3.54; 95% CI 1.23-10.17)., Conclusion: Different maternal characteristics were shown as predictors of medication use before and during pregnancy. However, medication use before pregnancy was shown as the most important predicting factor for the medication use in pregnancy.

Background: Observation of drug use patterns during pregnancy is necessary for the recognition of potential bad practices and improvement of safe drug use in pregnancy., Objective: To investigate prescription and over the counter drug use among Serbian women in the 6 months before pregnancy and in the first 6 months of pregnancy, and to evaluate the drugs used according to the risk to a fetus. Setting Six maternity care units and five community pharmacies., Method: A multi-center study was performed in Serbia during the period from March 2009-March 2010. A self-reporting questionnaire was used as a data source. Food and Drug Administration (FDA) risk classification system was used to determine the risk of used drugs for the fetus. Differences between subgroups were assessed using McNemar's test on paired proportions. Main outcome measure Proportion of women exposed to drugs or class of drugs., Results: The overall drug exposure was higher in pregnancy (34.7 %) than before pregnancy (29.9 %), p > 0.05, in the cohort of 311 pregnant women. A significantly greater prescription drug use, 19.0 versus 27.3 % of women, p < 0.05, and less selfmedication with over the counter drugs in pregnancy, 15.1 versus 8.7 %, p < 0.05, were observed. Commonly used drugs were musculoskeletal drugs, analgesics/antipyretics and respiratory system drugs before pregnancy (13.8, 12.5, and 6.4 % of women, respectively), and progestogens, analgesics/antipyretics, and antibiotics for the systemic use in pregnancy (9.0, 7.7, and 7.4 %, respectively). A greater exposure to drugs belonging to the FDA risk category A (3.9 vs. 60.8 %, p < 0.05), B (18.0 vs. 19.6 %, p > 0.05), C (10.0 vs. 10.3 %, p > 0.05) and D (2.9 vs. 10.9 %, p < 0.05), as well as less exposure to drugs belonging to category X (0.3 vs. 0 %, p > 0.05) were observed in pregnancy. Folic acid was used by 60.8 % of women in pregnancy, and by only 3.9 % before pregnancy., Conclusion: Besides higher overall drug use in pregnancy than before pregnancy, particularly the use of progestogens, and, subsequently, D category drugs, less selfmedication with over the counter drugs was observed in pregnancy. Insufficient use of folic acid before pregnancy requires public health service activities.

Rationale: In developed countries, cyclooxygenase 2 (COX-2) inhibitors were shown to be less costly than the combination of non-steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs) in treatment of patients with high risk of serious gastrointestinal (GI) adverse effects. It is questionable if such results apply to developing countries where health service costs are lower and there is high discrepancy between generic and patent protected drug prices. We analysed the direct cost of treatment with generic NSAIDs in combination with PPIs versus branded COX-2 inhibitors in patients with high risk of serious GI adverse effects from the perspective of the public health service in Serbia., Methods: Total cost of treatment of serious GI complications and the use of NSAID+PPI versus COX-2 inhibitors were calculated. A model for estimation of cost of treatment of NSAID+PPI versus COX-2 inhibitors which included the probability of developing serious GI adverse effects was developed., Results: Total cost of treatment of serious GI adverse effects resulted in an average of $814/patient. Considering the relative risk of such adverse effects for patients with four or more risk factors, the least costly treatment over 6 months was the use of celecoxib ($487). Compared with diclofenac+omeprazole, cost savings were estimated at $59 and $22 per patient with celecoxib and etoricoxib, respectively., Conclusion: Cost savings may be achieved by using COX-2 inhibitors in patients at high risk of GI adverse effects even in countries with moderate health care service expenditures. Such possibility requires further investigation., (© 2010 Blackwell Publishing Ltd.)

Major depressive disorder (MDD) is a common and serious illness of our times, associated with monoamine deficiency in the brain. Moreover, increased levels of cortisol, possibly caused by stress, may be related to depression. In the treatment of MDD, the use of older antidepressants such as monoamine oxidase inhibitors and tricyclic antidepressants is decreasing rapidly, mainly due to their adverse effect profiles. In contrast, the use of serotonin reuptake inhibitors and newer antidepressants, which have dual modes of action such as inhibition of the serotonin and noradrenaline or dopamine reuptake, is increasing. Novel antidepressants have additive modes of action such as agomelatine, a potent agonist of melatonin receptors. Drugs in development for treatment of MDD include triple reuptake inhibitors, dual-acting serotonin reuptake inhibitors and histamine antagonists, and many more. Newer antidepressants have similar efficacy and in general good tolerability profiles. Nevertheless, compliance with treatment for MDD is poor and may contribute to treatment failure. Despite the broad spectrum of available antidepressants, there are still at least 30% of depressive patients who do not benefit from treatment. Therefore, new approaches in drug development are necessary and, according to current research developments, the future of antidepressant treatment may be promising.

Objectives: To identify changes in prescribing patterns of antibiotic prophylaxis in caesarean delivery after introduction of local clinical guidelines. To identify changes in outcomes of prescribing antibiotics following the implementation of local clinical guidelines on antibiotic prophylaxis., Setting: University of Belgrade, Medical School, Clinic of Gynaecology and Obstetrics "Narodni front" Belgrade, Serbia., Method: A quantitative retrospective analysis of antibiotic use before (January-June 2005), and following (January-June 2006) implementation of guidelines on antibiotic prophylaxis in two wards. Patients who underwent caesarean section prior to (261) and following (281) introduction of local guidelines, participated in this study., Main Outcome Measures: Drug utilization cost presented as the number of DDD/100 bed days/eur, the average duration of hospital stay, number of wound infections., Results: There was a significant change in prescribing patterns of antibiotic prophylaxis in caesarean section following introduction of local guidelines. The use of ceftriaxone, amikacin and metronidazole decreased (57.47% vs. 11.74%; 9.19% vs. 4.27%; 61.69% vs. 46.26%, respectively). On the other hand, the use of "older" antibiotics such as gentamicin, cefuroxime, cefazolin and ampicillin increased (14.56% vs. 29.18%; 9.2% vs. 17.44%; 9.58% vs. 45.2% and 0% vs. 3.9%, respectively). DDD/100 bed days/eur analysis revealed a 47% decrease of total cost for prophylactic antibiotic treatment in caesarean section following local guideline implementation. In contrast, rate of wound infections and duration of hospital stay were not significantly different in both groups., Conclusion: In an attempt to ensure cost-effective prophylactic use of antibiotics in caesarean delivery, local clinical guidelines were introduced. They resulted in changes in prescribing patterns of antibiotics. There was a significant decrease in use of 'third' generation of cephalosporin's whereas the use of "older" antibiotics with proven efficacy and safety increased. In contrast, there was no significant change in treatment outcomes such as wound infection and average hospital stay.

Although often necessary for obtaining remission following major depressive disorder, combined antidepressant treatment is frequently associated with drug interactions and enhanced adverse drug effects. We investigated pharmacokinetic interactions following combined fluvoxamine and amitriptyline treatment and their impact on therapeutic efficacy and tolerability. Twenty-two inpatients with major depression [Hamilton Depression Scale (HAM-D) rating > or =18] were treated with either amitriptyline (75 mg/day), fluvoxamine (100 mg/day) or both. Blood samples, for determination of amitriptyline, its major metabolite nortritpyline, and fluvoxamine, were obtained after single dose administration and in steady-state. Therapeutic efficacy was evaluated using HAM-D and adverse drug effects were evaluated using the clinical global impression scale. Following combined treatment, steady-state plasma levels of nortriptyline were significantly decreased compared to monotherapy. HAM-D scores after two-week treatment showed that there was a better response to combined treatment. There was no significant difference in severity of adverse effects among groups. We observed a pharmacokinetic interaction between fluvoxamine and amitritpyline resulting in impaired metabolism of the later. However, no significant impact of the interaction on treatment safety was observed. Moreover, concomitant use of amitriptyline at 75 mg/day and fluvoxamine at 100 mg/day was well tolerated with a more prompt and stronger onset of clinical response compared to monotherapy in patients with major depression.

Background: Severe neurotoxicity has been observed after systemic high-dose and intrathecal methotrexate (MTX) treatment. The role of biochemical MTX-induced alterations of the folate and methyl-transfer pathway in the development of neurotoxic symptoms is not yet fully elucidated., Procedure: MTX, 5-methyltetrahydrofolate, calcium folinate, S-adenosylmethionine, and S-adenosylhomocysteine were measured in the cerebrospinal fluid (CSF) of 29 patients with acute lymphoblastic leukemia (ALL) who were treated with high-dose MTX (5 g/m(2)) followed by calcium folinate rescue (3 x 15 mg/m(2)) and/or intrathecal (8-12 mg) MTX. Two patients developed subacute MTX-associated neurotoxicity. CSF was obtained by lumbal puncture 1-3 weeks after administration of MTX and shortly after the occurrence of neurotoxicity. The analytes were measured using HPLC assays with UV and/or fluorescence detection., Results: In non-toxic patients, CSF concentrations of 5-methyltetrahydrofolate and S-adenosylmethionine were in the normal range 2 weeks after administration of high-dose and intrathecal MTX followed by rescue. In contrast, when these patients received intrathecal MTX without rescue, 5-methyltetrahydrofolate concentrations were significantly decreased 12 days after the first MTX administration. S-adenosylmethionine concentrations were significantly decreased up to 45 days. The two patients suffering from neurotoxicity had decreased levels of 5-methyltetrahydrofolate and S-adenosylmethionine during or following toxicity. S-adenosylhomocysteine was determined in all samples of neurotoxic patients but was below the limit of quantification in most samples of non-toxic patients. Calcium folinate was not detected; MTX was present only in samples obtained during its infusion., Conclusion: Intrathecal MTX without folinate rescue as well as MTX-associated neurotoxicity are likely to be associated with specific alterations of the folate and methyl-transfer pathway.

Objective: Interference of methotrexate (MTX) with the metabolism of homocysteine may contribute to MTX neurotoxicity. In this pilot study we measured the concentration of homocysteine and related metabolites in the cerebrospinal fluid (CSF) of patients with primary central nervous system lymphoma undergoing intensive treatment with MTX., Material and Methods: CSF samples from lymphoma patients (n = 4) were drawn at the end of high-dose MTX infusions (3-5 g/m2/24 h, HDMTX) and one day after intraventricular injections of MTX (3 mg, ICVMTX) or cytarabine (30 mg) and analyzed for homocysteine, cysteine, sulfur-containing excitatory amino acids (cysteine sulfinic acid, cysteic acid, homocysteine sulfinic acid and homocysteic acid), S-adenosylmethionine, 5-methyltetrahydrofolate and MTX. The concentration of homocysteine, cysteine and sulfur-containing excitatory amino acids were also measured in the CSF of a reference population not exposed to MTX. The Wilcoxon signed rank-test and the Friedman test were used to compare concentrations of homocysteine and its metabolites at various time-points during chemotherapy. Comparison of patient and control samples were performed using the Mann-Whitney U-test. Allelic variants of homocysteine metabolism previously shown to influence MTX neurotoxicity (MTHFR c.677C>T, MS c.2756A>G and Tc2 c.776C>G) were also analyzed., Results: After application of HD- and ICVMTX, the CSF homocysteine concentrations in the lymphoma patients were markedly elevated and significantly higher than those in the control group (p < 0.05, Mann-Whitney U-test), whereas 5-methyltetrahydrofolate was depleted. A rapid elevation of homocysteine sulfinic acid, a sulfur-containg amino acid which was not detected in the CSF of the control group, was observed. One patient developed confluent white matter brain changes visible using MRI. This patient had the lowest concentration of S-adenosylmethionine in the CSF and carried two risk alleles for MTX neurotoxicity., Conclusions: In this pilot study, MTX administered either intravenously or intraventricularly, induced marked biochemical alterations in the CSF. Whether these changes can be used to predict MTX-induced neurotoxicity at an early stage in treatment needs to be elucidated in larger clinical trials.

Goal of Work: During the renovation works at our institution, the incidence density for invasive aspergillosis (IA) increased from <0.5 to 0.99/1,000 inpatient days in 2001. As a direct response to this increased environmental risk, itraconazole (ITC) was administered for primary prophylaxis in pediatric cancer patients for whom a particular high risk of IA was anticipated due to prolonged severe neutropenia (>10 days), autologous stem cell transplantation, acute myeloblastic leukemia or relapsed acute lymphoblastic leukemia, or high-dose steroids >3 weeks., Materials and Methods: In this open-label, prospective observational study, ITC was given in ITC solution or capsule. Trough concentrations were measured in plasma with high-performance liquid chromatography after at least 7 days of treatment. Doses were adjusted to target plasma trough ITC concentrations > or =0.5 mg/l., Results: From 2001 to 2005, 39 pediatric cancer patients received 44 prophylactic ITC cycles; 102 trough plasma concentrations were measured after oral administration. Plasma target concentrations >0.5 mg/l were achieved with both formulations. A median dose of 8 mg kg(-1) day(-1) (3.5-16.0 mg kg(-1) day(-1)) was necessary in pediatric oncology patients. The bioavailability of the liquid formulation was significantly lower when the solution was given by a feeding tube. Adverse effects (gastrointestinal, elevated transaminases, and one hemolysis) which led to the cessation of the ITC prophylaxis were reported in 11% of all courses. No breakthrough infection was seen in this pediatric population., Conclusion: Oral ITC offers a feasible and inexpensive option for antifungal prophylaxis in selected pediatric cancer patients. Drug monitoring and meticulous consideration of possible interactions and adverse effects are mandatory.