Journal of Health Science and Medical Research, 2019
Objective: This study aimed to examine the contents of home pharmacies and medication use, as wel... more Objective: This study aimed to examine the contents of home pharmacies and medication use, as well as storage and disposal habits in urban and rural households in Serbia. Material and Methods: This prospective research was conducted within 70 households in Novi Sad (urban setting) and Laćarak (rural setting) from October 1, 2015 to January 15, 2016. The data were collected using a standardized questionnaire, as well as by direct examination of drugs stored in households. Results: The most common groups of drugs stored were cardiovascular drugs, drugs for the nervous system, antirheumatic products and antimicrobials. A high percentage of drugs for the alimentary tract were found stored in Laćarak, while drugs for the respiratory tract were discovered in Novi Sad. Prescription only medications (POMs) made up 69.7% of all medications in Laćarak and 60.6% in Novi Sad. POMs were purchased independently in high amounts (13.2% in Laćarak and 9.1% in Novi Sad). Presence of expired medicatio...
Highly active antiretrovial therapy (HAART) is a mainstay of treatment for patients with Human Im... more Highly active antiretrovial therapy (HAART) is a mainstay of treatment for patients with Human Immunodeficiency Virus (HIV). Given that lower HAART pill burdens have been shown to be associated with an increased duration of initial therapy, there is a need to understand the effect of daily pill burden on the duration of the initial regimen. The objective of this study was to estimate the effects of daily pill burden on the time to discontinuation of the initial HAART regimen. METHODS: A retrospective cohort design was used where adult, female, HIV-positive patients initiating therapy at the study clinic were included. A Kaplan-Meier curve was generated and a Cox proportional hazards model was developed to assess the impact of patient, regimen, and demographic characteristics on the hazard of discontinuation of the initial regimen. RESULTS: A total of 498 charts were reviewed, yielding a cohort of 115 adult female patients who initiated HAART at the study clinic. All study subjects were followed up from the initiation of HAART to treatment discontinuation. Patients treated with a 1 pill/day regimen had a significantly longer time to discontinuation than regimens of 2+ pills/day (mean duration of initial therapy 1574.97 days vs. 977.48 days, respectively, p=0.003). Compared to 1 pill/day regimens, 2+ pills/day regimens were associated with a higher hazard of discontinuation (hazard ratio (HR) =3.44with 95% confidence interval (CI) = 1.25, 9.48). Higher viral load and patients without insurance were also found to be significantly associated with higher hazards of discontinuation. CONCLUSIONS: The 1 pill/day regimen in the initial HAART treatment was associated with a lower hazard of discontinuation than any other regimen used.
[The choice of antimicrobial therapy in view of the most frequently isolated pathogens at the Insitute Of Surgery in the Clinical Center of Vojvodina]
PubMed, 2008
Several studies have reported high rate of antimicrobial resistance, particularly in strains isol... more Several studies have reported high rate of antimicrobial resistance, particularly in strains isolated from hospitals. The aim of this study was to review the pathogens associated with nosocomial infections at the Clinic for abdominal surgery, Clinic for urology, Clinic for orthopedic surgery and Clinic for resuscitation and anaesthesia of the Clinical Center of Vojvodina. The analysis of the collected data gave indecisive results. The percentage of positive cultures was too low to enable making therapeutic recommendations. The first-line antibiotics, according to the international reccomendations, should be included more often in sensitivity tests of isolated bacterial strains. Isolated bacteria were most frequently tested to the second and third-line antibiotics respectively, to which the resistance rate is becoming concerningly high.
pϭ0.31), respectively. CONCLUSIONS: Despite previous suggestions, statin therapy in normotensive ... more pϭ0.31), respectively. CONCLUSIONS: Despite previous suggestions, statin therapy in normotensive or hypertensive patients does not lead to reductions in systolic and diastolic blood pressure. Despite these results, however, the routine use of statins, especially in patients with hypertension should be always considered due to the essential reduction of cardiovascular events.
This study analyzed the cost-utility of everolimus ϩ exemestane (EVEϩEXE) versus placebo ϩ exemes... more This study analyzed the cost-utility of everolimus ϩ exemestane (EVEϩEXE) versus placebo ϩ exemestane (PBOϩEXE) in patients with HRϩ HER2-ABC. METHODS: The phase III BOLERO-2 study randomized 724 patients with HRϩ HER2-ABC and recurrence or progression during/after nonsteroidal aromatase inhibitor therapy to EVEϩEXE or PBOϩEXE. A survival partition model was developed to compare treatment with EVEϩEXE versus PBOϩEXE (UK health care perspective). The 18-month median follow-up data on progression-free survival and mortality were obtained from BOLERO-2. Weibull functions were used to extrapolate trial data beyond the follow-up period. Utilities from published sources were combined with trial data to calculate quality-adjusted life years (QALYs) associated with health state. Background health state costs (ie, non-intervention costs) were applied to calculate incremental costs. RESULTS: At 18 months' followup, ABC patients on EVEϩEXE gained 1.33 life years (LYs) and 0.76 QALYs versus 1.27 LYs and 0.65 QALYs with PBOϩEXE. Background health state and adverse event (AE) costs were £9,944 with EVEϩEXE versus £12,924 with PBOϩEXE. Excluding drug acquisition costs, use of EVEϩEXE resulted in cost savings of £2,980. When trial data were extrapolated to 5 years, EVEϩEXE led to a gain of 3.05 LYs and 1.46 QALYs versus 2.57 LYs and 1.16 QALYs with PBOϩEXE. Background health state and AE costs were £30,094 with EVEϩEXE versus £29,560 with PBOϩEXE. The incremental (non-intervention) cost was £534 (due to longer survival). CONCLUSIONS: These additional analyses from the BOLERO-2 study show that compared with PBOϩEXE, patients receiving EVEϩEXE experienced longer PFS, which translated to health gains in terms of both LYs and QALYs. EVEϩEXE was associated with savings in non-intervention costs over the initial trial period and a modest increase in nonintervention costs over the extrapolated 5-year time horizon.
Consumption of non-steroidal anti-inflammatory drugs in Serbia: a comparison with Croatia and Denmark during 2005–2008
European Journal of Clinical Pharmacology, Nov 24, 2010
Purpose To analyze the amount and pattern of use of non-steroidal anti-inflammatory drugs (NSAID... more Purpose To analyze the amount and pattern of use of non-steroidal anti-inflammatory drugs (NSAIDs) in Serbia and to compare these parameters with those in Croatia and Denmark. The prescribing pattern of NSAIDs in Serbia as a direct indicator of physicians’ knowledge of these agents was also assessed. Methods The use of NSAIDs in Serbia, Croatia, and Denmark was analyzed during a 4-year
tively. For hypertensive patients treated with statins (8 included trials) the standardized effec... more tively. For hypertensive patients treated with statins (8 included trials) the standardized effect size of DSBP and DDBP was 0.07 (95%CI:-0.07-0.21; pϭ0.33) and-0.12 (95%CI:-0.36-0.11; pϭ0.31), respectively. CONCLUSIONS: Despite previous suggestions, statin therapy in normotensive or hypertensive patients does not lead to reductions in systolic and diastolic blood pressure. Despite these results, however, the routine use of statins, especially in patients with hypertension should be always considered due to the essential reduction of cardiovascular events.
The aim of this study was to determine and describe trends in antibiotics utilization in Serbia o... more The aim of this study was to determine and describe trends in antibiotics utilization in Serbia over a ten-year period. Data were retrieved from publicly available annual reports (2010)(2011)(2012)(2013)(2014)(2015)(2016)(2017)(2018)(2019). The results were expressed as Defined Daily Dose (DDD) per 1000 inhabitants per day (DID). All calculations were performed using the DDD values for the 2020 Anatomical Therapeutic Chemical/Defined Daily Dose (ATC/DDD) version for each year of the study, to account for the DDD changes during the study period. Antibiotics were classified using the WHO Access, Watch, Reserve (AWaRe) classification. Total utilization of antibacterials for systemic use increased from 17.25 DID in 2010 to 28.65 DID in 2019. A statistically significant increasing trend in the use of the Watch category antibiotics was observed. A tendency towards use of broad-spectrum antibiotics, apparent by a statistically significant increase in the rate of utilization of broad-spectrum macrolides, quinolones and third-generation cephalosporins vs. narrow-spectrum ones, as well as a significant increasing trend in the use of quinolones was identified. Total antibiotic utilization was found to be well above the European average. Several specific problem areas were identified, which requires further efforts to improve antibiotic prescribing. The present study provides the information needed to facilitate antibiotic stewardship in Serbia further and proposes specific interventions to optimize antibiotic use in Serbia.
Background: The tyrosine kinase inhibitor erlotinib displays large inter-individual variability i... more Background: The tyrosine kinase inhibitor erlotinib displays large inter-individual variability in plasma PK. Erlotinib undergoes hepatobiliary clearance and is a substrate and/or inhibitor of different hepatic ABC and SLC transporters (P-gp, BCRP, OATPs). In this PET study we assessed hepatic disposition of 11 C-erlotinib both at micro-and therapeutic doses to investigate the involvement of carriermediated processes in the hepatic clearance of erlotinib. Methods: Six healthy volunteers (mean age: 27 ± 6 years) underwent two consecutive abdominal [ 11 C]erlotinib PET scans and arterial blood sampling. The first scan was performed after administration of a microdose of 11 C-erlotinib (< 20 µg). In the second scan a microdose of 11 C-erlotinib was administered at 3 hours after oral treatment with a therapeutic erlotinib dose (300 mg). Radiolabelled metabolites of 11 C-erlotinib in plasma were assessed with a solid-phase extraction protocol. PET and blood data were analysed with compartment modelling. Results: During the PET scans only a low amount (< 5%) of radiolabelled metabolites of [ 11 C]erlotinib was detected in plasma both for the micro-and therapeutic dose scans. As compared with the microdose scan, AUC values of concentration-time curves of 11 C-erlotinib in plasma were significantly increased in the therapeutic dose scan by 99 ± 27%, whereas AUC values in the liver and liver-to-plasma AUC ratios were decreased by 55 ± 5% and 77 ± 5%, respectively. For the therapeutic dose a significant decrease (-39 ± 18%) in the influx rate constant of 11 C-erlotinib from blood into hepatocytes was found, whereas the efflux rate constant from hepatocytes into gall bladder and bile duct remained unchanged. Conclusions: Our data show that liver uptake of a microdose of [ 11 C]erlotinib occurred via a carrier-mediated process, which became inhibited at therapeutic erlotinib doses. Active uptake transport of erlotinib into the liver may account for variability in plasma PK and potentially play a role in transporter-mediated drug interactions.
classified according to the first drug dispensing during 6 months from the discharge date. Patien... more classified according to the first drug dispensing during 6 months from the discharge date. Patients were categorized in low ischemic stroke (CHA2DS2-VASc) (LR, score= 0), moderate-risk (MR, score= 1), high-risk (HR, score≥ 2).Multivariable logistic regression was used to evaluate the associations between ischemic stroke and bleeding (HAS-BLED) risk with the choice of non-vitamin K antagonist oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) therapy. Results: A total of 1,963 patients were identified: 4.
Recently, there is growing evidence of inappropriate variation in use of certain medicines. In Se... more Recently, there is growing evidence of inappropriate variation in use of certain medicines. In Serbia the consumption of pentoxifylline, dihydroergotoxine, nicergoline, deproteinized calf blood extract (DCBE) and cinnarizine, drugs with uncertain clinical benefit (UCB drugs), with clinical trials with little evidence suggesting their clinical benefit, is unusually high. The aim of this study was to analyze the consumption of UCB drugs in second largest city in Serbia -Novi Sad, in 1984 and 2008., to compare with those in entire Serbia, Denmark and Norway, and to examine the potential impact on population budget. METHODS: The study included data on consumption of these medicines in 1984. and 2008., in Novi Sad. Data were obtained from all state-owned and private pharmacies on the territory of Novi Sad. The number of (DDD/1000 inh/day) was calculated using ATC/DDD methodology. RESULTS: Total consumption of analyzed drugs with uncertain clinical benefit in Novi Sad has surprisingly increased in 2008 (12,59DDD/TID) in comparison to 1984 (7.37DDD/TID). Also, their total consumption in entire Serbia in 2008. was higher than in Novi Sad (16,72DDD/TID) and even several dozens of times higher than in Denmark and Norway (0.2DDD/TID). The money which population spent for UCB drugs yearly was more than 90 Mill EU in Serbia Although different administrative and educational approaches were applied in Serbia, their use not only did not decrease, but has significantly increased throughout years. CONCLUSIONS: These results suggest the need for putting greater efforts into education of general population who buys the UCB medicines in high amounts on their own accord. The work is part of SerbianSP No41012.
Interaction of diclofenac and ketoprofen with cardioactive drugs in rats
European Journal of Drug Metabolism and Pharmacokinetics, Mar 1, 2009
The interaction of diclofenac and ketoprofen, both applied intraperitoneally in a dose of 8 mg/kg... more The interaction of diclofenac and ketoprofen, both applied intraperitoneally in a dose of 8 mg/kg for twenty-eight days, was assessed with cardioactive drugs in rats. Interaction was assessed on the basis of ECG records after the infusion of adrenaline, verapamil or lidocaine to the rats treated with diclofenac or ketoprofen vs control. The infusion time was measured in seconds to the moment of the appearance of the first heart reaction to the infusion of the cardioactive drug, then to the appearance of more frequent changes in the ECG record, and finally, to the occurrence of the toxic effect. It was also measured the plasma concentrations of sodium and potassium ions. As well as diclofenac and ketoprofen concentration, 2 hours after single and 28th dose. ECG patterns revealed no occurrence of cardiotoxic action of diclofenac and ketoprofen. The treatment with diclofenac caused significantly lower sodium plasma concentrations whereas the concentration of potassium was increased. Diclofenac concentrations were the same after a single and multiple doses, whereas concentrations of ketoprofen were significantly higher after a single dose than after its multiple applications.
European Journal of Pharmaceutical Sciences, Apr 1, 2019
Antibacterial drugs, including fluoroquinolones, can exert their therapeutic action only with ade... more Antibacterial drugs, including fluoroquinolones, can exert their therapeutic action only with adequate penetration at the infection site. Multiple factors, such as rate of protein binding, drug liposolubility and organ bloodflow all influence ability of antibiotics to penetrate target tissues. Microdialysis is an in vivo sampling technique that has been successfully applied to measure the distribution of fluoroquinolones in the interstitial fluid of different tissues both in animal studies and clinical setting. Tissue concentrations need to be interpreted within the context of the pathogenesis and causative agents implicated in infections. Integration of microdialysis-derived tissue pharmacokinetics with pharmacodynamic data offers crucial information for correlating exposure with antibacterial effect. This review explores these concepts and provides an overview of tissue concentrations of fluoroquinolones derived from microdialysis studies and explores the therapeutic implications of fluoroquinolone distribution at various target tissues.
Volume 35 Number 8S to optimize the managed entry of new drugs in the future through an iterative... more Volume 35 Number 8S to optimize the managed entry of new drugs in the future through an iterative process. This includes guidance for all key groups on future activities to achieve this. Results: There have been multiple demand-side activities among countries to manage the utilization of dabigatran. This included extensive prelaunch activities, risk-sharing arrangements, prescribing restrictions, and monitoring of prescribing postlaunch against agreed guidance. Clinical pharmacologists played a key role in a number of countries. Reimbursement was denied in some countries due to concerns with its budget impact and/or issues with excessive bleeding. Development of a new model and future guidance was proposed to better manage the entry of new drugs in the future, centring on 3 pillars of pre-, peri-, and postlaunch activities. This was accompanied by guidance to all key stakeholder groups, including health authorities, physicians, patients, and pharmaceutical companies on suggested activities pre-to postlaunch to reduce the likelihood of new drugs being withdrawn as well as enhance their chances of funding. This included guidance on key considerations that authorities should consider when evaluating risk-sharing arrangements or developing patient registries. Conclusion: Models for introducing new drugs are essential to optimize their prescribing especially where there are concerns. As a result, promote high prescribing standards postlaunch. Without such models, new drugs may be withdrawn prematurely and/ or struggle for funding.
developed to evaluate the relative effectiveness between the NOACs and warfarin for the primary e... more developed to evaluate the relative effectiveness between the NOACs and warfarin for the primary efficacy endpoint of stroke or systemic embolism (SE) and primary safety endpoint of major hemorrhage. Secondary endpoints included ischemic stroke, hemorrhagic stroke, SE, myocardial infarction, intracranial hemorrhage, gastrointestinal hemorrhage, cardiovascular-related mortality, and all-cause mortality. A probability of best treatment was calculated for each antithrombotic agent for the different outcomes. RESULTS: Dabigatran-150mg, rivaroxaban, and apixaban showed significant relative risk (RR) reductions over warfarin for stroke or SE (RRϭ0.65, 0.78, 0.79, respectively). However, indirect comparisons did not reveal significant differences between the individual NOACs. For the primary safety endpoint, dabigatran-110mg was significantly better than warfarin (RRϭ0.81) and rivaroxaban (RRϭ0.79) whereas apixaban showed significant reduction over warfarin, and rivaroxaban (RRϭ0.70, 0.75, 0.69, respectively). Significant differences between the NOACs were also found for secondary endpoints of hemorrhagic stroke, intracranial hemorrhage, and gastrointestinal hemorrhage. However, no significant findings were observed for cardiovascular and all-cause mortality. CONCLUSIONS: Overall, the NOACs showed varying levels and areas of improvement over warfarin. The analyses identified dabigatran-150mg and apixaban as the best option for the prevention of stroke or SE and major hemorrhage, respectively.
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