Ana Sabo

Diclofenac and ketoprofen liver toxicity in rat

SummaryIn the last years there appeared many articles about the adverse influence of non-steroidal anti-inflammatory drugs on the liver and heart. This study is concerned with the influence of the duration of treatment with diclofenac and ketoprofen on the macroscopic and microscopic changes in the liver, lungs, heart, and kidneys in rats. Experiments were carried out on mature Wistar strain rats. Animals of test groups received diclofenac and ketoprofen in a dose of 8 mg/kg/day (equivalent to the therapeutic dose for man) during 7 per os (p.o.) or 28 days intraperitoneally (i.p.), whereas controls received physiological solution p.o. A high morbidity was observed in the animals receiving diclofenac p.o. and somewhat lower in those treated with ketoprofen. On the other hand, the rats got through the 28-day i.p. treatment with both drugs mainly without significant complications. Macroscopic examinations revealed some changes in treated rats: distension of the stomach, ascites, fibrin deposits on the internal organs, lung effusion and the changes in color and structure of the liver. These changes were more frequent in the group of rats receiving diclofenac for the 7 days compared with those that received ketoprofen for the same time. It may be thought that the high mortality and macroscopic changes in the internal organs of experimental animals are a consequence of the microscopic changes in the liver and its lowered function.

Consumption of serum lipid-reducing drugs in Serbia compared with Scandinavian countries: a population-based study, 2004–2008

The aim of this study was to measure the consumption of serum lipid reducing drugs in Serbia from 2004 to 2008, to compare this data with that from Scandinavian countries, and to compare the consumption of lipid lowering drugs and the rate of mortality from cardiovascular diseases in these countries.

Consumption of non-steroidal anti-inflammatory drugs in Serbia: a comparison with Croatia and Denmark during 2005–2008

PurposeTo 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.MethodsThe use of NSAIDs in Serbia, Croatia, and Denmark was analyzed during a 4-year period (2005–2008). Data were retrieved from the annual reports of the Agency for Drugs and Medical Devices of Serbia, Croatia, and Denmark. Data on prescribing behavior were obtained from the Health Insurance Fund of Serbia and represent NSAIDs issued by prescription between 2005 and 2008. Results were expressed as the number of defined daily doses/1000 inhabitants/day. The drug utilization 90% method was also used.ResultsThe total consumption of NSAIDs in Serbia was higher than that in Croatia and Denmark. Diclofenac accounted for approximately 50% of NSAID consumption during the observation period, followed (in much smaller quantities) by ibuprofen. The most commonly prescribed medicine was diclofenac, followed, in much smaller amounts, by ibuprofen. There was no trend of a reduced consumption of diclofenac or of an increased use of ibuprofen during the study periodConclusionsThese data suggest that factors other than evidence-based medicine have a dominant effect on the use of NSAIDs in Serbia. Targeted education from independent sources in the prescribing, dispensing, and use of drugs is important to improve the quality of the prescribing behavior and the use of NSAIDs.

Anti-nociceptive and anti-inflammatory properties of 5alpha-reductase inhibitor finasteride in experimental animals

SummaryFinasteride is a potent drug which has been prescribed for the management of benign prostatic hyperplasia (BPH) for more than 20 years. Recent studies indicate that finasteride, as 5alpha-reductase inhibitor, can influence some central effects such as analgesia, neurosteroidogeneses and behavior. The purpose of this study was to investigate the analgesic effect of finasteride, to determine whether finasteride interact with morphine analgesia in tail-flick test and to examine the anti-inflammatory effect of this drug. Adult male Wistar rats (280–330 g) were used for the both of experiments. Tests were assessed on groups of 6 animals. The first control group (O) received water (1 ml/kg, p.o.), the second control group (OO) received the vehicle (olive oil, 1 ml/kg, p.o.) and the third group (F) received finasteride (0.5 mg/kg, p.o.) suspended in olive oil, every morning for 30 days. After 30 days of treatment, tailflick test and formalin-induced foot paw edema test were performed. Finasteride increased the average latency in seconds in comparison to both controls (10.06 vs. 9.16 and 8.66 s). It was 9.83% higher depression of pain in group F in comparison to O and 16.17% in comparison to OO, but the anti-nociceptive effect of finasteride at applied dose didn’t significantly differ compared to both controls (p >0.05). Chronic pre-treatment with finasteride didn’t interact with analgesic effect of morphine compared to O (p >0.05), but compared to OO finasteride fastened, increased and prolonged the analgesic effect of morphine at all measuring intervals, achiving statistical significance in 60 min (p<0.01). Finasteride also exhibited significant anti-inflammatory action (p<0.05) in comparison to OO, but It was not significantly different from the control O. Finasteride didn’t exert analgesic action, it increased morphine antinociception and showed chronic anti-inflammatory effect to some extent. This might be a useful contribution to high-light the pathogenesis of BPH. There is the need for further studies in order to confirm these results with more details.

The outpatient utilization of non-steroidal anti-inflammatory drugs in South Bačka District, Serbia.

Objective To evaluate the utilization of non-steroidal anti-inflammatory drugs (NSAIDs) in South Bačka District (SBD), Serbia. Setting State-owned and private pharmacies in SBD, a northern district of Serbia, with 605,720 inhabitants (according to the 2008 census). Method Data on the number of packages, size of packages, and retail price of NSAIDs (Anatomical Therapeutic Chemical (ATC) group M01A) from 1 January to 31 March 2008 were obtained from all state-owned and private pharmacies in SBD. This included NSAIDs bought without prescription and those issued by prescription (on the Health Insurance Companies List for Reimbursement). The number of defined daily doses/1000 inhabitants/day (DDD/1000 inh/day) was calculated. Within the DU90% (drug utilization 90%) segment, the proportion of high-, medium- and low-risk NSAIDs with respect to the risk of gastrointestinal (GI) bleeding was determined. Price/DDD was also calculated. Main outcome measure Consumption of drugs expressed as DDD/1000 inh/day. Results The total consumption of NSAIDs over a 3-month period was 48.31 DDD/1000 inh/day. Only four drugs were within DU90%: diclofenac, ibuprofen, nimesulide and meloxicam (62.14, 19.87, 5.77, and 5.73% of total NSAID consumption, respectively). All dispensed NSAIDs within the DU90% segment except nimesulide (which was exclusively purchased without prescription) were nearly equally purchased without prescription and issued by prescription. The average price per DDD within the DU90% segment was 0.17 Euro/DDD, whereas it was 0.30 Euro/DDD for NSAIDs beyond the DU90% segment. The pattern of use of NSAIDs according to their GI risk showed that medium-risk diclofenac accounted for 66.45%, whereas low-risk ibuprofen was estimated to be 21.25% within the DU90% segment. Conclusion Factors other than evidence-based medicine (such as poor health education in the past that led to long-lasting consequences on the cultural behaviour of the general population as well as on the prescribing habits of physicians) have a dominating impact on the use of NSAIDs in SBD. Targeted education from independent sources in the prescribing, dispensing and use of drugs is required to improve the quality of prescription and use of NSAIDs in Serbia.

Spline functions in convolutional modeling of verapamil bioavailability and bioequivalence. II: Study in healthy volunteers

SummaryThe pharmacokinetics of a new verapamil retard tablet formulation have been investigated in a randomized cross-over bioequivalence study on 12 healthy subjects. The drug was given orally at a single new or standard retard tablet dose of 240mg and at a single intravenous dose of 5mg. Plasma verapamil concentrations were determined by HPLC. New retard tablets produced peak plasma verapamil concentrations of 81.34±5.69μg/l, time to peak plasma concentrations of 4.91±0.89h and an AUC (0–24h) of 1291±103.4h-μg/l, with a terminal phase half-life of 55.1±14.9h. After intravenous administration verapamil exhibited biphasic elimination kinetics with a terminal plasma half-life of 2.36±0.42h and systemic clearance of 34.32+5.811/h. Bioavailability of the new peroral retard formulation ranged from 19.49+4.41% to 67.69+11.70%. Absorption rates and amounts were evaluated by means of the spline-convolutional method. Input rates for the new verapamil retard formulation ranged from 0.77±0.20mg/h to 5.57+1.58mg/h. The cumulative amount of verapamil input was 39.17+9.71% for the new retard tablets. All pharmacokinetic parameters for the new verapamil retard tablet formulation, were in reasonable agreement with the data obtained on already registered verapamil retard formulations, indicating their bioequivalence

Disposal of Unused Drugs: Knowledge and Behavior Among People Around the World

The purpose of this systematic review was to determine the practice of medication disposal around the world and get insight into possible association between environmental awareness and peoples behavior regarding this issue. A literature search (2005-2015) was performed to identify reports with quantitative data on disposal practices published in peer-reviewed literature. The most common method for disposal of unused medications in households is disposal in the garbage (Kuwait, United Kingdom, Lithuania, Qatar, Serbia, Ghana, Bangladesh, Malta and Saudi Arabia). The practice of flushing drugs into the sewage system still takes place in New Zealand, USA and Bangladesh. Only in Sweden and Germany, practice of returning drugs to pharmacy was practiced to a larger extent. The environmental impact of improper medication disposal is expected in countries with poorly functioning waste management schemes (Middle Eastern, Asian and African countries). Lack of the adequate information and clear instructions on proper manners of drug disposal was reported in many surveyed countries (USA, New Zealand, Bangladesh, Malta and Ireland). Clear and definite connection between knowledge about environmental detrimental effects of improper drug disposal and the preference towards disposal methods could not be established. Many respondents were generally concerned with issues of inadequate medicines discarding but the behavior regarding disposal of unused drugs often did not equate the awareness (Serbia, USA, Kuwait, Malta and UK). The current data emphasizes the global issue of improper medicine disposal, prevalent in environmentally-aware people.

Pharmacogenetic Biomarkers as Tools for Pharmacoepidemiology of Severe Adverse Drug Reactions

Preclinical Research

Analysis of expired medications in Serbian households.

Abstract Introduction An ongoing issue of expired medications accumulating in some households is a universal problem around the world. The aim of the study was to investigate the extent and structure of expired medications in Serbian households, and to determine which therapeutic groups generated the most waste. Methods This was an observational, cross-sectional study conducted in households in the city of Novi Sad, Serbia. The study had been performed over 8 month period (December 2011 - July 2012) and it consisted of personal insights into the medication inventory in households. Results Of 1008 families, 383 agreed to participate and complete the questionnaire (38.3% response rate). In almost a half of households (44.4%), expired medications were maintained. The amount of expired medications was 402 items, corresponding to 9.2% of total medications presented in surveyed households. The majority of expired medications (64.7%) was in solid dosage (tablets, capsules, granules, lozenges), following semisolid (ointments, creams, gel, suppositories) and liquid dosage forms (drops, syrups). Expired medications in the households belonged mostly to 3 categories: antimicrobials for systemic use (16.7%), dermatological preparation (15.9%) and medications for alimentary tract and metabolism (14.2%). Conclusions This study revealed that there were relatively large quantities of expired medications in Serbian households, with a high prevalence of antibiotics for systemic use, anti-inflammatory and antirheumatic products, and medications for alimentary tract and metabolism.

Cost-Effectiveness of Everolimus for Second-Line Treatment of Metastatic Renal Cell Carcinoma in Serbia

BACKGROUND New targeted therapeutics for metastatic renal cell carcinoma (mRCC) enable an increment in progression-free survival (PFS) ranging from 2 to 6 months. Compared with best supportive care, everolimus demonstrated an additional PFS of 3 months in patients with mRCC whose disease had progressed on sunitinib and/or sorafenib. The only targeted therapy for mRCC currently reimbursed in Serbia is sunitinib. OBJECTIVE The aim of this study was to estimate the cost-effectiveness and the budget impact of the introduction of everolimus in Serbia in comparison to best supportive care, for mRCC patients refractory to sunitinib. METHODS A Markov model was designed corresponding with Serbian treatment protocols. A health care payer perspective was taken, including direct costs only. Treated and untreated cohorts were followed up over 18 cycles, each cycle lasting 8 weeks, which covered the lifetime horizon of mRCC patients refractory to the first-line treatment. Annual discounted rates of 1.5% for effectiveness and 3% for costs were applied. Transitions between health states were modeled by time-dependent probabilities extracted from published Kaplan-Meier curves of PFS and overall survival (OS). Utility values were obtained from the appraisals of other mRCC treatments. One-way and probabilistic sensitivity analyses were done to test the robustness and uncertainty of the base-case estimate. Lastly, the potential impacts of everolimus on the overall health care expenditures on annual and 4-year bases were estimated in the budget-impact analysis. RESULTS The incremental cost-effectiveness ratio for everolimus was estimated at €86,978 per quality-adjusted life-year. Sensitivity analysis identified the hazard multiplier, a statistical approximator of OS gain, as the main driver of everolimus cost-effectiveness. Furthermore, probabilistic sensitivity analyses revealed a wide 95% CI around the base-case incremental cost-effectiveness ratio estimate (€32,594-€425,258 per quality-adjusted life-year). Finally, an average annual budgetary impact of everolimus in first 4 years after its potential reimbursement would be around €270,000, contributing to <1% of the total budget in Serbian oncology. CONCLUSIONS Everolimus as a second-line treatment of mRCC is not likely to be a cost-effective option under the present conditions in Serbia, with a relatively limited impact on its budget in oncology. A major constraint on the estimation of the cost-effectiveness of everolimus relates to the uncertainty around the everolimus effect on extending OS. However, prior to a final decision on the acceptance/rejection of everolimus, reassessment of the whole therapeutic group might be needed to construct an economically rational treatment strategy within the mRCC field.