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PDF File of All Submitted Abstracts APHAR 2012 Abstract Preview MEETING ABSTRACTS 18th Scientific Symposium of the Austrian Pharmacological Society (APHAR) Joint Meeting with the Croatian, Serbian and Slovenian Pharmacological Societies Graz, Austria, 20–21 September 2012 A1 Acknowledgements: This work was supported in part by the Antidepressant-like effects of benzodiazepine site inverse Ministry of Education and Science, Republic of Serbia, grant no. agonists in the rat forced swim test 175076. Janko Samardžić and Dragan I Obradović Institute of Pharmacology, Clinical Pharmacology and Toxicology, A2 Medical Faculty, University of Belgrade, 11129 Belgrade, Serbia Methadone-drugs interactions: possible causes of methadone- E-mail: [email protected] related deaths Vesna Mijatović1, Isidora Samojlik1, Stojan Petković2 and Nikša Background: There are three kinds of allosteric modulators acting 2 Ajduković through the benzodiazepine (BZ) binding site of the GABA 1 A Department of Pharmacology, Toxicology and Clinical receptor: positive (agonist), neutral (antagonist), and negative Pharmacology, Faculty of Medicine, University of Novi Sad, 21000 (inverse agonist) modulators. Agonists and inverse agonists 2 Novi Sad, Serbia; Department of Forensic Medicine, Faculty of commonly exert bidirectional influences on observed behavioral Medicine, University of Novi Sad, 21000 Novi Sad, Serbia parameters. In the present study we have investigated the E-mail: [email protected] modulation of behavioral responses to environmental novelty in two unconditioned paradigms: spontaneous locomotor activity (SLA) and Background: Methadone is an effective analgesic and it is widely forced swim test (FST), elicited by DMCM (methyl-6,7-dimethoxy-4- used to suppress withdrawal symptoms from other opiates. Its ethyl-beta-carboline-3-carboxylate), a non-selective inverse agonist, consumption is usually associated with concomitant drug use in in the dose range that previously did not produce anxiogenic effects heroin addicts, and this combination is a possible risk factor for and convulsions. lethal outcome. The aim of this study was to analyze characteristics Methods: SLA in the test cage (40 x 25 x 35 cm) during 30 min was of methadone-related deaths (MRDs), and to evaluate the recorded automatically, beginning 20 min after i.p. injections concomitant use of the drugs that can contribute to methadone (DMCM 0.1, 0.5 and 1 mg/kg) without any habituation. FST was toxicity. performed in a glass cylinder, 45 cm high, 20 cm diameter filled with Methods: To investigate MRDs, a 10-year retrospective study was water up to a height of 20 cm, with a temperature of 21–23 °C. Male carried out (2001–2010) at the Institute of Forensic Medicine in Novi Wistar rats were exposed to two swimming sessions (an initial 15- Sad, Clinical Centre of Vojvodina, Serbia. These data included age min pretest session, followed 24 h later by a 5-min test session). and sex of subjects, and drugs detected in post-mortem samples of The animals received i.p. 0.1, 0.5 and 1 mg/kg of DMCM or vehicle, blood and urine. Toxicological screening and quantification of drugs 20 min before the test session. A rat was considered immobile were carried out in blood and urine using gas chromatography-mass whenever it floated passively in the water and only made spectrometry. Methadone concentration in blood was defined to be movements necessary to keep its head above the water line. lower than 200 µg/L, 200–1000 µg/l, or higher than 1000 µg/L. Results: ANOVA showed a significant effect of treatment on the Results: A total number of 40 MRDs was identified (19.1% of all total immobility time of the animals during 30 min of monitoring of deaths associated with fatal opiate-related poisoning). The median spontaneous locomotor activity (p < 0.05). Namely, Dunnett's age of victims at the time of death was 31, whereas the majority of analysis showed that the highest applied dose of DMCM (1 mg/kg) them (80%) were male. The concentration of methadone in blood exerted the activity-decreasing effect related to vehicle. In FST and urine samples was quantified in 11 cases and in 9 of them it during the test session, ANOVA indicated statistically significant was lower than 200 µg/L (mean concentration 79.5 µg/L). In one effects of DMCM (p < 0.05) on the average immobility time of case it was 245 µg/L, whereas in the other one methadone was animals. Dunnett’s analysis showed that DMCM (1.0 mg/kg) detected only in urine in concentration of 1209 µg/L. In 7 cases only significantly increased immoblity, but at the lowest applied dose methadone was found (17.5 % of MRDs); 47.5% of MRDs was DMCM (0.1 mg/kg) decreased immobility, and exerted acute associated with other drugs – the average number of associated antidepressant-like effects. drugs was 3.5, while in blood samples of 35% of MRDs other illicit Conclusions: These data suggest that negative modulation at drugs were identified. The most frequent concomitants were one or GABAA receptors might have triggered the acute antidepressant-like more benzodiazepines (67.5% of MRDs), followed by antipsychotics effects in rats and these effects were not confounded by locomotor (15%), tramadol (15%) and antidepressants (12.5%). The most influences. On the other hand, these effects are not straightforward, commonly identified benzodiazepine was diazepam. because they exert a kind of bimodal influence. Furthermore, these Conclusions: In MRDs a low methadone level combined with other results encourage the synthesis of new BZ site ligands, aimed to drugs was most frequently noted. The mechanism of death cannot possess more selective affinity/efficacy profiles. be attributed to particular pathway. The most detected concomitants were well-known inhibitors, inducers or metabolic substrates of CYP3A4 and CYP2D6 involved in metabolism of methadone. APHAR 2012 Abstract Preview Moreover, they can increase the risk of torsades de pointes and of Background: The medicines for peptic ulcer and gastro- respiratory depressant effects of methadone. Further studies could esophageal reflux disease (ATC subgroup A02B) are among the clarify the possible mechanism of death where methadone is used most commonly prescribed class of drugs. The aim of this study was in combination with benzodiazepines in order to prevent MRDs. to analyze the pattern of consumption of histamine H2 receptor Acknowledgements: This research is part of project no. 41012 antagonists (H2RAs) and proton pump inhibitors (PPIs) in Serbia in which is financially supported by the Ministry of Science, Republic of 2010 in comparison with Croatia and Sweden. Serbia. Methods: The data on the consumption of medicines have been provided from the databases of the national regulatory agencies. A3 The results were expressed as the number of defined daily doses Use of ACE inhibitors in Serbia in 2010 per 1000 inhabitants per day (DID). A qualitative analysis was Boris Milijašević, Zdenko Tomić, Ana Sabo, Aleksandar Rašković carried out according to the drug utilization 90% (DU90%) approach. and Momir Mikov Results: The overall consumption of medicines from A02B Department of Pharmacology, Toxicology and Clinical subgroup in 2010 in Serbia was 22.9 DID, whereas in Croatia and Pharmacology, Faculty of Medicine, University of Novi Sad, 21000 Sweden was 32.8 DID and 48.6 DID, respectively. In Serbia, H2RAs Novi Sad, Serbia accounted for 71.8% (16.5 DID) of medicines used within A02B E-mail: [email protected] subgroup, while in Croatia H2RAs accounted for 37.3% (12.2 DID) and in Sweden 2.2% (1.1 DID). In the same year, the utilization of Background: Cardiovascular diseases are the most frequent cause PPIs in Serbia (6.5 DID) was more than three times lower than in of morbidity and mortality in many countries. That explains why Croatia (20.6 DID) and more than seven times lower than in medications for the treatment of cardiovascular diseases are group Sweden (47.3 DID). The bulk of prescription (DU90%) was made up of drugs with largest consumption, and ACE inhibitors take a large of 3 (out of 7) medicines in Serbia, 5 (out of 8) medicines in Croatia part in the consumption. The aim of this study was to analyze the and 5 (out of 14) medicines in Sweden. The most frequently used consumption of ACE inhibitors in Serbia in 2010 compared with medicine from the A02B subgroup in Serbia was ranitidine (56.0%, Norway, a country with a developed pharmacotherapeutic practice. i.e. 12.8 DID), in Croatia pantoprazole (36.5%, i.e.12.0 DID) and in Methods: The data about the use of ACE inhibitors in Serbia were Sweden omeprazole (81.3%, i.e. 39.0 DID). taken from the Agency for Drugs and Medical Devices of the Serbia. Conclusions: The overall utilization of the medicines for peptic The data about drug consumption in Norway were taken from the ulcer and gastro-esophageal reflux disease was notably lower in official website of the Norwegian Institute of Public Health. Serbia in comparison with Croatia and Sweden. Besides the Results: In Serbia, the use of drugs of first choice in the treatment quantity, the pattern of use showed remarkable differences. Most of hypertension was very uneven, where the consumption of ACE commonly used medicines from the A02B subgroup in Serbia were inhibitors was dominant. Opposed to this condition, the consumption H2RAs whereas in Croatia and Sweden were PPIs. These findings of the first choice antihypertensive drugs was very balanced in suggest that implementation of pharmacotherapeutic guidelines in Norway. Total consumption of ACE inhibitors in Serbia in 2010 year Serbia is needed in order to achieve harmonization in prescribing was 190.4 defined daily doses per 1000 inhabitants per day (DID) practice. and total consumption of ACE inhibitors in Norway in 2010 year was Acknowledgements: This research was financially supported by 51.7 DID.
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