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Pharmacogenetics in transplantion
Abstracts – XIX Congress PTF / Pharmacological Reports 67S (2015) 2–45
hippocampal cells subjected to glutamic acid or hypoxia. Daidzein and raloxifene bind to estrogen receptors with SERMs properties, whereas DIM is representative of SAhRMs. Treatment with glutamic acid (1 mM, 6 h) or oxygen deprivation (5% CO2/95% N2, 18 h) caused apoptosis and neurotoxicity in mouse cell cultures. Daidzein, raloxifene, and DIM (1.10 mM) inhibited the glutamate/hypoxia-induced loss of mitochondrial membrane potential, caspase-3 activity, and lactate dehydrogenase release. In siRNA ERb-/GPR30-transfected cells, daidzein did not inhibit the glutamate-induced effects. Similarly, in the hippocampal neurons with silenced expression of Era, raloxifene lost its anti-hypoxic capacity. Furthermore, in the cells transfected with siRNA AhR/ ARNT, DIM was no longer protective. Our data point to strong neuroprotective potential of SERM and SAhRM in the hippocampal cells undergoing excitotoxicity and hypoxia. They also provide evidence for a key role of ER/AhR/ARNT signaling pathways in neuroprotection mediated by daidzein, raloxifene, and DIM, which may contribute to development of new therapeutic strategies. This work was supported by The National Science Centre, Poland grant No. 2011/01/N/NZ3/04786. Joanna Rzemieniec and Agnieszka Wnuk are holders of scholarship from the KNOW sponsored by Ministry of Science and Higher Education, Republic of Poland. http://dx.doi.org/10.1016/j.pharep.2015.06.035 Safety and Opimization of Pharmacotherapy Optimization of antibiotic therapy Anna Wiela-Hojen´ska *, Magdalena Hurkacz, Krystyna Głowacka Department of Clinical Pharmacology, Wrocław Medical University, Wrocław, Poland *Corresponding author. Contemporary antimicrobial therapy should be directed by objective criteria which allow for maximal effectiveness of treatment with minimal side effects. The major problem with significant clinical implication is the fact that under-dosing of antibiotics appears common. Therapeutic concentrations are frequently not achieved, leading to multiple bacterial resistance, which is associated with increased patient mortality, length of inpatient stay, extended drug courses exposing the patient to potentially toxic side effects. Typical pharmacokinetic parameters (Cl, Vd, t0,5, AUC, Cmax) do not adequately describe the altered PK/PD properties, especially in critically ill patients. In recent years, the efficacy of antibiotics has been improved through the use of three basic markers such: Cmax/MIC for antibiotics with pronounced concentration-dependent killing (aminoglycosides, fluoroquinolones, daptomycin), AUC/MIC for antibiotics with weak concentration-dependent effects, but with prolonged persistent effects (glycopeptides, fluoroquinolones, azithromycin, tigecycline), and T>MIC for antibiotics with a weak or no concentration dependency (b-lactams, carbapenems, clarithromycin, erythromycin, linezolid). Moreover antibiotics are the most irrationally prescribed drug class. So implementation of special guidelines for the hospital scenario and strict adherence should be ensured to promote their rational use. The spontaneous reporting of the adverse reactions to antibiotics is very important for identification of threats in local population. Close collaboration between physicians, pharmacists, clinical pharmacologists, clinical pharmacists, microbiologists and patients results in improved quality of antibiotic therapy. http://dx.doi.org/10.1016/j.pharep.2015.06.036
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Pharmacogenetics in transplantion Mateusz Kurzawski Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Szczecin, Poland Allogenic solid organ transplantation has become a routine procedure in patients with end stage organ diseases. However, successful maintenance of graft function usually cannot be achieved without administration of immunosuppressive drugs. Immunosuppressants represent drugs of narrow therapeutic index, hence, drug levels must be kept within therapeutic range, which is absolutely crucial for graft function preservation. Drug and its metabolite concentrations depend on efficiency of patient individual metabolism, and, in case of immunosuppressive agents, many enzymes and transporters involved in their metabolism and distribution are encoded by highly polymorphic genes. Therefore, a large part of interindividual variability in drug dosage and response is of genetic, hereditary nature. Recently, many studies were undertaken to investigate the relationship between genetic factors, immunosuppressive agents’ pharmacokinetics and therapy outcome. Those studies include, among others, a classic pharmacogenetic example, thiopurine S-methyltransferase (TPMT) deficiency in relation to toxicity of azathioprine, an impact of CYP3A4/CYP3A5 genetic variants on pharmacokinetics of calcineurin inhibitors, or influence of UGT1A9 polymorphism on course of treatment with mycophenolic acid. This presentation summarizes the recent state of knowledge in the field of pharmacogenetics related to solid organ transplantation (including studies performed in the Polish population), trying to settle whether genetic testing for polymorphic variants of xenobiotic-metabolizing enzymes, transport proteins or drug targets could be used for making immunosuppressive therapy more efficient and safe. http://dx.doi.org/10.1016/j.pharep.2015.06.037 Pharmacovigilance in Poland – Present and future Daria Schetz 1,2, Ivan Kocic´ 3 1
Department of Clinical Toxicology, Medical University of Gdansk, Gdan´sk, Poland 2 Pomeranian Centre of Toxicology, Gdan´sk, Poland 3 Department of Pharmacology, Medical University of Gdansk, Gdan´sk, Poland Rational use of medicines is highly important for every society, not only with respect to the public finance but also to safety of pharmacotherapy. Evidence based medicine (EBM) and pharmacovigilance (PHV) are the fundamental strategies for improvement in this field, however implementation of the principals of EBM and PHV in practice is extremely difficult. Poland has one of the lowest rate of adverse drug effects reporting in European Union. The main reason is lack of properly functioning regional adverse drug reactions monitoring centers, that should identify the hazard-risk associated with pharmaceutical products. In Pomeranian province such regional center was created in 2012, and thereafter adverse drug reporting is significantly higher. The center is involved in prevention campaigns at the local level. Based on experience of Department of Pharmacology, MUG in Pomerania Province such information strategy contributes to increase awareness by providing current information about drug-related issues. The best example of this is three-fold increase in adverse drug reactions reporting in Pomerania province after the publication of our first
hippocampal cells subjected to glutamic acid or hypoxia. Daidzein and raloxifene bind to estrogen receptors with SERMs properties, whereas DIM is representative of SAhRMs. Treatment with glutamic acid (1 mM, 6 h) or oxygen deprivation (5% CO2/95% N2, 18 h) caused apoptosis and neurotoxicity in mouse cell cultures. Daidzein, raloxifene, and DIM (1.10 mM) inhibited the glutamate/hypoxia-induced loss of mitochondrial membrane potential, caspase-3 activity, and lactate dehydrogenase release. In siRNA ERb-/GPR30-transfected cells, daidzein did not inhibit the glutamate-induced effects. Similarly, in the hippocampal neurons with silenced expression of Era, raloxifene lost its anti-hypoxic capacity. Furthermore, in the cells transfected with siRNA AhR/ ARNT, DIM was no longer protective. Our data point to strong neuroprotective potential of SERM and SAhRM in the hippocampal cells undergoing excitotoxicity and hypoxia. They also provide evidence for a key role of ER/AhR/ARNT signaling pathways in neuroprotection mediated by daidzein, raloxifene, and DIM, which may contribute to development of new therapeutic strategies. This work was supported by The National Science Centre, Poland grant No. 2011/01/N/NZ3/04786. Joanna Rzemieniec and Agnieszka Wnuk are holders of scholarship from the KNOW sponsored by Ministry of Science and Higher Education, Republic of Poland. http://dx.doi.org/10.1016/j.pharep.2015.06.035 Safety and Opimization of Pharmacotherapy Optimization of antibiotic therapy Anna Wiela-Hojen´ska *, Magdalena Hurkacz, Krystyna Głowacka Department of Clinical Pharmacology, Wrocław Medical University, Wrocław, Poland *Corresponding author. Contemporary antimicrobial therapy should be directed by objective criteria which allow for maximal effectiveness of treatment with minimal side effects. The major problem with significant clinical implication is the fact that under-dosing of antibiotics appears common. Therapeutic concentrations are frequently not achieved, leading to multiple bacterial resistance, which is associated with increased patient mortality, length of inpatient stay, extended drug courses exposing the patient to potentially toxic side effects. Typical pharmacokinetic parameters (Cl, Vd, t0,5, AUC, Cmax) do not adequately describe the altered PK/PD properties, especially in critically ill patients. In recent years, the efficacy of antibiotics has been improved through the use of three basic markers such: Cmax/MIC for antibiotics with pronounced concentration-dependent killing (aminoglycosides, fluoroquinolones, daptomycin), AUC/MIC for antibiotics with weak concentration-dependent effects, but with prolonged persistent effects (glycopeptides, fluoroquinolones, azithromycin, tigecycline), and T>MIC for antibiotics with a weak or no concentration dependency (b-lactams, carbapenems, clarithromycin, erythromycin, linezolid). Moreover antibiotics are the most irrationally prescribed drug class. So implementation of special guidelines for the hospital scenario and strict adherence should be ensured to promote their rational use. The spontaneous reporting of the adverse reactions to antibiotics is very important for identification of threats in local population. Close collaboration between physicians, pharmacists, clinical pharmacologists, clinical pharmacists, microbiologists and patients results in improved quality of antibiotic therapy. http://dx.doi.org/10.1016/j.pharep.2015.06.036
11
Pharmacogenetics in transplantion Mateusz Kurzawski Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Szczecin, Poland Allogenic solid organ transplantation has become a routine procedure in patients with end stage organ diseases. However, successful maintenance of graft function usually cannot be achieved without administration of immunosuppressive drugs. Immunosuppressants represent drugs of narrow therapeutic index, hence, drug levels must be kept within therapeutic range, which is absolutely crucial for graft function preservation. Drug and its metabolite concentrations depend on efficiency of patient individual metabolism, and, in case of immunosuppressive agents, many enzymes and transporters involved in their metabolism and distribution are encoded by highly polymorphic genes. Therefore, a large part of interindividual variability in drug dosage and response is of genetic, hereditary nature. Recently, many studies were undertaken to investigate the relationship between genetic factors, immunosuppressive agents’ pharmacokinetics and therapy outcome. Those studies include, among others, a classic pharmacogenetic example, thiopurine S-methyltransferase (TPMT) deficiency in relation to toxicity of azathioprine, an impact of CYP3A4/CYP3A5 genetic variants on pharmacokinetics of calcineurin inhibitors, or influence of UGT1A9 polymorphism on course of treatment with mycophenolic acid. This presentation summarizes the recent state of knowledge in the field of pharmacogenetics related to solid organ transplantation (including studies performed in the Polish population), trying to settle whether genetic testing for polymorphic variants of xenobiotic-metabolizing enzymes, transport proteins or drug targets could be used for making immunosuppressive therapy more efficient and safe. http://dx.doi.org/10.1016/j.pharep.2015.06.037 Pharmacovigilance in Poland – Present and future Daria Schetz 1,2, Ivan Kocic´ 3 1
Department of Clinical Toxicology, Medical University of Gdansk, Gdan´sk, Poland 2 Pomeranian Centre of Toxicology, Gdan´sk, Poland 3 Department of Pharmacology, Medical University of Gdansk, Gdan´sk, Poland Rational use of medicines is highly important for every society, not only with respect to the public finance but also to safety of pharmacotherapy. Evidence based medicine (EBM) and pharmacovigilance (PHV) are the fundamental strategies for improvement in this field, however implementation of the principals of EBM and PHV in practice is extremely difficult. Poland has one of the lowest rate of adverse drug effects reporting in European Union. The main reason is lack of properly functioning regional adverse drug reactions monitoring centers, that should identify the hazard-risk associated with pharmaceutical products. In Pomeranian province such regional center was created in 2012, and thereafter adverse drug reporting is significantly higher. The center is involved in prevention campaigns at the local level. Based on experience of Department of Pharmacology, MUG in Pomerania Province such information strategy contributes to increase awareness by providing current information about drug-related issues. The best example of this is three-fold increase in adverse drug reactions reporting in Pomerania province after the publication of our first