12th Congres SRFTTC

Congress President
Prof. Dr. Victor Voicu University of Medicine and Pharmacy Bucharest, Fellow of the Romanian Academy
Congress Honorary Presidents:

Prof. Dr. Folke Sjoqvist, Prof. Dr. Florian Popa Professor Emeritus of Clinical Pharmacology, Karolinska Institute in Stockholm, Sweden Rector of University of Medicine and Pharmacy, Carol Davila, Bucharest Romania
Congress Honorary Vice-Presidents and International Scientific Commitee

Prof. Dr. Jiri Bajgar, Czech Republic Prof. Dr. Kim Brsen, Denmark Prof. Dr. Svein Dahl, Norway Prof. Dr. Hege Christensen, Norway Prof. Dr. Jaime Kapitulnik, Israel Prof. Dr. Franz Kerek, Germany Prof. Dr. Edward Krenzelok, USA Prof. Dr. Momir Mikov, Serbia Prof. Dr. Jose de Leon, USA Prof. Dr. Olavi Pelkonen, Finland Dr. Christos Potsides, Greece Dr. Stanislav Yanev, Bulgaria Prof. Dr. Horst Thiermann, Germany
Organizing Committee
Prof. Dr. Victor A. Voicu President
Dr. Vlad Negulescu Dr. Flavian Rdulescu Dr. Ec. Luminia Horhot
Scientific Committee
Prof. Victor Voicu President
Prof. Dr. Anca Buzoianu Dr. Gabriela Cioca Prof. Dr. Rodica Cinc Assoc. Prof. Dr. Dana Goa Prof. Dr. Ioan Lascr Prof. Dr. Sorin Leucua Prof. Dr. Florica Popescu Dr. Flavian Rdulescu Prof. Dr. Liviu Safta
Prof. Dr. Valentin Crlig
Prof. Dr. Oana Andreia Coman Prof. Dr. Iosefina C. Corciovei Prof. Dr. Carmen Cristescu Prof. Dr. Barbu Cuparencu Prof. Dr. Maria T. Dogaru Prof. Dr. Ioan Fulga Prof. Dr. Aurelia Nicoleta Cristea
Prof. Dr. Ctlina Lupuoru Prof. Dr. Radu Macovei Assoc. Prof. Dr. Ioan Magyar
Prof. Dr. Ionel Sinescu
Prof. Dr. Adrian Streinu-Cercel Prof. Dr. Vlaicu andor Assoc. Prof. Dr. Bogdan erb Assoc. Prof. Dr. Andrei Tica Prof. Dr. Coriolan Ulmeanu Prof. Dr. Gheorghe arlung Assoc. Prof. Dr. Daniel Vasile
Prof. Dr. Andrei Medvedovici Dr. Dalia Miron
Prof. Dr. Constantin Mircioiu Assoc. Prof. Dr. Cristina Mogoan Prof. Dr. Ostin Mungiu Prof. Dr. Mihai Nechifor
Prof. Dr. Victor Dumitracu Prof. Dr. Virginia Gligor
Prof. Dr. Mircea Pavelescu
Assoc. Prof. Dr. Aurelian Zugravu
Journal published in cooperation with:
National Institute of Infectious Diseases "Prof. Dr. Matei Bal"
Romanian Society of Pharmacology, Therapeutics and Clinical Toxicology Romanian Academy of Medical Sciences University of Medicine and Pharmacy "Carol Davila"
Academic Medical Database

CNCSIS Category: B+ Code: 605 NLM (National Medical Library) EBSCOhost IndexCopernicus getCITED
Vol. XV
Supplement II
June 2011
Founders Emanoil Manolescu
Mircea Angelescu
Liviu Ioan Miclea
Editor-in-Chief Therapeutics Adrian Streinu-Cercel (Professor, Member of Academy of Medical Science, Head of Department of Infectious Diseases, National Institute of
Infectious Diseases "Prof. Dr. Matei Bal", University of Medicine and Pharmacy Carol Davila Bucharest)
Editor-in-Chief Clinical Pharmacology and Toxicology Victor A. Voicu (Professor, Member of Romanian Academy, Head of Department of Pharmacology, Toxicology and Clinical Psychopharmacology,
University of Medicine and Pharmacy Carol Davila Bucharest)
International Scientific Board

Laure Aurelian (Professor, Senior Associate, The Johns Hopkins School of Public Health), d Hege Christensen (Professor, School of Pharmacy, University of Oslo, Norway), d Jaime Kapitulnik (Professor, The Hebrew University of Jerusalem, Israel), d Momir Mikov (Senior Lecturer, School of Pharmacy, University of Otago, New Zealand), d Stanislav Yanev (Professor, Head of Department Drug and Toxicology, Bulgarian Academy of Science, Bulgaria), d Olavi Pelkonen (Professor, Head of the Department of Pharmacology and Toxicology, University of Oulu, Finland), d Olivier Patey (Professor, Chef de service des maladies infectieuses et tropicales CHI, Villeneuve-Saint Georges, France), d George C. Rodgers (Professor of Pediatrics, Pharmacology and Toxicology, University of Louisville, Kentucky, USA), d Robert Smith (Professor, Brown Medical School, U.K), d Jean Paul Stahl (Professor, Rdacteur en chef de Mdecine et Maladies Infectieuses, Elsevier Maison, Grenoble, France), d Michel Urbain (Chief of Research Department, Societe de Etude et de Research Biologique, Paris, France), d Andrei Iagru (Department of Nuclear Medicine, Stanford University, USA) d Serafim Kastanakis (Professor, University of Crete, Greece)
Romanian Scientific Board Ioana Alina Anca (Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Eduard Apetrei (Professor, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Romanian Academy of Medical Science), d tefan Sorin Aram (Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Constantin Arion (Professor, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Romanian Academy of Medical Science), d Anca Buzoianu (Professor, University of Medicine and Pharmacy Iuliu Haieganu Cluj-Napoca) d Eugen Ciofu (Professor, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Academy of Medical Science), d Carmen Dorob (Professor, University of Medicine and Pharmacy Gr.T. Popa, Iassy), d Constantin Dumitrache (Professor, Member of Romanian Academy, University of Medicine and Pharmacy Carol Davila Bucharest), d Leonida Gherasim (Professor, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Romanian Academy of Medical Science), d Ioan Hulic (Professor, Member of Romanian Academy, University of Medicine and Pharmacy Gr.T. Popa, Iassy), d Daniela Ion (Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Ion Fulga (Professor, Head of Department of Pharmacotherapy and Pharmacology, University of Medicine and Pharmacy Carol Davila Bucharest), d Sorin Leucua (Professor, University of Medicine and Pharmacy Oradea), d Radu Macovei (Professor, Head of Department of ICU-Toxicology, University of Medicine and Pharmacy Carol Davila Bucharest), d Alina Manolescu (researcher, ICSMCF), d Nicolae Miu (Professor, University of Medicine and Pharmacy Iuliu Haieganu Cluj-Napoca), d Ostin C. Mungiu (Professor, Head of Department of Pharmacology and Clinical Toxicology, University of Medicine and Pharmacy Gr.T. Popa, Iassy), d Lucian Negruiu (Professor, University of Medicine and Pharmacy Victor Babe Timioara), d Dumitru Oreanu (Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Florian Popa (Professor, Chancellor of University of Medicine and Pharmacy Carol Davila Bucharest), d Irinel Popescu (Professor, Head
of Department of Surgery and Liver Transplant, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Academy of Medical Science), d Laureniu Mircea Popescu (Professor, Member of Romanian Academy, Head of Department of Celular Biology, University of Medicine and Pharmacy Carol Davila Bucharest), d Valeriu Popescu (Professor, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Romanian Academy of Science), d Florica Stniceanu (Professor, Univeristy of Medicine and Pharmacy Carol Davila Bucharest), d Dan Tulbure (Professor, Head of Department of ICU, University of Medicine and Pharmacy Carol Davila Bucharest), d Doina ulescu (Professor, University of Medicine and Pharmacy Iuliu Haieganu Cluj-Napoca), d Coriolan Ulmeanu (Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Doina Velican (Researcher, Member of Romanian Academy of Medical Science), d Florin Cruntu (Associate Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Adrian Gabriel Popescu (Associate Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Paraschiva Postolache (Associate Professor, University of Medicine and Pharmacy Gr.T. Popa, Iassy), d Alexandru Rafila (Associate Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Adriana Hristea (Lecture, University of Medicine and Pharmacy Carol Davila Bucharest), d Gabriela Leanu (Lecture, University of Medicine and Pharmacy Carol Davila Bucharest) d Ion Lic (Lecture, University of Medicine and Pharmacy Carol Davila Bucharest), d Raluca Papacocea (Lecture, University of Medicine and Pharmacy Carol Davila Bucharest), d George Jugulete (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Voichia Lzureanu (Assistant Professor, University of Medicine and Pharmacy Victor Babe Timioara), d Anca Macovei (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Anca Streinu-Cercel (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Andrei Tica (Associate Professor, University of Medicine and Pharmacy Craiova) d Mihail Tudosie (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest)
General Registrar of Editorial Board

Pharmacy Carol Davila Bucharest)
Editorial Office
Victoria Aram (Associate Professor, University of Medicine and Issue Editor Elisabeta Otilia Benea (Associate Professor, University of Medicine
and Pharmacy Carol Davila Bucharest) Monica Luminos (Associate Professor, University of Medicine and Pharmacy Carol Davila Bucharest)
Institutul Naional de Boli Infecioase Prof. Dr. Matei Bal, Pavilionul IV, Etaj 4 Dr. Calistrat Grozovici, Nr. 1, Sect. 2, Bucureti, C.P. 021105, O.P. 10 Email: terapeutica@terapeutica.ro cristina.negulescu@terapeutica.ro Published by Editura Rp.
Cristina Negulescu Oana Streinu-Cercel Ana-Maria Tudor Publishing Editor
CUI RO9954898, RC J40/7184/1997
Address: Str. Drumul Murgului nr. 2 sector 3, Bucureti, Tel/Fax: 031.80..40.513 E-mail: vlad.negulescu@terapeutica.ro Web: www.terapeutica.ro ISSN 2066-0170
Vlad Negulescu (Assistant Professor, University of Medicine and

Pharmacy Carol Davila Bucharest)
12-th International Congress of the Romanian Society of Clinical Pharmacology, Therapeutics and Toxicology 7-11 June 2011, Bucharest, Romania Copyright reserved 2011
CONGRESS PROGRAMME
7-th June 2011 Crowne Plaza Hotel

19.00 Welcome Concert, Crowne Plaza Hotel, Ballroom Piano Recital by Horia Mihail, concert soloist of the Romanian Radio Symphonic Orchestras Welcome Cocktail, Crowne Plaza Hotel, Ballroom
20.00
8-th June 2011 Crowne Plaza Hotel - Conference Room A

8.30 9.00 Opening Ceremony Prof. Dr. Victor A. Voicu, Prof. Dr. Edward P. Krenzelok, Prof. Dr. Hege Christensen, Prof. Olavi Pelkonen, Prof. Dr. Jaime Kapitulnik, Prof. Dr. Svein G. Dahl, Prof. Dr. Horst Thiermann, Prof. Dr. Jose de Leon, Prof. Dr. Franz Kerek, Prof. Dr. Momir Mikov, Prof. Dr. Stanislav Yanev, Prof. Dr. Christos Potsides, Prof. Dr. Mircioiu Constantin, Prof. Dr. Andrei Medvedovici
9.00-10.30
Conference Room A Chairs: Prof. Jaime Kapitulnik, Prof. Svein G. Dahl, Prof. Hege Christensen Toxokinetics as a key to the integrated toxicity risk assessment based primarily on nonanimal approaches Olavi Pelkonen A profile of acetaminophen (paracetamol) toxicity in the United State Edward P. Krenzelok Synergic effect of hyperglycemia and bilirubin on apoptosis of microvascular endothelial cells of the blood-brain barrier Clara Benaim, Shlomo Sasson, Jaime Kapitulnik Discussions Coffee break
Session I - Invited Speakers Lectures
9.00-9.30 9.30 - 10.00 10.00 - 10.30 10.30 - 10.45 10.45-11.00
XV, Vol.15, Supplement II/2011
12-th International Congress of Romanian Society of Clinical Pharmacology, Therapeutics and Toxicology
11.00-13.00
Conference Room A Chairs: Prof. Olavi Pelkonen, Prof. Jose de Leon, Prof. Constantin Mircioiu The future (or lack of future) of personalized prescription in psychiatry. Jose de Leon Molecular structure and ligand binding of monoamine trasporter proteins Svein G. Dahl Mechanisms involved in the pharmacokinetic interaction between atorvastatin and cyclosporine A Hege Christensen, Rune Amundsen, Anders Asberg Discussions Lunch
Session II - Invited Speakers Lectures
11.00-11.30 11.30-12.00 12.00-12.30 12.30- 12.45 13.00-14.00
14.00-15.30
Conference Room A Chairs: Prof. Edward P. Krenzelok, Prof. Stanislav Yanev, Prof. Andrei Medvedovici Prediction of the biological fate of oximes Victor A. Voicu, Flavian Rdulescu Why do patients die from intentional OP-insecticide poisoning in spite of proper use of antidotes? Horst Thiermann, Thomas Zilker, Florian Eyer, Franz Worek Host-guest inclusion of some cation type aldoximes on macrocyclic cavities: ESI/MS approach for fast screening Victor A. Voicu, Andrei Medvedovici, Florin Albu Disscusions Coffee break
Session III - Invited Speakers Lectures
14.00 14.30 14.30 15.00 15.00 15.30 15.30 - 15.45 15.30-15.45
15.45-19.00
Conference Room A Chairs: Prof. Franz Kerek, Prof. Horst Thiermann, Prof. Momir Mikov Drug absorbtion from the gastrointestinal tract and the influence of probiotics Momir Mikov, Hani Al-Salmi, Svetlana Goloorbin-Kon Counterfeit drugs: cure or threat Svetlana Goloorbin-Kon Immune system and drug metabolism interactions Stanislav Yanev Targeting the innate imune receptors, as promising approach for drug-discovering Franz Kerek, Victor A. Voicu Newer developments in enviromental risk assessment according to EU legislation Christos Y. Potsides Research concerning inclusion of DTPA Zn in microemulsions for improving its bioavailability and efficacy as decontaminant in managing radiological terrorist incidents Constantin Mircioiu, Victor A. Voicu, Marilena Jiquidi, Otilia Cintez, Eugen Reviu, Manuela Spiroiu, Flavian Rdulescu In vitro drug release methodologies for topical semisolid dosage forms Flavian Radulescu, Dalia Miron, Victor Voicu, Constantin Mircioiu Disscusions
Therapeutics, Pharmacology and Clinical Toxicology
Session IV - Invited Speakers Lectures
15.45 16.00 16.00 - 16.15 16.15 16.45 16.45 17.15 17.15 - 17.45 17.45 - 18.15
18.15 - 18.30 18.30 - 19.00

6
12-th International Congress of the Romanian Society of Clinical Pharmacology, Therapeutics and Toxicology
9-th June 2011 Crowne Plaza Hotel, Conference Rooms A Session V - Experimental Pharmacology
9.00-11.00
Conference Room A Chairs: Prof. Mihai Nechifor, Prof. Oana Andreia Coman
9.00 - 9.15
9.15 -9.30 9.30 - 9.45 9.45 - 10.00 10.00 - 10.15 10.15 - 10.30 10.30 - 10.45 10.45 - 11.00 11.00-11.15
Research about the plasma and saliva concentrations of bivalent cations in patients with oral malignant tumors Mihai Nechifor, Elena Luca, Irina Gradinaru, Eugenia Popescu, Mihaela Baican, Diana Ciubotariu, Florina Crivoi, Cristina Gales Influence of ceftazidime and moxifloxacin on sperm motility Elena Antohi, Cristina Gales, Mihai Nechifor Manganese influence on morphine physical dependence and brain reward system in rats Diana Ciubotariu, Ileana Palamaru, Mihai Nechifor Possible cannabinomimetic effects for high doses of metamizole sodium in mice H. Punescu, Eugenia Panaitescu, Isabel Ghi, Oana Andreia Coman, I. Fulga Possible potentiation between high doses of acetaminophen and FAAH inhibitors in central analgesia Oana Andreia Coman, H. Punescu, Isabel Ghi, I. Fulga The antioxidant N-acetylcysteine effect in physical effort to Race Horses Nicoleta Taus, Monica Potrovita, Valentin Necula, Antonela Diana Hirceaga Screening of oxime efficacy in the neurotoxic organophosporous compounds poisoning Cristina Sarbulescu Secara, B. Patrinichi, Rodica Alexandrescu, C Draghici, V.. A. Voicu Disscusions Coffee break
11.15-13.00
Conference Room A Chairs: Prof. Ctlina Elena Lupuoru, Prof. Vlaicu andor Paracetamol analgesia. cannabinoid connection andor Vl Amphetamine- myorelaxant agents interactions in an experimental model Cuparencu B, Albu Silvia, Safta L, andor Vl. Calcitonin in ulcer treatment andor Vl Cimetidine in experimental CCL4-induced hepatitis andor Vl The effects of novel copolymeric matrices for indomethacin in experimental somatic nociception Liliana Taru, Andra Sabina Valeanu, Loredana Ni, Aurica Chiriac Biocompatibility evaluation and investigation of magnesium soft mater vesicles effects on the cognitive processes in rats Liliana Tartau, Catalina Elena Lupusoru, Diana Ciubotariu, Viorel Melnig Features, mechanisms and morphometric correlation of endothelium-dependent relaxation, as revealed by time-course analysis and the use of different precontraction agents Hogas MM, Serban IL, Oprisa C, Tucaliuc ES, Hurjui L, Nechifor M, Serban DN Lunch
7
Session VI - Experimental Pharmacology
11.15 - 11.30 11.30 - 11.45 11.45 - 12.00 12.00 - 12.15 12.15 - 12.30 12.30 - 12.45 12.45 - 13.00
13.00-14.00
7-11 June 2011, Bucharest, Romania
9.00-10.15
Conference Room B Chairs: Prof. Coriolan Ulmeanu, Prof. Florin Popescu Acute liver failure in acute poisoning in children Coriolan Ulmeanu, Gabriela Viorela Niescu, Elena Mdlina Petran Crystalluria - The prevalence in pediatric poisoning Gabriela Viorela Niescu, Alexandru Ulmeanu, Coriolan Ulmeanu Toxic and hypersensitivity reactions to contact with Cnidarians Florin-Dan Popescu, Vieru Mariana, Adriana Mihaela Tudose, Florica Popescu Antidote versus non-specific treatment of acute poisoning in children Ioan Magyar, Alina Maghiar, Adriana Moldovan, Carmen Pantis, Mohamed Bouyakhrichan Lead poisoning caused by boilers used to plum brandy distillation Mitrut Anca Oana, Gofita Eliza, Mitrut Paul, Calina Daniela Disscusions Coffee break
Session VII - Clinical Toxicology
9.00 - 9.15 9.15 - 9.30 9.45 - 10.00 10.00 - 10.15 10.15 - 10.30 10.15 - 10.30 10.30-10.45
10.45-13.00
Session VIII - Pharmacogenetics and Clinical Pharmacology

Conference Room B Chairs: Prof. Anca Dana Buzoianu, Prof. Florica Popescu
10.45 - 11.00
11.00 - 11.15 11.15 - 11.30 11.30 - 11.45 11.45 - 12.00 12.00 - 12.15 12.15 - 12.30 12.30 - 12.45 12.45 - 13.00 13.00-14.00
Genotype-phenotype correlations between the alleles of the CYP2C19 polymorphism and pharmacokinetic parameters in romanian epileptic patients Buzoianu Anca Dana, Bocan Ioana Corina, Maier Codruta, Trifa AP, Militaru Claudia, Major Z What are the essential Pharmacological knowledge, skills and attitudes for medical students ? Buzoianu Anca Dana Pharmacogenetics of the side effects concerning atypical antipsychotic medication Popescu Florica, Mitrulescu Bianca, Popescu F.D, Nicoli Elena Raluca, Ionete Oana Mariana The influence of pharmacogenetics studies on individualized cancer chemotherapy Elena-Raluca Nicoli, Florica Popescu, Alina Cimpoeru, Gabriela Avram, Mihai Ioana CETP Inhibitors: a new therapy in atherosclerotic cardiovascular disease Lavinia Codrua Gligor, Rzvan Gligor, erban Gligor, Virginia Gligor Study of the sensitivity to antibiotics of Staphylococcus aureus strains isolated from genital infections Mitrut Anca, Calina Daniela, Gofita Eliza, Rosu Lucica, Mitrut Paul The management of acute bacterial pneumonia in elderly patients Mitrut Anca Oana, Calina Daniela Mitrut Paul, Gofita Eliza Research on Ceftazidime - induced neurotoxicity in in-patients with renal diseases Buleandra Carmen, Georgescu Costinela, Nechifor Mihai Disscusions Lunch
12-th International Congress of the Romanian Society of Clinical Pharmacology, Therapeutics and Toxicology
14.00-16.00
Session IX- Clinical Pharmacology and Therapeutics

Conference Room A Chairs: Assoc. Prof. Daniel Vasile, Prof. Radu Spineanu
14.00 - 14.15 14.15 - 14.30 14.30 - 14.45 14.45 - 15.00
15.00 - 15.15
15.15 - 15.30
15.30 - 15.45 15.45 - 16.00 15.15 - 15.30
Spider bites causing cutaneous adverse reactions Mariana Vieru, Florin-Dan Popescu, Florica Popescu Pharmacotoxicological aspects related to Latrodectism Florica Popescu, Florin-Dan Popescu, Mariana Vieru Confirming Gilbert Syndrome by Rifampin Test Spineanu Radu, Cheregi Simona, Heredea Liliana, Szilgyi Ariana, Szilgyi Gheorghe Role of extracellular contrast agents in hepatocarcinoma evaluation Cristiana Iulia Dumitrescu, Daniela Dumitrescu, Anca Berbecaru Iovan, Maria Bogdan, Mihaela Burlacu, Alexandru Ciobanu, Popescu Florica The role of contrast agents in computed tomography to detect and characterize focal liver disease Cristiana Iulia Dumitrescu, Daniela Dumitrescu, Sergiu Cazacu, Anca Berbecaru Iovan, Maria Bogdan, Mihaela Burlacu, Cornel Tambura, Popescu Florica 25 years of fluoxetine: how far are we from an optimal treatment for depression? Nicolae Florin Taina, Daniel Vasile, Octavian Vasiliu, Andrei Gabriel Mangalagiu, Beatrice Stanescu Nightmare pharmacologic treatment in posttraumatic stress disorder- a systematic literature review Nicolae Florin Taina, Daniel Vasile, Octavian Vasiliu, Andrei Gabriel Mangalagiu Disscusions Coffee break
BIOGRAPHY
OLAVI PELKONEN
Olavi Pelkonen has MD (1973) and PhD degrees (1973). He was a post-doctoral fellow at the National Institutes of Health, Bethesda, Maryland (1976-1977) and 1978-2010 been Associate and Full Professor of Pharmacology as well as Head of the Department in Oulu, Finland. He has been as a visiting professor in Spain, UK and Australia. He has been participating, also as a working group leader, in European Union COST Actions (since 1986, the latest Action B25 Physiologically based Pharmacokinetic and Pharmacodynamic Modelling in 2005-2009) and in Framework Programme consortia (since 1991, also as a coordinator of the project EUROCYP Integration of in vitro approaches to study drug metabolism and drug interaction in drug development in human). He has >300 original and review articles in international scientific journals, mainly on various aspects of drug and carcinogen metabolism, especially by cytochrome P450 enzymes, and its regulation by genetic and environmental factors and he is a HighlyCited Researcher in pharmacology and toxicology (ISI-Thomson). His current interests include the development of in vitro and in silico methods for drug development and chemical risk assessment. In this respect, he has been participating in multi-year Pharma projects in Finland, with the support from The Academy of Finland, Finnish Technology Research Centre and Drug Industry. He has expert roles at ECVAM and EMA (a co-opted member in toxicology), among others, and advisory roles in Finnish drug development service entities. In 2003, he gave The Oswald Schmiedeberg Lecture at the University of Tartu. In 2007, he was awarded The Bo Holmstedt Memorial Lecture Award by EUROTOX and he was a plenary lecturer in IUPHAR WorldPharma2010 Congress in Copenhagen in 2010.
10
INVITED SPEAKERS LECTURES
TOXICOKINETICS AS A KEY TO THE INTEGRATED TOXICITY RISK ASSESSMENT BASED PRIMARILY ON NON-ANIMAL APPROACHES
Olavi Pelkonen University of Oulu Department of Pharmacology and Toxicology, Finland
Abstract. Toxicity risk assessment is moving away from descriptive animal toxicity studies towards mechanistic in vitro screening systems and their integration with various types of computational approaches, including modelling and simulation. The use of omics techniques and high-throughput screening are some of the emerging tools to ensure predictive toxicity risk assessment. Toxicokinetics (TK) is the endpoint that informs about the penetration into and fate within the body of a toxic substance, including the possible emergence of metabolites, and their absorption, distribution, metabolism and excretion (ADME). Currently, when there is an increasing reliance on non-animal testing approaches, toxicokinetics has been identified as a key element to integrate the results fron in silico, in vitro and in vivo studies. There are several crucial contributions from TK knowledge in integrated risk assessment. TK is needed to estimate the range of target organ doses that can be expected from realistic external exposure scenarios. This information is crucial for determining the dose range that should be used for in vitro testing. TK is necessary to convert the in vitro results, generated at tissue/cell or sub-cellular level, into dose response or potency information relating to the entire target organism, i.e. the human body. For the optimal use of TK knowledge it is imperative that in all in vitro toxicity testing systems the behaviour of the compound under study is investigated, to produce data on disposition (biotransformation and transport) and concentration-response relationships. In silico approaches such as QSARs, read across etc, allow further quantitation of specific processes needed for the prediction of TK in vivo. Physiologically based toxicokinetic modelling (PBTK) is currently regarded as the most adequate approach to simulate the fate of compounds in the human body and can be used to estimate the relevant exposure at organism level from measured in vitro concentrations, and vice versa. However, validation is currently a bottleneck and novel approaches are needed to ensure that mechanistic and integrative risk assessment could be employed to a full extent.
11
BIOGRAPHY
EDWARD P. KRENZELOK
Dr. Krenzelok is Director of the Pittsburgh Poison Center and the Drug Information Center at the University of Pittsburgh Medical Center, a Professor of Pharmacy and Pediatrics at the University of Pittsburgh and the Dr. Gordon J Vanscoy Endowed Chair in Pharmacy. He received his Bachelor of Science degree in Pharmacy from the University of Wisconsin in 1971 and his Doctor of Pharmacy degree from the University of Minnesota in 1974. Dr. Krenzelok is active in numerous professional toxicology and medically related societies and associations and is a Past-President of the American Academy of Clinical Toxicology. He is board-certified in clinical toxicology by the American Board of Applied Toxicology and has been awarded the distinction of being a Fellow in the American Academy of Clinical Toxicology. In 2009 Dr. Krenzelok received the American Academy of Clinical Toxicology Career Achievement Award. Dr. Krenzelok is former member of the Board of Directors of the American Association of Poison Control Centers. He is a former Chair of the United States Pharmacopeia Clinical Toxicology and Substance Abuse Committee, a former member of the Food and Drug Administration Nonprescription Drug Advisory Committee, a consultant to the FDA Drug Safety and Risk Management Advisory Committee, on the editorial boards and review panels of numerous medical and toxicology journals and is the author of several hundred scientific publications and book chapters and the editor of three books.
12
A PROFILE OF ACETAMINOPHEN (PARACETAMOL) TOXICITY IN THE UNITED STATES

Edward P Krenzelok Pittsburgh Poison Center and Drug Information Center, University of Pittsburgh Medical Center
Abstract. Over 25 billion doses of acetaminophen (paracetamol) and in excess of 200 million prescriptions for acetaminophen-opioid combination products are sold in the United States every year. As a consequence of its ubiquitous presence, acetaminophen toxicity is a common problem. While acetaminophen is a safe pharmaceutical when used properly, the ingestion of an excessive amount results in the depletion of glutathione and the potential development of hepatotoxicity. Furthermore, the abuse of combination products that contain acetaminophen and an opioid (e.g., oxycodone, hydrocodone) is rampant and a leading cause of accidental death in adults. Acute ingestions account for 85% of all acetaminophen exposures. However, nearly 21% of the acetaminophen-opioid combination exposures have a supratherapeutic chronic component which creates treatment decision challenges. With regard to gender, females are implicated in approximately 59% of the ingestions. In children less than six years of age, 74% of the exposures involve acetaminophen alone compared to less than 10% of the exposures in adults over 20 years of age where the ingestion of acetaminophen-opioid combination products predominates. Ninety-three percent of the fatalities occur in adults over 20 years of age and only 0.8% in children less than six years of age. Since acetaminophen overdosage is responsible for such a high percentage of acute liver failure cases in the United States, the U.S. Food and Drug Administration has proposed a number of strategies to reduce the incidence of acetaminophen-related hepatotoxicity. The first enacted strategy is to establish a maximum acetaminophen dose of 325 mg in all acetaminophen-opioid combination products. Several recommendations have been proposed for consideration.
13
BIOGRAPHY
JAIME KAPITULNIK
Born in Buenos Aires, Argentina. After completing his high school studies, and following one year of studies at the Faculty of Medicine of the Universidad of Buenos Aires, he immigrated to Israel in 1963. He studied at the Hebrew University of Jerusalem (Faculty of Science), and received his PhD in Biochemistry (Faculty of Medicine) in 1974. After a two-year post-doctoral period in the USA (at Hoffmann-LaRoche, Nutley, New Jersey), he returned to the Hebrew University of Jerusalem and joined the Department of Pharmacology of the Faculty of Medicine and the Division of Pharmacology of the Faculty of Dental Medicine. He chaired the Department of Pharmacology (1994-2000), was Director of the Adolf and Clara Brettler Research Center in Molecular Pharmacology and Therapeutics of the School of Pharmacy (2000-2007), Vice-Dean for Special Projects at the Faculty of Medicine (2002-2006), and Provost of the Rothberg International School of the Hebrew University of Jerusalem (2004-2007). Since 1994 he is a member of the Executive Committee of the Drug Metabolism Section of IUPHAR (1998-2002: Secretary; 2002-2006: Vice-President; 2006-2010: President). He was also a member of the Management Committees of COST B15 and B25 Actions of the European Union (representing Israel). He was a Visiting Scientist at the Laboratory of Molecular Carcinogenesis (National Cancer Institute, NIH, Bethesda, Maryland), the Department of Pharmacology of the Biocentrum (University of Basel), and the Department of Molecular and Cell Biology of the Karolinska Institute (Stockholm). He teaches undergraduate courses of Pharmacology for students of Medicine, Dental Medicine and Veterinary Medicine, and delivers an advanced graduate course in Drug Metabolism for MSc and PhD students. Since 2010 he is the Specialty Chief Editor of Frontiers in Drug Metabolism and Transport. Research activities: effects of oxidative stress on the regulation of cytochrome P450 gene expression; the cytoprotective role of bilirubin as an endogenous antioxidant and its capacity to activate the Aryl hydrocarbon receptor in the absence of UDP-glucuronosyl transferase; effects of bilirubin on glucose transport in the blood-brain barrier.
14
SYNERGISTIC EFFECT OF HYPERGLYCEMIA AND BILIRUBIN ON APOPTOSIS OF MICROVASCULAR ENDOTHELIAL CELLS OF THE BLOOD-BRAIN BARRIER
Clara Benaim, Shlomo Sasson and Jaime Kapitulnik Department of Pharmacology, Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem Abstract. The bloodbrain barrier (BBB) is a physical and functional barrier that regulates the entrance of many drugs and chemicals into brain cells regardless of their molecular size. Carrier-mediated transport systems in the BBB, that are active in the efflux of drugs and chemicals, include the P-glycoprotein pump (Pgp/MDR1/ABCB1) and non-Pgp multidrug-resistance proteins (MRPs). These transporters limit the influx of these compounds, thus protecting the brain from their toxic effects. Very importantly, they also affect the efflux of endogenous compounds, as is the case with bilirubin (BR), a neurotoxic catabolite of heme. Thus, BRdrug competition for BBB-mediated efflux may affect the entrance of both BR and drugs into the brain. Diabetes causes changes in BBB transport which may affect drug and glucose delivery to the brain. Glucose transporter 1 (GLUT1) is the major transporter responsible for the entry of glucose into the brain. We have previously shown in vascular endothelial cells (VEC) that BR significantly augmented the rate of glucose transport, GLUT1 expression, and plasma membrane localization of GLUT1 in these cells. BR also reversed the high glucose (23 mM)-induced downregulation of the glucose transport system in VEC. Pathological concentrations of BR in the vascular compartment (jaundice) may thus influence the cellular handling of glucose in diabetes, including its delivery to the brain. We now show that BR increases dose-dependently the apoptosis of bEnd.3 cells, a line of microvascular endothelial cells derived from the BBB. Switching these cells from a low glucose (5.5 mM) to a high glucose (23 mM) containing medium increased the magnitude of BR-mediated apoptotic events in a synergistic fashion.
15
BIOGRAPHY
JOSE DE LEON
A native of Bilbao, Spain, Dr. Jose de Leon received his medical training at the University of Navarra in Spain. He came to the United States in 1987 to hone his research skills in psychiatry. He completed fellowships in clinical research and clinical psychopharmacology in Philadelphia. In 1991 was named Research Assistant Professor in the Department of Psychiatry at the Medical College of Pennsylvania and Hahnemann University. In 1995, he was promoted to Research Associate Professor. He and his family moved to Lexington, Kentucky, in 1996 where Dr. de Leon progressed from Associate Professor to Professor in the Colleges of Medicine and Pharmacy, University of Kentucky (UK). He has directed the Mental Health Research Center at Eastern State Hospital (ESH) for 15 years, and served as ESH staff physician for the treatment-refractory unit for 8 years. He no longer manages patients, but as a state consultant for the Department for Mental Health, Developmental Disabilities and Addiction Services, he assists clinicians caring for patients with complex psychiatric illnesses at public facilities all over Kentucky by sharing his psychiatric and medical expertise with psychiatrists at state mental health and mental retardation facilities. He investigates deaths and recommends specific interventions for improving care standards; and is working on developing specialized pharmacological guidelines for mental retardation facilities. The pharmacological guidelines are being published in the journal Research in Developmental Disabilities. His ongoing work with UK psychiatric residents and pharmacists at ESH has resulted in several articles, and special recognition awards by the residents. An expert in schizophrenia, psychopharmacology and pharmacogenetics, Dr. de Leons research career has been prolific. He has received grants from the NIMH, NARSAD and the industry. To date, he has published more than 210 peer-reviewed letters and articles in scientific journals included in PubMed. They include one letter in Science, 30 publications in the Journal of Clinical Psychiatry, 21 publications in Schizophrenia Research and 19 publications in the Journal of Clinical Psychopharmacology. The SCI (Science Citation Index) and the SSCI (Social Science Citation Index) are indexes developed by the Institute of Scientific Information (ISI) to reflect the number of times that articles are cited and are used to calculate the impact factor of journals. According to a computer search in the ISI Web of Science in February 2011, Dr. de Leons scientific publications have been cited in the literature more than 4000 times. Hirsch (PNAS 102:16569-72, 2005) proposed the h index to summarize a researchers articles. Dr. de Leons h index is 36 (he has at least 36 articles with 36 citations). His three-year risperidone pharmacogenetic study of 560 Kentucky subjects which focused on the cytochrome P450 2D6 (CYP2D6) gene laid the groundwork for his most ambitious study. From 2003 through 2007, over 4500 subjects were recruited at three state hospitals, identifying subjects with unusual CYP2D6 and CYP2C19 genetic profiles. The first article of this study was published in January 2009. He has collaborated with several research groups in Spain and has facilitated the career development of Spanish researchers who have become internationally known in the areas of schizophrenia, bipolar disorder and suicide. Since 1998, Dr. de Leon has been a Visiting Professor at the Federico Oloriz Neuroscience Institute, Medical School, University of Granada, Granada, Spain. He often combines family visits to Spain with lectures and teaching opportunities in order to educate Spanish physicians in the latest developments in pharmacogenetics and psychopharmacology, and inspire them to conduct psychiatric research. From 2003 to 2009, he has been a Voluntary Professor at the Department of Statistics, Science School, Universidad Nacional, Medellin, Colombia. Dr. de Leon is often invited to lecture in other countries. He has been a member of the advocacy group, the National Alliance for the Mentally Ill (NAMI) since 1989. He has spoken at NAMI state and local meetings several times and is always happy to advocate on behalf of persons and families challenged with mental illness and/or mental retardation issues.
16
THE FUTURE (OR LACK OF FUTURE) OF PERSONALIZED PRESCRIPTION IN PSYCHIATRY

Jose de Leon University of Kentucky, Mental Health Research Center at Eastern State Hospital
Abstract. Rapid technological advances in genetics have created conceptual chaos regarding the genetics of drug response. Terms for differing concepts are used interchangeably: pharmacogenetics with pharmacogenomics, personalized medicine with personalized prescription. Biomarker has many definitions. The author prefers the concept of personalized prescription and uses it with implications beyond pharmacogenetics by considering all scientific information valid for prescribing medication. Genetics may not be crucial for all drugs. In this comprehensive view, clinicians must consider genetic, environmental and personal variables when prescribing medication and incorporate some basic pharmacological principles: (1) safety and efficacy, (2) pharmacokinetics and pharmacodynamics, (3) therapeutic window and prescriber's role, and (4) idiosyncratic and dose-related adverse drug reactions. Personalized prescription in the clinical environment can be expressed in two main ways: as personalized selection of the drug and as personalized dosing. The future, or lack of future, of personalized drug selection and of personalized dosing in psychiatry is reviewed. Currently, the author thinks that, in psychiatry, pharmacogenetic tests have some potential in two areas: (1) excluding some drugs for some unusual patients (HLA-B*1502 genotyping in Asians for carbamazepine), and (2) using pharmacokinetic genes for personalizing dosing in narrow therapeutic window drugs. In the short term, there is dubious potential for other pharmacogenetic tests and no potential for pharmacogenetic testing to ascertain the best drug for each patient. Personalized dosing has immediate application if one understands it as the use of our current scientific knowledge of genetic, environmental and personal variables to determine dosing; its sole requirement is well-trained psychiatrists.
17
BIOGRAPHY
SVEIN G. DAHL
Svein G. Dahl has worked 7 years in the pharmaceutical industry, including 3 years as the Director of Reseach at Jouveinal/Parke Davis, Paris, France. He has been a Professor of Pharmacology at the Faculty of Medicine, University of Troms, Norway, since 1982, and is the head of their Medical Pharmacology and Toxicology Research Group. He is a member of the Council of Scientists of the Human Frontier Science Program (HFSP), the Governing Board of the International Neuroinformatics Coordinating Facility (INCF), the steering group for the Norwegian Research Councils Nevro Nor initiative, and of the Board of directors of Orthogenics AS (Norway). He has served as a board member of Jouveinal/Parke Davis (France), COST Action B15 (EU), European College of Neuropsychopharmacoloy, Scandinavian College of Neuropsychopharmacoloy, Lytix Biopharma (Norway), and other international professional organizations. An important part of his research has been related to the clinical and basic pharmacology of CNSactive drugs. He was the first in the world to demonstrate how combined computational and molecular graphics techniques could be used to make a three-dimensional model of a drug target (the dopamine D2 receptor, 1989), and to simulate the molecular dynamics of drug-receptor interactions. Such methods are now used in virtually all pharmaceutical companies and research institutions in the world. The group has since focused on studies of the molecular structure and mechanisms of drugs, receptors and transporter proteins. He was honored with election as a foreign corresponding fellow of the American College of Neuropsychopharmacology (ACNP) in 1990, included in the ACNPs Pioneers in Psychopharmacology gallery in 2007, and elected as the Norwegian Portrait of Science by the European Federation of Pharmaceutical Industries and Associations (EFPIA) in 2008. His most recent publications (2008 - 2010) are on modeling of different physiological, pharmacokinetic and pharmacodynamic systems, and of molecular targets for antidepressant drugs.
18
MOLECULAR STRUCTURE AND LIGAND BINDING OF MONOAMINE TRANSPORTER PROTEINS

Svein G. Dahl Medical Pharmacology and Toxicology Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Troms, Norway Abstract. Transporter proteins in biological membranes may be divided into channels, which function as selective pores that open in response to a chemical or electrophysiological stimulus, and active carrier proteins using an energy producing process to translocate a substrate against a concentration gradient. Secondary active transporters use the movement of a solute down a concentration gradient to drive the translocation of another substrate across a membrane and against a concentration gradient. The secondary transporters include the neurotransmitter:sodium symporters (NSS family), glucose transporters, and the Escherichia coli lactose permease symporter (Lac Permease). Secondary transporters are very distinct in terms of sequence and function, and transport a wide variety of substances including the monoamine neurotransmitters dopamine, serotonin and noradrenalin. Members of the NSS family are the target of many currently used psychotropic drugs and several substances of abuse. The serotonin transporter (5HTT) and the norepineprine transporter (NET) are the main sites of action of antidepressant drugs, and the dopamine transporter (DAT) is the main site of action of cocaine and other substances of abuse. The rational design of novel drugs interfering with monoamine reuptake is limited by the scarcity of structural information about these transporter proteins. We and others have therefore used molecular modeling techniques to generate 3-dimensional (3D) models of monoamine transporters, based on homology with bacterial membrane transporters and information obtained from site directed mutagenesis studies. 3D modeling of monoamine transporters relies on the availability of experimental 3D structures that may be used as templates. When the crystal structure of a bacterial homologue of the human monoamine neurotransmitter transporters from Aquifex aeolicus (LeuTAa) was reported in 2005, this represented a breakthrough in the structural/functional analysis of monoamine transporters, and provided the possibility of using a homology modeling approach to generate 3D molecular models of NSS family members. These models have demonstrated how transporters may undergo substantial conformational changes during the transport cycle. When performing docking studies on such models, the structural flexibility of transporters should therefore be considered. The conformational flexibility of membrane transporters suggest that different transporter inhibitors may bind to different conformations of the transporter. Computational methods based on accurate molecular transporter models represent a useful tool in the discovery of safer and more efficient drugs acting on membrane transporters.
19
BIOGRAPHY
HEGE CHRISTENSEN
Current appointment: Professor in Pharmacology, School of Pharmacy, Department of Pharmaceutical Biosciences, University of Oslo, Norway (since 2007) Previous appointments: Scientific assistent, School of Pharmacy, University of Oslo, Norway (1985-1986) Drug consultant, Lvens kemiske Fabrik, Norway (1986-1987) Ph.D. research fellow, Norwegian Defence Research Establishment, Kjeller, Norway (1988-1991) Senior Scientist at ICIT (The International Cardiology Research Institute), Oslo, Norway (1991-1992)
Associate professor, School of Pharmacy, Department of Pharmaceutical Biosciences, University of Oslo, Norway (1992-2007)
Sabbatical 2004-2005: University of Sheffield, Section of Molecular Pharmacology and Pharmacogenetics, Sheffield, U.K. Research activities: The research area is pharmacokinetics with special focus on processes involved in determining bioavailability, distribution and elimination of drugs. A main area is optimisation of drug therapy based on interindividual variability in cytochrome P450-mediated drug metabolism and drug transport, which appears to be of major importance for variability in drug response between individuals. Several projects are related to drug metabolism and transport studies and drug interaction studies, both in vitro in human liver cells and microsomes and by in vitro-in vivo extrapolations. Publications: 33 full papers, 1 book chapter, > 55 abstracts. Teaching Undergraduate and postgraduate teaching for Pharmacy students, School of Pharmacy, University of Oslo (from 1992 until now): Basic pharmacology (Neurobiology, CNS and Cardiovascular Pharmacology) Pharmacokinetics (including laboratory courses in drug metabolism) Pharmacotherapy Several courses in Continuing Education for Pharmacists: Pharmacotherapy in Psychiatric diseases, Neurology and Cardiovascular diseases Pharmacokinetics (drug-drug interactions) Other relevant activities: Delegate in Management Committee in COST ACTION B25 Physiologically based Pharmaco-Toxicokinetics and Dynamics (2005-2009) Member of the Programme Committee and Co-chair of the Pharmaceutical Sciences World Congress (3rd World Congress of the Board of Pharmaceutical Sciences of FIP), Amsterdam, 22-25 April 2007
20
MECHANISMS INVOLVED IN THE PHARMACOKINETIC INTERACTION BETWEEN ATORVASTATIN AND CYCLOSPORINE A

Hege Christensen, Rune Amundsen and Anders sberg Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway Abstract. Due to a high incidence of dyslipidaemia following solid organ transplantation, HMG-CoA reductase inhibitors (statins) are frequently used in transplant recipients, and concomitant use of the calcineurin inhibitor cyclosporine A (CsA) increases systemic exposure of statins. CsA has been shown to increase the systemic exposure of atorvastatin severalfold, while another calcineurin inhibitor tacrolimus (Tac) did not show such an effect. The mechanism behind the interaction between atorvastatin and CsA has been discussed to be primarily due to inhibition of membrane transport, but it has also been proposed that CYP3A4 inhibition is involved. CsA has been reported to inhibit CYP3A4, P-glycoprotein, organic anion transporting polypeptide 1B1 (OATP1B1) and some other uptake transporters. The aim of the present study was to investitate the potential of CsA and Tac to inhibit the OATP1B1-mediated uptake of atorvastatin in an in vitro model and to explore to what extent CsA and Tac inhibit CYP3A-mediated metabolism. In vitro-in vivo extrapolations (IVIVE) were performed in order to elucidate which mechanisms might be of most importance in an in vivo setting. The inhibitory effect of CsA and Tac on cellular uptake of atorvastatin via OATP1B1 was investigated in an in vitro over expression whole cell model (HEK293 cells). Inhibition of OATP1B1 mediated uptake of atorvastatin by CsA was about 90-fold more potent than inhibition by Tac, and inhibition constants (Ki) obtained were 0.014 and 1.30 M, respectively. Co-incubation as compared with pre-incubation with CsA showed a 20-fold lower inhibitory capacity. The IVIVE showed that clinically obtainable concentrations of CsA, but not Tac, inhibit OATP1B1 transport of atorvastatin. CsA inhibition ranged from 28 to 77 % within a dosing interval, while it was below 1 % for Tac, considering free concentrations and assuming competitive inhibition. This does not fully explain the clinically observed interaction with CsA, suggesting that a more complex inhibitory mechanism may be present. This study provides evidence that OATP1B1 inhibition is a relevant mechanism for the interaction observed between CsA and atorvastatin. In the literature inhibition of CYP3A-mediated metabolism of atorvastatin has also been proposed to be involved in the interaction with CsA, thus in the present study the possible inhibitory effect of CsA and Tac on CYP3A4 and CYP3A5 metabolism in vitro was investigated. The experiments were performed with the CYP3A probe substrate midazolam and the inhibitory effect of CsA and Tac on the formation of 1-OH midazolam in insect microsomes expressing CYP3A4 or CYP3A5 and in human liver microsomes (HLM) were studied. CsA was shown to be a competitive inhibitor of CYP3A4 with a Ki of 0.9 M, and CsA did not inhibit CYP3A5. Tac showed a time-dependent inhibition of CYP3A4 and CYP3A5 in insect microsomes, but interestingly in HLM the inhibitory effect of Tac was less pronounced and the effect was not time-dependent. The maximum unbound plasma concentration of CsA and Tac will be much lower than the Ki values found in this study. Thus the clinical relevance of CYP3A4 inhibition by CsA will most certainly be limited. However, the IVIVE indicated that inhibition with CsA and Tac might play a moderate role on CYP3A4-mediated intestinal metabolism.
21
BIOGRAPHY
VICTOR A. VOICU
Fellow of Romanian Academy; General Secretary of Romanian Academy (2002-2006). Professor, Head of Department of Clinical Pharmacology, Toxicology and Psychopharmacology, Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest. The medical studies performed as a military student at the Faculty of General Medicine in Bucharest, completing his M.D. degree in 1962; in 1970 he defended the PhD thesis on Homeostasis and pharmacodynamic reactivity of vegetative nervous system in acute irradiation syndrome. He has been assistant professor at the Department of Pharmacology in Bucharest (1963-1966), researcher at the Center for Radiobiology and Molecular Biology (1964-1970), head of Laboratory of Pharmacodynamics, Army Center for Medical Research (1970), professor (from 1972) and head of Department of Pharmacology, Faculty of Medicine, Craiova (from 1973); from 1974 is senior physician and, starting from 1985, commander (director) of Army Center for Medical Research; Major General and head of Medical Directorate of National Defense Ministry (1990-1995); from 1993, professor of toxicology at the Faculty of Medicine in Bucharest; he founded the first Department of Pharmacology in the Faculty of Medicine Craiova and the first Department of Clinical Pharmacology, Toxicology and Psychopharmacology in the Romanian medical school (University of Medicine and Pharmacy Carol Davila Bucharest). Some original research topics are to be mentioned: he described and defined the cholinergic muscarinic mechanism of OP-induced hypothermia (1976), the potentiating synergism between antimuscarinics and tricyclic antidepressants and its value in OP compounds antidotism (1974), PK/PD or TK/TD correlations as fundamental tools for identification and anticipation of the safety, efficacy and / or toxicity profiles of drugs or toxicants etc. Another field is represented by the epigenetic mechanisms for effects of chronic treatment with antipsychotics and their consequences on therapeutics, as well as defining some criteria and mechanisms in the evaluation of drugs with active metabolite (including the transport across membranes, blood-brain barrier etc.), essential aspects for treatment individualization in major pathology frames. He is co-author of the finite interactions theory dealing with drug-receptor interactions as an interaction between a molecule and a given biological structure, having essentially the properties of a continuous structure. The results of his research activity are found in more than 330 paper published in Romania or abroad, monographs, and books e.g.: The enzymatic mechanisms in pharmacodynamics (1977); Pharmacology (1980); The pharmacology of ergot alkaloids (1981); Elements of clinical pathopharmacology (1987); The therapy of ocular pathologies (1989); Pharmacological mechanisms at membranar interfaces, paper awarded with the Daniel Danielopolu prize by the Romanian Academy (1994); Clinical toxicology (1997); The psychopharmacology and clinical toxicology of drugs of abuse (2005). The results of his recent research from the field of PD/PK and TD/TK correlations and their consequences on pharmacotherapeutics were published in Basic and Clinical Pharmacology and Toxicology (2010), Analit.Letter (2010), J.Pharm. Biomed.Analysis (2010) etc. These works are added to the 25 patents, referring especially to new drug preparations, the majority of them applied (Atox, drug for counteracting and treating the toxic effects of OP compounds; Dixidextetracaina 70, drug for sub-arachnoid hyperbaric anesthesia; Composition for drug with antispastic action; analgesic-antispastic; antihypertensive; collagenic bandage for treatment of wounds and burns etc.). President of the Romanian Society for Clinical Pharmacology, Therapeutics and Toxicology SRFTTC (from 1991), member of the Academy of Medical Sciences, Romania, President of the Scientific Council of National Medicine Agency (from 1998), member of the Council of European Association of Clinical Pharmacology and Therapeutics (1997), member of the Working Group of European Association of Antitoxic Centers and of Clinical Toxicologists for Certification of Antitoxic Centers; elected member of American College of Clinical Pharmacology, of American Chemical Society etc. As president of SRFTTC, he organized the 12 national and international editions of the Congress of Clinical Pharmacology, Therapeutics and Toxicology.
22
PREDICTION OF THE BIOLOGICAL FATE OF OXIMES
Victor A Voicu, Flavian Radulescu University of Medicine and Pharmacy Carol Davila Bucharest, Department of Clinical Pharmacology, Toxicology and Psychopharmacology, Bucharest, Romania.
Abstract. Although oximes represent one of the major antidotal tools of the atropine-oxime-anticonvulsant triad, generally, their current use in the experimental and clinical research reveals some essential aspects: the oximes are not equally active against OP, especially against the nerve agents and there is no broadspectrum reactivator. the differences between the oximes, on one side, and their kinetic behaviour versus nerve agents, on the other side, are illustrated by the PK/PD (oximes) and TK/TD (OP) correlations (Voicu VA et al, 2010), difference that finally explains their reduced efficacy against the neurotoxicity of OP nerve agents. the increase of lipophilicity, the decrease of the polar character of oximes, respectively, leads to an increase of their acute toxicity (Lorke et al, 2009), aspect anticipated by Bodor et al (1975), Pro-2-PAM having a good BBB permeability, but also a consequent neurotoxicity. The therapeutic effects of the compounds with high lipophilicity dont seem to be significantly higher compared to the reference oximes. In this context, the authors have performed an analysis of available literature data for the most studied oximic compounds (with PK evaluations), based on the ADME predictions performed with various specialized software (ADMET Predictor, PreADMET on-line platform, ChemAxon). These predictions have been focused on the most relevant molecular descriptors. Last but not least, these molecular descriptors have been correlated with the biological fate for the analyzed compounds. It has been confirmed the direct correlation between the logP and the acute toxicity (1/LD50), relevant for both oral route (the bioavailability being an essential element), and parenteral routes, mainly percutaneous one. Also, there is a good correlation between logP and the apparent volume of distribution Vd, this time a relation of proportionality. The direct correlation is also valid between the acute toxicity (1/LD50) and Vd for the analyzed compounds. There are some non-homogeneity for the transfer across BBB, suggesting the implication of other forms of transport than the passive diffusion. This type of analysis performed on a large number of compounds allows a more relevant evaluation of structure activity relationship, focusing mainly on the molecular descriptors determinants of their kinetic behavior and their correlation with a series of biological parameters, essential for their specific therapeutic efficacy.
23
BIOGRAPHY
HORST THIERMANN
Horst Thiermann studied medicine at the University of Regensburg (Germany) and at the Technical University Munich (Germany) where he finished his doctoral thesis (MD) in 1988. From 1987 to 1989 he worked at the Bundeswehr Hospital Munich in the departments of anesthesiology and surgery and joined the Bundeswehr Institute of Pharmacology and Toxicology, Munich in 1989. Towards his qualifications as a Pharmacologist and Toxicologist (1996) and as a Clinical Pharmacologist (2002) he was working in research fellowships at the Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig Maximilians-University Munich and at MDS Pharma Services, Hhenkirchen-Siegertsbrunn, Germany. In 2005 Horst Thiermann has hablitated (postdoctoral university lecturing qualification) at the Technical University of Munich as an external scientist and pursues his venia legendi (Privatdozent, University Lecturer) in Pharmacology and Toxicology at the same university. Since 2006 he is heading the Bundeswehr Institute of Pharmacology and Toxicology. This institute is the German national competence centre on medical aspects against chemical warfare agents. The scientific focus is directed towards the improvement of medical countermeasures (e.g. therapeutic strategies) against poisoning by chemical warfare agents as well as the verification of exposure to such toxicants.
24
WHY DO PATIENTS DIE FROM INTENTIONAL OP-INSECTICIDE POISONING IN SPITE OF PROPER USE OF ANTIDOTES?
Horst Thiermann1, Thomas Zilker2, Florian Eyer2, Franz Worek1
1. 2.
Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany, Department of Clinical Toxicology, II. Medical Clinic, Technical University, Munich, Germany
Abstract. Objective: For optimal therapy of organophosphorus pesticide (OP) poisoning administration of antimuscarinic compounds, e.g. atropine, and oximes is suggested. Atropine should be applied according to signs and symptoms and oximes should be given as long as reactivation of inhibited acetylcholinesterase is possible (1,2). Although this strategy, together with advanced intensive care treatment should result in good outcome, lethality is still high. Therefore, the cause of death in patients, who were treated accordingly was analysed. Methods: During a clinical study in Germany, patients were treated with obidoxime (250 mg i.v. followed by infusion of 750 mg/24 h), atropine according to demand, and the necessary supportive care. The clinical course of the patients was assessed and the conditions associated with lethal outcome analysed in detail. Results: Almost all patients ingested OP pesticides for suicidal purpose. Although therapeutic strategies were directed to achieve optimal reactivation of inhibited acetylcholinesterase 7 out of 34 patients died (2). In poisoning with diethyl-OP compounds unconsciousness and severe circulatory insufficiency dominated the early phase of the very fast developing cholinergic crisis. In contrast, in poisoning with dimethyl-OP compounds several patients were able to communicate when the emergency physician arrived on the spot and critical situations developed more frequently not until several hours after poison intake. The patients needed antidotes for 3.6 days (median (throughout), 1.2 28.3 days) in case of diethyl-OP and for 5.2 days (0.8 17.7 days) in case of dimethyl-OP poisoning. Artificial ventilation was necessary for 16.0 (3.6 37.6 days) and 6.7 (0.8 22.8 days) in diethyl- and dimethyl OP-poisoning. The frequency and patterns of complications were quite similar in both types of poisoning. Only two patients died during cholinergic crisis (death on day 21 and 16 after ingestion). Both of them had ingested extremely high amounts of parathion and no reactivation was possible. Finally they died due to severest respiratory dysfunction. Four patients, in whom initially reactivation was achieved, died 18, 23, 19 or 38 days after poison ingestion from complications that were no longer related to cholinergic crisis (peritonitis from a stress ulcer, lung embolism, pneumonia). In one other patient with oxydemeton methyl poisoning clinical conditions on admission were already deleterious. Here neither antidotes nor advanced intensive care could improve conditions nor restore health. Conclusion: While optimized antidotal treatment together with advanced intensive care is usually effective in treatment of cholinergic signs and symptoms in most patients with OP-poisoning. However, severe non-cholinergic complications may be responsible for high death rates.
25
BIOGRAPHY
ANDREI VALENTIN MEDVEDOVICI
Present position: a. Professor at the University of Bucharest, Faculty of Chemistry, Department of Analytical Chemistry b. Scientific Director, LaborMed Group Key qualifications: Teaching skills; Skills in operating HPLC, SFC, GC, MS equipments, including hyphenation; Experience in environmental analysis, food chemistry, pharmaceutical formulations, clinical analysis; Experience in analytical method development and validation, qualification of analytical methods and equipments. Editorial board member: Journal of Liquid Chromatography & Related Technologies (Taylor & Francis Group, U.S.A.) ISSN 1082-6076 (paper) Bioanalysis (Future Science Ltd., U.K.) ISSN 1757-6199; Advisory board member for journals: Analytical and Bioanalytical Chemistry; Journal of Chromatography A; Journal of Chromatography B; Journal of Pharmaceutical and Biochemical Analysis; Chromatographia; Analytical Letters; Revue Roumaine de Chimie; Revista de Chimie; Evaluation board member: CNCSIS; RENAR; ARACIS Publications: ISI publications: 92 (80 in journals abroad Romania); Non-ISI publications: 13 (11 in journals abroad); Journals: J. Chromatogr. A; J. Chromatogr. B; Talanta; Water Research; Chirality; Chromatographia; J. High Resolut. Chromatogr.;J. Appl. Toxicol.;J. Incl. Phen. Macrocycle Chem.; J. Sep. Science; J. Pharm. Biomed. Anal.; J. Liq. Chromatogr. & Rel. Tehnol.; J. Chemometrics; J. Chem. Inf. & Computer Sci.; Chem. Eur. J.; J. Microcol. Sep; Microchem. J.; Sep. Sci. & Technol.; Biomed. Chromatogr.; J. Catalysis; Eur. J. of Drug Metab. and Pharmacokinetics; Eur. Pharm. Rev.; Analli di Chimica; Chemia Analityczna; Arzneimittel Forschung; Comptes Rendues Chimie; LC-GC International; Int. Env. Technol.; Anal. Letters; Bioanalysis; Rev. Roum. Chimie; Analele Univ. Bucureti; Southern Brazilian J. of Chem.; Proceedings Int. Sympos. Capillary Chromatogr. (Riva de Garda, 1993, 1994, 1996). Books/Chapters in books & encyclopedias: 25 (14 in publications abroad); Membership of professional bodies: Romanian Analytical Chemical Society; Awards: C.D. Nenitescu Award of the Romanian Academy, December 2009. Posters > 40 (16 to congresses/ symposia abroad); Plenary lectures, Keynotes: > 70 (15 abroad); Cumulated Impact Factor: 160.34 Cumulates Citation Index: 541 (419 without self-citations); h-Index: 12
26
HOST-GUEST INCLUSION OF SOME CATION TYPE ALDOXIMES IN MACROCYCLIC CAVITIES: ESI/MS APPROACH FOR FAST SCREENING
Victor Voicu1,2, Andrei Medvedovici3, Florin Albu4 University of Medicine and Pharmacy Carol Davila, Department of Pharmacology, Toxicology and Clinical Psychopharmacology, 2. Romanian Army Center for Medical Research 3. University of Bucharest, Faculty of Chemistry, Department of Analytical Chemistry 4. Bioanalytical Laboratory, SC Labormed Pharma SA
1.
Abstract. Inclusion of active ingredients in macrocyclic cavities is widely used to enhance on the stability of the host compound in physiological media or for an increased absorption (transfer through biological barriers). Usually, hydrophobic compounds are included in externally hydrophilic cavities for increasing their solubility in aqueous media, thus controlling their release from the formulation and consequently enhancing their bioavailability. Contrarily, cation type aldoximes used as AChE reactivators are highly polar compounds, their in-vivo transport through biological membranes being seriously affected by means of such a molecular characteristic. It may be of a real practical interest to study the possibility of inclusion of cationic type aldoximes in macrocyclic cavities in order to reduce their solubility in water, to improve their absorption and to increase their stability in physiological media. Advances in the construction of novel hosts with applications in supramolecular chemistry have generated an increasing demand of new analytical techniques for studying their binding properties with minimal sample consumption. The binding properties of a host and the characterization and evidence of the host-guest formation in solution have been obtained from many conventional methods including nuclear magnetic resonance, UV-Vis and fluorescence spectrometry, circular dichroism, X-ray diffraction, light scattering, calorimetry, conductometry, scanning tunneling or atomic force microscopy, and computer simulations. Mass spectrometry is an additional quite recent tool for studying non-covalent interactions in the gas phase and probing molecular recognition. In the present work, our interest was focused on the possibility of a fast screening of the interaction ability of different cation type aldoximes in macrocyclic cavities as crown ethers and functionalized calixarenes by means of electrospray mass spectrometry. The mixture of the host and guest congeners in a liquid aqueous/polar organic solvent phase is directly introduced in an atmospheric pressure electrospray ion source, followed by the MS or MS/MS analysis of the resulting ions. Formation of the complexes is supported by the observation of host-guest cluster ions. The method may be used only for fast screening of the interaction between hosts and guest. Deep insights about inclusion/non-inclusion features in the cavity and type of interactions are then obtained through detailed structural investigation techniques such 1H and 13C NMR or FTIR.
27
BIOGRAPHY
MOMIR MIKOV
Member of: Serbian Medical Society, Serbian Pharmacological Society (Member of the board), Section of Toxicology- Serbian Medical Society (Member of the board), International Society for the Study of Xenobiotics, Controlled Release Society New Zealand , Australian Pharmaceutical Sciences Association 2006-, Head of Clinical pharmacology Section of Serbian Medical Society 2009Positions: Professor in Pharmacology and Toxicology University of Novi Sad, Medical Faculty and University Pristina Kosovska Mitrovica (Medicine and Dentistry and English Medical Studies in Novi Sad), Professor in Pharmacology and Toxicology Medical Faculty University of Banja Luka,, Professor in Pharmacology and Toxicology Pharmaceutical Technology group University of Novi Sad, School of Pharmacy, Medical Faculty, University of Novi Sad, Serbian Poison regulatory committee member, Senior Lecturer School of Pharmacy, University of Otago, New Zealand, Professor Pharmacy Faculty, University of Monenegro Postdoctoral research: UK, London, St Marys Hospital Medical School, Department of Biochemical Pharmacology Imperial College, 1986-1989 Collaboration: Department of Pharmacology, Medical Faculty University of Banja Luka (Bosnia and Herzegovina), Department of Pharmacology and Toxicology, Medical Faculty University of Skopje (Macedonia), Department of Pharmacology Medical Faculty University of Podgorica (Montenegro), Bulgarian Academy of Sciences, Institute of Physiology, Toxicology Department, Research Activities Research on drug metabolism in vivo and in vitro, Development of analytical methods for metabolic studies, Inventor of bile acids as new antidiabetic agents, Study director/principal investigator/clinical investigator on more than 60 bioequivalence and controlled clinical trials Supervisior of more than 20 PhD amd MSci postgraduate students nationally and internationally Distinctions: Award for Science Serbian Medical Society, Award For Contribution and Education in the field of Xenobiotic Metabolism and Toxicity in Balkan Countries, Award Military Pharmaceutical Laboratories of Greek Army, Author of more than 100 publications: books, journal articles, invited lectures and 4 patents
28
DRUG ABSORPTION FROM THE GASTROINTESTINAL TRACT AND THE INFLUENCE OF PROBIOTICS
Mikov M.1, Al-Salmi H.2, Golocorbin-Kon S.1
1. 2.
Department of Pharmacology and Toxicology, Medical Faculty Novi Sad Serbia Biomedical Engineering, Medical School, McGill University, Montreal, Canada
Abstract. Drug absorption across the gastrointestinal tract occurs by a combination of passive diffusion and active transport. Barriers to absorption include enterocyte tight junctions, the mucus layer, efflux transporters and the metabolic barrier consist of intestinal mucosa and gut flora. The absorption, metabolism and systemic availability of some orally administered drugs can be influenced by the metabolic activity of gut microflora and modified by disease and probiotics. Probiotics are live, ingestible microorganisms that provide benefits to the health and well-being of the host. They have been shown to be beneficial in a wide range of conditions including infections, allergies, and metabolic disorders such as diabetes. Combinations of different bacterial strains can be used as probiotics but the mixture of Lactobacillus and Bifidobacteria is a most common choice. Recently, the Ussing chamber has been used to investigate drug permeation through different tissues and the transporters involved. In our work it was used to investigate the effect of probiotics on permeation of antidiabetics like glicalazide and bile acid derivatives. We have also investigated the influence of probiotics on absorption in healthy and diabetic animals on the absorption of bile acid derivative, gliclazide and sulphasalazine metabolism. In our experiments probiotic pre-treatment in healthy animals decreased the permeation of gliclazide but the same treatment in diabetic animals improved the drug permeation which was impaired in diabetic subjects without any probiotic treatment Probiotic treatment decreased bile acid derivative (monoketocholic acid MKC) absorption and lowered blood glucose in healthy and diabetic rats. The reduction of MKC absorption in probiotic treated healthy and diabetic rats results most likely from the induction of presystemic elimination of MKC by gut bacteria. It was found also that probiotic treatment significantly increased sulphasalazine degradation in mucus of the ileum and colon and that probiotics alter the enzymatic activities of bacteria in gut contents in different manner than in gut mucus. The modification of gut flora with probiotics is one of important factors influencing drug absorption and metabolism. Acknowledgement: This project has been supported by the Ministry of Science of the Republic of Srpska Research Grant 2010-2011.
29
BIOGRAPHY
FRANZ KEREK
Education Chemistry, Babes-Bolyai University of Cluj (Romania) Doctoral Thesis, Stereochemistry of Carbodiimides (1972), Prof. G. Ostrogovich Alexander von Humboldt post-doctoral fellowship 1973-5, University of Bochum (Germany) Natural Products Chemistry, (Prof. Gnther Snatzke) Carrier University Politehnica Timisoara (Romania) Assoc. Prof. Organic Chemistry -> 1975 Research Institute for Chemistry of the Romanian Academy (Timisoara) Head of the Department for Natural Products Chemistry ->1988 Max-Planck-Institute for Biochemistry Martinsried, 1992-> present Managing Director of the DoNatur and SiNatur GmbH in Munich 1997-> present Scientific achievements -First optically active cyclo-phosphorus compounds (chiral catalysis) -Method to disclose the absolute configuration of natural substances by Circular Dichroism spectra of their mono-dentate metal ion complexes -Permethylation of carbohydrates (very high citation index paper) Discoveries, patents Isolation and structural disclose of the novel drug substance MCS with characterization of its analgesic and immunosuppressive mechanism (1996-2009) Preclinical and clinical development of the novel anti-rheumatic drug MCS-Injection with successful Phase II clinical study in the treatment of osteoarthritis (2002-2008) Discovery of the novel Cysteine-rich plant proteins hellethionins (2003) Discovery and characterization of the Sub-nano-Silicic-Acid SNSA the first biologically active silicon compounds (2005-2008)
30
TARGETING THE INNATE IMMUNE RECEPTORS, AS PROMISING APPROACH FOR DRUG-DISCOVERY

Franz Kerek1, Victor A. Voicu2
1. 2.
Max-Planck-Institute for Biochemistry and DoNatur, Martinsried, Germany University of Medicine and Pharmacy Carol Davilla, Bucharest, Romania Abstract. Identification of the Toll-like Receptors (TLRs) and the cognate RAGE and NOD receptorfamilies opened new insights into the mechanism of the innate immune system that detects pathogens and mounts their efficient annihilation. Innate immunity plays a crucial role in modulation of the adaptive immunity including the malfunction of this system as manifested e.g. in the autoimmune diseases. This novel insight suggests therapeutic interventions in inflammatory diseases and autoimmune pathologies already at the level of the innate immunity. Despite of considerable efforts to develop novel drugs for the modulation of the innate immune response, so far no synthetic drug substance was authorised in this field for the human therapy. One possible reason of the failures with single-molecule drug-substances is that the receptors of the innate system such as TLRs, NOD etc., did not work according to the classical lock-key model. Conversely to the single molecular ligand mechanism of the classical pharmacology the innate immune receptors are activated in nature by substance mixtures (e.g. LPS for TLR-4) comprising only common structural elements such as the Pathogen or Damage associated molecular patterns (PAMP; DAMP). It seems therefore a more promising approach to investigate substance mixtures instead of a single molecule antagonist in suppressing the over-activation of the innate immune response. However, this strategy with drug substance mixtures faces major problems, such as to assure the reproducible composition and rigorous quality control of these very complex mixtures. Possible management of these difficulties is either by applying of sophisticated analytical techniques or by providing adequate methods for the quantitative assay of the immune-specific structural patterns in the complex mixture. The therapeutic potential of the innate immune approach and the connected difficulties are illustrated by own experience of the authors. Development of the MCS-substances for the therapy of arthritis pain, with an already successful Phase II clinical trial is a successful example to treat pain and inflammatory diseases by adequate substance mixtures able to down-regulate the pathological over-activation of the innate immune response.
31
BIOGRAPHY
CHRISTOS. Y. POTSIDES
Dr. Christos. Y. Potsides obtained his BSc in Biochemical Pharmacology, MSc in General and Medical Microbiology from University College London, Postgraduate Diplomas in Electron Microscopy, Biotechnology from Birckbeck College London, Immunology from Kings College London and Toxicology from the University of Athens Medical School. In 1993 he received his Ph D in Pharmacology and in 1997 his DSc in Pharmaceutical Microbiology from the University of Novi Sad. He has worked for 25 years in the Pharmaceutical Industry, mainly in QC, Manufacturing and Regulatory Affairs. Since 2003 he works as an Assessor in the National Organization for Medicines, Athens, Greece. He has published 52 articles in International and National Journals, his work has been cited in numerous publications and books, and has organized seminars in Pharmacy and Pharmacology, is a member of various Scientific committees and represents Greece in various EU institutions. Membership of societies Greek Society of Medicinal Chemistry (President 1994-1998), EDCTP Founding Member (HIV, Malaria, TB), 2000, Convocation of the University of London, ECDC Scientific Advisor 2007- present, Panhellenic Association of Pharmacists (h.m) Honorary vice presidentships : 2 Scientific boards Greek Representative of the Military Pharmaceutical Laboratories - Scientific Sector, 1993-2000, Greek Representative of the Ministry of Development Scientific Sector, 2000-2003 Greek Representative (Assessor) of the Ministry of Health and Social Solidarity Medicinal Products Sector, 2003- present, Expert- European Union- Brussels, 2000- present Expert- Council of Ministers of the European Union, Consilium- Brussels,2009- present. Scientific participations Round Table member: 14, Plenary Lectures: 19 Visiting Professor: 2 Universities Member of international editorial board: 1
32
NEWER DEVELOPMENTS IN ENVIRONMENTAL RISK ASSESSMENT ACCORDING TO EU LEGISLATION

Christos. Y. Potsides National Organization for Medicines
Abstract. Research on the fate and effects of pharmaceuticals in the environment is now a very important issue and has progressed significantly over the past years. Over 100 pharmaceuticals have been identified in rivers, lakes, and coastal waters throughout Europe and the United States in concentrations of parts per billion to parts per trillion. Work in the EU so as to provide a legislative process for investigating this issue begun about two decades ago resulting in the provision of the EMEA Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use namely EMEA/CHMP/SWP/4447/00. This guideline was further refined, largely through the efforts of the EMEA safety Working Group as well as Experts in Academia and Industry and incorporates recent developments, eg. the fate of antibiotics and hormones, and has been officially in force since December 2006. The guidance applies only to potential environmental risks that are a consequence of people storing, taking, and excreting medicines. It involves the preparation of a Risk protocol through the process of Risk Assessment which is defined as the determination of the quantitative or qualitative value of risk related to a concrete situation and a recognized threat. The EMEA risk assessment protocol is a tiered process that begins with a rough calculation of the aquatic predicted environmental concentration (PEC) of the new drug. The risk assessment is divided into a Phase I exposure assessment and a Phase II analysis of fate and effects. Generic products are not exempted from an ERA. About 50 new drugs are granted Marketing Authorization in the United States each year. Roughly a dozen of those are predicted to occur above the trigger concentration requiring them to undergo the first level, or Tier A, of risk assessment testing. The use of the Guideline up to March 2011, in a pan European level has proved to be most effective and it is seen as an appropriate response to an emerging issue which includes possible risks not just from pharmaceuticals but also from personal care products.
33
BIOGRAPHY
CONSTANTIN MIRCIOIU
Career: I. Didactic: Professor of Applied Mathematics and Biostatistics, University of Medicine and Pharmacy, 1990 II. Professional Pharmacist in a Laboratory for production of solid and semisolid drugs, 1982-1984. Chief of the Department of Medical Computing of the Radiobiology Laboratory at Fundeni Clinical Hospital,1975-1982. Positions: Head of the Dept. of Applied Mathematics and Biostatistics, University of Medicine and Pharmacy "Carol Davila", Dean of the Faculty of Pharmacy, Bucharest, 2004-2008, Chancellor 2008 Head of Dept. of Biopharmacy, Army Center for Medical Research , European Center for Validation of Alternative Methods Scientific Advisory Committee, Ispra Fields of Specialisation Main field biopharmacy and pharmacokinetics Other fields pharmaceutical technology, biostatistics Current research activities Fundamental research concerning the physicochemical component of the action mechanism of drug molecules at the membranar interfaces; Mathematical methods applied in biopharmacy, pharmacokinetics, toxokinetics and clinical pharmacy; Applied research in pharmaceutical technology in antidote design, dissolution, bioanalytics and bioequivalence of drugs. Director for Bioequivalence studies at Biopharmacy & Pharmacol Res S. A. Part of research published (70 in scientific journals and volumes), books ("Pharmacological mechanisms at membranar interfaces", Romanian Academy Publ. House, 1994; Mathematics Applied in Pharmacy, 2000, Biostatistics 2005, associated editor for NBC Risks. Current Capabilities and Future Perspectives for Protection, NATO Science Series, Kluwer Academic Publishers, Dordrecht/Boston/London, 1999) , Biostatistics, Fundamental Pharmacokinetics etc Affiliations: Member of the Academy of Medical Sciences American Association of Pharmaceutical Scientists Awards: Prize "Daniel Daniepolu" of Romanian Academy, 1994
34
RESEARCH CONCERNING INCLUSION OF DTPA ZN IN MICROEMULSIONS FOR IMPROVING ITS BIOAVAILABILITY AND EFFICACY AS DECONTAMINANT IN MANAGING RADIOLOGICAL TERRORIST INCIDENTS
Constantin Mircioiu1,3, Victor A. Voicu2,3, Marilena Jiquidi3, Otilia Cinteza4, Eugen Reviu3, Manuela Spiroiu4, Flavian Radulescu1 1. Department of Applied Mathematics and Biostatistics, Faculty of Pharmacy 2. Department of Clinical Pharmacology, Toxicology and Psychopharmacology, Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, Romania. 3. Army Center for Medical Research, Bucharest, Romania. 4. Department of Physical Chemistry, Faculty of Chemistry, University of Bucharest, Romania.
Abstract. Background. The aim of the present study was to develop a bioavailable and efficient DTPA microemulsion formulation designed for decorporation of internal contamination with radionuclides. Methods. Model microemulsions containing sodium bis (2-ethylhexyl) sulfosuccinate (AOT) as surfactant and isopropyl myristate as oily phase were prepared and the capability of microemulsions to embed and deliver hydrophilic active substances such as DTPA-Zn was evidenced. The influence of electrolytic character of these active substances and the hydrophobicity of oil phase on the microemulsion structure, water solubilization capacity, Hamaker constant and interfacial elasticity were established. Microemulsions from biocompatible components were prepared using vegetable oils and alkyl polyglucoside surfactant. The pharmacokinetics of [(65)Zn]-DTPA encapsulated was evaluated in rats after a single or multiple intraperitoneal administration, comparatively with DTPA solution and a control lot. Extent and rate of decontamination were evaluated. Findings. In all three cases, control lot, Zn-DTPA solution and ZnDTPA microemulsion kinetics of the effect included two different evolutions of whole-body radioactivities. In first day appeared an abrupt decrease of radioactivity followed by a slow, exponential decrease in the following days. In all three treatments, lower single dose of DTPA, higher single dose and higher, repeated doses, the extent of effect was somewhat greater for solution than for microemulsion. It the second phase the rate of elimination was in all cases higher in case of microemulsions. Interpretation. It was concluded that following the obtained results, embedding of DTPA in microemulsion could result in a better effect for complete treatment of internal contamination
35
BIOGRAPHY
YANEV STANISLAV
Dr. Yanev Stanislav received his MD from University of Medicine, Sofia, Bulgaria in 1967 and his PhD in toxicology from Institute of Physiology, BAS, Sofia, Bulgaria in 1972. He has been a professor at Department of Drug Toxicology, Institute of Neurobiology, BAS, Sofia, Bulgaria since 1985. Dr Yanev Stanislav is a member of the following scientific associations: International Society for Studying of Xenobiotics, European Society for Biochemical Pharmacology, EUROTOX, and Bulgarian Pharmacological Society. He was (1998-2006) councilor in the board of the Section of Drug Metabolism IUPHAR. He is involved in international and national grants investigating drug metabolism and toxicity. He is author of more than 100 scientific publications on international journals and conference proceedings in the field of reactive drug metabolites produced by cytochrome p-450 system, pharmacokinetics, drug interactions on the level of drug metabolism, xenobiotics cell toxicity.
36
IMMUNE SYSTEM AND DRUG METABOLISM INTERACTIONS
Stanislav Yanev Department Drug Toxicology, Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria
Abstract. Numerous experimental and clinical data suggest that the major system (host defense) that protects humans from infectious organisms interacts with the principal system that affords protection from chemicals including drugs (drug metabolizing enzymes). This interaction has the potential to produce severe and occasionally life-threatening complications in drug therapy during episodes of infectious disease or other pathological changes of immune system. The loss of cytochrome P450 is now considered to be a multifactorial and frequent consequence of stimulation of immune system after infection and inflammation. In most cases that is accompanied with no other signs of toxicity of affected organs (liver, kidney, brain). Few examples exist for immunosupression after induction of cytochrome p450 (dioxins). Experimental evidences: In animal models, cytochrome P450 is depressed by various types of: infections, including bacterial (e.g., Listeria monocytogenes, Actinobacillus pleuropneumonia, Chlamydia trachomatis), viral (e.g., Encepahalomyocarditis virus, murine retrovirus LP-BM5), and parasitic infections (e.g., Fasciola hepatica, Plasmodium berghei); vaccines (e.g. BCG, B.pertussis vaccine); experimental diseases (e.g. rat ajuvant polyarthritis, AA). The cytochrome P450 down-regulation is time, dose and immune stimulus dependent. It coincides with the maximum immune response in genetically sensitive animals. Inhibition of drug metabolism appeared mainly after stimulation of cellular immunity and interferon production: Clinical evidences: Thereare many documented examples of compromised drug metabolism in humans with impaired immune system after(e.g., influenza, HIV, adenovirus). The magnitude of cytochrome P450 depression in humans is highly variable, and it has been proposed that high initial drug levels may predispose infected individuals to exaggerated pharmacological responses as a result of the down regulation of the drug metabolizing enzymes. These interactions continue to cause problems, such as toxicity, during drug treatment in patients with infections, following vaccination, in cancer patients receiving interferon or cytokine therapy, and in situations where host defense is activated. For example, in man, acute viral infections of the upper respiratory tract, bacterial pneumonia and BCG vaccination are able to reduce the clearance of theophylline by down-regulating multiple isoforms of the hepatic cytochrome P450. Theophylline plasma levels in bronchitis children increased during influenza epidemics. Quinine blood levels were increased during Plasmodium falciparum malaria infections.Which CYP isoforms are more affected after immune stimulation: Decreased activities of liver CYP 1A1, 1A2, 2A6, 2B6 and 3A4 are the most affected in infected rats. In humans CYP2A6, CYP2A7 and CYP2C19 were down-regulated in HBV- and/or HCV-infected livers compared with normal livers. Some liver enzyme activities as CYP 2E1 and CYP 4A, alcohol dehydrogenase and N-acetyltranspherase were even found to be increased in AA or LPS treated rats. Mechanisms of cytochrome p450 depression by immunostimulation seems to imply the secretion of pro-inflammatory mediators like cytokines (IL-1, IL-2, IL6, TNF), interferones (, , ), NF-B by immune cells and bacterial endotoxins (LPS), which contribute for decreased CYP protein synthesis through transcriptional suppression and mRNA destabilization. Inflammatory mediators down regulate also inducible P450 expression by influencing different intracellular receptors pathways as aryl hydrocarbon receptor (AhR), PPAR, the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR).
37
Immunostimulants would also activate directly or indirectly (via MAF secretion) macrophages or Kupffer cells leading to the secretion of reactive oxygen species (ROS) and NO and ultimately to the loss of CYP mRNA. In this context there are some experimental evidences that safer immunostimulator should be a drug with some antioxidant properties.
IN VITRO DRUG RELEASE METHODOLOGIES FOR TOPICAL SEMISOLID DOSAGE FORMS

Flavian Radulescu, Dalia Miron, Victor Voicu, Constantin Mircioiu University of Medicine and Pharmacy Carol Davila Bucharest, Bucharest, Romania
Abstract. Vertical diffusion cell system are currently recommended by the The Topical/Transdermal Ad Hoc Advisory Panel for the USP Performance Tests of Topical and Transdermal Dosage Forms as main tools for evaluation of drug release profiles from semisolid dosage forms. A draft monograph was issued in 2009 for hydrocortisone 1% cream, as a possible performance verification test reference standard. The current regulatory approach on topical products registration imposes either clinical or pharmacodynamic proofs of equivalence between the innovator and generic drug formulation. Dermatopharmacokinetic (DPK) or microdyalisis (DMD) techniques have been reported as alternative tools for product performance evaluation, but their use must considered the absorption pattern and the site of action. Currently, there are several reports of in vitro in vivo correlations or of rank ordering, but their accurate analysis must consider also several other parameters, generally defining qualitative (Q1), quantitative (Q2) or structural (Q3) equivalence. The paper presents the relevance of accurate selection for membrane characteristics (nature, porosity, surface available for diffusion), receptor media composition or characteristics of active pharmaceutical ingredient for the similarity evaluation of in vitro drug release profile (IVR). Also, the available experimental devices and their possible application will be analyzed. Correlations between physical characteristics (rheological behavior and flow curves modeling) and IVR rate and DMD/DPK data will be presented for different drug products.
38
COUNTERFEIT DRUGS: CURE OR THREAT
Svetlana Goloorbin-Kon Faculty of Pharmacy, University of Montenegro and Departmnt of Pharmacy, Medical Faculty Novi Sad, Serbia
Abstract. Counterfeit medicines are medicines that are deliberately and fraudulently mislabelled with respect to identity and/or source. All kinds of medicines have been counterfeited, branded and generic. Counterfeit medicines may include products with the correct or with the wrong ingredients, without active or with insufficient or too much active ingredients, or with fake packaging. Since counterfeit drugs first time have appeared, they have been more sophisticated and more difficult for detection. The estimate is that up to 1% of medicines available in the developed World are likely to be counterfeit. This figure rises to 10% globaly, although in some developing countries it is 50%. World Health Organization estimate is that 50% of medicines available via the internet are counterfeit. The knowledge of counterfeit drugs should be used for the education of the pharmacy and medicine students, health professionals and patients. Pharmacists and doctors should stay vigilant and report suspicious products, and consider conterfeits as a possible cause of adverse reactions or therapeutic failure. Patients should report to their pharmacists and doctors if they suspect any irregularity with their medication, if they experience side effects or a decrease in beneficial effect. The cruicial step in the prevention of counterfeit medicines is the supply from reliable sources, licenced pharmacies.
39
BIOGRAPHY
KIM BRSEN
Scientific training and appointments 1995- Professor in human pharmacology with emphasis on pharmacogenetics, University of Southern Denmark in Odense Honorary offices 1995-2007 Member of the Executive Committee of the European Association for Clinical Pharmacology and Therapeutics (EACPT) (Co-opted 2007-10) 1996-99 Member of the Executive Committee of the Scandinavian Society of Clinical Psychopharmacology 1997 Chairman of the Professional Executive Committee of Infomatum A/S (main provider of product independent drug information in Denmark) 1999-2003 Vice-chairman of EACPT 2000-8 Secretary, Clinical Division, IUPHAR 2006- Member of the Executive Committee, IUPHAR 2001- President of the 5th EACPT Congress, Odense Denmark 2010- President of the 16th World Congress on Basic and Clinical Pharmacology (WorldPharma2010) Editorial boards 1994-2007 European Journal of Clinical Pharmacology and Therapeutics 2001-7 Therapeutic Drug Monitoring Scientific Tutorials Awards 1991 The Ole J. Rafaelsen Award in Biological Psychiatry 2005 The Poulsson Award Editorships Brosen K (ed.). A Guide to Training in Clinical Pharmacology in Europe 1999, Odense University Press, Odense, Denmark Kampmann JP, Brsen K, Nielsen-Kudsk F and Nyborg N (eds.). Basic and Clinical Pharmacology 1999, 2nd edition, FADL, Copenhagen, Denmark Kampmann JP, Brsen K, Simonsen U (eds). Basic and Clinical Pharmacology (in Danish) 2007, 3rd edition, FADL, Copenhagen, Denmark 2003- Editor of Basic & Clinical Pharmacology & Toxicology Publications Approximately 235 publications including 150 original papers in international journals with peer review. Main topics: pharmacokinetics, drug-drug interactions, drug metabolism and the CYP2C19 and CYP2D6 polymorphisms. Kim Brsen is among the most cited pharmacologists during 1990 to 2004 (www.ISIHighlyCited.com)
40
PHARMACOGENETICS IN MODERN CLINICAL PHARMACOLOGY RESEARCH

Kim Brsen, MetteMarie Hougaard Christensen, Troels Bergmann, Rasmus Steen Pedersen, Charlotte Brasch-Andersen Institute of Public Health, ClinicalPharmacology, University of Southern Denmark
Abstract. Pharmacogenetics is the science of how inheritance influences interindividual differences in dug response. The term wascoined in 1959, and for the subsequent 45 years research in the field was dominated by the study in the geneticpolymorphisms in drug metabolizing enzymes, notably N-acetyltransferase 2 (NAT-2), thiopurinemethyltransferase (TPMT) and in particular cytochrome P450 (CYP). The human genome contains 57 CYP genes and 33 pseudogenes, and genetic polymorphisms have been established for CYP2D6, CYP2C19, CYP2C9, CYP2C8 and CYP2B6. Even for the apparently nonpolymorphic CYPs CYP1A2 and CYP3A4/5 show a major genetic influence in function. Evidence is accummulating that drug passage across cell membranes involves the actions of drug transporters. Drug transporters are integral cell membrane proteins that mediate active or facilitated transport of drugs across the epithelial cell membranes of the intestine and the kidneys, liver cells and endothelial cells just to mention a few. In thisway drug transporters exert an influence on the absorption, distribution and excretion of drugs. So far 48 species of the polyspecificATP Binding Cassette (ABC) transporters and more than 325 species of the SoLuteCarrier (SLC). Genetic and environmental differences in drug transporters thus are important sources of interindividual diferences in drug actions. Results from our recent research on paclitaxel and metformin will illustrate some of these important concepts.
41
EXPERIMENTAL PHARMACOLOGY
RESEARCH ABOUT THE PLASMA AND SALIVA CONCENTRATIONS OF BIVALENT CATIONS IN PATIENTS WITH ORAL MALIGNANT TUMORS
Mihai Nechifor1, Elena Luca2, Irina Gradinaru2, Eugenia Popescu3, Mihaela Baican4, Diana Ciubotariu1, Florina Crivoi2, Cristina Gales5 1.Pharmacology Department, "Gr.T.Popa University of Medicine and Pharmacy Iasi,Romania 2.Protetics Department, "Gr.T.Popa University of Medicine and Pharmacy Iasi,Romania 3.Oro-Maxilar Surgery, "Gr.T.Popa University of Medicine and Pharmacy Iasi,Romania 4.Biophysics Department, "Gr.T.Popa University of Medicine and Pharmacy Iasi,Romania 5.Histology Department, "Gr.T.Popa University of Medicine and Pharmacy Iasi,Romania
Abstract. We tested the plasma and saliva concentrations of some bivalent cations in patients with oro-maxilar malignant tumors.In this study were included 56 patients with malign tumors of oro-maxilar area without metastasis .The histological types of malignant oral tumors were:lips carcinoma(30), tongue carcinoma(14), gum mucosal carcinoma(5), others(7).Separately there were determined the cationic concentrations in 27 adult patients with parotid gland malignant tumors.The main histological types of benign tumors was..A group of 20 healthy volunteers was the control group.The determinations of plasma and saliva concentrations of calcium , magnesium , copper and zinc were performed by atomic absorbtion spectrophotometry method. The obtained data were statistically interpreted.Anatomopathological examination (optical microscopy) was performed for all cases.There weret included in the study pregnant or breastfeeding women, patients with bleeding from the oral cavity , with tooth metallic prothesis or fractures.The ionic concentrations were determined before chemotherapic or surgical treatment. The obtained data showed that zinc plasma concentration was significantly decreased in malignant tumors group(1,320,21mg/l in the control group vs 0,910,11 mg/l in tumors group p<0,05), the ratio between the plasma zinc/copper was decreased in tumor group(1,120,14 vs 1,370,48 p<0,05).The saliva magnesium concentration is increased in tumors group (3,730,4mg/l vs 3,160,27mg/l in control group p<0,05). The salivary Zn2+ concentration was significantly higher in normal group compared to parotid gland tumors group.The results showed that the zinc plasma and saliva concentrations are decreased in malignant tumor patients and the salivary ratio between t-Mg/t-Ca is increased in the neoplastic tumors of oro-maxilar area ,particularly in parotid gland tumors.We consider that the variation of these plasma and salivary ionic concentrations is involved in the development of malignant oro-maxilar tumors.
42
INFLUENCE OF CEFTAZIDIME AND MOXIFLOXACIN ON SPERM MOTILITY

Elena Antohi1, Cristina Gales2, Mihai Nechifor3
1. 2. 3.
Physician Ph.D, Department of Hystology, Gr. T. Popa University of Medicine and Pharmacy Iasi Romania Department of Pharmacology, Gr. T. Popa University of Medicine and Pharmacy Iasi Romania
Abstract. Sperm motility is a crucial factor for fertilization. We tested the influence of two antibacterial antibiotics(ceftazidime and moxifloxacin) in vivo on adult Wistar male rats and in vitro bovine sperm. The antibiotics were tested both in vivo and in vitro: ceftazidime (GlaxoSmithKline) in vivo dose of 50 mg/kgbody/day given intraperitoneally and 250 mg/kgbody/ day for 10 days, and in vitro ceftazidime 165 mg and 330 mg for each sample, moxifloxacin (Bayer AG) in vivo in a dose of 30 mg/kgbody/day for 7 days. For in vitro study the antibiotics were administrated directly into the sperm before the test Control groups of Wistar rats and bovine sperm have not received any substance. Our data showed that in vivo doses of ceftazidime and moxifloxacin tested were significantly reduced (p <0.01) sperm motility, ceftazidime at a dose of 50 mg/kgbody/day, respectively 250 mg/kgbody/day reduced sperm motility with 85.36% respectively 83.79% between the effect of two doses ofceftazidime no significant differences. Moxifloxacin at a dose of 30 mg/kgbody/day reduced sperm motility with 85.81%. In vitro study ceftazidime and moxifloxacin were significantly reduced (p <0.001) sperm motility compared with control samples We consider it necessary to give greater attention to the influence of antibacterial antibiotics used in medical practice on sperm motility.
43
MANGANESE INFLUENCE ON MORPHINE PHYSICAL DEPENDENCE AND BRAIN REWARD SYSTEM IN RATS
Diana Ciubotariu1, Ileana Palamaru2, Mihai Nechifor1 1 Pharmacology Department, University of Medicine and Pharmacy Gr. T. Popa Iai 2 Public Health Institute, Iai Romania
Abstract. Manganese plays many roles in the brain including an effect on dopamine neurotransmission, . Dopamine is an essential neurotransmitter for reward system and addiction development. Conditioned place preference (CPP) paradigm investigates rewarding effects of different agents. This study investigated manganese effects on morphine physical dependence and morphine induced CPP. Experiments were performed on adult Wistar male rats. In order to induce dependence, morphine was administered in progressively increasing doses for 10 days (from 5 to 90 mg/kg/day, 2 daily administrations). On day 11, naloxon was administered to induce opiate withdrawal, which was evaluated in a group receiving only morphine (described schedule) vs. two groups, which received, during opiate dependence inducement phase, MnCl2, 0.02 and 0.04mmol/kg/day, 10 days. For morphine-induced CPP we used three chambers conditioning apparatus. Pre-conditioning (day 1): Natural animal preference towards chambers is determined: rat spends 15 minutes in the apparatus (communication between chambers opened). Main chamber where it spends most of the time is referred to as preferred, and the other as non-preferred. Conditioning (days 2 9). Communication between compartments is closed. In days 2, 4, 6 and 8, animals received: morphine, 3 mg/kg, immediately before placing the animal in the non-preferred chamber. In days 3, 5, 7 and 9, rats received saline, and immediately after they were placed in the preferred chamber. Post-conditioning (day 10). Preference towards main chambers is again measured for 15 minutes. The intensity of morphine-induced CPP was evaluated in a group receiving only morphine during conditioning vs. two groups which received MnCl2, 0.2 and 0.4mmol/kg, 2 hours before each morphine administration. Both MnCl2 doses decreased the intensity of morphine dependence (global withdrawal score for evaluated withdrawal symptoms was 133,89,27 in morphine only treated group, 117,76,36 in group treated with MnCl2, 0.02 mmol/kg/day p<0.01 vs. morphine only treated group, and 112,27,71 in group treated with MnCl2, 0.04 mmol/kg/day p<0.001 vs. morphine only treated group). Morphine, 3 mg/kg/administration induced CPP (time spent in non-preferred chamber increased from 218.325.22 seconds pre-conditioning to 741.881.62 seconds post-conditioning, p<0.001). MnCl2, 0.4mmol/kg, determined a slight aversive effect. MnCl2 decreased morphine CPP intensity (time spent in the conditioning chamber increased by 244.2058.34% in morphineonly treated group, by 192,2840,99% in group treated with morphine+MnCl2, 0.2 mmol/kg, p<0.05, and by only 168,2052,39% in group treated with morphine+MnCl2, 0.4 mmol/kg, p<0.01). . MnCl2 determined a significant reduction in intensity of morphine dependence and on morphine stimulatory effects on the reward system.
44
POSSIBLE CANNABINOMIMETIC EFFECTS FOR HIGH DOSES OF METAMIZOLE SODIUM IN MICE

H. Punescu, Eugenia Panaitescu, Isabel Ghi, Oana Andreia Coman, I. Fulga Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, UMF Carol Davila, Bucharest
Abstract. Aim: A possible cannabinomimetic effect for paracetamol was described, but not yet for metamizole sodium. The present study tried to determine if high doses of metamizole sodium had the four effects characteristic for the profile of cannabinoid receptor type 1 agonists (mice tetrad). Material and methods: 8-10 albino mice were used for each experiment. The experiments were carried out according to the Institutional Ethic Board. The parameters measured were: time to licking paw and to jump in hot plate test at 55C, number of horizontal and vertical movements for 5 minutes in activity cage, rectal temperature measurements and time of immobility in a modified bar test. Doses used were 250, 500 and 1000 mg/kg body weight (bw) for hot plate, 250 and 500 mg/kg bw for sedative effect evaluation and 1000 mg/kg bw for rectal temperature measurement and catalepsy assessment. Control groups received saline 0.1 ml/10g bw. Levene test followed by Tukey test or Tamhane test were used for statistic analysis.
45
POSSIBLE POTENTIATION BETWEEN HIGH DOSES OF ACETAMINOPHEN AND FAAH INHIBITORS IN CENTRAL ANALGESIA
Oana Andreia Coman, H. Punescu, Isabel Ghi, I. Fulga Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, UMF Carol Davila, Bucharest
Abstract. Aim. The present study tried to determine if the combination between acetaminophen (described as a cannabinomimetic drug in high doses) and ibuprofen or URB597 -both fatty acid amide hydrolase (FAAH) inhibitors- administered in subanalgesic doses, could interact in hot plate test. Material and methods. The experiments were carried out according the Institutional Ethic Board. 10 albino mice were used for each experiment. Substances used, doses and route of administration were: acetaminophen 600 mg/kg body weight (bw), orally administered, and ibuprofen 30 mg/kg bw or URB597 2.5 mg/kg bw respectively, intraperitoneally administered. Doses were chosen according to pretests (using the writhing test) for the three substances. The doses chosen for ibuprofen and URB 597 were ineffective (subanalgesic) in the writhing test. The dose of acetaminophen used was greater than LD50 in mice but equal to ED70 in writhing test. The parameters measured were time until liking paw and time until jump. The statistic analysis used ANOVA or nonparametric tests. Results. Unlike some results presented in literature, neither substance was analgesic at doses of 600 mg/kg bw (acetaminophen), 30 mg/kg bw (ibuprofen) and of 2.5 mg/kg bw (URB597) respectively, for the liking paw parameter. An association of 600 mg/kg bw acetaminophen and 30 mg/kg bw ibuprofen and an association of 600 mg/kg bw acetaminophen and 2.5 mg/kg bw URB597 were analgesic for the same parameter. Conclusions. At the doses administered acetaminophen, ibuprofen and URB597 were not analgesic in the hot plate test, but a potentiation between acetaminophen and ibuprofen, and between acetaminophen and URB597 respectively was obtained. Acetaminophen-ibuprofen and acetaminophen-URB597 associations possibly acted by influencing the endocannabinoid system.
46
THE ANTIOXIDANT N-ACETYLCYSTEINE EFFECT IN PHYSICAL EFFORT TO RACE HORSES

Nicoleta Taus1, Monica Potrovita2, Valentin Necula2, Antonela Diana Hirceaga1, Laurian Taus3
1. 2. 3.
Transilvania University of Brasov, Faculty of Medicine, 56 Nicolae Balcescu Street, Brasov, Romania Sanitary Veterinary and Food Safety Direction of Brasov, Romania Clinical Hospital Brasov
Abstract. Purpose. This paper tries to demonstrate the existence of the effort-induced oxidative stress, throughout the measurement of the superoxide dismutase, the antioxidant N-acetylcysteine effect, and the observation of the age related anti-oxidant capacity changes. Materials and Methods.The experimental study has been made using Lipitan race horses, 6, 12 and 15 years old, from the Sambata de Jos Stud, under the permission of the Directia Sanitara Veterinara Brasov (DSV Brasov). The detection of the superoxide dismutase reaction in the serum has been similar to that described by Beauchamp and Fridovich. Results and conclusion. In the study made with the agreement and collaboration of DSV Brasov, we have noticed a 25.95% decrease of the SOD values after the physical effort, compared to the initial values obtained before effort. Comparing the SOD values before effort in the horses at extreme ages ( 6 and 15 years old), we observe a value of 92.37 for the 6 year-old horses and one of 102.8 for the 15 year-olds. This information shows that there is an increase of the enzyme activity with aging. The antioxidant N-acetylcysteine prevented SOD decrease.
47
SCREENING OF OXIME EFFICACY IN THE NEUROTOXIC ORGANOPHOSPOROUS COMPOUNDS POISONING

Cristina Sarbulescu Secara1, Bogdan Patrinichi1, Rodica Alexandrescu1, Constantin Draghici1, Victor. A. Voicu1,2
1. 2.
Army Centre of Medical Research, Bucharest Romania University of Medicine & Pharmacy Carol Davilla, Bucharest Romania
Abstract. Aim: selection of a compound with oxime structure, as AChE reactivator, with sufficient efficacy to decrease the acute toxicity of soman; to increase the oxime selected efficacy by using galantamine, a centrally acting cholinesterase inhibitor and nicotinic ligand, which can cross the blood brain barrier. Methods: The soman DL50 value experimentally established in the study: 80 g/kg/s.c. The following soman doses were administered to the poisoned and treated study groups: 240g/kg/s.c (3 DL50); 280 g/kg/s.c (3,5 DL50) and 300 g/kg/s.c(3,75 DL50) respectively. Four Wistar rats study groups (each containing 10 animals) were used. The study was based on testing the efficacy of HI6, at 1/10 DL50 dose, in a complex antidotal formula (ATOX), which also contains atropine (17.6 mg/kg), scopolamine (5mg/kg) and imipramine (25mg/kg). The above formula, i.m. administered, 1 minute after poisoning, was associated with galantamine (8 mg/kg p.o - 30 minutes prior the poisoning), and experimentally tested. The following antidote formula was used as reference: pyridostigmine (8,1 mg/kg p.o.- 30 minutes prior the poisoning), and ATOX-HI6,. The protective ratio and hystopathological analyses were the screening parameters used in the study, in order to show the proposed objectives. Results: The protective ratio of the ATOX-HI6 formula without pre-treatment was 3. The protective index of the reference formula was 3,5. The protective index of the experimentally tested antidote formula containing galantamine and ATOX- HI6, was 3,75. Soman induced neurodegeneration in the hippocampus, pyriform cortex and amygdale, were not detected 72 hours after soman poisoning, when galantamine is used. The seizures level was decreased. Conclusions: The AChE inhibitor and neuroprotector compound galantamine administered as pre-treatment, increase, more than pyridostigmine, the atropine oxime efficacy by increasing the protective ratio, and decreasing soman neurotoxicity. Thus galantamine as pre-treatment emerges as superior antidote therapy against the soman toxicity.
48
PARACETAMOL ANALGESIA. CANNABINOID CONNECTION
andor Vlaicu Department of Pharmacology and Toxicology. UMF Iuliu Haieganu Cluj-Napoca.
Abstract. Excellent antipyretic and analgesic effects of paracetamol contrasts with the lack of antiinflammatory action. This discrepancy may be explained by the incapacity of paracetamol to inhibit induced cyclooxigenases on the peroxide rich inflammatory site. Central nociceptive effect of paracetamol is significant. In the brain one metabolite of paracetamol (o-amino-phenol) is conjugated with arachidonic acid resulting N-arachidonoylphenolamine (AM 404). The reaction is catalyzed by fatty acid amide hydrolase (FAAH), involved in anandamide endocannabinoid degradation, with structural resemblance to AM 404. Analgesic effects of paracetamol are correlated with cerebral concentrations of AM404. AM404 may increase anandamide concentration by FAAF inhibition and somewhat also by inhibiting its membrane transport. Nociceptive effects of both paracetamol and AM404 are prevented by type1 cannabinoid receptor antagonists (CB1), and also in CB1 knock-out animals. Endocannabinoid system involvement in paracetamol effects are indirect, cause AM404 does not have affinity for CB1, but acts on type 1 vaniloid receptors (TPRV1). Probably AM 404 increases anandamide concentration, which can act as antinociceptive on TPRV1. Moreover AM404 activates partly central opioid and serotoninergic mechanisms involved in pain perception and analysis.
49
AMPHETAMINE- MYORELAXANT AGENTS INTERACTIONS IN AN EXPERIMENTAL MODEL

Cuparencu Barbu, Albu Silvia, Safta Liviu, andor Vlaicu Department of Pharmacology and Toxicology. UMF Iuliu Haieganu Cluj-Napoca.
Abstract. Introduction The adrenergic nervous system modulates the neuro-muscular transmission, mostly enhancing it. Amphetamine, an indirect-acting sympathomimetic amine by its catecholamine-releasing effect affords relevant opportunities to undertake a pharmacological analysis of the interactions between adrenergic drugs and myorelaxant agents. Material and methods. The experiments were carried out in male albino Wistar Bratislava rats, weighing 150-200g, fed a standard diet. As myorelaxing drugs, d-tubocurarine and pancuronium were used. The experiments were performed on Julou- Courvoisier test which consists in the following procedure. The animals were suspended with the forelegs on a horizontal bar. The ability of the rats to maintain this position during 20 seconds was determined. The incidence, the latency and the duration of muscle myorelaxation were noted. d-tubocurarine was given in doses from 0.084 to 0.138 mg/kg. Pancuronium was administered in doses of 0.225 to 0.3 mg/ kg. Amphetamine was tested in acute conditions in association with both myorelaxants. It was administered intraperitoneally in doses of 1-5-10 mg/kg, fifteen minutes prior to myorelaxants. Results Amphetamine alone, in all administered doses has nonsignificant effects on the incidence, latency and duration of d-tubocurarine-induced myorelaxation. In experiments in which pancuronium was coadministered with amphetamine, it was ijjected in a dose of 0.25 mg/kg, whereas amphetamine was given in the doses already mentioned. In a dose of 10 mg/ kg, amphetamine prolonged the latency of pancuronium effect. Other doses failed to have any significant effect on the experimental parameters. Conclusions Amphetamine has minimal effects on the myorelaxation induced by d-tubocurarine and pancuronium. Only the highest dose of amphetamine delays the appearance of the myorelaxation brought about by pancuronium.
50
CALCITONIN IN ULCER TREATMENT
Abstract. Material and method We worked on 3 experimental ulcer models: restraint, indomethacin and reserpine. Animals were kept in starvation for 12 hours before ulcerogenesis. Calcitonin was administered in different doses, 3 times in 8 hours, and then the animals were sacrificed. Stomach was studied and mucosa was examined on a microscope. Ulcerogenic parameters considered were incidence, number and severity of ulcerations. In the reserpine model specific weight of rumen and glandular region was determined and also plasma calcium and magnesium levels. Results Restrained animals were treated with 4 types of calcitonin doses: 12,5-25-50 and 100 UI/kg. Antiulcerous effect is spectacular regardless of dose. With the indomethacin model the following interval of doses were used: 2.5- 5-10 -20 UI/kg. Protective effect is present only at large doses. Reserpine groups were injected with 1-10-100 UI/kg calcitonin. Calcitonin decreases incidence, number and severity of ulcerations starting from 10UI/kg. 100 UI/kg decreases rumen weight and reduces mucosal edema at this location. Reserpine increases plasma calcium, calcitonin prevents this effect. On plasma magnesium, reserpine and calcitonin have synergistic effect. Conclusions. Calcitonin has significant and dose-dependent antiulcerous effects on all 3 experimental models. Calcitonin has a cytoprotective effect on gastric mucosa by prostaglandin release. In addition, inhibition of gastric secretion contributes to this effect.
51
CIMETIDINE IN EXPERIMENTAL CCL4-INDUCED HEPATITIS
Abstract. Introduction. Carbon tetrachloride (CCl4) causes liver damage by biotransformation in reactive compounds by the CYP450 system. Cimetidine as microsomial enzyme inhibitor can influence the livertoxic ability of CCl4. Material and method. Experiments were done on 3 species of male rodents from UMF Iuliu Hatieganu Cluj-Napoca Biobase: mice (20-32g), rats (100-168g) and guinea pigs (300-600g). For each species 4 groups were formed with 10 animals each. Group I (control) was injected intraperitoneally (i.p.) with oleum helianthi, group II i.p.with 25 micromoles/kg cimetidine, twice a day for 3 days, Group III received s.c., on single dose 2.5 ml CCl4, diluted in oleum helianthi, and group IV was treated with cimetidine and CCl4, this latter concomitently with the last dose of cimetidine. Except mice, animals were sacrificed after 24 hours after the CCl4 dose. Blood were drawn form retroorbital sinus to determine ASAT, ALAT, gamma GT, cholinesterase. Livers and kidneys were studied, weight indexes were calculated. Morphopathologic samples were dyed with hematoxilin-eosin and Sudan III. Rezults. Cimetidine has insignificant enymatic and morphopatologic effects in all 3 species. CCl4 increases ASAT and ALAT significantly, also liver weight and induces centrolobular necrosis and steatosis. Cimetidine does not alter transaminases or liver morphology. In rat, after CCl4 treatment there are high values of ASAT and ALAT, also liver weight, and lipid distrophy and centrolobular necrosis. Cimetidine alleviates significantly morphopathologic image and reduces plasma enzymes considerably. Cimetidine administration at the above mentioned doses in mice treated with CCl4 causes death in most animals, so in this case sacrifice took place at 9 hours after CCl4. CCl4induces increas of ASAT, but even more for ALAT. Microscopic image shows micronecrosis and macrovacuolar distrophy. Cimetidine association beside the brutal lethal effect augments CCl4 effects on transaminases. Conclusions. Acute CCl4 induces necrotic liver damage in all 3 species. Transaminases are elevated, especially in rats. Cimetidine has differential effects on CCl4-induced liver toxicity on the 3 species. In guinea pig cimetidine has only a minimal effect on enzyme and morphopatologic parameters, in rat it has a protective effect, and in mouse the interaction is lethal.
52
THE EFFECTS OF NOVEL COPOLYMERIC MATRICES FOR INDOMETHACIN IN EXPERIMENTAL SOMATIC NOCICEPTION
Liliana Taru1, Andra Sabina Valeanu2, Loredana Ni3, Aurica Chiriac3
1. 2. 3.
Department of Pharmacology, Faculty of Medicine, Gr.T. Popa University of Medicine and Pharmacy, Iasi University of Agricultural Sciences and Veterinary Medicine, Iasi LAMINAST Laboratory, P. Poni Institute of Macromolecular Chemistry, Iasi
Abstract. The development of analgesic drugs formulations may represent a future challenge to develop promising agents for regional drug delivery in inflammatory and painful conditions. Polymeric systems are used to prepare drugs sustained-release formulations because of their safety and stability. Using an original methodology we achieved novel indomethacin-loaded copolymeric networks which were previously characterized by Fourier transform infrared (FTIR), scanning electron microscopy (SEM) and thermo-gravimetric (TG) analyses in order to investigate their microstructure and thermal stability. The aim of our study was the in vivo biocompatibility evaluation and the experimental researches on the effects of the indomethacinloaded copolymeric matrices in a somatic pain model in mice. Method: The experiments were carried out on white Swiss mice (20-25 g), divided into 6 groups of 7 animals each, treated orally as follows: Group I (Control): 0,1ml/10g weight; Group II (IND): indomethacin 5mg/kbw (IND); Group III (1 M): polyhydroxyethyl methacrylate (HEMA) 10% + polyvinyl alcohol (APV); Group IV (1 IND): HEMA 10% + APV + IND 5mg/kbw; Group V (3 M): HEMA 10% + undecan 3,5% + APV; Group VI (3 IND): HEMA 10% + undecan 3,5% + APV + IND 5mg/kbw. Biocompatibility testing was based on determination of the hemodynamic, immune and biochemical profile of animals treated with indomethacin and with indomethacin-loaded copolymeric matrices. The following parameters: complete blood count, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT) and lactic dehydrogenase (LDH) activity, opsonic serum capacity (OC), phagocytic (PC) and bactericidal capacity (BC) of peritoneal macrophages were also evaluated. The nociceptive somatic testing was performed using hot plate assay. Experimental protocols were implemented according to recommendations of the University Committee for Research and Ethical Issues and to the guidelines of the IASP (International Association for the Study of Pain) Committee for Research and Ethical Issues. Data were statistically analyzed with SPSS software for Windows using ANOVA method. Results: Laboratory analysis did not show significant differences of leucocyte formula elements, GOT, GPT and LDH levels, nor immune parameters (OC, PC, BC), between control mice group (IND) and groups treated with 1 M, 1 IND, 3 M, 3 IND. In our experimental conditions, data analysis revealed that, 1 IND and 3 IND administration resulted in increasing of latency time response in hot plate test, statistically significant compared with indomethacin. Conclusions: Both indomethacin copolymeric matrices 1 IND and 3 IND proved good in vivo biocompatibility after oral administration in mice and antinociceptive effects in this somatic pain model in mice.
53
BIOCOMPATIBILITY EVALUATION AND INVESTIGATION OF MAGNESIUM SOFT MATER VESICLES EFFECTS ON THE COGNITIVE PROCESSES IN RATS
Liliana Taru1, Ctlina Elena Lupuoru1, Diana Ciubotariu1, Viorel Melnig2 1 Department of Pharmacology, Gr.T. Popa University of Medicine and Pharmacy, Iasi, Romania 2 Department of Physics COMB Laboratory, Faculty of Physics, Al. I. Cuza University, Iasi, Romania
Abstract. The objectives of this study, consists of biocompatibility evaluation and experimental researches on the effects of magnesium soft mater vesicles on memory processes performance in rats. Method: The soft matter vesicles were made by magnesium chloride immobilization inside lipid vesicles coated in polysaccharide chitosan and structurally analyzed using Malvern Zetasizer Nano ZS ZEN-3500 model. The experiments were carried out with white male Wistar rats (200250g) distributed into 3 groups of 7 animals each, treated orally (using an eso-gastric device) 7 consecutive daily administration, as follows: Group I (Control): distilled water 0,1ml/10g weight; Group II (Mg): magnesium chloride 200mg/kbw; Group III (Mg vesicles): magnesium chloride 200mg/kbw entrapped in soft vesicles. In the 8-th day of the experiment blood samples were taken from retro-orbitary plexus to assess blood count, phagocytic capacity of peripheral neutrophils and serum complement activity, important elements for biocompatibility evaluation. Spatial memory performance was assessed by recording spontaneous alternation behavior in a single session in Y-maze. Data were presented as +/- SD and significance was analyzed using SPSS for Windows version 17.0 and ANOVA method. The experiments were performed according GR.T. Popa University of Medicine and Pharmacy guidelines, for handling, and use of experimental animals. Results: Magnesium entrapped vesicles were found to have a mean Zeta potential of +36.1mV and a mean size of 129.56nm. Laboratory analysis showed no significant differences of blood count, phagocytic capacity of peripheral neutrophils and serum complement activity values, between magnesium lipid vesicles and control group. In our experimental conditions, magnesium entrapped vesicles, significantly increased spontaneous alternation percent in Y-maze test, which suggest the improvement of short-term memory. Conclusions: Magnesium soft matter vesicles proved similar immune responses with control group, after oral administration in rats, indicative of good in vivo biocompatibility. Our research revealed that 7 consecutive days administration of magnesium entrapped in lipid vesicles have been associated with the enhancement of cognitive functions in rats.
54
FEATURES, MECHANISMS AND MORPHOMETRIC CORRELATION OF ENDOTHELIUM-DEPENDENT RELAXATION, AS REVEALED BY TIME-COURSE ANALYSIS AND THE USE OF DIFFERENT PRECONTRACTION AGENTS
Hoga MM1, erban IL1, Oprisa C1, Tucaliuc ES1, Hurjui L1, Nechifor M2, erban DN1
1. 2.
Departments of Physiology, Gr. T. Popa University of Medicine and Pharmacy, Iasi, Romania Pharmacology, Gr. T. Popa University of Medicine and Pharmacy, Iasi, Romania
Abstract. The importance of endothelium-derived hyperpolarizing factor (EDHF) in endotheliumdependent relaxation (EDR) is influenced by multiple factors, including vascular territory and caliber, pre-existing tone and its determining factors. Using isometric myography, we noticed that in rat mesenteric resistance arteries (RMA2; 2-nd order branches) EDHF-mediated relaxation is increased when precontraction is induced by prostaglandin F2 alpha (PGF) compared to phenylephrine (PHE) and we investigated the participation of certain K+ channels (Serban IL & Serban DN (2006) J Muscle Res Cell Motil 26(1):71). Here we extend the study on more proximal vascular fragments; from mesenteric arcade and from 1-st order branches and we evaluate the phasic (rapid, transient, ample) and tonic (slower and weaker) EDHF-mediated EDR. The EDHF component of EDR is stronger distally only when precontraction is induced by PHE. Moreover, morphometric analysis shows a strong inverse correlation between the magnitude of EDHF response and arterial caliber. Other authors have shown that EDHF increases in relative importance distally, but we show that this change in EDR profile depends upon the contracting agent used, with implications regarding the physiological relevance of accumulated data refering to EDHF and nitric oxide as mediators of EDR in resistance arteries. Based on our new observations presented here we currently extend our previously published results regarding EDR mechanisms and the way they are influenced by various factors, such as magnesium concentration, homocysteine, steroids, chronic inflammation, etc.
55
CLINICAL TOXICOLOGY
ACUTE LIVER FAILURE IN ACUTE POISONING IN CHILDREN
Coriolan E Ulmeanu, Gabriela Viorela Niescu, Elena Mdlina Petran Antitoxic Pediatric Center, Childrens Clinical Emergency Hospital Grigore Alexandrescu Bucharest
Abstract. Acute liver failure is a multiorganic disease characterized by severe liver cell necrosis and severe encephalopathy in a patient with no previous liver diseases (Kings College criteria). Toxicants are usually drugs and chemicals that act directly on the liver (eg. carbon tetrachloride) or during a hipersensitivity reaction (eg. sulfamids). In our country paracetamol starts to become first toxicant encountered in acute liver failure, followed by mushrooms that induce phalloidian syndrome. Sodium valproate treatment in in children with epilepsia is frequently related with liver toxicity in first 4-6 month of treatment. Elevated value of amoniemia and transaminase levels forces treatment discontinuity and suplimentation with L carnitine. Positive acute liver failure diagnosis starts with a suggestive history liver toxicity exposure and lab findings with an elevated level for ALT- value double then normal and ALT/FAL five times normal value. Liver failure is characterized by coagulation alterations: Protrombin level < 50% Coagulation factor V level < 50% ALT > 10 000 UI amoniemia level > 100 UI/l Authors made an analysis of about 205 cases of acute poisoning with paracetamol and 56 cases of mushroom poisoning.
56
CLINICAL TOXICOLOGY
CRYSTALLURIA THE PREVALENCE IN PEDIATRIC POISONING
Gabriela Viorela Niescu, Alexandru Ulmeanu, Coriolan Ulmeanu Pediatric Poisoning Centre Grigore Alexandrescu Hospital Bucharest.
Abstract. Introduction. A lot of substances that produce acute poisoning in children can produce crystalluria that represents the precipitation of some exogenous products or toxic metabolites in the urinary tract. Toxic crystalluria can produce an acute obstructive nephropathy and then acute renal failure with acute tubular necrosis .The medicines that can induce toxic crystalluria are the following: triamtherene, sulfonamides, vitaminD3, acetazolamide ,topiramate or furosemide (to premature ). Out of the non drug substances the ethylene glycol is the most frequently involved in the crystalluria production. Objective. to analyze the cases with crystalluria production , admitted in the Pediatric Poisoning Centre Grigore Alexandrescu Hospital Bucharest during a five years period. Material and methods. There were analyzed all the cases with poisoning that could produce crystalluria that were admitted between : 01.04.2006-01.04.2011. Results. In the mentioned periode 10 cases with toxic crystalluria were admitted ; out of them : 7 cases with ethylene glycol , 2 cases with vitamin D3 and 1 case with topiramate. The urine exam made the definite diagnosis highlighting the presence of the crystals in the urine.The diagnosis was completed with blood investigations and abdominal ultrasound. The treatment consisted in: antidote administration in all the cases with ethylene glycol(ethanol intravenous ) , corticotherapy in poisoning with vitamin D completed with supportive and symphtomatic treatment. Conclusions. Toxic crystalluria are rare entity in pediatric toxicology being able to have severe potential even life threatening. The definite diagnosis is based on correct urine exam. The correct and carried out treatment represents in the majority of the situations the chance of the patient's survival.
57
CLINICAL TOXICOLOGY
TOXIC AND HYPERSENSITIVITY REACTIONS TO CONTACT WITH CNIDARIANS

Florin-Dan Popescu1, Vieru Mariana1, Adriana Mihaela Tudose1, Florica Popescu2
1. 2.
Department of Allergology, University of Medicine and Pharmacy Carol Davila Bucharest, Romania Department of Pharmacology, University of Medicine and Pharmacy Craiova, Romania
Abstract. Cnidarian venoms from several marine aquatic species are toxic to humans. Sea wasp Chironex fleckeri is the most toxic box jellyfish, with severe local and systemic envenomation manifestations. Irukandji syndrome is most likely due to exposure to Carukia barnesi venom. These cubozoans may sting in tropical marine waters. Stings of Portuguese man-of-war or bluebottle Physalia physalis, a hydrozoan class siphonophore, found also in the Mediterranean Sea, are painful and more frequently reported. Rhizostoma pulmo (in the warm season) and Aurelia aurita (in the cold season) are the most widespread scyphozoans in the Black Sea. The most common manifestation in jellyfish stings is painful urticarial eruption or irritant dermatitis at the site of contact. Rhizolysin is a cytolysin with no phospholipase A activity, isolated from the nematocysts of Rhizostoma pulmo. Actinia equina (European sea anemone) is an aggressive anthozoan with several toxins (equinatoxins, equistatin, acrorhagins, neurotoxins) in its nematocysts, which can cause discomfort and pain in humans at contact. Larval forms of the scyphomedusa Linuche unguiculata, sea anemone Edwardsiella lineata or other cnidarian larvae may induce the seabather's eruption, a pruritic hypersensitivity dermatitis. Larvae of E. lineata were found to infect the comb jelly Mnemiopsis leidyi, this ctenophore being also accidentally introduced in the Black Sea thirty years ago.
58
CLINICAL TOXICOLOGY
ANTIDOTE VERSUS NON-SPECIFIC TREATMENT OF ACUTE POISONING IN CHILDREN

Ioan Magyar1, Alina Maghiar2, Adriana Moldovan3 Carmen Pantis4, Mohamed Bouyakhrichan4
1. 2. 3. 4.
Department of Pharmacology, Faculty of Medicine & Pharmacy, University of Oradea Department of Paediatrics, Faculty of Medicine & Pharmacy, University of Oradea Department of Toxicology, Faculty of Medicine & Pharmacy, University of Oradea Department of Intensive Care Unit, County Clinical Hospital, Faculty of Medicine & Pharmacy, University of Oradea
Abstract. Introduction.Acute poisoning with various substances is one of the reasons for concern in the emergency child pathology. Although their frequency is quite low (75 / 22793 patients per year in 2009) the problems of diagnosis and treatment is often an important challenge for many physicians involved in pediatric emergency activity. Material and method.In this study 75 cases of acute poisoning with various substances were admitted in the emergency department between 01.01 2009 and 31.12.2009. Results.The distribution regard to their gender shows a slightly higher proportion of male patients (40/35, M / F).Most cases of poisoning is noted in the category 1-4 years (31; 2 / 11, M / F), followed by the 11-18 years group (22; 13 / 9, F / M) and 4-11 years goup (16; 9 / 7, F / M). Although within the 0-1 category only six cases were recorded, the average period of hospital admittance was higher but in the male patients (4.25) compared with 1-4 years category (2.20) or 11 18 years (2.00). Drug poisoning is still most common in children 39% (29 cases). It is followed by organic solvent poisoning by ingestion or inhalation (9%), organic-phosphorus pesticides (8%), mushrooms (8% ), and toxic houseplants (7%).The alcohol and carbon monoxide was recorded in equal proportions of 5%. Other chemicals were rat poisons (warfarin), nitrites and mercury. All cases had an improved clinical evolution.The average period of hospitalization was 2.61 days. Nonspecific treatment such as gastric lavage and activated charcoal was mostly used, in 93% of cases, and antidote was used in 4% of cases. In three cases specific antidotes were used. It is fitomenadion ( vitamin K) for poisoning with oral anticoagulants, ascorbate (vitamin C) for poisoning nitrites and trihexifenidil for metoclopramide overdose. The rest of 3% have received symptomatic therapy. Conclusions.In most cases of children intoxications, often significantly results are obtained by using non-specific measures as compared to specific ones, respectively antidotes.
59
CLINICAL TOXICOLOGY
LEAD POISONING CAUSED BY BOILERS USED TO PLUM BRANDY DISTILLATION

Mitru Anca Oana1, Gofita Eliza2, Mitru Paul3, Clina Daniela4
1. 2. 3. 4.
Phd, University of Medicine and Pharmacy, Toxicology Department, Craiova, Romania Professor, University of Medicine and Pharmacy, Toxicology Department, Craiova, Romania Associate Profesor, University of Medicine and Pharmacy, Internal Medicine, Craiova, Romania Lecturer, University of Medicine and Pharmacy, Clinical Pharmacology Department, Craiova, Romania
Abstract. Introduction. The saturnism is a medical condition caused by increased levels of the heavy metal lead in the body. Routes of exposure to lead include contaminated air, food, soil, water, occupational exposure and also unusual environmental sources as traditional medicine, traditional cosmetics, traditional earthenware for storage or cooking and boilers used for plum brandy distillation. Material and Methods. 12 cases of lead poisoning in adults: 10 men and 2 women, mean age 556 years were found. They manifested unexplained abdominal pain, headache and anemia. We measured the lead blood level using atomic absorption spectrometry. We evaluated biological parameters, liver biochemical tests and hematological tests at all the patients. Results. In 7 patients the blood lead level was between 180 250 micrograms/l and in 5 patients the blood lead level was between 250 350 micrograms/l. Search for the source of the lead led to the discovery that all the patients drank plum brandy distilled in traditional boilers that release lead. Traditional boilers used in the plum brandy distillation should be considered as a source of high lead exposure especially in country areas. Conclusions. Lead poisoning caused by the use of plum brandy is common. It causes anemia, abdominal pain and neurological manifestations. The measure of lead blood level using atomic absorption spectrometry is useful for diagnosis and treatment.
60
CLINICAL PHARMACOLOGY
GENOTYPE-PHENOTYPE CORRELATIONS BETWEEN THE ALLELES OF THE CYP2C19 POLYMORPHISM AND PHARMACOKINETIC PARAMETERS IN ROMANIAN EPILEPTIC PATIENTS
Buzoianu Anca Dana, Bocan Ioana Corina, Maier Codruta, Trifa AP, Militaru Claudia, Major Z University of Medicine and Pharmacy Iuliu Hatieganu, Cluj Napoca, Romania
Abstract. The aim of the study was to evaluate the influence of genetic status on the metabolism of valproic acid (VPA) and to make the correlation between the genotype and the phenotype of the metabolizing status of the patients, measured in plasma levels of VPA. Materials and method: 80 patients with a mean age of 39.251.59, either with idiopathic or secondary epilepsy, evaluated in the Neurology Clinic of Cluj-Napoca were included. Steady state plasma concentration of VPA were determined using the GC/FID technique to all patients under a stable treatment for at least 1 month. We considered therapeutic level between 50-100 g/mL. Using the PCR-RFLP method weve determined allelic variant of CYP2C19*2 and CYP2C19*3. Results: 62% of the patients had therapeutic level of VPA, while 20% had sub-therapeutic and 18% of the patients supra-therapeutic level of it. 22.5% of the patients were heterozygous for CYP2C9*2, and 1.25% were homozygous, while 21.25% of the patients were heterozygous for CYP2C9*3. Regarding CYP2C19*2 16.25% of the patients were heterozygous and 7.5% of them homozygous. The polymorphism of CYP2C19*3 was absent. There were no significant correlation between the genetic status and the plasma concentrations of VPA. Conclusions: The different allelic expression of CYP2C9 and CYP2C19 have no statistically significant influence on plasmatic level of VPA.
61
WHAT ARE THE ESSENTIAL PHARMACOLOGICAL KNOWLEDGE, SKILLS AND ATTITUDES FOR MEDICAL STUDENTS ?
Buzoianu Anca Dana University of Medicine and Pharmacy, Cluj Napoca Department of Clinical Pharmacology
Abstract. Aims: to identify the knowledge, skills and attitudes that should be considered essential for students in medical programs regarding basic and clinical pharmacology. Our paper try to describe the main recommendations for the development of a pharmacology curricula which should take the form of a core curriculum , mandatory for all students, representing about two thirds of the course content, and special study modulesrepresenting about one third of the course for which the student should be offered a range of optional courses for study in depth. The core curriculum itself is at the moment only broadly defined, being argued that curricula must be integrated both horisontally and vertically with interdisciplnary synthesis rather than coordination. The pharmacology curriculum should emphasise learning by the student, partly self directed and partly faculty directed. Another important issue is to define the practical skills that must be learned by our students starting with the third year, not only writing a prescription, but all the practical facts essential to do by themselves. In the same time we must teach the students the appropiates attitudes regarding the proper use of drugs. In this paper we try to define the content of the core curricula and the essential practical skills and attitudes that must be achieved by students after the graduation of the pharmacology course in our Faculty.
62
PHARMACOGENETICS OF THE SIDE EFFECTS CONCERNING ATYPICAL ANTIPSYCHOTIC MEDICATION

Popescu Florica1, Mitrulescu Bianca1, Popescu Florin Dan2, Nicoli Elena Raluca1, Ionete Oana Mariana1
1. 2.
UMF Craiova, UMFCarol Davila Bucharest
Abstract. The development of novel, atypical antipsychotics was well embraced thanks to their lower incidence of extrapyramidal side effects. Anyway as with all pharmacotherapy, patient response is often different and these novel molecules are not without their own side effect profile, most notably weight gain, hypertension, diabetes mellitus. Also it is known that inter-individual variations in response to drug treatment are, in part, due to polymorphisms of the genes encoding drug targets. The importance of the serotonin system in psychiatric symptomatology and several side effects of antipsychotic drugs is well established, because during brain development, the serotonin (5-HT) system, which is commonly target by antipsychotic drugs, controls neuronal specification, differentiation, and phenotype maintenance. The genes that are involved in the pharmacogenetic of the antypsihotics side effects concerne the cytochrome P450 family as CYP2D6, CYP1A2, CYP3A4. In conclusion, it is important to establish the profile of the side effects that characterize atypical antipsihotics and the pharmacogenetics of metabolic syndrome complications.
63
THE INFLUENCE OF PHARMACOGENETICS STUDIES ON INDIVIDUALIZED CANCER CHEMOTHERAPY

Elena-Raluca Nicoli1, Florica Popescu1, Alina Cimpoeru2, Gabriela Avram2, Mihai Ioana2
1. 2.
Department of Pharmacology, University of Medicine and Pharmacy of Craiova Department of Cellular and Molecular Biology, University of Medicine and Pharmacy of Craiova
Abstract. Important heterogeneity in the efficacy and toxicity of chemotherapeutics is observed within
cancer patients. One important approach to improve treatment outcomes may be the drug pathway profiling in advance of therapy. The chemotherapy drugs can lead to systematic toxicity and altered antitumor response as a consequence of the presence or absence of specific genetic variations. To benefit of an individualized therapy there are a lot of studies being analyzed about the effects of polymorphisms in drug metabolizing enzymes (TPMT, DPYD, UGT1A1, GSTP1, TYMS) and drug targets on the toxicity and response to commonly used chemotherapy drugs. Pharmacogenetics strategies could be used to identify patients at risks for adverse reactions. Analyzing TPMT (Thiopurine methyltransferase) gene polymorphisms, it has been noticed some important variations (TPMT*2, TPMT*3A and TPMT*3C) which have been associated with low TPMT enzyme activity and correlated with the fact that the heterozygous patients for these alleles have intermediate TPMT levels and tolerate approximately 65% of standard mercaptopurine dosage, instead of homozygous patients which are at high risk for severe toxicity and require reductions in drugs doses. Dihydropyrimidine dehydrogenase (DPYD) inactivates 5-florouracil (5-FU), a commonly administrated chemotherapy agent used in combination therapy for different types of cancer, and the decreased DPYD activity is associated with a severe toxicity of 5-FU. A reduced activity of UGT1A1 (UDP-Glucuronosyltransferase 1A1) can be correlated with a high risk of severe toxicity from irinotecan (its active form -SN38- can be inactivated through glucuronidation by a member of the UDP- Glucuronosyltransferase family) including dose limiting diarrhea and neutropenia, but by an evaluation of the presence of UGT1A1*28 allele it can be predictable the risk for severe or even fatal toxicity from irinotecan and therefore allowing a selection of a lower dose or an alternative therapy. This brief abstract of chemotherapeutics pharmacogenetics its a start to perform our research in Department of Pharmacology and the Department of Cellular and Molecular Biology from the University of Medicine and Pharmacy of Craiova allowing stratifications of patients into treatment groups thus individualizing their therapy in a colorectal cancer study. Actually are being studied the candidate genes from this type of cancer and in the next stage we will focus pharmacogenetic studies in close correlation with the clinical evaluation of the patients from our research for individualizing cancer therapy, minimizing toxicity, while maximizing efficacy.
64
CETP INHIBITORS: A NEW THERAPY IN ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

Lavinia Codrua Gligor1, Rzvan Gligor2, erban Gligor3, Virginia Gligor2
1. 2. 3.
MD, Selfmed Polyclinic, Timisoara MD,PhD, Vasile Goldis Western University, Department of Pharmacology, Arad MD,PhD, West University, Timisoara
Abstract. Recently a special interest occurred for the research and development of compounds for reduction of atherosclerosis and diminishing the risk of cardiovascular diseases to the patients diagnosed with dyslipidemia. In order to reduce the cardiovascular risk there are several strategies, one of them is by increasing the low level (under 40 mg/dL) of HDL-Cholesterol. HDLCholesterol has several biological actions (e.g. anti-inflammatory, anti-thrombosis, antioxidant a. a.) The main mechanism by which HDL-cholesterol reduce cardiovascular risk is probably the increase of reverse transportation of cholesterol, the excess from the tissues being transformed in HDL and transported to the liver to be metabolized or eliminated. The cholesterol transfer from HDL to VLDL and LDL is catalyzed by Cholesterol Esther Transfer Protein (CETP). Inhibitors of this protein will lead to a high increase of plasmatic HDL. Presently there are two CETP inhibitors in phase 3 of clinical trials: anacetrapib and dalcetrapib. Anacetrapib is a selective CETP inhibitor, active in oral administration; it has been evaluated in the 1st and 2nd phase of clinical trials for the treatment of primer and mixed hypercholesterolemia. Dalcetrapib is currently being tested in several clinical trials, with a dosage of 900 mg for 4 weeks. In this case a reduction of 37% in CETP activity, an increase of 34% of HDL-Cholesterol and a decrease of 7% of LDL-Cholesterol occurred. The study of a third CETP inhibitor (torcetrapib) was stopped because of an increased all-cause mortality and also of an increased in cardiovascular events, partly explained by dose-dependent increases in blood pressure and by stimulating of the aldosterone production (with effect in steroids synthesis). Recently it was shown that these off target effects can be attributed to compound toxicity and does not target its mechanism of action. Under these conditions, CETP inhibition as a therapeutic strategy, remains a viable option.
65
STUDY OF THE SENSITIVITY TO ANTIBIOTICS OF STAPHYLOCOCCUS AUREUS STRAINS ISOLATED FROM GENITAL INFECTIONS
Mitru Anca1, Clina Daniela2, Gofia Eliza3, Rou Lucica4, Mitru Paul5
1. 2. 3. 4. 5.
Phd, University of Medicine and Pharmacy, Toxicology Department, Craiova, Romania Lecturer, University of Medicine and Pharmacy, Clinical Pharmacology Department, Craiova, Romania Professor, University of Medicine and Pharmacy, Toxicology Department, Craiova, Romania Professor, University of Medicine and Pharmacy, Microbiology Departament, Craiova, Romania Associate Profesor, University of Medicine and Pharmacy, Internal Medicine, Craiova, Romania
Abstract. Objective. Staphylococcus aureus is an important cause of pelvic inflammation and gynecological infections.It can cause salpingitis, metroanexite, cervical, vaginal, vaginal lesions train. The purpose of this study was to isolate and identify strains of Staphylococcus aureus in vaginal secretion and their antibiotic susceptibility testing. Material and method. 128 vaginal secretion cultures were investigated, Staphylococcus aureus was present in 37 (28.90%) cases. For each positive culture was made an antibiogram using Kirby-Bauer method and the resuts were calculated according to the critical diameter of antibiotics microdisks used. Microdisks were used with the following antibiotics: clindamycin, ofloxacin, amikacin, cefotaxime, levofloxacin, azithromycin, doxycycline, amoxicillin clavulanic acid, piperacillin -tazobactam, ampicillin sulbactam, rovamicine. Results. We have obtained the following results: sensitivity to clindamycin 22%, ofloxacin 20%, metronidazole 20%, amikacin14%, azithromycin 13%, rovamicine 10%. Conclusion. Our survey data are consistent with the results of recent studies showing more frequent involvement of Staphylococci aureus in the lower genital infections and pelvic inflammation. Perform sensitivity testing is essential in guiding therapy, and in the management of cost effective.
66
THE MANAGEMENT OF ACUTE BACTERIAL PNEUMONIA IN ELDERLY PATIENTS

Mitru Anca Oana1, Clina Daniela2, Mitru Paul3, Gofia Eliza4
1. 2. 3. 4.
Phd, University of Medicine and Pharmacy, Toxicology Department, Craiova, Romania Lecturer, University of Medicine and Pharmacy, Clinical Pharmacology Department, Craiova, Romania Associate Profesor, University of Medicine and Pharmacy, Internal Medicine, Craiova, Romania Professor, University of Medicine and Pharmacy, Toxicology Department, Craiova, Romania
Abstract. Background. The therapy of the acute bacterial pneumonia in elderly patients represents yet a major problem, because the number of resistant bacterial strains are arising. So, it is necessary to find new strategies for empirical therapy. We purpose to present the most important regimes of antibiotic therapy used and the therapeutical results to find some correlation between the aproach of the ethiologic treatment and the obtain results. Methods. We have studied 67 patients with acute bacterial pneumonia, hospitalised in Internal Medicine Departament, Clinical Emergency Hospital of Craiova, Romania; who were shared into more groups variying with the age and the principal ethiologic agents. It was observed the ethiological therapy, the results, the conditions associated to the therapeutical failure. Results. The ehiological therapy have performed with a single antibiotic in 34 cases ( 50,7%) and with two or three antibiotics in 33 cases ( 43,3%). The 3rd generation cephalosporines were the most frequent used antibiotics, especially Ceftriaxone. In 31 cases the choise of the ethiologic therapy have made according with the antibiograms. The mean duration of treatment and the time until the improvement of the clinical signs was more shorter in the cases treated with cephalosporines of 3rd generation or with the association of antibiotics. In 61 cases (91,1%) it was obtained recovery, in 50 cases (74,6%) complete recovery, 6 cases remained with minor sequelles and 5 cases remained with cronic respiratory failure. Conclusions. For better therapeutical results in future, it is necessary to use the newgeneration of antibiotics.
67
RESEARCH ON CEFTAZIDIME - INDUCED NEUROTOXICITY IN INPATIENTS WITH RENAL DISEASES

Buleandra Carmen1, Georgescu Costinela2, Nechifor Mihai3
1. 2. 3.
General Practitioners ( Family Medicine) Galati, Romania Dunarea de Jos University of Galati, The Medicine and Pharmacy Faculty, The Functional Science Department Department of Pharmacology Gr.T.Popa University of Medicine and Pharmacy Iasi,Romania
Abstract. The adverse reactions of antibacterial drugs are an important problem in medical therapeutics. Nonconvulsive status epilepticus is an unusual side effect of cephalosporin therapy, with only a few isolated cases reported. Cases of ceftazidime(3rd generation cephalosporin) neurotoxicity have been sporadically reported in patients with chronic renal insufficiency and recurrent urinary tract infections. We retrospectively studied the neurological adverse reactions of patients with chronic renal insufficiency and recurrent urinary tract infections who were treated with ceftazidime .In this study were include a number of 216 adult patients hospitalized (March 2009 - March 2011) in Galati County Hospital, Nephrology and Urology Departments. Our data showed that 5 cases of ceftazidime treated patients developed temporospatial disorientation, confusion, agitation, myoclonus and convulsions. Nonconvulsive status epilepticus developed in 2 men and 3 women, with a mean (+/- SD) age of 63 +/- 4 years, while receiving intravenous ceftazidime. The latency, the period between the start of treatment and neurological deterioration, was 2 and 4 days (range: 1-10 days). With temporospatial disorientation 3 patients, myoclonus 1 patient and convulsions 1 patient. Intravenous diazepam suppressed the epileptiform activity completely in 4 patients and partially in the other 1. Ceftazidime were withdrawn, and antiepileptic therapy was started for all patients. All patients improved, 2 patients in less than 24 hours and the remainder within 2 to 7 days. The neurotoxicity of ceftazidime might be underestimated in clinical practice and the frequency of its neurotoxic effects may be insufficiently recognized.
68
CLNICAL PHARMACOLOGY
SPIDER BITES CAUSING CUTANEOUS ADVERSE REACTIONS
Mariana Vieru1, Florin-Dan Popescu1, Florica Popescu2

1. 2.
Department of Allergology, University of Medicine and Pharmacy Carol Davila Bucharest, Romania Department of Pharmacology, University of Medicine and Pharmacy Craiova, Romania
Abstract. The European spider fauna (order Araneae) comprises many species of which several are alien. Spiders are arthropods with eight legs and chelicerae that inject venom. Some of them possess chelicerae strong enough to penetrate human skin. The majority of spider bites in humans are not significant, but rarely, the clinical manifestations can include necrotic wounds and, sometimes, systemic toxicity. Brown recluse (Loxosceles spp.) spiders are arachnid species known to cause necrotic arachnidism. Loxoscelism is associated with localized pain, erythema, and edema followed by the development of local necrosis caused mainly by the enzyme sphingomyelinase D. Spiders known to have dermonecrotic venom are found in the family Sicariidae. Among the alien spiders species which may be considered as theoretically dangerous to humans comprise the sicariids, especially Loxosceles rufescens (the Mediterranean recluse spider). The frequency of Loxosceles spider bites seems to be overestimated, and it may be possible that these alien species did not reach relevant densities or even did not establish in the long term in certain areas, such as some regions of the Balkans. Other spiders found in Romania, such as Cheiracanthium punctorium, Lycosa singoriensis, Tegenaria domestica and Tegenaria agrestis, may cause local adverse reactions, and very rarely systemic manifestations.
69
PHARMACOTOXICOLOGICAL ASPECTS RELATED TO LATRODECTISM

Florica Popescu1, Florin-Dan Popescu2, Mariana Vieru2
1. 2.
Department of Pharmacology, University of Medicine and Pharmacy Craiova, Romania Department of Allergology, University of Medicine and Pharmacy Carol Davila Bucharest, Romania
Abstract. Latrodectus spiders (family Theridiidae) are present all around the world, Latrodectus tredecimguttatus, commonly known as the Mediterranean black widow or steppe spider, being the one representative for the South of Europe and warm Mediterranean regions. In Romania, this spider was first collected fifty years ago in the Danube Delta, and seven years ago its presence was detected in the northern part of Eforie Sud, in a narrow area that separates the lake Techirghiol from the Black Sea, and in Agigea, on a rocky beach. Bites of Latrodectus induce a clinical syndrome named latrodectism. A potent vertebrate specific neurotoxin, alpha-latrotoxin, is involved in the pathogenesis. Because of its autonomic and neurotoxic actions, latrodectism may present local, regional and sometimes systemic manifestations, with rare life-threatening complications. Painful muscle contractions are reported in Latrodectus tredecimguttatus bites. Symptomatic treatment schedules include analgesics, usually opioids, and benzodiazepines. Specific antivenom therapy is not usually required. In some countries, it is considered that the risk of adverse reactions to black widow spider antivenin of equine origin, such as anaphylaxis or serum sickness, is greater than the risk of major complications due to the venom itself.
70
CONFIRMING GILBERT SYNDROME BY RIFAMPIN TEST
Spineanu Radu, Cheregi Simona, Heredea Liliana, Szilgyi Ariana, Szilgyi Gheorghe University of Oradea, Faculty of Medicine and Pharmacy, Romania
Abstract. Introduction. Gilbert syndrome is an autosomal recessive disorder, characterized by asymptomatic unconjugated hyperbilirubinemia, accidentally revealed, usually in adolescence, after fasting, dehidratation, intercurrent febril disease or vigorous exercise. Diagnosis is confirmed by following investigations: fasting with 400kcal/day, nicotinic acid test and rifampin test. Objective. To reveal the validity of rifampin test in Gilbert syndrome diagnose. Material and method. Two patients were explored. A 12 years old boy who presented unconjugated hyperbilirubinemia of 2.5 and 2.8mg/dL during two acute infectious episodes. Another boy aged 15 years, presented 2.9 mg/dL unconjugated bilirubin while vomiting in the context of appendiceal colic. All the other liver function test results were normal. After solving triggers and normalizing serum bilirubin levels, patients were administered 600 mg rifampin. Unconjugated bilirubin was measured at 0,2,3,4,20 and 24 hours. Results. First patients values were: 0.6; 0.8; 0.8; 1.0; 1.7; 1.9 mg/dL. Second patients results were: 0.6; 0.7; 0.8; 1.1; 1.8; 2.2 mg/dL. In both cases bilirubin level normalized within 30 hours (0.8 mg/dL, irrespective 0.7 mg/dL). Therefore, rifampin test significantly increases unconjugated bilirubin in Gilbert syndrome patients, until three abouve the basal value. Conclusion. Whereas fasting test is uncomfortable for children and nicotinic acid challenging is positive in all unconjugated hyperbilirubinemia cases, we consider that rifampin test is sensitive and specific, in order to be recommended in exploring and clinically confirming Gilbert syndrome. Keywords: Gilbert syndrome, rifampin test
71
THE ROLE OF CONTRAST AGENTS IN COMPUTED TOMOGRAPHY TO DETECT AND CHARACTERIZE FOCAL LIVER DISEASE
Cristiana Iulia Dumitrescu1, Daniela Dumitrescu2, Sergiu Cazacu3, Anca Berbecaru Iovan1, Maria Bogdan1, Mihaela Burlacu2, Cornel Tambura2, Popescu Florica1
1. 2. 3.
Department of Pharmacoloy Department of Radiology and Medical Imaging Department of Internal Medicine 5th year University of Medicine and Pharmacy of Craiova
Abstract. Introduction. The use of contrast agents iv in computed tomography examens permit correct diagnosis of the lesions. Material and Methods. We conducted a prospective study of 100 patients aged between 23 and 72 years. The criteria for inclusions in this study were the presence of liver lesions identified by ultrasound one mounth earlier. Computed tomography exam was perfomed before and after intravenous administration of the contrast (120ml Ultravist), by determining lesions density. Contrast medium was administered by intravenous bolus injection (1,5-2ml kg/c; 2-5ml/sec). We found various liver pathological lesions such as: cyst, abcesses, benign tumors, malignant tumors (including metastatis). We found that uptake of the contrast was different: fast enhancement: hemangioma, hypervascular tumor (focal nodular hyperplasia, adenoma, capillary hemangioma), peripherally hypervascular tumor (metastasis); late enhancement (hypervascular tumor: metastasis, well differentiated hepatocarcinoma). Conclusions: Most liver lesions shows characteristic enhancement reducing problems of differential diagnosis.
72
ROLE OF EXTRACELLULAR CONTRAST AGENTS IN HEPATOCARCINOMA EVALUATING

Cristiana Iulia Dumitrescu1, Daniela Dumitrescu2, Anca Berbecaru Iovan1, Maria Bogdan1, Mihaela Burlacu2, Alexandru Ciobanu2, Popescu Florica1
1 2 3
Department of Pharmacoloy Department of Radiology and Medical Imaging Department of Internal Medicine 5th year University of Medicine and Pharmacy of Craiova
Abstract. Introduction. Magnetic resonance imaging (MRI) can be considered the most accurate modality to image the liver. The use of extracellular contrast agents by modifying the proton relaxation time makes evident liver injury. The most used contrast agents are chelates of gadolinium, that diffuses rapidly into the vascular space, eliminated by the kydney, have long half-lyfe of 90minutes, do not show nephrotoxicity and can be administrated to pacients with chronic renal failure. Material and Methods. The study was perfomed in 50 pacients, aged between 30 and 72 years, in wich thr abdominal ultrasound showed focal liver lesions. were excluded from the study pacients with vascular clips, cochlear implants, heart metal valves. Non-contrast sequences include fast spin echo sequence with short and long echo-times (T1 and T2 images), in phase and opposed phase T1 gradient echo images and fat suppression with T2 fast spin echo sequences (with thickness between 6-10mm for liver parenchyma and 1-4mm for exploration vessels). The contrast medium dose was 0,1-0,3mmol Gd/Kg body weight, analyzing the three phases arterial, portal and equilibrum. Multiplanre reconstructions were perfomed with a better evaluation of vascular structures. Results. We found various liver pathological lesions such as: chyst, adenoma, focal nodular hyperplasia, hemangioma, cholangiocarcinoma, hepatocarcinoma, metastasis. HCC was noted in three of the cases examined, showing hiposemnal T1 and hypersemnal T2. One of the examinated cases showed hiposemnal T1 and T2 capsula. Using contrast agent revealed an intense enhancemant of tumore nodule and hiposemnal capsule in arterial phase and marked enhancemant (hypersemnal) of capsule in late phases. Two cases had portal vein and hepatic veins invasions with the presence of intraluminal thrombosis wich had marked enhancemant in arterial phase and incomplete aspect in late phase. Conclusions. Use of extracellular contrast magnetic resonance allowed the diagnosis of HCC, even in small cirrhotic liver.
73
25 YEARS OF FLUOXETINE: HOW FAR ARE WE FROM AN OPTIMAL TREATMENT FOR DEPRESSION?
Nicolae Florin Taina1, Daniel Vasile2, Octavian Vasiliu1, Andrei Gabriel Mangalagiu1, Beatrice Stanescu1 Psychiatry Department, University Military Emergency Hospital Dr. Carol Davila, Bucharest, Romania Pharmacology, Toxicology and Clinical Psychopharmacology Department, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
1. 2.
Abstract. Fluoxetine appeared on the european market in 1986 and became one of the most disputed drug in the antidepressant class. Although arguably the first selective serotonin reuptake inhibitor, fluoxetine resisted to the test of time and was associated with a great deal of positive and less positive effects. However, a long list of designed, theory-driven created antidepressants that target serotonin, norepinephrine, dopamine or melatonin neurotransmission have appeared in the last 25 years. There are, nevertheless, multiple problems associated with antidepressants administration: discontinuation syndrome (not met during fluoxetine treatment), anxiety exacerbation during the first weeks, long time until the onset of drugs action etc. A recent multicentric study, STAR*D, showed rather disappointing results: only about half of the depressed patients became symptom-free after two different antidepressants and the percentage of remission significantly decreased from one treatment to the next, in the same patient, even when strong drugs combinations or monoamine oxidase inhibitors were used. There is also an FDA warning on all antidepressants regarding the possibility of increasing the risk of suicidal behavior in patients younger than 24, based on several correlational studies. Therefore, although there are many antidepressants on the market and newer neuro-biochemical targets for development of such drugs are proposed, we are still able to treat efficiently only one in two patients diagnosed with major depression, while looking for the possibility of some important adverse events.
74
NIGHTMARE PHARMACOLOGIC TREATMENT IN POSTTRAUMATIC STRESS DISORDER - A SYSTEMATIC LITERATURE REVIEW

Nicolae Florin Taina1, Daniel Vasile2, Octavian Vasiliu1, Andrei Gabriel Mangalagiu1, Anioara Banic1, Diana Gabriela Ojog1 Psychiatry Department, University Military Emergency Hospital Dr. Carol Davila, Bucharest, Romania Pharmacology, Toxicology and Clinical Psychopharmacology Department, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
1. 2.
Abstract. Background: Increased population exposure to natural or manmade disasters leads to the overcoming of coping strategies and development of stress related disorders. Nightmares stand as a core dimension of posttraumatic stress disorder (PTSD) because of their impact over the patients life quality, functional impairment and significant discomfort. Objective: The investigation of the possibility to formulate evidence-based recommendations for the nightmares treatment in PTSD, based upon the existing data analysis. Methods: We conducted a systematic literature review of published studies identified in PubMed database, through february 2011, using several keywords - PTSD, nightmare, drug treatment, and individual drug names used for PTSD treatment. The initial search returned 55 results and, after the application of inclusion and exclusion criteria, only 26 articles remained to be analyzed. Grades of recommendations for the PTSD associated nightmares treatment have been established according to the Oxford Center for Evidence-Based Medicine levels of evidence. Results: About 1480 patients have been treated with different types of drugs. Most of the data retrieved consisted in low quality case reports, chart reviews, retrospective and open label trials. The most investigated substance is prazosin, with 2 randomized placebo-controlled clinical trials and several open label trials, case reports and chart reviews, therefore this drug can be considered a grade A recommendation. Venlafaxine has been evaluated in 2 randomized, placebo controlled clinical trials and was found to be no better than placebo. Other antidepressants (duloxetine, mirtazapine, trazodone, fluvoxamine) were associated with data from case reports, chart reviews and open label trials that usually found a positive response (decreased nightmare frequency and intensity). A small open label trial and a case report series associated antipsychotics with positive response, therefore the grade of evidence is considered to be C in this case. Metoprolol seemed to precipitate PTSD in a case report. Clonazepam, evaluated in 6 patients, was found to be ineffective in PTSD associated nightmares. Low quality data, but positive in terms of end points, was obtained for nabilone, topiramate, nefazodone, cyproheptadine, buspirone and phenelzine (grade C). Conclusions: Because level A evidence does exist only for prazosin and level C recommendation could be formulated only for a few agents (some of them with low tolerability), further exploration of treatments in PTSD related nightmares should be conducted.
75
POSTERS
ETIOLOGY OF TOXIC COMA IN CHILDREN A SIX-YEAR RETROSPECTIVE STUDY IN A PEDIATRIC EMERGENCY DEPARTMENT
Stanca Simona, Petran Mdlina, Ulmeanu Coriolan, Niescu Viorela Pediatric Poisoning Centre, Emergency Clinical Hospital for Children Grigore Alexandrescu Bucharest, Romania
Abstract. Objective. To study the prevalence of coma due to acute poisoning in children examined in a Pediatric Emergency Department. Methods. We analyzed all the children who attended the Emergency Department in our hospital during six year period: 1 january 2005- 31 December 2010. We analized data using the following criteria: consciousness status assessed by Glasgow Scale, type of poisoning, distribution by age, gender, or reason for presentation (accidental or intentional). Results. Between 2005 and 2010, 538 children with coma were registred out of the total number of 82.581 examined in the Emergency Department, representing 0,65%. Toxic coma was diagnosed in 305 cases representing 56,69% of comatose patients. The main poisons leading to coma were: ethanol: 140 cases 45,9% and drug poisoning : 115 cases 37,7%, such as: benzodiazepines, tricyclic antidepressants, Dentocalmin ( lidocaine, menthol, phenol ), barbiturates, antihypertensives, HIN. Other toxicants were: pesticides, hydrocarbons, carbon monoxide, ethnobotanical substances ( street drugs ), heroin. In 11,8% (44 cases) of cases with toxic coma the etiology was unknown at the time of presentation, being established later in the Toxicology Department. According to the reason for presentation we noted 70% intentional poisoning and 30% accidental poisoning. Conclusion: Despite its prevalence, toxic coma is still one of the most severe life-threatening situations in pediatric pathology. Toxic etiology represents the main cause of coma in children admitted and treated in Emergency Clinical Hospital for Children Grigore Alexandrescu. The use of medicines in combination with ethanol in acute poisoning has become a reality in recent years and also the abuse of ethnobotanical substances. These combination are used as recreational drugs or in suicidal attempts. The combination of ethanol with medicines increases the severity of poisoning and the depth of coma.
76
POSTERS
DYSTONIC SYNDROMES IN ACUTE POISONING IN CHILDREN
Nitescu Gabriela Viorela, Ulmeanu Alexandru, Vivisenco CI, Ulmeanu Coriolan Bucharest Pediatric Poisoning Centre
Abstract. Objective. To analyze the cases of acute poisoning which develop dystonic syndromes in children. Material and method. We conducted a retrospective study of all cases of dystonic syndromes admitted in the Pediatric Poisoning Centre SCUC Grigore Alexandrescu, Bucharest over a period of 18 months. We studied the etiology of these cases, noted the age, gender and provenience of the patients, the treatment they received and the mean duration of their hospitalization. Results. Between November 1st 2010 and April 1st 2011, 51 cases of dystonic syndromes caused by poisoning were admitted in the Pediatric Poisoning Centre SCUC Grigore Alexandrescu, Bucharest, representing 5,36% of all 951 cases of acute poisoning. The etiology was as follows: haloperidol - 2 cases , levomepromazinum 1 case, metoclopramide 24 cases, olanzapine 3 cases, prochlorperazine 1 case, propericiazine 1 case, quetiapine 1 case, risperidone 15 cases and zuclopenthixol 3 cases. In this group 22 cases were male gender (43%) and 29 cases were female gender (57%). The following age distribution was noted: less than 1 year - 3 patients (5,88%), 1-5 years - 20 patients ( 39,21%), 6-10 years - 13 patients (25,49%), 11-15 years - 9 patients (17,64%) and 16-18 years 6 patients (11,76%). The urban/ rural distribution was: urban - 20cases (39,21%) and rural 31 cases (60,78%). In all cases, the clinical manifestations ceased after the administration of diazepam and trihexyphenidyl, the mean period of hospitalization being 2 days. Conclusions. Dystonic syndromes represent a rather rare eventuality in acute poisoning in children, but they are very impressive both for the child and for the family. In all cases, the outcome was spectacular after the treatment initiation and none of the patients experienced relapse of signs and symptoms during the following 72 hours.
77
POSTERS
PREHOSPITAL MANAGEMENT IN ACUTE POISONING COMPLICATED WITH SHOCK IN CHILDREN

Elena Mdlina Petran, Simona Stanca, Coriolan Emil Ulmeanu Pediatric Center, Childrens Clinical Emergency Hospital Grigore Alexandrescu Bucharest
Abstract. Definition. Shock is an entity clinically defined, with multiple etiologies. It is recognized in most cases of death in children all over the world. Shock may involve all body organs and systems. Positive diagnostic and therapy initiation delays may lead from compensated shock to multiple organ and system failure. Objective. evaluation of prehospital management in acute poisoning complicated with shock in children. Materials and method. 78 cases of acute poisoning complicated with shock in children brought in Emergency Department in Childrens Clinical Emergency Hospital Grigore Alexandrescu Bucharest were analyzed. All of them are from Bucharest and South Romania. Shock definition criteria were present in all cases. They include tachycardia, mild tachypnea, mild capillary refill time (more then 2-3 sec), low blood pressure and irritability. There were excluded all cases where severe neurological alterations (convulsions, coma) are induced by direct action of the toxicant without other signs of shock. Results. In 78 cases, 22 were brought directly from home to EU department by family - 28,2% and 56 71,8% by ambulance: 19 cases initially to the hospitals - 33,8% and 37 cases 66,2% in EU department. At home: in 4 cases inappropriate maneuvers were done by parents. They also called emergency medical services. None received activated charcoal, because it is not available in our country for home administration. Emergency medical services ambulance: 3 cases were found in cardio respiratory arrest. BLS maneuvers were applied and in 2 cases ALS maneuvers oro tracheal intubation and mechanical ventilation. 38 cases had i.v. treatment with 5% dextrose or normal saline. In their medical sheets there was not specified the rhythm of administration. 22 cases had oxygen on facial masque and 2 cases on endotracheal tube. During transport none received activated charcoal. 2 patients received physiological antidote: atropine organophosphate poisoning (diazinon); this specific treatment was initiated in other hospitals. Conclusion. In most of the cases none approved medical and therapeutic protocol in acute poisoning in children was applied by SMURD and ambulance teams and a special conclusion was that there are no specific antidotes available for usage in none of this medical services; this is very important, as being known as the first hour of evolution in an acute poisoning is critical.
78
POSTERS
THE BRONCHOSPASM AND RECURRENT COUGH AFTER CARBOCYSTEINE IN CHILDREN

Ioan Magyar1, Alina Maghiar2, Adriana Moldovan3, Carmen Pantis4, Sava Cristian2 Department of Pharmacology, Faculty of Medicine & Pharmacy, University of Oradea Department of Paediatrics, Faculty of Medicine & Pharmacy, University of Oradea 3. Department of Toxicology, Faculty of Medicine & Pharmacy, University of Oradea 4. Department of Intensive Care Unit, County Clinical Hospital, Faculty of Medicine & Pharmacy, University of Oradea
1. 2.
Abstract. Introduction. Carbocysteine and acetylcysteine are drugs with mucolytic and expectorant properties widely used in respiratory desease in adults but also in children. N-acetylcysteine is also used as donor of SH groups in the drug overdose such as in the acetaminophen poisoning. Respiratory pathology is very frequent in children, thus it is obvious that these drugs are widely prescribed to these patients. However, acetylcysteine and carbocysteine are well known drugs which promote bronchospasm. They are contraindicated or should be used with caution in children with asthma, recurrent wheezing or other bronchospastic illnesses. Material and method. In the emergency department, in the first three months of the 2011 year, we recorded 20 children presenting either recurrent and prolonged cough, or even bronchospasm. Results.These symptoms were closely related to the administration of expectorant and mucolytic syrups with carbocysteine. In the most times these drugs were used as self-medication, without a recommendation of physician. We consider these issues as treatment mistakes from parents side, who dose to their children any mucolytic or expectorant medicine found at hand. Medical consultation and a careful medical history may lead to recommandation of lighter mucolytics and expectorants, such as plant extracts, in children with respiratory diseases of mild or moderate severity. A final aspect is the increasing of the incidence of recurrent wheezing and asthma in children of preschool age. Conclusion. This should cause us to carefully physical examination, type of cough and history of the child (spastic bronchitis, asthma or recurrent wheezing) when we intend to prescribe a mucolytic drug such as carbocysteine. In these cases we consider useful to chose and recommend any softer and more easily tolerated by children mucolytics and expectorant drugs.
79
POSTERS
RELIABLE HPLC METHOD FOR THERAPEUTIC DRUG MONITORING OF FREQUENTLY USED PARACETAMOL
Daliborca Cristina Vlad1, Victor Dumitrascu1,2, Adinela Cimporescu1, Mihaela Duma1, Ioana Ana2, Dorin Ana2, Beatrice Barac2
1. 2.
Laboratory Department, Emergency County Hospital, Timisoara, Romania. Pharmacology Department, ``Victor Babes`` University of Medicine and Pharmacy, Timisoara, Romania;
Abstract. Introduction. Therapeutic drug monitoring(TDM) of acetaminophen(paracetamol,N(4-hydroxyphenil)-acetamida) is necessary for an optimal treatment start-up,changes in dose,when systemic availability/effectiveness is questioned or toxicity is suspected.Among other methods,HPLC(High Performance Liquid Chromatography) is most popular used for paracetamol quantification. Material and methods. Blood samples of 10volunteers dosed with 1000mg paracetamol were centrifuged at 1800xg for 10minutes.The separation was performed on a reversed-phase C18 column under isocratic conditions using 80:20(v/v) mixture of 0.1%formic acid in water and 0.1%formic acid in acetonitrile as the mobile phase with a flow rate of 1 ml/min.The detection of paracetamol was performed at wavelength of 254 nm.The human plasma samples were deproteinized with 20%perchloric acid in water,obtained supernatants after centrifugation and concentration were injected in the chromatographic system.The sample preparation consisted in liquid:liquid extraction. Results. The method showed good linearity(r>0.9936) over the range of 0.4-200g/mL plasma. Linearity for standards was tested assaying by triplicate 8 levels of concentrations ranging from 0.4 to 200g/mL in drug-free plasma.Standards and quality control samples were randomly positioned throughout each analytical run.The best analysis time was obtained through isocratic elution using a mobile phase consisting of 0.1%formic acid in water and 0.1%formic acid in acetonitrile. Conclusions.The validated method cover both therapeutic(2.5-25 g/mL) and toxic(>150 g/mL) plasma levels. Versatility,wide range in linearity in detectors,simplicity of sample preparation of this method make the HPLC the method of choise for TDM of paracetamol.Our developed assay is simple,accurate and can be successfully applied in therapeutic drug monitoring of paracetamol,and can also have wide applications in toxicological studies and drug interactions.
80
POSTERS
RP-HPLC (REVERSE-PHASE HIGH PERFORMANCE LIQUID CHROMATOGRAPHY) FOR PARACETAMOL QUANTIFICATION IN HUMAN SERUM AND URINE
Victor Dumitrascu1,2, Daliborca Cristina Vlad2, Adinela Cimporescu2, Mihaela Duma2, Adelina Cheverean1, Ioana Malia1, Simona ipo1, Rodica Cinc1
1. 2.
Pharmacology Department, ``Victor Babes`` University of Medicine and Pharmacy, Timisoara, Romania; Laboratory Department, Emergency County Hospital, Timisoara, Romania.
Abstract. Introduction. N-(4-hydroxyphenyl)-acetamide (paracetamol, acetaminophen) is a para-aminophenol derivatite and deethylated active metabolite of phenacetin,commonly used as antipyretic and analgesic drug because of his antiinflamatory action. Aim. to develop a simple method for simultaneously identification and quantification of paracetmol in human serum and urine. Methods. Serum and urine test samples were obtained from 10 healthy volunteers after a single dose of paracetamol (1000mg),and collection was realized from 0 to 12 hours post-dose. Prior to analysis,urine samples were frozen at -20C.Serum samples were centrifuged 10 minutes at 4C,1800 xg,the upper layer was transferred in Eppendorf tubes and frozen at -20C until analysis.Analyte free - serum and urine used for the preparation of calibration standards and QC(quality control) samples were obtained from healthy volunteers and screened for interfering peaks prior to use.Low and high QC samples were run in duplicate. Chromatographic separation was obtained using a Pursuit XRs C18 column(150 x 3.0 mm, 5m) at a flow rate of 1 ml/min. Detection was performed at 254 nm.Regression equation generated from standard samples was used to quantify test and QC samples.To evaluate the inter-day variability of standards and QC samples, 6 validation runs were conducted on separate days. Results.The results showed that the method is linear( r>0,99 ) over the concentration range of 100-20000 g/mL for urine samples,and 0.4-200 g/mL for serum samples. Conclusions. A sensitive, accurate and precise method can be capable of quantifying paracetamol whitin the same analytical run in plasma and urine.This method can also be applied to studies that examine drug interferences.
81

12th Congres SRFTTC

Enviado por

Dados do documento

Direitos autorais

Formatos disponíveis

Compartilhar este documento

Compartilhar ou incorporar documento

Opções de compartilhamento

Você considera este documento útil?

Este conteúdo é inapropriado?

Direitos autorais:

Formatos disponíveis

12th Congres SRFTTC

Enviado por

Direitos autorais:

Formatos disponíveis

Congress President

Congress Honorary Presidents:

Congress Honorary Vice-Presidents and International Scientific Commitee

Prof. Dr. Valentin Crlig

Prof. Dr. Ionel Sinescu

Prof. Dr. Andrei Medvedovici Dr. Dalia Miron

Prof. Dr. Victor Dumitracu Prof. Dr. Virginia Gligor

Prof. Dr. Mircea Pavelescu

Assoc. Prof. Dr. Aurelian Zugravu

Journal published in cooperation with:

National Institute of Infectious Diseases "Prof. Dr. Matei Bal"

Academic Medical Database

Founders Emanoil Manolescu

Liviu Ioan Miclea

International Scientific Board

General Registrar of Editorial Board

Cristina Negulescu Oana Streinu-Cercel Ana-Maria Tudor Publishing Editor

CUI RO9954898, RC J40/7184/1997

Vlad Negulescu (Assistant Professor, University of Medicine and

7-th June 2011 Crowne Plaza Hotel

8-th June 2011 Crowne Plaza Hotel - Conference Room A

Session I - Invited Speakers Lectures

9.00-9.30 9.30 - 10.00 10.00 - 10.30 10.30 - 10.45 10.45-11.00

XV, Vol.15, Supplement II/2011

Session II - Invited Speakers Lectures

11.00-11.30 11.30-12.00 12.00-12.30 12.30- 12.45 13.00-14.00

Session III - Invited Speakers Lectures

14.00 14.30 14.30 15.00 15.00 15.30 15.30 - 15.45 15.30-15.45

Session IV - Invited Speakers Lectures

18.15 - 18.30 18.30 - 19.00

Session VI - Experimental Pharmacology

7-11 June 2011, Bucharest, Romania

Session VII - Clinical Toxicology

Session VIII - Pharmacogenetics and Clinical Pharmacology

Therapeutics, Pharmacology and Clinical Toxicology

Session IX- Clinical Pharmacology and Therapeutics

14.00 - 14.15 14.15 - 14.30 14.30 - 14.45 14.45 - 15.00

15.30 - 15.45 15.45 - 16.00 15.15 - 15.30

XV, Vol.15, Supplement II/2011

Therapeutics, Pharmacology and Clinical Toxicology

INVITED SPEAKERS LECTURES

XV, Vol.15, Supplement II/2011

Therapeutics, Pharmacology and Clinical Toxicology

INVITED SPEAKERS LECTURES

A PROFILE OF ACETAMINOPHEN (PARACETAMOL) TOXICITY IN THE UNITED STATES

XV, Vol.15, Supplement II/2011

Therapeutics, Pharmacology and Clinical Toxicology

INVITED SPEAKERS LECTURES

XV, Vol.15, Supplement II/2011

Therapeutics, Pharmacology and Clinical Toxicology

INVITED SPEAKERS LECTURES

THE FUTURE (OR LACK OF FUTURE) OF PERSONALIZED PRESCRIPTION IN PSYCHIATRY

XV, Vol.15, Supplement II/2011

Therapeutics, Pharmacology and Clinical Toxicology

INVITED SPEAKERS LECTURES

MOLECULAR STRUCTURE AND LIGAND BINDING OF MONOAMINE TRANSPORTER PROTEINS

XV, Vol.15, Supplement II/2011

Therapeutics, Pharmacology and Clinical Toxicology

INVITED SPEAKERS LECTURES

MECHANISMS INVOLVED IN THE PHARMACOKINETIC INTERACTION BETWEEN ATORVASTATIN AND CYCLOSPORINE A

XV, Vol.15, Supplement II/2011

Therapeutics, Pharmacology and Clinical Toxicology

INVITED SPEAKERS LECTURES

PREDICTION OF THE BIOLOGICAL FATE OF OXIMES