Plínio Cunha Sathler1, André Luiz Lourenço2, Carlos Rangel Rodrigues3, Luiz Cláudio Rodrigues Pereira da Silva4, Lucio Mendes Cabral4, Alessandro Kappel Jordão5, Anna Cláudia Cunha5, Maria Cecília Bastos Vieira5, Vitor Francisco Ferreira5, Carla Eponina Carvalho-Pinto6, Hye Chung Kang7, Helena Carla Castro8. 1. Programa de Pós-graduação em Patologia, HUAP, Departamento de Patologia, UFF, Niterói, RJ, Brazil; LABiEMol, Instituto de Biologia, Departamento de Biologia Celular e Molecular UFF, Niterói, RJ, Brazil; LabTIF, Faculdade de Farmácia, UFRJ, Rio de Janeiro, RJ, Brazil. Electronic address: pliniocs@yahoo.com.br. 2. Programa de Pós-graduação em Patologia, HUAP, Departamento de Patologia, UFF, Niterói, RJ, Brazil; LABiEMol, Instituto de Biologia, Departamento de Biologia Celular e Molecular UFF, Niterói, RJ, Brazil. 3. ModMolQSAR, Faculdade de Farmácia, UFRJ, Rio de Janeiro, RJ, Brazil. 4. LabTIF, Faculdade de Farmácia, UFRJ, Rio de Janeiro, RJ, Brazil. 5. Departamento de Química Orgânica, Instituto de Química, UFF, Niterói, RJ, Brazil. 6. Laboratório de Patologia Experimental, Departamento de Imunologia, Instituto de Biologia, UFF, Niterói, RJ, Brazil. 7. Laboratório de Hematologia Clínica, HUAP, Departamento de Patologia, UFF, Niterói, RJ, Brazil. 8. LABiEMol, Instituto de Biologia, Departamento de Biologia Celular e Molecular UFF, Niterói, RJ, Brazil. Electronic address: hcastrorangel@vm.uff.br.
Abstract
BACKGROUND: Cardiovascular diseases are the most frequent cause of morbidity and mortality worldwide. Among the most important cardiovascular diseases are atherothrombosis and venous thromboembolism that present platelet aggregation as a key event. Currently, the commercial antiplatelet agents display several undesirable effects, which prompt the search for new compounds with better therapeutic index, more efficient body distribution and mechanism. METHODS: In this work we characterized in vivo and in vitro the antithrombotic and toxicological profiles of novel antiplatelet N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides derivatives also comparing them with aspirin. In addition we also analyzed the stability of the more active compound after encapsulation in PLGA or PCL nanoparticles and the release profile of these new nanosystems. RESULTS: The biological results revealed not only the selective effect against arachidonic acid-induced platelet aggregation mainly for compounds 2c, 2e and 2h but also their in vivo active profile on thromboembolism pulmonary animal model with better survival rates (e.g. 82%) than aspirin (33%). The overall toxicological profile was determined by in vitro (MTT reduction tests, neutral red uptake in kidney VERO cells and hemolysis assays) and in vivo (pulmonary embolism) assays that pointed 2c as the most promising derivative with potential as a lead compound. By using the nanoprecipitation technique 2c was loaded into PLGA and PCL nanoparticles showing controlled release profile over 21days according to our drug release tests. CONCLUSION: According to our results compound 2c is the most interesting derivative for further studies as it showed the best activity and toxicological profile also allowing the nanoencapsulation process. Thus 2c may assist in determining a new potential therapy with favorable pharmacokinetics for treatment of thrombotic disorders.
BACKGROUND:Cardiovascular diseases are the most frequent cause of morbidity and mortality worldwide. Among the most important cardiovascular diseases are atherothrombosis and venous thromboembolism that present platelet aggregation as a key event. Currently, the commercial antiplatelet agents display several undesirable effects, which prompt the search for new compounds with better therapeutic index, more efficient body distribution and mechanism. METHODS: In this work we characterized in vivo and in vitro the antithrombotic and toxicological profiles of novel antiplatelet N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides derivatives also comparing them with aspirin. In addition we also analyzed the stability of the more active compound after encapsulation in PLGA or PCL nanoparticles and the release profile of these new nanosystems. RESULTS: The biological results revealed not only the selective effect against arachidonic acid-induced platelet aggregation mainly for compounds 2c, 2e and 2h but also their in vivo active profile on thromboembolism pulmonary animal model with better survival rates (e.g. 82%) than aspirin (33%). The overall toxicological profile was determined by in vitro (MTT reduction tests, neutral red uptake in kidney VERO cells and hemolysis assays) and in vivo (pulmonary embolism) assays that pointed 2c as the most promising derivative with potential as a lead compound. By using the nanoprecipitation technique 2c was loaded into PLGA and PCL nanoparticles showing controlled release profile over 21days according to our drug release tests. CONCLUSION: According to our results compound 2c is the most interesting derivative for further studies as it showed the best activity and toxicological profile also allowing the nanoencapsulation process. Thus 2c may assist in determining a new potential therapy with favorable pharmacokinetics for treatment of thrombotic disorders.
Authors: Max Seidy Saito; André Luiz Lourenço; Hye Chung Kang; Carlos Rangel Rodrigues; Lucio Mendes Cabral; Helena Carla Castro; Plínio Cunha Satlher Journal: Int J Exp Pathol Date: 2016-07-05 Impact factor: 1.925
Authors: Michael J Page; André L Lourenço; Tovo David; Aaron M LeBeau; Fiore Cattaruzza; Helena C Castro; Henry F VanBrocklin; Shaun R Coughlin; Charles S Craik Journal: Nat Commun Date: 2015-10-01 Impact factor: 14.919
Authors: André Luiz Lourenço; Max Seidy Saito; Luís Eduardo Gomes Dorneles; Gil Mendes Viana; Plínio Cunha Sathler; Lúcia Cruz de Sequeira Aguiar; Marcelo de Pádula; Thaisa Francielle Souza Domingos; Aline Guerra Manssour Fraga; Carlos Rangel Rodrigues; Valeria Pereira de Sousa; Helena Carla Castro; Lucio Mendes Cabral Journal: Molecules Date: 2015-04-20 Impact factor: 4.411