title: In vitro and in vivo analysis of the antithrombotic and toxicological profile of new antiplatelets N-acylhydrazone derivatives and development of nanosystems: determination of novel NAH derivatives antiplatelet and nanotechnological approach.
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.
  
  
  CONCLUSIONS
  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.affiliation: 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.
authors.forename: Plínio Cunha
authors.initials: PC
authors.lastname: Sathler
authors.affiliation: 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.
authors.forename: André Luiz
authors.initials: AL
authors.lastname: Lourenço
authors.affiliation: ModMolQSAR, Faculdade de Farmácia, UFRJ, Rio de Janeiro, RJ, Brazil.
authors.forename: Carlos Rangel
authors.initials: CR
authors.lastname: Rodrigues
authors.affiliation: LabTIF, Faculdade de Farmácia, UFRJ, Rio de Janeiro, RJ, Brazil.
authors.forename: Luiz Cláudio Rodrigues Pereira
authors.initials: LC
authors.lastname: da Silva
authors.affiliation: LabTIF, Faculdade de Farmácia, UFRJ, Rio de Janeiro, RJ, Brazil.
authors.forename: Lucio Mendes
authors.initials: LM
authors.lastname: Cabral
authors.affiliation: Departamento de Química Orgânica, Instituto de Química, UFF, Niterói, RJ, Brazil.
authors.forename: Alessandro Kappel
authors.initials: AK
authors.lastname: Jordão
authors.affiliation: Departamento de Química Orgânica, Instituto de Química, UFF, Niterói, RJ, Brazil.
authors.forename: Anna Cláudia
authors.initials: AC
authors.lastname: Cunha
authors.affiliation: Departamento de Química Orgânica, Instituto de Química, UFF, Niterói, RJ, Brazil.
authors.forename: Maria Cecília Bastos
authors.initials: MC
authors.lastname: Vieira
authors.affiliation: Departamento de Química Orgânica, Instituto de Química, UFF, Niterói, RJ, Brazil.
authors.forename: Vitor Francisco
authors.initials: VF
authors.lastname: Ferreira
authors.affiliation: Laboratório de Patologia Experimental, Departamento de Imunologia, Instituto de Biologia, UFF, Niterói, RJ, Brazil.
authors.forename: Carla Eponina
authors.initials: CE
authors.lastname: Carvalho-Pinto
authors.affiliation: Laboratório de Hematologia Clínica, HUAP, Departamento de Patologia, UFF, Niterói, RJ, Brazil.
authors.forename: Hye Chung
authors.initials: HC
authors.lastname: Kang
authors.affiliation: LABiEMol, Instituto de Biologia, Departamento de Biologia Celular e Molecular UFF, Niterói, RJ, Brazil. Electronic address: hcastrorangel@vm.uff.br.
authors.forename: Helena Carla
authors.initials: HC
authors.lastname: Castro
mesh_terms: D000328:Adult; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D002522:Chlorocebus aethiops; D004337:Drug Carriers / Q000737:chemistry; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D019344:Lactic Acid / Q000737:chemistry; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry; D036103:Nanotechnology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011655:Pulmonary Embolism / Q000188:drug therapy; D014230:Triazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014709:Vero Cells
chemical_list: D004337:Drug Carriers; D006834:Hydrazines; D010975:Platelet Aggregation Inhibitors; D014230:Triazoles; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C019289:carbohydrazide
keywords: Antiplatelet; Haemostasis; N-acylhydrazone derivatives; Nanotechnology; Thromboembolism