dúvidas denucci@ arquivo etapas de desenvolvimento de medicamentos

Dvidas denucci@dglnet.com.brArquivo Etapas de desenvolvimento de medicamentos.ppt(med-unicamp-segundo ano) Sitewww.gdenucci.com

Desenvolvimento de um Medicamento Aumento escalonado da doseTolernciaIn vitro PK/PDAnimal PK/PDDose (Conc)Resposta clnicaEficciaSeleo da DoseVols sadiosPopulao PK/PDGrandes ensaios clnicosPK/PD em populaoespeciaisVigilncia ps-mercadoFase ITestes Clnicos (Humanas)Testes Pr-clnicosFase IIFase IIIFase IVPoucos pctesMuitos pctesPopulaoTestes em animais

Testes Pr-clnicos para Fase ITestes in vitro genotoxicidade

Testes in vivo duas espcies animais (uma no roedora) por duas semanas

Testes ClnicosFase I voluntrios sadiosFase II pacientes para prova conceitualFase III grande nmero de pacientes estudos multicntricosFase IV vigilncia ps-mercado pesquisa sobre novas indicaes

Testes in-vitroTestes de Genotoxicidade:Teste de AmesTeste de Microncleo(eritrcitos de rato)Teste em Linfoma de rato (timidina-quinase)

Requisito Toxicolgico para Estudos Fase ITeste de AmesAdministrao crnica por duas semanas em duas espcies animais, sendo uma no roedora

ANNEX Laboratory investigationsHEMATOLOGY: Blood collected on EDTAErythrocytesHemoglobinMean Cell VolumePacked Cell VolumeMean Cell Hemoglobin ConcentrationMean Cell HemoglobinThrombocytesLeucocytesDifferential White Cell count with cell morphologyReticulocyte countBlood collected on sodium citrateProthrombin TimeActivated Partial Thromboplastin Time FibrinogenAnd optional:Bone marrow smearsBone marrow differential cell count

ANNEX Laboratory investigationsBLOOD BIOCHEMISTRY:Blood collected on lithium heparinate Sodium Creatinine Potassium Total bilirubin Chloride Cholesterol Calcium Triglycerides Inorganic Phosphorus Alkaline phosphatase Glucose Aspartate aminotransferase Urea Alanine aminotransferase Total proteins Albumin Albumin/globulin ratio

Or optional:Blood collected without anticoagulant Total proteinsProtein electrophoresis including Albumin andAlbumin/Globulin ratio

ANNEX Laboratory investigations

URINALYSIS:

VolumeGlucose pHBilirubin Specific gravityNitrites Cytology of sedimentBlood AppearanceKetones ColorUrobilinogen Proteins

Ames Test (Salmonella typhimurium)

Bacterial reverse mutation assays are widely used to evaluate the mutagenic potential of chemicals, formulations, or extracts. The most common assay involves the use of amino acid-requiring strains of Salmonella typhimurium and is commonly referred to as the "Ames Test".

In the absence of an external amino acid source (histidine for Salmonella), the cells cannot grow to form colonies unless a reversion of the mutation allows the synthesis of the amino acid to resume.

Spontaneous reversions occur with each of the strains. However, some compounds induce a mutagenic response and thereby increase the number of revertant colonies substantially over the spontaneous reversion level.

The bacterial reverse mutation assay involves the measurement of revertant colony frequencies that are obtained when Salmonella strains are treated in the presence and absence of a test article.

Positive and negative controls are included for each strain tested. Metabolic activation using rat liver S9 is included to mimic the in vivo activity of the liver enzymes in transforming some pro-mutagens to mutagens

Effect of CRIS031 in Ames test using S. typhimurium strain (TA 98)

Effect of CRIS031 in Ames test using S. typhimurium strain (TA 100)

Effect of CRIS031 in Ames test using S. typhimurium strain (TA 1535)

Effect of CRIS031 in Ames test using S. typhimurium strain (TA 1537)

ConclusionThe compound CRIS031 showed no mutagenic effects on Salmonella typhimurium tester strains TA 98, TA 100, TA 1535 and TA 1537 neither in the presence nor in the absence of a metabolically active microsomal S9 fraction from rat liver using standard Ames test.

Projetos Nitrofurano

Outras drogas

Nitrofuranos

Validao da Metodologia para outras MatrizesAvaliao da real toxicidade causada pelos nitrofuranos

Outras Drogas

Estabelecer metodologia para deteco de outras drogas (cloranfenicol, nitroimidazlicos, dapsona)

Avaliao da Toxicidade

- Testes in vitro

- Testes in vivo

Avaliao do potencial txico em Humanos

Verificar a biodisponibilidade dos nitrofuranos

- Verificar a biodisponibilidade de seus metablitos