Dúvidas
Arquivo
Etapas de desenvolvimento de medicamentos.ppt
(med-unicamp-segundo ano)
Site
www.gdenucci.com
Dúvidas
Arquivo
Etapas de desenvolvimento de medicamentos.ppt
(med-unicamp-segundo ano)
Site
www.gdenucci.com
Desenvolvimento de um MedicamentoDesenvolvimento de um Medicamento
Aumento escalonado Aumento escalonado da doseda doseAumento escalonado Aumento escalonado da doseda dose
TolerânciaTolerânciaTolerânciaTolerânciaIn vitro PK/PDIn vitro PK/PDAnimal PK/PDAnimal PK/PDIn vitro PK/PDIn vitro PK/PDAnimal PK/PDAnimal PK/PD
Dose (Conc)Dose (Conc)Resposta clínicaResposta clínicaDose (Conc)Dose (Conc)Resposta clínicaResposta clínica
EficáciaEficáciaEficáciaEficácia
Seleção da DoseSeleção da DoseSeleção da DoseSeleção da Dose
Vols sadiosVols sadiosVols sadiosVols sadios
População PK/PDPopulação PK/PDGrandes ensaios clínicosGrandes ensaios clínicosPopulação PK/PDPopulação PK/PDGrandes ensaios clínicosGrandes ensaios clínicos
PK/PD em populaçãoPK/PD em populaçãoespeciaisespeciaisPK/PD em populaçãoPK/PD em populaçãoespeciaisespeciais
Vigilância Vigilância pós-mercadopós-mercadoVigilância Vigilância pós-mercadopós-mercado
Fase IFase IFase IFase I
Testes Clínicos (Humanas)Testes Clínicos (Humanas)Testes Clínicos (Humanas)Testes Clínicos (Humanas)Testes Pré-clínicosTestes Pré-clínicosTestes Pré-clínicosTestes Pré-clínicos
Fase IIFase IIFase IIFase IIFase IIIFase IIIFase IIIFase III
Fase IVFase IVFase IVFase IVPoucos pctesPoucos pctesPoucos pctesPoucos pctes
Muitos pctesMuitos pctesMuitos pctesMuitos pctesPopulaçãoPopulaçãoPopulaçãoPopulação
Testes em animaisTestes em animaisTestes em animaisTestes em animais
Testes Pré-clínicos para Fase I
• Testes in vitro – genotoxicidade
• Testes in vivo – duas espécies animais (uma não roedora) por duas semanas
• Testes in vitro – genotoxicidade
• Testes in vivo – duas espécies animais (uma não roedora) por duas semanas
Testes Clínicos
• Fase I – voluntários sadios
• Fase II – pacientes para prova conceitual
• Fase III – grande número de pacientes – estudos multicêntricos
• Fase IV – vigilância pós-mercado – pesquisa sobre novas indicações
• Fase I – voluntários sadios
• Fase II – pacientes para prova conceitual
• Fase III – grande número de pacientes – estudos multicêntricos
• Fase IV – vigilância pós-mercado – pesquisa sobre novas indicações
Testes in-vitro
• Testes de Genotoxicidade:
• Teste de Ames
• Teste de Micronúcleo(eritrócitos de rato)
• Teste em Linfoma de rato (timidina-quinase)
• Testes de Genotoxicidade:
• Teste de Ames
• Teste de Micronúcleo(eritrócitos de rato)
• Teste em Linfoma de rato (timidina-quinase)
Requisito Toxicológico para Estudos Fase I
• Teste de Ames• Administração crônica por duas semanas em
duas espécies animais, sendo uma não roedora
ANNEX Laboratory investigationsANNEX Laboratory investigations
HEMATOLOGY:HEMATOLOGY: Blood collected on EDTABlood collected on EDTA ErythrocytesErythrocytes
HemoglobinHemoglobinMean Cell VolumeMean Cell VolumePacked Cell VolumePacked Cell VolumeMean Cell Hemoglobin ConcentrationMean Cell Hemoglobin ConcentrationMean Cell HemoglobinMean Cell HemoglobinThrombocytesThrombocytesLeucocytesLeucocytesDifferential White Cell count with cell morphologyDifferential White Cell count with cell morphologyReticulocyte countReticulocyte count
Blood collected on sodium citrateBlood collected on sodium citrate Prothrombin TimeProthrombin Time
Activated Partial Thromboplastin TimeActivated Partial Thromboplastin Time FibrinogenFibrinogen
And optional:And optional:Bone marrow smearsBone marrow smearsBone marrow differential cell countBone marrow differential cell count
ANNEX Laboratory investigationsANNEX Laboratory investigations
HEMATOLOGY:HEMATOLOGY: Blood collected on EDTABlood collected on EDTA ErythrocytesErythrocytes
HemoglobinHemoglobinMean Cell VolumeMean Cell VolumePacked Cell VolumePacked Cell VolumeMean Cell Hemoglobin ConcentrationMean Cell Hemoglobin ConcentrationMean Cell HemoglobinMean Cell HemoglobinThrombocytesThrombocytesLeucocytesLeucocytesDifferential White Cell count with cell morphologyDifferential White Cell count with cell morphologyReticulocyte countReticulocyte count
Blood collected on sodium citrateBlood collected on sodium citrate Prothrombin TimeProthrombin Time
Activated Partial Thromboplastin TimeActivated Partial Thromboplastin Time FibrinogenFibrinogen
And optional:And optional:Bone marrow smearsBone marrow smearsBone marrow differential cell countBone marrow differential cell count
ANNEX Laboratory investigationsANNEX Laboratory investigations
BLOOD BIOCHEMISTRY:BLOOD BIOCHEMISTRY:Blood collected on lithium heparinateBlood collected on lithium heparinate SodiumSodium CreatinineCreatinine PotassiumPotassium Total bilirubinTotal bilirubin ChlorideChloride CholesterolCholesterol CalciumCalcium TriglyceridesTriglycerides Inorganic PhosphorusInorganic Phosphorus Alkaline phosphataseAlkaline phosphatase GlucoseGlucose Aspartate aminotransferaseAspartate aminotransferase UreaUrea Alanine aminotransferaseAlanine aminotransferase Total proteinsTotal proteins AlbuminAlbumin
Albumin/globulin ratioAlbumin/globulin ratio
Or optional:Or optional:Blood collected without anticoagulantBlood collected without anticoagulant Total proteinsTotal proteins Protein electrophoresisProtein electrophoresis including Albumin andincluding Albumin and
Albumin/Globulin ratio Albumin/Globulin ratio
ANNEX Laboratory investigationsANNEX Laboratory investigations
BLOOD BIOCHEMISTRY:BLOOD BIOCHEMISTRY:Blood collected on lithium heparinateBlood collected on lithium heparinate SodiumSodium CreatinineCreatinine PotassiumPotassium Total bilirubinTotal bilirubin ChlorideChloride CholesterolCholesterol CalciumCalcium TriglyceridesTriglycerides Inorganic PhosphorusInorganic Phosphorus Alkaline phosphataseAlkaline phosphatase GlucoseGlucose Aspartate aminotransferaseAspartate aminotransferase UreaUrea Alanine aminotransferaseAlanine aminotransferase Total proteinsTotal proteins AlbuminAlbumin
Albumin/globulin ratioAlbumin/globulin ratio
Or optional:Or optional:Blood collected without anticoagulantBlood collected without anticoagulant Total proteinsTotal proteins Protein electrophoresisProtein electrophoresis including Albumin andincluding Albumin and
Albumin/Globulin ratio Albumin/Globulin ratio
ANNEX Laboratory investigationsANNEX Laboratory investigations
URINALYSIS:URINALYSIS:
VolumeVolume GlucoseGlucose pHpH BilirubinBilirubin
Specific gravitySpecific gravity NitritesNitrites Cytology of sedimentCytology of sediment BloodBlood
AppearanceAppearance KetonesKetones ColorColor UrobilinogenUrobilinogen
ProteinsProteins
ANNEX Laboratory investigationsANNEX Laboratory investigations
URINALYSIS:URINALYSIS:
VolumeVolume GlucoseGlucose pHpH BilirubinBilirubin
Specific gravitySpecific gravity NitritesNitrites Cytology of sedimentCytology of sediment BloodBlood
AppearanceAppearance KetonesKetones ColorColor UrobilinogenUrobilinogen
ProteinsProteins
Ames TestAmes Test ( (Salmonella typhimuriumSalmonella typhimurium))
Bacterial reverse mutation assays are widely used to evaluate the Bacterial reverse mutation assays are widely used to evaluate the mutagenic potential of chemicals, formulations, or extracts. The most mutagenic potential of chemicals, formulations, or extracts. The most common assay involves the use of amino acid-requiring strains of common assay involves the use of amino acid-requiring strains of Salmonella typhimuriumSalmonella typhimurium and is commonly referred to as the "Ames and is commonly referred to as the "Ames Test". Test".
In the absence of an external amino acid source (histidine for In the absence of an external amino acid source (histidine for SalmonellaSalmonella), the cells cannot grow to form colonies unless a reversion of ), the cells cannot grow to form colonies unless a reversion of the mutation allows the synthesis of the amino acid to resume.the mutation allows the synthesis of the amino acid to resume.
Spontaneous reversions occur with each of the strains. However, some Spontaneous reversions occur with each of the strains. However, some compounds induce a mutagenic response and thereby increase the compounds induce a mutagenic response and thereby increase the number of revertant colonies substantially over the spontaneous number of revertant colonies substantially over the spontaneous reversion levelreversion level..
The bacterial reverse mutation assay involves The bacterial reverse mutation assay involves the measurement of revertant colony the measurement of revertant colony frequencies that are obtained when frequencies that are obtained when SalmonellaSalmonella strains are treated in the presence and absence strains are treated in the presence and absence of a test article. of a test article.
Positive and negative controls are included for Positive and negative controls are included for each strain tested. Metabolic activation using each strain tested. Metabolic activation using rat liver S9 is included to mimic the rat liver S9 is included to mimic the in vivoin vivo activity of the liver enzymes in transforming activity of the liver enzymes in transforming some pro-mutagens to mutagenssome pro-mutagens to mutagens
Effect of Effect of CRIS031 CRIS031 in Ames test using S. in Ames test using S. typhimurium strain (TA 98)typhimurium strain (TA 98)
Effect of Effect of CRIS031 CRIS031 in Ames test using S. in Ames test using S. typhimurium strain (TA 100)typhimurium strain (TA 100)
Effect of Effect of CRIS031 CRIS031 in Ames test using S. typhimurium in Ames test using S. typhimurium strain (TA 1535)strain (TA 1535)
Effect of Effect of CRIS031 CRIS031 in Ames test using S. typhimurium in Ames test using S. typhimurium strain (TA 1537)strain (TA 1537)
ConclusionConclusion
““The compound The compound CRIS031CRIS031 showed no mutagenic effects on showed no mutagenic effects on Salmonella typhimuriumSalmonella typhimurium tester strains TA tester strains TA 98, TA98, TA 100, TA100, TA 1535 and TA1535 and TA 1537 neither in the presence nor in the 1537 neither in the presence nor in the absence of a metabolically active microsomal S9 fraction absence of a metabolically active microsomal S9 fraction from rat liver using standard Ames test.”from rat liver using standard Ames test.”
ProjetosProjetos
Nitrofurano Nitrofurano
Outras drogasOutras drogas
NitrofuranosNitrofuranos
Validação da Metodologia para outras MatrizesValidação da Metodologia para outras MatrizesAvaliação da real toxicidade causada pelos Avaliação da real toxicidade causada pelos nitrofuranosnitrofuranos
Outras DrogasOutras Drogas
Estabelecer metodologia para detecção de Estabelecer metodologia para detecção de outras drogas (cloranfenicol, outras drogas (cloranfenicol, nitroimidazólicos, dapsona)nitroimidazólicos, dapsona)
Avaliação da ToxicidadeAvaliação da Toxicidade
- Testes in vitro- Testes in vitro
- Testes in vivo- Testes in vivo
Avaliação do potencial tóxico em Humanos
- Verificar a biodisponibilidade dos nitrofuranosVerificar a biodisponibilidade dos nitrofuranos
- Verificar a biodisponibilidade de seus metabólitos- Verificar a biodisponibilidade de seus metabólitos
