RESUMO
PURPOSE: To assess the usefulness of 0.0015% tafluprost and 0.5% timolol fixed-dose combination (TT-FDC) for glaucoma, the ocular hypotensive effect of TT-FDC and concentration of tafluprost and timolol in the aqueous humor were compared with those of the concomitant administration of 0.0015% tafluprost and 0.5% timolol with or without an appropriate administration interval. METHODS: The ocular hypotensive effect was assessed by intraocular pressure (IOP) measurement in cynomolgus monkeys. Drug penetration into the aqueous humor was estimated by the concentrations of tafluprost acid (active metabolic form of tafluprost) and timolol, which were measured using liquid chromatography-tandem mass spectrometry after administration of tafluprost and timolol to Sprague Dawley rats. RESULTS: The ocular hypotensive effect of TT-FDC was equivalent to that of the concomitant administration of timolol and tafluprost at a more than 5-min interval in monkeys. However, the ocular hypotensive effect of the concomitant administration of timolol and tafluprost without an interval (-2.8 ± 0.2 mmHg at peak IOP reduction) was significantly weaker compared with TT-FDC (-4.3 ± 0.5 mmHg at peak IOP reduction, P = 0.008 vs. concomitant administration of timolol and tafluprost) in monkeys. The aqueous humor concentration of the second administered drug (tafluprost) was not affected by the dosing conditions, whereas the concentration of the first instilled drug (timolol) without the interval was lower than that with a 5-min interval (1,200 ng · h/mL vs. 1,890 ng · h/mL in AUC0-4) in rats. CONCLUSION: TT-FDC demonstrates a clear benefit by preventing efficacy loss without an appropriate interval in experimental animal models.
Assuntos
Anti-Hipertensivos/farmacologia , Glaucoma/tratamento farmacológico , Prostaglandinas F/farmacologia , Timolol/farmacologia , Administração Oftálmica , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacocinética , Humor Aquoso/metabolismo , Cromatografia Líquida/métodos , Modelos Animais de Doenças , Combinação de Medicamentos , Feminino , Glaucoma/patologia , Pressão Intraocular/efeitos dos fármacos , Macaca fascicularis , Masculino , Hipertensão Ocular/tratamento farmacológico , Prostaglandinas F/administração & dosagem , Prostaglandinas F/farmacocinética , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/métodos , Timolol/administração & dosagem , Timolol/farmacocinéticaRESUMO
Optimization of compounds 5 and 6 led to the discovery of VEGF inhibitor 10g which reduced CYP inhibition. It was highly active in vitro (VEGF induced HUVEC proliferation assay) and showed efficacies in three disease models in vivo (cancer, RA, and AMD).
