RESUMO
The neurotransmitter serotonin (5-hydroxy tryptamine or 5HT) regulates key physiological processes in nematodes such as locomotion and feeding. PAPP (p-amino-phenethyl-m-trifluoromethylphenyl piperazine) is a known agonist of the 5-HT(1Hc) receptor of the barber pole worm, Haemonchus contortus. In this study, PAPP was highly active against L3-stage larvae of H. contortus and Trichostrongylus colubriformis in an in vitro larval migration assay, with EC50 values of 9.36 and 11.8 microM, respectively, that were comparable to levamisole (10.2 microM) and superior to pyrantel (55.39 microM). When administered orally or subcutaneously to nematode infected gerbils, PAPP provided >99% efficacy against H. contortus and >98% efficacy against Teladorsagia circumcincta at 100 mg/kg, comparable to levamisole at 10 mg/kg. Drug titration revealed significant activity down to 50 mg/kg against these two species. Spectrum was limited, however, with somewhat lower efficacy (83%) in T. colubriformis infected gerbils at 100 mg/kg. Oral delivery of hydrochloride, acetate and phosphate salts of PAPP to nematode infected gerbils did not result in an increase in either potency or spectrum. The finding that PAPP exhibits significant anthelmintic activity suggests that the nematode-specific serotonergic system is a viable target for future anthelmintic discovery.
Assuntos
Anti-Helmínticos/farmacologia , Piperazinas/farmacologia , Trichostrongyloidea/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Gerbillinae , Larva/efeitos dos fármacos , Estrutura Molecular , Piperazinas/químicaRESUMO
The design and synthesis of dual PPAR gamma/delta agonist (R)-3-{2-ethyl-4-[3-(4-ethyl-2-pyridin-2-yl-phenoxy)-butoxy]-phenyl}propionic acid is described. This compound dose-dependently lowered plasma glucose in hyperglycemic male Zucker diabetic fatty (ZDF) rats and produced less weight gain relative to rosiglitazone at an equivalent level of glucose control.
Assuntos
Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , PPAR delta/agonistas , PPAR gama/agonistas , Animais , Glicemia/metabolismo , Relação Dose-Resposta a Droga , Desenho de Fármacos , Feminino , Meia-Vida , Humanos , Hipoglicemiantes/farmacocinética , Indicadores e Reagentes , Insulina/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Rosiglitazona , Relação Estrutura-Atividade , Tiazolidinedionas/farmacologia , Aumento de Peso/efeitos dos fármacosRESUMO
A new series of analogues of 4-(4-fluorophenyl)-2-methylthio-thiophene-3-carbonitrile (1) were synthesized and evaluated for their in vitro and in vivo anthelmintic activity against Haemonchus contortus.
Assuntos
Anti-Helmínticos/síntese química , Haemonchus/efeitos dos fármacos , Tiofenos/síntese química , Tiofenos/farmacologia , Animais , Anti-Helmínticos/farmacologia , Cinética , Estrutura Molecular , Relação Estrutura-Atividade , Tiofenos/químicaRESUMO
We have studied the effect of methylene blue on GSH and GSSG levels in rat blood, liver and kidney. Methylene blue treatment increases GSH levels and PBG-synthetase activity in erythrocytes while liver and kidney GSH and GSSG levels remain constant. These results indicate that methylene blue effect on PBG-synthetase activity in rat erythrocytes is mediated by an increase in blood GSH levels.