RESUMO
Afoxolaner is an isoxazoline compound characterized by a good safety profile and extended effectiveness against fleas and ticks on dogs following a single oral administration. In vitro membrane feeding assay data and in vivo pharmacokinetic studies in dogs established an afoxolaner blood concentration of 0.1-0.2 µg/ml to be effective against both fleas (Ctenocephalides felis) and ticks (Dermacentor variabilis). Pharmacokinetic profiles in dogs following a 2.5mg/kg oral dosage demonstrated uniform and predictable afoxolaner plasma concentrations above threshold levels required for efficacy for more than one month. Dose ranging and a 5-month multi-dose experimental study in dogs, established that the 2.5mg/kg oral dosage was highly effective against fleas and ticks, and produced predictable and reproducible pharmacokinetics following repeated dosing. Mode of action studies showed that afoxolaner blocked native and expressed insect GABA-gated chloride channels with nanomolar potency. Afoxolaner has comparable potency between wild type channels and channels possessing the A302S (resistance-to-dieldrin) mutation. Lack of cyclodiene cross-resistance for afoxolaner was confirmed in comparative Drosophila toxicity studies, and it is concluded that afoxolaner blocked GABA-gated chloride channels via a site distinct from the cyclodienes.
Assuntos
Antiparasitários/farmacologia , Canais de Cloreto/metabolismo , Isoxazóis/farmacologia , Naftalenos/farmacologia , Sifonápteros/efeitos dos fármacos , Carrapatos/efeitos dos fármacos , Animais , Antiparasitários/sangue , Antiparasitários/farmacocinética , Antiparasitários/uso terapêutico , Baratas/efeitos dos fármacos , Doenças do Cão/tratamento farmacológico , Doenças do Cão/fisiopatologia , Cães , Drosophila melanogaster/efeitos dos fármacos , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Feminino , Infestações por Pulgas/tratamento farmacológico , Infestações por Pulgas/prevenção & controle , Infestações por Pulgas/veterinária , Isoxazóis/sangue , Isoxazóis/farmacocinética , Isoxazóis/uso terapêutico , Masculino , Naftalenos/sangue , Naftalenos/farmacocinética , Naftalenos/uso terapêutico , Oócitos/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Distribuição Aleatória , Infestações por Carrapato/tratamento farmacológico , Infestações por Carrapato/prevenção & controle , Infestações por Carrapato/veterinária , Xenopus laevisRESUMO
Quinolinones and naphthyridinones with C7 N-t-butyl piperidine substituents were found to be potent p38 MAP kinase inhibitors. These compounds significantly suppress TNF-alpha release in both cellular and LPS-stimulated whole blood assays. They also displayed excellent PK profiles across three animal species. Quinolinone at 10 mpk showed comparable oral efficacy to that of dexamethasone at 1 mpk in a murine collagen-induced arthritis model.