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 laevisAssuntos
Bombas de Infusão , Pressão Sanguínea/fisiologia , Falha de Equipamento , Humanos , Complicações Intraoperatórias , Masculino , Erros Médicos , Microcomputadores , Pessoa de Meia-Idade , Revascularização Miocárdica , Nitroglicerina/administração & dosagem , Nitroglicerina/efeitos adversos , Segurança , Vasodilatadores/administração & dosagem , Vasodilatadores/efeitos adversosRESUMO
Pain crisis in metastatic disease can be a therapeutic dilemma when differing mechanisms contribute to severe hyperalgesia and neuropathic pain. We discuss clinical presentation and management of excruciating pain from severe lower limb venous outflow obstruction in an opioid tolerant, terminally ill patient with locally invasive and metastatic adenocarcinoma of the cervix. This case illustrates how pain crises at end of life can be successfully managed by using a rational, complementary, multimodal approach. Key points include possible mechanisms of pain from venous outflow obstruction, benefit of hyperbaric subarachnoid bupivacaine, opioid rotation to methadone, and use of ketamine by mouth.