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Medicinas Complementárias
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1.
J Pharmacol Exp Ther ; 342(3): 642-53, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22637724

RESUMEN

The Kv1.3 channel is a recognized target for pharmaceutical development to treat autoimmune diseases and organ rejection. ShK-186, a specific peptide inhibitor of Kv1.3, has shown promise in animal models of multiple sclerosis and rheumatoid arthritis. Here, we describe the pharmacokinetic-pharmacodynamic relationship for ShK-186 in rats and monkeys. The pharmacokinetic profile of ShK-186 was evaluated with a validated high-performance liquid chromatography-tandem mass spectrometry method to measure the peptide's concentration in plasma. These results were compared with single-photon emission computed tomography/computed tomography data collected with an ¹¹¹In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugate of ShK-186 to assess whole-blood pharmacokinetic parameters as well as the peptide's absorption, distribution, and excretion. Analysis of these data support a model wherein ShK-186 is absorbed slowly from the injection site, resulting in blood concentrations above the Kv1.3 channel-blocking IC50 value for up to 7 days in monkeys. Pharmacodynamic studies on human peripheral blood mononuclear cells showed that brief exposure to ShK-186 resulted in sustained suppression of cytokine responses and may contribute to prolonged drug effects. In delayed-type hypersensitivity, chronic relapsing-remitting experimental autoimmune encephalomyelitis, and pristane-induced arthritis rat models, a single dose of ShK-186 every 2 to 5 days was as effective as daily administration. ShK-186's slow distribution from the injection site and its long residence time on the Kv1.3 channel contribute to the prolonged therapeutic effect of ShK-186 in animal models of autoimmune disease.


Asunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Canal de Potasio Kv1.3/antagonistas & inhibidores , Proteínas/farmacología , Linfocitos T/efectos de los fármacos , Absorción/efectos de los fármacos , Absorción/inmunología , Animales , Artritis/tratamiento farmacológico , Artritis/inmunología , Artritis/metabolismo , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Humanos , Concentración 50 Inhibidora , Canal de Potasio Kv1.3/inmunología , Canal de Potasio Kv1.3/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Macaca fascicularis , Bloqueadores de los Canales de Potasio/inmunología , Bloqueadores de los Canales de Potasio/farmacocinética , Bloqueadores de los Canales de Potasio/farmacología , Proteínas/farmacocinética , Ratas , Ratas Sprague-Dawley , Saimiri , Linfocitos T/inmunología , Linfocitos T/metabolismo , Distribución Tisular/efectos de los fármacos , Distribución Tisular/inmunología
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