RESUMEN
Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market. At the same time, the current regulatory paradigm for screening new drugs causing long QT syndrome is preventing drugs from reaching the market, sometimes inappropriately. In this study, we report the results of a first-of-a-kind clinical trial studying late sodium (mexiletine and lidocaine) and calcium (diltiazem) current blocking drugs to counteract the effects of hERG potassium channel blocking drugs (dofetilide and moxifloxacin). We demonstrate that both mexiletine and lidocaine substantially reduce heart-rate corrected QT (QTc) prolongation from dofetilide by 20 ms. Furthermore, all QTc shortening occurs in the heart-rate corrected J-Tpeak (J-Tpeak c) interval, the biomarker we identified as a sign of late sodium current block. This clinical trial demonstrates that late sodium blocking drugs can substantially reduce QTc prolongation from hERG potassium channel block and assessment of J-Tpeak c may add value beyond only assessing QTc.
Asunto(s)
Antiarrítmicos/uso terapéutico , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/tratamiento farmacológico , Bloqueadores de los Canales de Sodio/efectos adversos , Adulto , Antiarrítmicos/farmacocinética , Bloqueadores de los Canales de Calcio/farmacocinética , Bloqueadores de los Canales de Calcio/uso terapéutico , Estudios Cruzados , Diltiazem/farmacocinética , Diltiazem/uso terapéutico , Quimioterapia Combinada , Electrocardiografía/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Femenino , Fluoroquinolonas/efectos adversos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Lidocaína/farmacocinética , Lidocaína/uso terapéutico , Masculino , Mexiletine/farmacocinética , Mexiletine/uso terapéutico , Moxifloxacino , Fenetilaminas/efectos adversos , Estudios Prospectivos , Sulfonamidas/efectos adversos , Adulto JovenRESUMEN
In 16 healthy males bioavailability of Mexicord (Polfa) was studied, in comparison with mexiletine of foreign made. Bioavailability extent (EBA) of Mexicord was over 99% in comparison with a standard drug. Comparative study of antiarrhythmic activity and side effects was performed in 32 patients with frequent ventricular premalure beats and nearly in a half of them resistant to antiarrhythmic agents. Mexicord was effective in 47% of treated patients, and side effects (most often nausea) were observed in 28% of patients, but only in 1 case therapy withdrawal was necessary. Statistical study proved a lack of significant differences in antiarrhythmic effectiveness and side effects between Mexicord (Polfa) and a drug of foreign made.