ABSTRACT
Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market.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.
Subject(s)
Anti-Arrhythmia Agents/therapeutic use , Long QT Syndrome/chemically induced , Long QT Syndrome/drug therapy , Sodium Channel Blockers/adverse effects , Adult , Anti-Arrhythmia Agents/pharmacokinetics , Calcium Channel Blockers/pharmacokinetics , Calcium Channel Blockers/therapeutic use , Cross-Over Studies , Diltiazem/pharmacokinetics , Diltiazem/therapeutic use , Drug Therapy, Combination , Electrocardiography/drug effects , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Female , Fluoroquinolones/adverse effects , Heart Rate/drug effects , Humans , Lidocaine/pharmacokinetics , Lidocaine/therapeutic use , Male , Mexiletine/pharmacokinetics , Mexiletine/therapeutic use , Moxifloxacin , Phenethylamines/adverse effects , Prospective Studies , Sulfonamides/adverse effects , Young AdultABSTRACT
Female rats were treated with the nonsteroidal estrogen antagonist clomiphene citrate for the first 5 days postpartum. The expectation was that clomiphene would influence the sexual development of these animals as is the case with sexually immature animals treated with steroidal compounds. Analysis showed that treatment with clomiphene completely disrupted the adult sexual behavior of the female. In five consecutive days of testing the experimental females were never observed to mate. They were mounted significantly less often than controls, suggesting that the males were less attracted to them than to normal females. The initial suggestion that clomiphene might affect the sexual behavior of females has been supported; however, further research must be done to identify the underlying mechanism of the change.
