Intrauterine and neonatal manifestations of congenital long QT syndrome are associated with a high cardiac risk, particularly when atrioventricular block and excessive QT prolongation (. 600 ms) are present. In a female newborn with these features, treatment with propranolol and mexiletine led to complete reduction of arrhythmia that was maintained 1.5 years later. High throughput genetic analy...

particularly difficult cases in whom standard treatment had failed. In three of them mexiletine alone controlled the arrhythmia, but only at the cost of intolerable adverse effects. Combined treatment with mexiletine and propranolol, which have different actions and different adverse effects, enables arrhythmia to be suppressed through co-operative antiarrhythmic action. Since adverse effects h...

The mechanism of cytochrome P450(CYP)-catalyzed hydroxylation of primary amines is currently unclear and is relevant to drug metabolism; previous small model calculations have suggested two possible mechanisms: direct N-oxidation and H-abstraction/rebound. We have modeled the N-hydroxylation of (R)-mexiletine in CYP1A2 with hybrid quantum mechanics/molecular mechanics (QM/MM) methods, providing...

Gating properties of Na(+) channels are the critical determinants for the state-dependent block by class I antiarrhythmic drugs; however, recent site-directed mutagenesis studies have shown that the Na(+) channel selectivity filter region controls drug access to and dissociation from the binding site. To validate these observations, we have exploited a naturally occurring cardiac Na(+) channel ...

rac-Mexiletine is an orally effective class 1b antiarrhythmic agent used to treat ventricular arrhythmias. In vivo experiments have demonstrated. It is predominantly metabolized by the liver with < 10% excreted as unchanged drug. The major mammalian metabolites have been identified as p-hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM). The purpose of our study was to determine whether ...

Congenital long QT syndrome (LQTS) with atrioventricular block is a rare and malignant arrhythmia, which usually responds poorly to traditional beta-blocker therapy. We describe a male neonate with LQTS with ventricular tachycardia and 2:1 atrioventricular block. This patient's sister had similar presentation and died suddenly at the age of 8 months despite beta-blocker and pacemaker therapy. O...

Vecchietti S, Grandi E, Severi S, Rivolta I, Napolitano C, Priori SG, Cavalcanti S. In silico assessment of Y1795C and Y1795H SCN5A mutations: implication for inherited arrhythmogenic syndromes. Am J Physiol Heart Circ Physiol 292: H56–H65, 2007. First published September 15, 2006; doi:10.1152/ajpheart.00270.2006.—The effects of two SCN5A mutations (Y1795C, Y1795H), previously identified in one...

The use of antiarrhythmic drugs to suppress ventricular arrhythmias in pediatric patients with a structurally or hemodynamically abnormal heart appears to improve long-term prognosis. The previously successful use of phenytoin to treat serious ventricular arrhythmias led to the investigation for an alternative antiarrhythmic agent, in the same antiarrhythmic drug class, for those patients who d...

Oxaliplatin, a platinum-based chemotherapeutic agent, causes an acute peripheral neuropathy triggered by cold in almost all patients during or within hours after its infusion. We recently reported that a single administration of oxaliplatin induced cold hypersensitivity 2 h after the administration in mice. In this study, we examined whether standard analgesics relieve the oxaliplatin-induced a...