Conquinine - CAS 56-54-2

While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2Hz to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk.

Background:; In the daily clinical practice, patients with atrial fibrillation (AF) lasting more than 48h (or not datable at all) are not uncommon. In long-lasting AF changes in electrophysiological features (electrical remodeling) can occur, resulting in a loss of sensibility to most antiarrhythmic drugs. There is strong evidence that the main mechanism involved in electrical remodeling is a global shortening in refractory period. To assess safety and efficacy of quinidine in pharmacological cardioversion of long-lasting AF, compared with propafenone and amiodarone. ;Methods and Results:; Ninety consecutive patients with AF lasting more than 6 weeks were randomized to amiodarone (5mg\kg bolus, then 15mg\kg in 24h) , propafenone (2 mg\kg bolus then 0.007mg\kg for 2h), and quinidine (275mg of quinidine arabogalattan sulphate per os every 2h for 8h maximum) for pharmacologic cardioversion. All patients had been previously treated with adequate oral anticoagulation and had been submitted to transthoracic echocardiogram. The 3 groups of patients did not differ for baseline and echocardiographic characteristics. Sinus rhythm was restored in 16 patients treated with quinidine (53%), compared with 6 patients (20%) in the amiodarone and propafenone groups (p<0.

Mexiletine is a low clearance drug which undergoes extensive metabolism in man. In vitro studies with human liver microsomes have suggested that major oxidation pathways of mexiletine are predominantly catalyzed by the genetically determined debrisoquine 4-hydroxylase (cytochrome P450IID6) activity. In this study, we investigated the role of debrisoquine polymorphism and the effects of low dose quinidine, a selective inhibitor of cytochrome P450IID6, on the disposition of mexiletine. Fourteen healthy volunteers, 10 with the extensive metabolizer (EM) and 4 with the poor metabolizer (PM) phenotype, received a single 200-mg dose of mexiletine hydrochloride orally on two occasions (1 week apart), once alone and once under steady-state conditions for quinidine (50 mg QID). During the phase mexiletine alone, total clearance, nonrenal clearance and partial metabolic clearance of mexiletine to hydroxymethylmexiletine, to m-hydroxymexiletine and to p-hydroxymexiletine were decreased in PM compared to EM (all P less than .05). In EM, quinidine decreased mexiletine total clearance from 621 +/- 298 to 471 +/- 214 ml/min (mean +/- S.D.; P less than .05) and mexiletine nonrenal clearance from 583 +/- 292 to 404 +/- 188 ml/min (P less than .