ABSTRACT
The ventricular proarrhythmic actions of five class III antiarrhythmic agents were compared in the Carlsson rabbit model. In adrenergically stimulated anesthetized rabbits, azimilide, clofilium, dofetilide, sematilide, and d,l-sotalol caused premature ventricular contractions and nonsustained and sustained ventricular tachyarrhythmias (NSVT and SVT) at pharmacologically equivalent intravenous doses that increased QTc intervals 20% (ED20). There were no significant differences between agents in the percentage of rabbits with serious arrhyhthmias at the ED20 doses of 5.2, 0.033, 0.015, 0.66, and 2.8 mg/kg i.v., respectively. Proarrhythmia was dose-dependent. Linear regression analysis of arrhythmia score versus log dose estimated the NSVT doses as 6.2, 0.055, 0.0089, 1.5, and 5.7, respectively. Analysis of arrhythmia states during a 10-min window after infusion when QTc prolongation was 20% showed that the compounds differed significantly in the proportion of time treated rabbits spent in SVT and combined NSVT and SVT. Rabbits treated with azimilide spent significantly less time in SVT and combined NSVT and SVT, followed in order of increasing time by d,l-sotalol, sematilide, clofilium, and dofetilide.
Subject(s)
Adrenergic alpha-Agonists/pharmacology , Anti-Arrhythmia Agents/pharmacology , Arrhythmias, Cardiac/physiopathology , Imidazoles/pharmacology , Imidazolidines , Methoxamine/pharmacology , Piperazines/pharmacology , Animals , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/metabolism , Disease Models, Animal , Female , Hemodynamics , Hydantoins , Male , Phenethylamines/pharmacology , Procainamide/analogs & derivatives , Procainamide/pharmacology , Quaternary Ammonium Compounds/pharmacology , Rabbits , Sotalol/pharmacology , Sulfonamides/pharmacologyABSTRACT
This study assessed steady-state azimilide pharmacokinetics and pharmacodynamics in 119 healthy male and female volunteers. Parallel groups of 18-40-year-old subjects received doses of 35, 100, 150 or 200 mg day(-1) for up to 14 days, with 1, 2 or 3 days of loading. Another group of > 55-year-old subjects received 100 mg day(-1) with a 3-day loading regimen. There was a slight overshoot of steady-state (24%) after loading, but concentrations decreased to steady-state by day 7. Mean peak steady-state azimilide concentrations ranged from 186 to 1030 ng mL(-1) across the 35-200 mg day(-1) dose range, while mean trough steady-state azimilide concentrations ranged from 108 to 549 ng mL(-1). Azimilide pharmacokinetics were proportional to dose, except for renal clearance, and did not differ between 18-40-year-old and > 55-year-old subjects. Pharmacodynamics did not differ across dose groups. The mean maximum effect (Emax) ranged from 24 to 28% change in QTc from baseline. The concentration needed to attain one half Emax ranged from 432 to 542 ng mL(-1) across dose groups. Equilibration was rapid between blood and the biophase, with equilibration half-lives of less than 1 min.
Subject(s)
Anti-Arrhythmia Agents/pharmacology , Anti-Arrhythmia Agents/pharmacokinetics , Imidazoles/pharmacology , Imidazoles/pharmacokinetics , Imidazolidines , Piperazines/pharmacology , Piperazines/pharmacokinetics , Administration, Oral , Adolescent , Adult , Anti-Arrhythmia Agents/administration & dosage , Drug Administration Schedule , Female , Humans , Hydantoins , Imidazoles/administration & dosage , Male , Piperazines/administration & dosageABSTRACT
Utilizing the UIC Vascular Laboratory Registry, we retrospectively analysed the significance of side to side middle cerebral artery (MCA) flow velocity differences. Side to side differences > 15 percent measured by transcranial Doppler were considered asymmetric. Asymmetric subjects had 5 times greater chance of having significant cervical carotid narrowing on either side on Duplex Doppler and a 3.7 times greater chance of having a stroke on brain CT or MRI. MCA flow velocity asymmetry is a marker for underlying carotid disease and stroke.
