Document 0495
 DOCN  M9650495
 TI    A randomized, double-blind, placebo-controlled, dose-ranging study of
       dofetilide in patients with inducible sustained ventricular
       tachyarrhythmias.
 DT    9605
 AU    Echt DS; Lee JT; Murray KT; Vorperian V; Borganelli SM; Crawford DM;
       Friedrich T; Roden DM; Department of Medicine, Vanderbilt University
       School of Medicine,; Nashville, Tennessee, USA.
 SO    J Cardiovasc Electrophysiol. 1995 Sep;6(9):687-99. Unique Identifier :
       AIDSLINE MED/96098524
 AB    INTRODUCTION: Dofetilide is a new antiarrhythmic agent with potent IK
       blocking properties in vitro. We developed a dose-ranging,
       placebo-controlled study design to define the range of effective doses
       and to evaluate the clinical electrophysiology of intravenous dofetilide
       in patients in whom sustained ventricular tachycardia or fibrillation
       was reproducibly inducible at baseline electrophysiologic testing.
       METHODS AND RESULTS: The initial four patients received low doses that
       were increased in subsequent groups of four if adverse effects were
       absent. In each group of four patients, one patient was randomly
       assigned to placebo (double blind). Twenty-four patients were studied at
       six incremental loading and maintenance infusion regimens. Dofetilide
       (0.1 to 8.0 ng/mL) produced concentration-related increases in the %
       delta of QT (r = 0.79, P < 0.001), QTc (r = 0.60, P = 0.02), RR (r =
       0.62, P < 0.02), and right ventricular effective refractory period
       (cycle length 600 msec; r = 0.68, P = 0.04). Placebo produced no changes
       in any of these measurements. Sustained ventricular tachycardia or
       ventricular fibrillation was no longer inducible in 1 of 6 patients
       receiving placebo and 8 of 18 receiving dofetilide (4 to 13 sec
       nonsustained ventricular tachycardia was induced in 4 of these 8). One
       patient developed torsades de pointes at a high concentration (5.3
       ng/mL). CONCLUSIONS: We conclude that: (1) dofetilide produces
       concentration-related IK blocking effects in patients; (2) an
       incremental dose-ranging study design aids in identifying the range of
       doses demonstrating electrophysiologic effects and efficacy; (3) a
       concomitant placebo group provides important data to assess
       reproducibility of results over time; and (4) further studies of
       dofetilide's efficacy and toxicity should be conducted.
 DE    Adolescence  Adult  Aged  Anti-Arrhythmia Agents/*ADMINISTRATION &
       DOSAGE/PHARMACOKINETICS  Double-Blind Method  Electrocardiography
       Female  Human  Infusions, Intravenous  Male  Middle Age
       Phenethylamines/*ADMINISTRATION & DOSAGE/PHARMACOKINETICS
       Sulfonamides/*ADMINISTRATION & DOSAGE/PHARMACOKINETICS  Support,
       Non-U.S. Gov't  Tachycardia, Ventricular/*DRUG
       THERAPY/METABOLISM/PHYSIOPATHOLOGY  CLINICAL TRIAL  JOURNAL ARTICLE
       RANDOMIZED CONTROLLED TRIAL

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).