The Evaluation of New Antiarrhythmic Drugs

1. Front Matter

   Pages I-XIV

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2. How to Evaluate a new Antiarrhythmic Drug: The Challenge of Sudden Cardiac Death

   1. How to Evaluate a New Antiarrhythmic Drug: The Challenge of Sudden Cardiac Death

      • Joel Morganroth

      Pages 1-4

3. Pre-Clinical Evaluation of a New Antiarrhythmic Agent

   1. Relationships between Effects on Cardiac Electrophysiology and Antiarrythmic Efficacy

      • Brian F. Hoffman

      Pages 5-15

   2. What Animal Models Should Be Used to Define Antiarrhythmic Efficacy? Acute Dog Models

      • Leonard S. Dreifus, Masahito Naito, Eric L. Michelson

      Pages 17-32

   3. Description of Chronic Canine Myocardial Infarction Models Suitable for the Electropharmacologic Evaluation of New Antiarrhythmic Drugs

      • E. L. Michelson, J. F. Spear, E. N. Moore

      Pages 33-46

   4. Non-Canine Animal Models for Evaluating Antiarrhythmic Efficacy

      • E. Neil Moore, Joseph F. Spear, Eric L. Michelson

      Pages 47-68

   5. Defining the Pharmacodynamics and Pharmacokinetics of New Antiarrhythmic Drugs

      • Robert E. Kates

      Pages 69-85

4. Chronic Studies in Patients with Non-Hemodynamically Significant Ventricular Arrhythmics

   1. How Should Holter Monitoring Analysis Be Performed?

      • C. L. Feldman

      Pages 87-102

   2. Long-Term Ambulatory Electrocardiographic Recording in the Determination of Efficacy of New Antiarrhythmic Agents

      • Joel Morganroth

      Pages 103-111

   3. Evaluation of Antiarrhythmic Drugs. Should the Lown Classification Be Used as a Measure of Efficacy?

      • R. W. F. Campbell

      Pages 113-121

   4. General Group Discussion: Holter Monitoring

      • Joel Morganroth, E. Neil Moore, Leonard S. Dreifus, Eric L. Michelson

      Pages 123-135

5. Study Designs: Chronic Patients

   1. Introduction

      • D. M. Krikler

      Pages 137-138

   2. Proposed New Means of Evaluating Anti-Arrhythmic Drugs

      • Robert Temple

      Pages 139-147

   3. Parallel or Crossover Designs in Evaluation of Antiarrhythmic Therapy

      • Helena Chmura Kraemer

      Pages 149-157

   4. General Group Discussion: Study Designs: Chronic Patients

      • Joel Morganroth, E. Neil Moore, Leonard S. Dreifus, Eric L. Michelson

      Pages 159-178

6. Acute Studies in Patients with Hemodynamically Significant Significant Ventricular Arrhythmias

   1. Acute Drug Testing as a Part of a Systematic Approach to Antiarrhythmic Drug Therapy

      • Philip J. Podrid

      Pages 179-191

   2. Role of Electrophysiology Testing to Define Drug Efficacy

      • Douglas P. Zipes

      Pages 193-212

   3. What Should the Study Design Be to Test New Antiarrhythmic Drugs in Patients with Acute Myocardial Infarction, Digitalis Toxicity and Other Acute Problems

      • Roger A. Winkle

      Pages 213-232

7. Special Considerations

   1. What Baseline Electrophysiologic Data Should Be Obtained in a Pharmacologic Study of an Antiarrhythmic Drug?

      • Kenneth M. Rosen, Boris Strasberg, Edwin Palileo

      Pages 233-246

   2. Assessment of the Hemodynamic and Inotropic Effects of Antiarrhythmic Drugs

      • R. S. Aronson, S. Siskind, E. H. Sonnenblick

      Pages 247-270

Thus, there are now several chronic canine myocardial infarction­ ventricular tachyarrhythmia models which are available for the evaluation of new antiarrhythmic drugs (Table I). The available models fulfill many, but not all of the requirements for an ideal chronic arrhythmia model (Table 11). The sustained arrhythmias initiated in these models using programmed pacing presumably have the same localized reentrant mechanism that characterizes chronic human myocardial infarction and chronic coronary 26 artery disease. However, these models are not suitable for determining whether a new drug will abolish spontaneous ly-occurring PVCs. In addition, these models are of unproven value in the study of acute spontaneously­ occurring sudden death; although recently initiated, provocative work may shed further light on this subject. Most importantly, the available models do seem well-suited to the evaluation of new drugs intended for use in chronic coronary artery disease patients at risk for sustained reentrant ventricular tachycardia or VF. Notably, the results of preliminary electropharmacologic studies in these canine models parallel closely those findings reported in human patients with sustained life-threatening ventricu­ lar tachyarrhythmias (Table Ill). Therefore, increased use of these chronic models for new antiarrhythmic drug testing is strongly recommended. TABLE II Ideal vs Available Chronic Canine - Arrhythmia Models Ideal Available 1. (a) Arrhythmia mechanism comparable to Yes patients with chronic CAD: Reentry (b) Pathophysiology similar (e. g. , atherogenic CAD) No 2. Susceptible to: (a) spontaneous PVCs No l No (b) spontaneous VT/VF (c) inducible VT/VF Yes 3.

• arrhythmia
• drugs
• electrophysiology
• myocardial infarction
• pharmacodynamics
• physiology
• sudden cardiac death

• The Lankenau Hospital, Philadelphia, USA

  Joel Morganroth, Leonard S. Dreifus, Eric L. Michelson

• School of Veterinary Medicine, University of Pennsylvania, Philadelphia, USA

  E. Neil Moore

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