Promising new direction for antifibrillatory drug development

Zosia Chustecka

May 19, 2000

Fri, 19 May 2000 14:11:44

 

1. Proc Natl Acad Sci U S A 2000; 97: 6061-6066

 

Los Angeles, CA - New experimental evidence obtained with the antiarrhythmic drug bretylium "points to a promising new direction for antifibrillatory drug development," according to researchers in California. The experimental work, reported by Dr Alan Garfinkel (University of California School of Medicine, Los Angeles) and Dr Young-Hoon Kim (Cedars-Sinai Medical Center), appears in the May 16, 2000 issue of the Proceedings of the National Academy of Science of the United States of America [1].

A POSSIBLE TRIUMPH IN A FIELD LITTERED WITH FAILED THERAPIES

To date, antifibrillatory drugs have been largely unreliable and unsuccessful, and a spate of clinical trials in recent years have produced results that are disappointing at best and disastrous at worst, the researchers comment. New effective drugs are desperately needed, for ventricular fibrillation (VF) remains the leading cause of cardiac death.

The hope for new, effective drugs stems from a deeper understanding of how bretylium works. Although it is the only approved drug that results in chemical defibrillation, bretylium is not used clinically for ambulatory patients because of its profound autonomic side effects, Garfinkel et al explain. But it can serve as a prototype for developing novel antifibrillatory agents, and they propose that their study provides a template for the screening of potential new drugs.

 

" T he new findings of Garfinkel et al gi ve us good reason to be hopeful "

 

Their study was conducted in isolated swine heart preparations, and shows that bretylium acts in accord with the "restitution hypothesis" of VF. This is a relatively new theory about the origin of wavebreaks (where one wave of electrical excitation splits into two). These wavebreaks are a key event in maintaining VF, and the restitution theory states they are determined by the slope of the action potential duration (APD) restitution curve (in which APD is plotted against the preceding diastolic interval). Garfinkel et al show that bretylium flattens this restitution curve, prevents wavebreak, and so prevents fibrillation. It even converts existing fibrillation, either to a periodic state (ventricular tachycardia (VT), which is much more easily controlled) or to quiescent healthy tissue, they comment. In the six experiments they performed, four showed a transition of VF to VT, whereas the other two had their VF terminated and converted to quiescent, excitable tissue (ie chemical defibrillation).

HYPOTHESIS IS PROMISING BUT NOT SUPPORTED BY ALL STUDIES AND EXPERIMENTS
 

2. Karma A. New paradigm for drug therapies of cardiac fibrillation. Pre-publication copy of a Proceedings of the National Academy of Sciences article 00-1847, a commentary on 99-4926 (Garfinkel et al).

 

In an accompanying commentary by Dr Alain Karma (Department of Physics and Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston)[2], the author points out that not all computer-modeling studies and experiments to date support the restitution hypothesis. "One of the main challenges is to sort out the relative importance of fixed and dynamic heterogeneities in the genesis and maintenance of VF, as well as to elucidate further the nature of the electrical activity inside the ventricular wall. Whether antifibrillatory drugs developed within the new paradigm of the restitution hypothesis can ultimately be successful in controlling VF will depend largely on the results of this quest," he says, but adds that "the new findings of Garfinkel et al give us good reason to be hopeful."



Cited sources

1. Proc Natl Acad Sci U S A 2000; 97: 6061-6066

2. Karma A. New paradigm for drug therapies of cardiac fibrillation. Pre-publication copy of a Proceedings of the National Academy of Sciences article 00-1847, a commentary on 99-4926 (Garfinkel et al).


Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....