Precautions for Use and Adverse Effects of Vesnarinone
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Drug Safety 2004; 27 Suppl. 1: 11-18 0114-5916/03/0001-0011/$30.00/0 & Adis Data Information BV 2004. All rights reserved.
Precautions for Use and Adverse Effects of Vesnarinone Potential Mechanisms and Future Therapies Barry D. Bertolet Cardiology Associates of North Mississippi, Tupelo, Mississippi, USA
Abstract
This article reviews the precautions and adverse effects associated with vesnarinone use, and the potential mechanisms responsible for these complications as well as suggested treatment strategies. Vesnarinone, a quinolinone derivative, improves the haemodynamics and quality of life in patients with congestive heart failure (CHF); however, it is associated with the adverse effects of increased sudden cardiac death and neutropenia. These adverse effects have limited the application of vesnarinone to the general population but perhaps with continued research into vesnarinone-induced neutropenia and advances in arrhythmia management, the risk/ benefit ratio of vesnarinone may become favourable. For now, the use of vesnarinone should be limited to patients with CHF who have demonstrated a poor response to other cardiac medications and devices. These patients should be closely monitored for both cardiac and non-cardiac adverse effects.
Vesnarinone (OPC-8212), a quinolinone derivative, was introduced in the late 1980s as a positive inotropic agent for symptomatic left ventricular dysfunction. While vesnarinone improved shortterm haemodynamics, congestive symptoms, and quality of life, mixed survival results were noted in [1-3] Consistent across all the the clinical trials. clinical trials, however, was the risk of neutropenia. This article reviews the precautions and adverse effects associated with vesnarinone use, and the potential mechanisms responsible for these complications as well as suggested treatment strategies. 1. Precautions for Vesnarinone Use Vesnarinone has been primarily studied in symptomatic New York Heart Association (NYHA) class III or IV heart failure patients who have failed conventional heart failure medical therapy, including ACE inhibitors, diuretics, digoxin, and vasodilator therapy. These patients had
no acute ischaemic symptoms, overt arrhythmias, or reversible causes of heart failure. After the recognition of agranulocytosis as a possible vesnarinone adverse effect, patients at a higher risk of neutropenia were also excluded from the studies. The various mechanisms of action of vesnarinone result in a slowing of the heart rate, prolongation of the action potential, and suppression of the delayed outward potassium current. As a precaution, patients receiving -blockers, antiarrhythmic medications, and those requiring higher dose digoxin, were also excluded from the studies. The exclusion criteria from the larger clinical trials are listed in table I. Vesnarinone requires the hepatic cytochrome P450 (CYP) system for conversion into its primary [4] metabolite, OPC-18692. While the clinical implications are undetermined, drugs that affect the CYP pathway (table II) should be used wi
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