Indication:
CHF - congestive heart failure
Summary-
Vesnarinone is a new positive inotropic agent that appear to be effective in the management
of CHF. Because of its unique mechanism of action involving inhibition of cytokines,
vesnarinone may prove to be a useful alternative in the long term management of this
patient population.
It appears to be well tolerated with the exception of the relatively high incidence of
reversible neutropenia. Because of this potentially serious toxicity the clinical utility
of vesnarinone remains to be determined.
Although vesnarinone is currently available in Japan, all research ended in the U S on
July,31, 1996
Pharmacology/ Pharmacokinetics:
Pharmacology-
Vesnarinone, a quinolone derivative , is an oral inotropic agent with very little to no
effect on heart or myocardial oxygen consumption.The mechansm of action is largely
unknown. It may be related to a slight inhibition of PDE III which causes an increase
in cyclic AMP and finally an increase in the inward calcium current. There is also
a reduction in potassium current.
In addition, vesnarinone inhibits the production and release of cytokinases such as
TNF-alpha, IL-1, IL-2, and IFN -gamma. This inhibition may relate directly to its effficay
as an inotropic agent.
Pharmacokinetics-
The pharmocokinetic parameters of vesnarinone were evaluated in 21 healthy volunteers
in a two-phase nonblinded trial. In phase I subjects received vesnarinone in a sequentially
ascending single dose ranging from 7.5mg to 240mg. In phase II, three subjects received
vesarinone 30mg for three days.
The elimination half-life was 44.7 +/- 1.2 hour and the clearance 0.284 +/- 0.018L/hr.
The drug was extensively metabolised with only 11% to 27% (mean 17.7%), being excreted unchanged in the urine.
The authors concluded that elimination of venarinone is dose-dependent and that plasma
concentrations are proportional to the dose administration.
Clinical Studies-
In two small , uncontrolled trials , vesnarinone was administered to a total of 20 patients
with CHF, significant hemodynamic and functional improvement was seen, In a small
placebo controlled study, eight patients with chronic, stable , moderate CHF received
venarinone 60mg/day or placebo for 4 to 8 weeks.
Patients were then crossed over to the alternate treatment group. Symptomatic
improvements was noted in four patients while receiving vesnarinone. In addition,
vesnarinone caused an increased contractility of the left ventricle . Mild to moderate
dyspnea and fatigue on excertion was seen in all patients receiving placebo.
In two placebo controlled trials double-blind trials, a total of 159 patients with CHF were
randomised to receive vesnsarinone 60mg/day or placebo for 12 weeks. In both trials,
there was an improvement in the quality and life and reduction in severity or progression
of heart failure in patients receiving vesnarinone.
The long term use of venarinolne was evaluated in a double-blind trial involving
477 patients with CHF. Patients were randomised to receive vesnarinone 60mg/day or
placebo for 6 months.
Patients receiving vesnarinone experienced an improvement in their quality of life
and reduction in morbidity and mortality when compared to patients receiving
placebo. In the initial design of this trial , patients could also be randomised to receive
vesnarinone 120mg/day. However, the treatment group was stopped after the the first
253 patients had been enrolled because of a significant increase in mortality.
These trials suggest that vesnaronone may have a narrow therapeutic window.
Manufacturer Details