TORONTO — Interim data suggest that oxypurinol, a xanthine oxidase inhibitor, significantly increased left ventricular ejection fractions in patients with heart failure after just 4 weeks, Joshua Hare, M.D., reported at the annual meeting of the Heart Failure Society of America.
These are early and provocative data, but they are early human data with the chronic use of oxypurinol, “and I think it's very exciting,” Dr. Hare said.
Dr. Hare, director of the heart failure/cardiac transplant program at Johns Hopkins University in Baltimore, is a consultant for and has a financial interest in Cardiome Pharma Corp., which is developing the drug.
Xanthine oxidase is upregulated in heart failure, and is clearly a source of oxidative stress, Dr. Hare said. Targeting xanthine oxidase represents a potential new treatment strategy for patients with heart failure.
Oxypurinol is the active metabolite of allopurinol, a drug that has been used since the early 1960s to suppress uric acid formation in patients with gout. Initial clinical results in nine patients with heart failure showed that allopurinol improved cardiac mechanical efficiency by 40% and cardiac pressure efficiency by 22%.
Oxypurinol may improve myocardial contractility by increasing sensitization of the cardiac myofilaments to calcium. Moreover, it may do so without increasing myocardial oxygen consumption. Most inotropic drugs improve myocardial contractility, but they also increase myocardial oxygen consumption, which worsens the myocardial ischemia and possibly leads to arrhythmias.
“We've traditionally thought of oxidative stress as something that destroys cell membranes and proteins, but as we are clearly uncovering now, there is a critical role for free radicals in nitric oxide and signaling,” Dr. Hare said. “And it may be this signaling element that is the target of our therapy.”
In a trial conducted in Argentina, 48 patients with heart failure were enrolled in a phase II, proof-of-principle study, and randomized to placebo or 600 mg of oxypurinol daily added to best conventional therapy for 4 weeks.
Interim data from the trial, led by Horatio Cingolani, M.D., of the National University of La Plata (Argentina), showed that left ventricular ejection fractions significantly increased from 35% to 38% in the oxypurinol group and decreased from 30% to 29% from baseline in the placebo group. There was no statistical difference in 6-minute walk scores from baseline between the two groups.
Two ongoing studies should be completed this year, including a phase II trial of oxypurinol infusions in patients with heart failure of ischemic etiology and a 24-week, phase II/III trial of oral oxypurinol in 400 patients with heart failure.