ITI-214 Parkinson’s drug may be useful for heart failure patients

A drug in a class of compounds called phosphodiesterase (PDE) type I inhibitors, is currently in clinical trials for Parkinson’s disease, and has shown an increase in the strength on the heart muscle’s contractions in dogs and rabbits.

Researchers at Johns Hopkins Medicine conducted in vivo research on effects of the drug and are now in early clinical trials.

Principle investigator, Professor of Cardiology at the Johns Hopkins University, David Kass said, “Our results are intriguing because so far it’s been largely uncharted territory to come up with a way of increasing contractility that doesn’t ultimately hurt patients.”

There are many drugs currently available that manage and treat heart failure, however those that strengthen the contractions of the heart muscle carry dangerous side effects, such as the development of an irregular heartbeat.

ITI-214, the drug presently in clinical trials, inhibits PDE1 – an enzyme which breaks down other messenger molecules inside the cell. Initially testing the drug on mice, the team decided to test on dogs, rabbits and isolated rabbit heart cells, as the PDE1 enzyme is known to have a vastly different form in humans than in mice.

Dogs and rabbits have a PDE1 composition more similar to humans, commented Prof Kass.

The effects of this drug were tested on dogs before and after inducing heart failure, with the drug at different doses, given both orally and intravenously. The dogs were given at least one day between treatments.

At an oral dose of 10 milligrams per kilogram of body weight, the drug increased the amount of blood pumped out by 50 percent in healthy hearts. In failing hearts, this was reduced to 30 percent. When given intravenously, the drug had a similar, albeit more rapid, effect.

In healthy dogs, heart rate increased by 40 percent, which could be dangerous for heart failure patients; however, researchers found that in dogs with heart failure, no significant difference in heart rate before or after drug administration, was measured.

The team went on to investigate the method of action of the drug in rabbit hearts, comparing it to drugs which cause irregular heartbeats. It was found that these drugs increase levels of calcium, whereas ITI-214 did not, and so works in a different manner.

“Our results show that inhibiting PDE1 produces different changes…and so we hope that we can bypass the calcium-mediated and potentially deadly arrhythmias,” said Dr Grace Kim, co-author of the study.

“We are anticipating similar positive benefits on heart function but with much less toxicity.”

The Centre for Disease Control and Prevention estimates heart failure affects over 5.7 million people in the U.S. and contributes to huge numbers of deaths worldwide.

Researchers suggest the drug may have value for treating heart failure in the future and are now testing the drug in heart failure patients, after successful trials in healthy volunteers.

The team published their findings in Circulation.