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| Researchers have found a drug undergoing separate clinical trials may be effective treating Parkinson's disease symptoms and strengthen the heart, according to animals tests. Photo by hywards/Shutterstock |
By Allen Cone, UPI
A drug undergoing separate clinical trials may be effective treating Parkinson's disease symptoms as well as strengthen the heart, according to animal tests.
ITI-214, a member of a class of compounds known as phosphodiesterase type I inhibitors, is currently in a phase 1/2 clinical study for the treatment of Parkinson's disease and a phase 1/2 clinical study in heart failure.
The heart findings were published Friday in the American Heart Association journal Circulation.
The drug is being developed Intra-Cellular Therapies, Inc., a New York-based company developing treatment of neuropsychiatric and neurodegenerative diseases and diseases of the elderly, including Parkinson's and Alzheimer's disease.
[post_ads]"Our results demonstrate that ITI-214, unlike other pharmacological approaches, increases heart contractility through a novel mechanism of action that may lead to efficacious and safer therapies for patients," principal investigator Dr. David Kass, a professor of cardiology at Johns Hopkins University School of Medicine and a company consultant, said in a Intra-Cellular press release.
Current drugs, including dobutamine, improve the strength of the heart muscle's contractions, but they also dangerous complications such as developing an irregular heartbeat.
The researchers found their new compound works differently than current drugs.
"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," Kass said in a Hopkins press release.
ITI-214, which inhibits the enzyme PDE1, is among the larger phosphodiesterase family of more than 100 such proteins. PDEs break down one or both of two molecules -- cAMP and cGMP -- which are messengers inside cells.
PDE inhibitors stop the breakdown of cAMP and cGMP by causing them to build up so they can influence proteins to alter the cell.
Unlike rats, dogs and rabbits have a PDE1 composition more similar to humans, Kass said.
Six dogs were surgically outfitted with sensors and heart pacemakers. ITI-214 was tested before and after inducing heart failure by running the pacemaker rapidly for approximately three weeks.
Different doses, both orally and intravenously, were used.
With an oral dose of 10 milligrams for every kilograms via a peanut butter-covered pill, ITI-214 increased the amount of blood pumped out by the heart each minute by 50 percent in the healthy hearts and by 32 percent in the failing hearts.
It increased the strength of the heart's contractions by almost 30 percent and dilated the blood vessels. Intravenous administration resulted in similar and more rapid effects.
"We were pretty agnostic about what we would find and didn't necessarily expect anything that novel," Kass said. "To my knowledge, no study had reported increased heart contraction strength from a PDE1 inhibition before."
Dogs with failing hearts had no significant difference in heart rate before and after the drug.
In healthy dogs, the drug also raised their heart rate to a dangerous level -- approximately 40 beats per minute on average.
Researchers were concerned about fatal complications, including developing wildly irregular heartbeats, like with inhibitors of PDE3, including amrinone and milrinone.
"This was the boogeyman in the room," Kass said. "The new drug produced many of the same heart and artery changes that PDE3 inhibitors do, so we naturally worried whether it worked in a similar way and might also have complications. So we tested them side by side."
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In isolated muscle cells from 13 rabbit hearts, the way the two drugs acted differently.
With PDE3 inhibitors, calcium levels rose and the cells contracted more strongly than without the inhibitor. But with PDE1, the cell's calcium levels didn't rise
"Our results show that inhibiting PDE1 produces different changes than blocking PDE3, and so we hope that we can bypass the calcium-mediated and potentially deadly arrhythmias that have plagued PDE3 inhibitors," co-lead author Grace Kim, a postdoctoral fellow in Kass' lab, said. "We are anticipating similar positive benefits on heart function but with much less toxicity."
Kass also said ITI-214 also appears to function differently than dobutamine. In tests of healthy, anesthetized rabbits, it appears the drug might be working on cAMP with a different signaling system in the heart that uses adenosine.
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