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Trial Shows Clot Prevention Drug Safe, Reversible

EKG graphic

(PublicDomainPictures, Pixabay)

18 December 2015. An early-stage clinical trial of an experimental drug to prevent blood clots during heart surgery shows the drug prevents platelet accumulation, while still safe and temporary to prevent excess bleeding. The study by a team at Tufts University Medical Center in Boston and Sinai Hospital of Baltimore appears in yesterday’s issue of the journal Arteriosclerosis, Thrombosis and Vascular Biology published by American Heart Association (paid subscription required).

Researchers led by Tufts medical center biochemist Athan Kuliopulos are seeking new ways to prevent excess bleeding that can occur during heart surgery such as angioplasties that restore blood flow through coronary arteries. These procedures often use drugs to prevent platelets in blood from accumulating into clots during surgery, but those same drugs increase the risk of heavy bleeding, increasing risks to patients.

The team tested a new type of drug for preventing platelet clots, for safety and chemical actions in the body, among individuals with heart conditions or symptoms who could later be candidates for heart surgery. The drug code-named PZ-128 is a class of drugs called pepducins developed by Kuliopulos and colleagues at Tufts medical center. Pepducins first target receptors on surface membranes of cells, but then penetrate inside the cell to block or activate receptors, in this case protease-activated receptor-1 that emits an enzyme promoting platelet accumulations.

The clinical trial tested PZ-128 with a group of 31 individuals in Baltimore, age 43 to 74, either diagnosed with coronary artery disease, or with two or more risk factors for developing the condition, such as high blood pressure, smoking, or diabetes. Participants received infusions of PZ-128 at various dosage levels, with researchers looking primarily for adverse events and monitoring the patients’ vital signs and cardiovascular conditions for 30 days. The study team also looked for changes in platelet levels and clotting characteristics for 7 days following infusions.

The results show PZ-128 affects only the platelet levels of participants in the study, with no other effects of the drug on bleeding, coagulation, or heart functions. Depending on the dose received, PZ-128 inhibits platelet accumulations in 30 minutes to 6 hours following infusions, with the highest doses preventing 80 to 100 percent of platelets from forming clots.

As important, the effects of PZ-128 are temporary, completely clearing the blood of participants in 1 to 8 days. A currently approved drug, vorapaxar, also addresses the protease-activated receptor-1 to prevent formation of platelet clots in people who had heart surgery or with peripheral artery disease, but that drug has long-lasting effects and is not meant to be used in urgent conditions, such as during surgery.

The authors plan an intermediate-stage trial with 600 individuals having angioplasty or with acute blockages of blood flow to the heart. Kuliopulos with Tufts colleague and co-author Lidija Covic founded the company Anchor Therapeutics in Cambridge, Massachusetts that licensed pepducin technology from Tufts for commercialization. Anchor is developing treatments for metabolic disease, inflammation, cardiovascular disease, and regenerative medicine.

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