Researchers at Queen Mary University of London believe they have found the first indications that a combination of two types of drugs could protect against clots that cause heart attacks and strokes, but at lower doses than when the drugs are prescribed separately.
In an oral presentation on 12 December at the Pharmacology 2017 congress at the Queen Elizabeth II Conference Centre in London, Dr Paul Armstrong, a post doctoral fellow in the Centre for Immunobiology at Queen Mary’s Blizard Institute, said: “The use of lower doses may help to alleviate the adverse side effects that are associated with each of these drugs.”
So far, the research has only been conducted in the lab and in mice, and further research is needed, including clinical trials in patients; however, the drugs tested are already being used to prevent various types of blood-clotting conditions and diseases in humans. “Our research provides the proof of concept that a combination of currently approved drugs at low doses provides a new way to prevent dangerous blood clotting with fewer side effects,” he said.
Dr Armstrong and his colleagues have been studying the relationship between three biological compounds (nitric oxide, prostacyclin and adenosine diphosphate (ADP)) and the processes involved in blood thickening and clotting (thrombosis), in particular their role in platelets.
“Platelets circulate in the blood and stick together when a blood vessel is damaged, but it is also this sticking together when they are not supposed to that lies behind heart attacks and strokes,” he explained. “Nitric oxide and prostacyclin act to increase cyclic nucleotides, which are chemical messengers that keep platelets in a non-sticky state as they circulate in the blood. In contrast, ADP is released upon platelet activation as a stimulatory message to surrounding platelets to become activated and start to clot, thereby amplifying the response. It is this ADP signalling that is targeted by one of the types of drugs – P2Y12 inhibitors – to prevent the blood clotting and, therefore, heart attacks and strokes.”
The researchers treated anaesthetised mice in three ways: either they were given lower than normal doses of the prasugrel, which is a P2Y12 inhibitor, or cinaciguat together with dipyridamole – drugs that act to increase and preserve cyclic nucleotide production – or a combination of all three.
They found that mice treated with the three drugs combined had significantly lower levels of blood clotting and, unlike prasugrel alone, or cinaciguat with dipyridamole, prevented blood vessels from become blocked (occluded) in two-thirds of mice.
“The combination of these three drugs provided good anti-thrombotic protection,” said Dr Armstrong. “Critically, however, this novel combination requires lower doses of each drug than is currently prescribed, thanks to the relationship we had previously discovered between nitric oxide, prostacyclin and ADP.
“These are positive signs but our next step is to test how these drugs work together in healthy volunteers. Importantly, the drugs we have tested are all safe to use in humans so we would hope for any benefits to be translated through to patients in a timely manner.”
The most serious side effect associated with pasugrel is the risk of bleeding; with dipyridamole and cinaciguat, the most serious side effects are related to their effects on lowering blood pressure and causing headaches.
Pharmacology 2017 is the annual congress of the British Pharmacology Society. Pharmacology is the study of the uses, effects and modes of action of drugs.
Abstract no: OB041, “Anti-thrombotic efficacy of cyclic nucleotide modulators in combination with a P2Y12 inhibitor”, Oral communications, cardiovascular and respiratory pharmacology III session, 14.45-16.45 hrs GMT, Tuesday 12 December.
Find out more about studying Pharmacology and Innovative Therapeutics at Queen Mary University of London.
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