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Platelet Adhesion and Aggregation Under Flow using Microfluidic Flow Cells
Published on: October 27, 2009
Trifenagrel: a chemically novel platelet aggregation inhibitor
S L Abrahams1, R J Hazen, A G Batson
1Department of Pharmacology, Burroughs Wellcome Co., Research Triangle Park, North Carolina.
Summary
Trifenagrel is a novel platelet aggregation inhibitor that works by blocking arachidonate cyclooxygenase. It effectively reduces platelet aggregation with minimal gastrointestinal irritation in rodents, unlike aspirin.
Area of Science:
- Pharmacology
- Biochemistry
- Gastroenterology
Background:
- Platelet aggregation is a key process in thrombosis.
- Arachidonate cyclooxygenase (AA) inhibitors are widely used but can cause gastrointestinal (GI) side effects.
- Novel compounds with potent anti-platelet activity and reduced GI toxicity are needed.
Purpose of the Study:
- To characterize the anti-platelet activity and mechanism of action of trifenagrel.
- To evaluate the gastrointestinal safety profile of trifenagrel in preclinical and clinical models.
- To compare the GI effects of trifenagrel with aspirin.
Main Methods:
- In vitro assays measuring platelet aggregation induced by arachidonate (AA) and collagen.
- In vivo studies in guinea pigs and rats assessing oral administration and ex vivo platelet aggregation.
- Human studies evaluating ex vivo platelet aggregation after oral dosing.
- Assessment of gastric mucosal AA cyclooxygenase inhibition and GI irritation in rodents, dogs, and humans.
- Measurement of fecal blood loss in humans.
Main Results:
- Trifenagrel HCl is a potent inhibitor of AA- and collagen-induced platelet aggregation (IC50 = 0.3-3.0 microM).
- Oral administration of trifenagrel in guinea pigs resulted in sustained ex vivo inhibition of platelet aggregation.
- Trifenagrel inhibited the second phase of ADP-induced platelet aggregation in humans for up to 6 hours.
- The mechanism involves reversible inhibition of platelet AA cyclooxygenase.
- Trifenagrel inhibited gastric mucosal AA cyclooxygenase but caused minimal GI irritation in rodents.
- In dogs and humans, trifenagrel caused GI irritation, potentially as a local irritant.
- Compared to aspirin, trifenagrel showed significantly less gastric irritation and fecal blood loss in humans.
Conclusions:
- Trifenagrel is a potent inhibitor of platelet aggregation with a novel mechanism of action.
- It exhibits a favorable gastrointestinal safety profile in rodents, with reduced irritation compared to aspirin in humans.
- Trifenagrel's unique properties may offer a therapeutic advantage for conditions requiring anti-platelet therapy with lower GI risk.
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