Pharmacological manipulation of the thromboxane pathway in blood platelets.
Interference with blood platelet thromboxane A2 (TxA2)-formation using aspirin has proven to be clinically efficient in the prevention of arterial thrombosis. The protection, however, is far from absolute and during recent years we have witnessed the development of new classes of drugs with more specific impact on TxA2-dependent pathways of platelet activation. Thromboxane synthase inhibitors (TSI) act on the thromboxane synthase, thus preventing the formation of TxA2, and causing a shunting of the prostaglandin cyclic endoperoxide metabolism towards other prostanoids, such as the platelet inhibitory PGD2 and PGI2, the latter when endothelial cells are present that can 'steal' platelet derived cyclic endoperoxides. TSI, however, do not block the formation of the cyclic endoperoxides. Since those products themselves can also act on the TxA2-receptor, the net effect of a TSI will be the result of a complex balance of pro- and anti-aggregatory prostanoids. Known thromboxane receptor antagonists (TRA) inhibit the interaction of both TxA2 and the cyclic endoperoxides with the receptor in a competitive way, but do not change the relative levels of the different prostaglandins formed. The combination of the two actions leads to a stronger influence on in vivo, ex vivo and in vitro laboratory tests as can be seen when a TSI and TRA are used in combination, or when a drug is studied that has both characteristics. Additional data show that such a double-action drug is able to quickly reduce levels of beta-thromboglobulin, a marker for ongoing in vivo platelet activation, in patients with obstructive arterial disease.
Hoet
B
B
Center for Thrombosis and Vascular Research, K.U Leuven, Belgium.
Deckmyn
H
H
Arnout
J
J
Vermylen
J
J
D000818:Animals; D000991:Antithrombins / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D010421:Pentanoic Acids / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D000991:Antithrombins; D007093:Imidazoles; D010421:Pentanoic Acids; D011725:Pyridines; C029166:dazoxiben; D011464:Epoprostenol; D013930:Thromboxane-A Synthase; C060219:ridogrel; D001241:Aspirin