Antiplatelet effect of a new inhibitor of thromboxane synthase and thromboxane A2 receptors.
The effect on platelets of a new molecule denominated MED 27 (1-methyl-5-(4-methylbenzoyl)pyrrole-2-acetic acid 2-(theophylline-7-yl)ethyl ester, CAS 104333-87-1) was investigated. In vitro in the rat and using scalar doses of adenosine 5-diphosphate as challenge, the substance was found to be a platelet antiaggregating agent; in human platelets this effect was also found using stimuli such as epinephrine, collagen, arachidonic acid (AA), platelet aggregating factor (PAF) and U46619 (15-hydroxy-11 alpha,9 alpha-epoxymethanoprosta-5,13-dienoic acid). MED 27 ex vivo induced a dose-dependent inhibition of rat platelet aggregation at doses much lower than that of acetylsalicylic acid (ASA). Confirmation of the antiplatelet effect was obtained through in vitro human thromboxane B2(TXB2) synthase inhibition and MED 27 was very active compared with various non-steroidal anti-inflammatories (NSAIDs). These findings were confirmed in vivo in the rat: in this model MED 27 demonstrated dose-dependent and long-lasting activity. The drug was also found to be a TXA2 receptor antagonist and in this case also, the effect was dose-dependent and of long duration. In summary, MED 27 dually inhibits both thromboxane synthase and thromboxane receptors. It compares favourably with other NSAIDs of reference as an antiplatelet agent; this is also true when compared with ASA which, as opposed to MED 27, lacks any effect on TXA2 receptors.
Tubaro
E
E
Medosan Ricerca S.r.l., Albano Laziale, Roma, Italy.
Belogi
L
L
Mezzadri
C M
CM
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000097:blood; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology; D013929:Thromboxane B2 / Q000097:blood / Q000378:metabolism*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D010975:Platelet Aggregation Inhibitors; D017482:Receptors, Thromboxane; C103846:MED 27; D013929:Thromboxane B2; D013806:Theophylline; D013930:Thromboxane-A Synthase; D015232:Dinoprostone