Focused antithrombotic therapy: novel anti-platelet salicylates with reduced ulcerogenic potential and higher first-pass detoxification than aspirin in rats.
The use of aspirin as an anti-platelet drug is limited by its propensity to induce gastric injury and by its adverse effect on vascular prostacyclin formation. Two phenolic non-steroidal anti-inflammatory drugs (salicylic acid and diflunisal) were modified by esterification with a series of O-acyl moieties. The short-term ulcerogenic in vitro and in vivo anti-platelet properties, pharmacodynamic profiles, and extent of hepatic extraction of these phenolic esters were compared with aspirin (acetylsalicylic acid). The more lipophilic esters (longer carbon chain length in O-acyl group) show significantly less gastrotoxicity in stressed rats than does aspirin after a single oral dose. The in vitro and in vivo anti-platelet studies show that these phenolic esters inhibited (1) arachidonate-triggered human platelet aggregation and (2) thrombin-stimulated rat serum thromboxane A2 production by platelets in the clotting process almost as effectively as aspirin. The hepatic extractions of these O-acyl derivatives are significantly higher than those of aspirin. The pharmacodynamic studies show that these O-acyl derivatives of salicylic acid and diflunisal probably bind to, or combine with, the same site on the platelet cyclooxygenase as aspirin. Replacing the O-acetyl group with longer chain O-acyl moiety in this series of phenolic esters markedly reduced the potential of these agents to induce short-term gastric injury but did not lessen their activity as inhibitors of platelet aggregation. These non-acetyl salicylates may therefore represent a novel class of anti-platelet drugs with less ulcerogenic potential.
Hung
D Y
DY
Department of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, Australia.
Mellick
G D
GD
Masci
P P
PP
Whitaker
A N
AN
Whitehouse
M W
MW
Roberts
M S
MS
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000473:pathology; D001241:Aspirin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D004061:Diflunisal / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D008099:Liver / Q000378:metabolism*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013256:Steroids; D013276:Stomach Ulcer / Q000517:prevention & control*; D013928:Thromboxane A2 / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D013256:Steroids; D013928:Thromboxane A2; D004061:Diflunisal; D001241:Aspirin