Thromboxane , synthesis

All NSAIDs except aspirin inhibit cyclooxygenase reversibly. Inhibition by aspirin, caused by the covalent acetylation of the enzyme, is irreversible. In platelets most NSAIDs block thromboxane synthesis more than that of prostacyclin and the overall effect is therefore inhibition of platelet aggregation. This effect is already noticeable at low doses. Because of the irreversible nature of the enzyme inhibition by aspirin and the fact that in platelets the novo enzyme synthesis is not possible the aggregation inhibitory effects of aspirin last several days. 

Thrombus Formation. The thromboxanes, especially TXA2, cause platelet aggregations that result in blood clot formation.73 It is unclear whether excessive thrombus formation (as in deep vein thrombosis or coronary artery occlusion) is initiated by abnormal thromboxane production. Certainly, inhibition of thromboxane synthesis will help prevent platelet-induced thrombus formation in individuals who are prone to specific types of excessive blood clotting.84... 

Mechanism of NSAID Action Inhibition of Prostaglandin and Thromboxane Synthesis... 

Garlic (Allium sativum) is thought to have several beneficial cardiovascular effects, such as lowering blood pressure and serum lipid, and antithrombotic activity. Garlic oil has been reported to interrupt thromboxane synthesis, thereby inhibiting platelet function. 

Bydlowski, S.P., D Amico, E.A., and Chamone, D.A. 1991. An aqueous extract of guarana (Paullinia cupana) decreases platelet thromboxane synthesis. Braz. J. Med. Biol. Res. 24, 421-424. 

A sequence within the cytoplasmic tail of GpIIb independently activates platelet aggregation and thromboxane synthesis. 

Israds SJ, Odaibo FS, Robertson C, McMillan EM, McNicol A. Defident thromboxane synthesis and respcHise in platelets from premature infants PedialrRes 1997 41 218-23... 

Halushka PV, Rogers RC, Loadholt CB, Colwell JA Increased platdet thromboxane synthesis in diabetes mellitus. J Lab Clin Med 1981 97 87-96... 

VanRollins M. (1995). Epoxygenase metabolites of docosahexaenoic and eicosi >elItaenoic acids inhibit platelet aggregation at concentrations below those affecting thromboxane synthesis. J. Pharmacol. Ejqytl. TherapeuL 274,798-804. 

Aspirin s permanent inactivation of the anucleate platelet is also responsible for the cumulative effect seen with repeated daily dosing below 100 mg (25). Daily administration of 30 to 50 mg of aspirin has been shown to lead to complete suppression of platelet thromboxane synthesis in 7 to 10 days (25, 30, 31). This, in turn, leads to inhibition of platelet aggregation and prolongation of the bleeding time, a clinical test often useful in identifying patients with platelet functional defects for further study and characterization (28,32). 

While aspirin significantly inhibits peripheral prostaglandin and thromboxane synthesis, paracetamol is less potent as a synthetase inhibitor than the NSAIDs, except in the brain, and paracetamol has only a weak anti-inflammatory action. It is simple to ascribe the analgesic activity of aspirin to its capacity to inhibit prostaglandin synthesis, with a consequent reduction in inflammatory edema and vasodilatation, since aspirin is most effective in the pain associated with inflammation or injury. However, such a peripheral effect cannot account for the analgesic activity of paracetamol, which is less well understood. 

Hanley SP, Bevan J, Cockbill SR, Heptinstall S. Differential inhibition by low-dose aspirin of human venous prostacyclin synthesis and platelet thromboxane synthesis. Lancet 1981 1(8227) 969-71. 

PGI2. In vitro stndies have shown that COX-2 expression is up-regulated in endothelial cells by laminar shear stress (73). Furthermore, selective COX-2 inhibitors reduce systemic PGI-2 production in healthy volunteers (74). The clinical implications of these observations are unknown. In theory, COX-2 selective NSAIDs might increase the risk of thromboembolic cardiovascular events because of preferential inhibition of endothehal prostacychn synthesis without corresponding inhibition of platelet thromboxane synthesis, but no rehable data are available on the occurrence of cardiovascnlar events in patients treated with COX-2 selective or non-selective NSAIDs. 

Patients undergoing esophagectomy are at increased risk of acute lung injury, perhaps related to increased concentrations of thromboxane in the postpulmonary circulation. In 38 consecutive patients undergoing esophagectomy, perioperative ketoconazole, which inhibits thromboxane synthesis, reduced the incidence of acute lung injury (4). 

Racemic kavain, a component of kava, has been shown to have antiplatelet effects, presumably owing to inhibition of cyclooxygenase, and thus inhibition of thromboxane synthesis (29). Antiplatelet effects have not been observed in vivo. 

Makheja AN, Vanderhoek JY, Bailey JM. Inhibition of platelet aggregation and thromboxane synthesis by onion and garlic. Lancet 1979 1 781. 

The inhibitors of COX enzymes are called nonsteroidal antiinflammatory drugs (NSAIDs) that are prescribed to relieve pain and fever. They stop prostaglandin and thromboxane production. Acetylsalicylic acid (aspirin) was used for this for many years and it was eventually discovered to acetylate a serine residue involved in the dioxygenase action of cyclooxygenases. A second class of NSAIDs, typified by ibuprofen (commonly called Advil or Motrin), inhibits catalysis by attaching irreversibly to cyclooxygenases. Aspirin and ibuprofen inhibit all prostaglandin and thromboxane synthesis. 

Prostacyclins and thromboxanes, synthesis of 84S449 79T2705. Prostaglandin endoperoxides, thromboxanes, prostacyclins, synthesis and... 

Other investigators have shown that oily garlic extracts, which contain ajoene, are able to inhibit enzymes necessary for arachidonic acid conversion to thromboxane (Srivastava anad Tyagi, 1993). Makheja et al. (1979) demonstrated the effect of garlic oil on platelet thromboxane synthesis. Human and rabbit platelets were incubated with garlic oil, resulting in almost complete... 

An in vitro study demonstrated that the concentrations of an aqueous extract of garlic required to inhibit ADP, epinephrine, and collagen-induced platelet aggregation were much less than those needed to inhibit thromboxane production (Srivastava, 1984). This finding suggests that inhibition of thromboxane synthesis is not the only mechanism by which garlic inhibits platelet aggregation. 

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