Thromboxane inhibition

Thromboxane inhibition in gram-negative sepsis fails to improve survival. In Samuelsson, B., Paoletti, R. and Ramwell, P. (eds.) Advances in Prostaglandin, Thromboxane and Leukotriene Research, Vol. 12, pp. 117-120. (New York Raven Press)... 

Among other heterocyclic compounds tested for thromboxane inhibiting activity, pyridine and some pyridine derivatives were found to be active [133,134]. Pyridine was equipotent to imidazole in this respect. Substitution in the 3- or 4-position with a hydrophobic group increased the inhibitory potency, while substitution in the 2-position rendered the molecule inactive [134,135]. Nicotinic acid (pyridine-3-carboxylic acid) had a weak inhibitory effect on thromboxane synthetase but it was less potent than pyridine [133,136]. 

A number of 7 oxabicyclo[2.2.1]heptane prostaglandin analogues were synthesized and evaluated as potential thromboxane synthetase inhibitors or thromboxane antagonists. Several of the compounds tested were shown to be TXA2 antagonists, judged from platelet aggregation and thromboxane inhibition tests. Two of the compounds also inhibited arachidonic acid induced bronchoconstriction [266]. 

NS AIDs Cyclooxygenases (COX-1, COX-2) l Prostaglandins l Thromboxanes l Sensitization of sensory neurons f Inhibition of spinal neurons Nonselective gastrointestinal ulcers, perforation, bleeding, renal impairment COX-2 thrombosis, myocardial infarction, stroke... 

NSAIDs inhibit cyclooxygenases (COX), the enzymes that catalyze the transformation of arachidonic acid (a ubiquitous cell component generated from phospholipids) to prostaglandins and thromboxanes. Two isoforms, COX-1 and COX-2, are constitutively expressed in peripheral tissues and in the central nervous... 

COX-2 synthesises PGI2 (prostacyclin) and the high incidence of myocardial infarctions with selective COX-2 inhibitors has been attributed to inhibition of COX-2 in vascular tissues. Prostacyclin, made by blood vessel walls, inhibits aggregation of platelets and maintains a balance with thromboxane. Thromboxane, which is released by platelets, promotes clotting. Prostacyclin is synthesised mostly by COX-1, but in humans selective COX-2 inhibition reduces its biosynthesis in vivo. This reduced synthesis may lead to an overactive thromboxane system and increased risk of thromboembolism. 

Aspirin is an important antiplatelet drug that acts by inhibiting production of thromboxane A2. 

SUZUKI T, SAKAI H, IKARI A, TAKEGUCHI N (2000) Inhibition of thromboxane A(2)-induced Cl(-) secretion by antidiarrhea drug loperamide in isolated rat colon. J Pharmacol Exp Ther. 295 233-8. 

Inhibition of phospholipase A2, thromboxane B4 and enhancement of prostacyclin production (Raederstorff et al., 2002 Qureshi and Qureshi, 1992). 

A thrombotic tendency is present in diabetes due to an imbalance between prostacyclin and thromboxane. Lipid peroxides and newly generated free radicals are thought to inhibit the vasodilator and anti-platelet effects of endothelial-derived prostacyclin, but stimulate platelet cyclooxygenase activity, thereby promoting the production of thromboxane A2. This leads to vasoconstriction and platelet aggregation - the concept of peroxide vascular tone (Halliwell and Gutteridge, 1989). 

The advent of COX-2-selective inhibitors has led to unexpected results. By selectively inhibiting the COX-2 isoform, COX-2-selective NSAIDs increase the risk of cardiovascular events in certain patientsP COX-2 is responsible for the production of prostacyclin, a vasodilatory and antiplatelet substance. On the other hand, COX-1 controls the production of thromboxane A2, a vasoconstrictor and platelet aggregator. Selective inhibition of COX-2 results in decreased prostacyclin levels in the face of stable thromboxane A2 levels. An imbalance in the thromboxane A2 prostacyclin ratio ensues, which creates an environment that favors thrombosis. 

The widely used platelet inhibitor aspirin or acetylsalicylic acid, by acetylating the enzyme cyclooxygenase, inhibits platelet function by preventing the formation of thromboxane A2 and the synthesis of prostaglandin I2 (PGI2) (68). Aspirin has been used in combination with other antiplatelet agents such as ticlopidine, which inhibits ADP-induced platelet aggregation (69). 

The plant is known to contain chelerythrine chloride, which inhibits the aggregation of rabbit platelet in vitro via inhibition on thromboxane formation and phosphoinosi-tides breakdown (30). Chelerythrine, which occurs in members of the family Papaver-aceae, has been reported to inhibit the enzymatic activity of protein kinase C and to exert cell-growth inhibitory effect via the induction of apoptosis in numerous cancer cell lines (31,32). What is the topoisomerase activity of chelerythrine ... 

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