Thromboxane platelet effects

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). 

Rao AK, Koike K, Day HJ, Smith XB, Holmsen H. Bleeding disorder assodated albumin-dq>endent partial defidency in platelet thromboxane production. Effect of albumin on aradiidcmate metabolism in platelets. Amo J Clin. Path 1985 83 687-696. 

Cardiovascular effects of prostaglandins are more complex. The coagulation system is clearly modulated by platelet-derived thromboxanes, which have procoagulation effects and the anticoagulative effects of endothelial cell-derived prostacyclin. Thromboxanes are clearly COX-1 derived because platelets do not express COX-2. The source of endothelial cell prostacyclin production is less clear with both enzymes expressed and mixed opinions on the relative contribution of the two enzymes. Recent results with Vioxx, a selective COX-2 inhibitor, imply a modest effect on myocardial infarction rate in patients taking the compound but do not define whether this is caused by a change in ratio simply by a lack of platelet effect or that inhibition of endothelial cell prostacyclin also skews the pro- and anticoagulant ratio. 

When hydroxyacids (11 -HETE and 15-HETE) are produced as byproducts of the cyclooxygenase pathway, inhibition is effected by cyclooxygenase inhibitors as indomethacin and flurbiprofen [159,160]. Indomethacin inhibits formation of thromboxane in platelets effectively at 2.8 X 10 M, while no inhibitory effect was seen on the formation of 12-HETE at 2.8 X 10" M [164]. In leukocytes, however, inhibition of lipoxygenases at an indomethacin concentration of lO " M has been reported [245]. 

Animal cells can modify arachidonic acid and other polyunsaturated fatty acids, in processes often involving cyclization and oxygenation, to produce so-called local hormones that (1) exert their effects at very low concentrations and (2) usually act near their sites of synthesis. These substances include the prostaglandins (PG) (Figure 25.27) as well as thromboxanes (Tx), leukotrienes, and other hydroxyeicosanoic acids. Thromboxanes, discovered in blood platelets (thrombocytes), are cyclic ethers (TxBg is actually a hemiacetal see Figure 25.27) with a hydroxyl group at C-15. 

Few areas of organic medicinal chemistry in recent memory have had so many closely spaced pulses of intense research activity as the prostaglandins. Following closely on the heels of the discovery of the classical monocyclic prostaglandins (prostaglandin El, F2, A2, etc.), with their powerful associated activities, for example, oxytocic, blood pressure regulating, and inflammatory, was the discovery of the bicyclic analogues (the thromboxanes, prostacyclin) with their profound effects on hemodynamics and platelet function. More recently, the non-... 

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 ... 

Poland, platelet-inhibiting effects have been observed with bisarylpyridazines of type (70, R = H, Me, Br, Cl R2 = H, Me) [270]. In France, the arylidenedi-hydropyridazines (71) and (72) have been investigated [271, 272]. They have been found to inhibit thromboxane biosynthesis. 

Platelet Inhibition Ginger extract has been found to inhibit platelet aggregation induced by arachidonic acid, epinephrine, ADP, and collagen (Srivastava 1984). The extract s ability to inhibit cyclooxygenase activity and thromboxane levels correlated well with inhibition of platelet aggregation (Srivastava 1984 Mustafa et al. 1993). The type of preparation used also affects platelet inhibition, because roasted and charcoal of ginger were effective, while ether extracts of raw and dried ginger were not (Wu et al. 1993). 

Srivastava KC. (1989). Effect of onion and ginger consumption on platelet thromboxane production in humans. Prostaglandins Leukot Essent Fatty Acids. 35(3) 183-5. 

M) and human ISN (8.3 /platelet thromboxane production below 200 //M [152], Oral activity in GPB (20 mg/kg PO) was seen as well. A series of very similar compounds, where the carboxyl group of (51) was replaced by a wide variety of substituents at various positions of the ring, was disclosed in a patent from Otsuka [153]. In agreement with other SAR reports, replacement of the t-butyl groups by methyls enhanced 5-LO inhibition, but decreased oral activity in CPE. 

Figure 11.31 Effects of endothelial cells, via prostacyclins, and platelets, via thromboxanes, on aggregation of platelets. Aggregation of platelets plays an important role in thrombosis. The drug inhibited COX-2 and hence prostacyclin formation. However, both COX-1 and COX-2 are present in platelets so COX-1 continues to produce thromboxane.

Selective COX-2 inhibitors are ideal agents to combine with chemoradiotherapy for several reasons. First, they have been shown to enhance the effect of various chemotherapeutic agents and radiation on cancer cells. Second, selective COX-2 inhibitors are relatively safe. They do not have severe gastrointestinal toxicity, which is common in many nonselective NSAIDs. For example, celecoxib, a selective COX-2 inhibitor which is currently being used for patients with arthritis, is 375-fold more selective for COX-2 compared to COX-1 (94), and in large randomized, multicenter, placebo-controlled, double-blind trials conducted in patients with rheumatoid arthritis, celecoxib proved to be less toxic than nonselective inhibitors of COX-1 and COX-2, and no more toxic than a placebo (95). Third, high-dose celecoxib (600 mg bid) has no effect on serum thromboxane or platelet function (96). This is obviously important in patients receiving... 

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. 

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