Of thromboxane

The synthesis of thromboxane Bj, the hydrolytic deactivation product of thromboxane A2, provided this material for studies of metabolism and bioactivity, and also for the development of a radioimmunassay. Two different synthetic routes were developed. 

A stereocontrolled route to the native form of thromboxane B2 was carried out starting with a-methyl-D-glucoside (Ref. 3). 

In the first total synthesis of thromboxane A2, lactone 340 is opened by potassium trimethylsilanolate 97 to give the potassium salt 341 [120]. The potassium salt of the methoxymethyl ether of salicylic acid is prepared likewise [121], as are... 

CoUagen-induced activation of a platelet phospholipase A2 by increased levels of cytosolic Ca results in hberation of arachidonic acid from platelet phospho-hpids, leading to the formation of thromboxane A2 (Chapter 23), which in turn, in a receptor-mediated fashion, can further activate phospholipase C, promot-ing platelet aggregation. 

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. 

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). 

Banerjee AK, Peters TJ Experimental nonsteroidal anti-inflammatory drug-induced enteropathy in the rat Similarities to inflammatory bowel disease and effect of thromboxane synthetase inhibitors. Gut 1990 3 i 1358— 1364. 

Virtually all of the above cited studies were uncontrolled and involved acute oral or intravenous ISDN/ISMN administration followed within hours by in vitro platelet activity assessment. In contrast, Sinzinger et al. showed in an uncontrolled trial that oral ISDN (100 mg daily) administered to coronary artery disease patients over four weeks inhibited ADP-induced aggregation in platelet-rich plasma in vitro and reduced the number of circulating platelet aggregates and platelet production of thromboxane... 

The functional significance of thromboxane A2 inhibition by kava is not certain. More needs to be understood about the functions of prostaglandins in the CNS, but given the inhibition of GABAA by thromboxane A2, kava s suppression of thromboxane A2 synthesis could conceivably contribute to its anxiolytic and sedative effects. More research is needed to determine if this mechanism of action is physiologically significant at normal kavalactone concentrations. 

Piccirillo et al. 1994). The effects of thromboxane A2 were examined in nondepressed, normai individuals. Thromboxane A2 was found to have direct CNS effects on hemodynamic, ACTH, and cortisol responses (Cudd 1998). Whether ginger has a significant effect on these processes and whether it has an antistress or antidepressant effect is speculative, but the eicosanoid activities of ginger and relationship to depression warrant further investigation. 

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