Prostacyclin biosynthesis

Quite recently, a French group reported on the synthesis of 2-substituted 5-arylidene-pyridazinones as represented by the general formula (21, R1 = Ph, 2-ClC6H4 R2 = Ph(CH2)2, PhCO). These compounds were found to exhibit significant dose-dependent analgesic activity (phenylquinone-induced writhing test in mice oral administration) [92]. For a novel type of aminopyridazine-derived inhibitors of prostacyclin biosynthesis, see [93],... 

Most drug treatment in the past focused acutely on the painful vasodilation phase. The efficacy of dihydroergotamine apparently results from its vasoconstrictor effects. NSAIDs inhibit prostacyclin biosynthesis and reduce the intensity, but not the frequency, of attacks.Newer therapies have addressed prevention of attacks. 

Figure 6.5 Percent change in thromboxane A2 and prostacyclin biosynthesis, measured as excretion of their urinary metabolites, 2,3-dinor-thromboxane (Tx) 82 and 2,3-dinor-6-keto-prostaglandin (PG) respectively, in response to a thromboxane A2/prostaglandin endoperoxide receptor antagonist (L636,499) alone and in combination with a thromboxane synthase inhibitor (U63,557A) in the chronic canine model of coronary thrombosis. (Note that occlusion did not occur in dogs treated with the combination therapy)...

A second, potentially confounding, factor is that, at the doses of aspirin used, prostacyclin biosynthesis is markedly depressed. Whether prostacyclin limits platelet activation in this disease is not known. However, prostacyclin... 

In addition to their effects on coronary thrombosis, prostaglandins may play a role in modulating the degree of tissue injury in acute myocardial infarction. Infusion of prostacyclin in the isolated perfused heart limits hypoxic injury independent of its effects on tissue perfusion or platelet function, suggesting that prostacyclin exerts a direct myoprotective effect . Prostacyclin biosynthesis increases markedly following acute myocardial infarction in... 

FitzGerald, G.A., Pedersen, A.K. and Patrono, C. (1983). Analysis of thromboxane and prostacyclin biosynthesis in cardiovascular disease. Circulation, 67, 1174-1175... 

Fitzgerald, G., Smith, B., Pedersen, A.K. and Brash A. (1984). Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N. Engl ]. Med., 310, 1065-1068... 

We conclude that so far eicosapentaenoic acid has proved to be a very poor substrate for the prostaglandin endoperoxide synthetase (cyclooxygenase + peroxidase) in every species or organ tested, irrespective of whether this enzyme is connected with prostaglandin-, thromboxane- or prostacyclin-biosynthesis. 

Platelet homeostasis is maintained by a delicate balance in the transformation of endoperoxide II to thromboxane Ag (reducing the intraplatelet cAMP level which is followed by aggregation) and to prostacyclin (doing the reverse). Prostacyclin biosynthesis takes place in the endothelial cells of arteries, whereas the thromboxanes are synthesized in the collagen. Thus collagen-stimulated platelet aggregation takes place only at points of endothelial damage. 

Whittle BJR (1981) Temporal relationship between cyclooxygenase inhibition as measured by prostacyclin biosynthesis and the gastrointestinal damage induced by indomethacin in the rat. Gastroenterology 80 94—98... 

Mong S, Miller J, Wu H, Clark M, Gleason J, Crooke ST. Leukotriene D4 receptor-mediated synthesis and release of arachi-donic acid metabolites in guinea pig lung induction of thromboxane and prostacyclin biosynthesis by leukotriene D4. J Pharmacol Exp Ther 1986 239 63-70. 

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