Thromboxanes functions

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-... 

Rats fed a purified nonlipid diet containing vitamins A and D exhibit a reduced growth rate and reproductive deficiency which may be cured by the addition of linoleic, a-linolenic, and arachidonic acids to the diet. These fatty acids are found in high concentrations in vegetable oils (Table 14-2) and in small amounts in animal carcasses. These essential fatty acids are required for prostaglandin, thromboxane, leukotriene, and lipoxin formation (see below), and they also have various other functions which are less well defined. Essential fatty acids are found in the stmctural lipids of the cell, often in the 2 position of phospholipids, and are concerned with the structural integrity of the mitochondrial membrane. 

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). 

Dietary polyunsaturated fatty acids (PUFAs), especially the n-3 series that are found in marine fish oils, modulate a variety of normal and disease processes, and consequently affect human health. PUFAs are classified based on the position of double bonds in their lipid structure and include the n-3 and n-6 series. Dietary n-3 PUFAs include a-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) whereas the most common n-6 PUFAs are linoleic acid, y-linolenic acid, and arachidonic acid (AA). AA is the primary precursor of eicosanoids, which includes the prostaglandins, leukotrienes, and thromboxanes. Collectively, these AA-derived mediators can exert profound effects on immune and inflammatory processes. Mammals can neither synthesize n-3 and n-6 PUFAs nor convert one variety to the other as they do not possess the appropriate enzymes. PUFAs are required for membrane formation and function... 

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. 

Figure 11.26 The structures of the prostaglandin E series produced from three polyunsaturated fatty acids containing 20 carbon atoms but a different number of double bonds. The number of double bonds in the three different acids produces prostaglandins of the E series with a different number of double bonds outside the cyclopentane ring. It is this number which influences the function of the prostaglandin and similarly the function of prostacyclins and thromboxanes (see text). Note, PGEi has one double bond, PGE2 has two double bonds and PGE3 has three double bonds outside the cyclopentane ring.

The fats also have a plastic function as they are included in cell membranes and other cell structures. The central and peripheral nervous systems are rich in lipids. PNFA are included in cell membranes, with their most significant function being the synthesis of cell hormones — prostaglandins. The properties of cell membranes as well as their interaction with external factors depend on the relation of PNFA concentration in cell components. In humans, prostaglandins are created not only in tissues but also in thrombocytes (thromboxanes) and in leucocytes (leukotrienes). The biological action of thrombocytes is extremely variant and depends on PNFA type which are the basis for fatty acid creation. 

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... 

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