Cardiovascular disease Thromboxane

Aspirin (acetylsalicylic acid, Figure 7.9) is a derivative of salicyclic acid, which was first used in 1875 as an antipyretic and antirheumatic. The usual dose for mild pain is 300-600 mg orally. In the treatment of rheumatic diseases, larger doses, 5-8 g daily, are often required. Aspirin is rapidly hydrolysed in the plasma, liver and eiythrocytes to salicylate, which is responsible for some, but not all, of the analgesic activity. Both aspirin and salicylate are excreted in the urine. Excretion is facilitated by alkalinisation of the urine. Metabolism is normally very rapid, but the liver enzymes responsible for metabolism are easily saturated and after multiple doses the terminal half-life may increase from the normal 2-3 h to 10 h. A soluble salt, lysine acetylsalicylic acid, with similar pharmacological properties to aspirin, has been used by parenteral administration for postoperative pain. Aspirin in low doses (80-160 mg daily) is widely used in patients with cardiovascular disease to reduce the incidence of myocardial infarction and strokes. The prophylaxis against thromboembolic disease by low-dose aspirin is due to inhibition of COX-1-generated thromboxane A2 production. Because platelets do not form new enzymes, and COX-1 is irreversibly inhibited by aspirin, inhibition of platelet function lasts for the lifetime of a platelet (8-10 days). 

The current thinking concerning the role of aspirin in the prevention of cardiovascular disease is that it is beneficial in the event of myocardial infarction and stroke. It is effective because, in platelets small amounts of aspirin acetylate irreversibly bind to the active site of thromboxane A2, a potent promoter of platelet aggregation. 

Allman et al. (1995) noted that platelet EPA levels were more than double for individuals fed flaxseed oil compared to sunflower oil group. Platelet EPArarachidonic acid ratio (i.e., marker for thromboxane production and platelet aggregation potential) increased in the flaxseed group, thus a protective effect against cardiovascular disease, over LA-rich oils, would be expected. Their findings support the decreased platelet aggregation observed in hyperlipidemic subjects fed flaxseed (Bierenbaum et al., 1993). 

Dazoxiben, an inhibitor of thromboxane-Aj but not of prostacyclin synthesis, is being evaluated in cardiovascular disease. 

Many of the chronic conditions — cardiovascular disease, diabetes, cancer, obesity, autoimmune diseases, rheumatoid arthritis, asthma, and depression — are associated with increased production of thromboxane Aj (TXAj), leukotriene 84 (LTB4), II ip, lL-6, tumor necrosis factor (TNF), and C-reactive protein. All these factors increase by increases in omega-6 fatty acid intake and decrease by increases in omega-3 fatty acid intake, either ALA or EPA and DHA. EPA and DHA are more potent, and most studies have been carried out using EPA and DHA. 

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

Prostaglandins of the A- and E-series lower the blood pressure. Thromboxanes and carbacyclins are used for the treatment of cardiovascular diseases. Corresponding drugs are e.g. alprostadU (Prostavasin , Schwarz Pharma, Ono Pharmaceutical) or Uoprost (Ilomedin , Bayer/Schering). Prostaglandins of the E- and F-series, like dinoprostone (Minprostin E2 , Pharmacia and Upjohn/Pfizer) and dinoprost (Minprostin F2 , Pharmacia and Upjohn/Pfizer) lead to contractions of the uterine smooth muscle, and are used for termination of pregnancy and in obstetrics. 

As indicated earlier, platelet aggregation due to thromboxanes is important, but overproduction can yield clots, so control of homeostasis is desirable. Much of the elinical interest is in inhibiting this enzyme. Most of the issues are with cardiovascular diseases related to platelet function. Genetic variations have been considered in relation to aspirin tolerance in asthmatics [1698] and acute urticaria induced by nonsteroidal antiinflammatory dmgs [1699]. P450 5A1 signaling relationships with eaneer have also been eonsid-ered [1700, 1701]. 

As mentioned earlier, prostacyclin is a powerful vasodilator and inhibits platelet adhesion and undesired cell growth. Although this view may be overly simplistic, prostacyclins are a counterbalance to thromboxanes in a yin and yang relationship. Thus, the action of P450 8A1 balances that of P450 5A1. Several of the genetic variants (Sect. 7.39.3, vide supra) have been related to diseases, particularly cardiovascular disease... 

Cardiovascular risk increasing evidence is surfacing that NSAID use, but particularly the use of COX-2 selective NSAIDS, elevates the risk of cardiovascular morbidity and mortality. This is especially true in patients with preexisting cardiovascular disease. Thrombotic cardiovascular events are related to a relative increase in thromboxane and a relative diminution in prostacycline. Since most selective as well as nonselec-tive NSAIDS affect this relative imbalance of thromboxane over prostacycline they are all implicated in increasing the risk for thrombotic cardiovascular events [6]. However, naproxen appears to be risk-neutral with regard to cardiovascular events and may in fact be somewhat cardioprotective due to its nonselectivity [7j. 

J. M. Bailey (1979), Prostaglandins, thromboxanes and cardiovascular disease. Trends Biochem. Sci. 4, 68-71. 

The adversary relationship between prostacyclin (PGI2) and thromboxane-A2 (TXA2), which modulates coronary blood vessel caliber [112] and platelet aggregation [113], presents opportunities for therapeutic intervention in cardiovascular diseases. Substances that inhibit TXA2 synthetase or interfere at the TXA2 receptor... 

Attempts to demonstrate disease-reduction benefit with respect to cardiovascular disease by selenium intervention have proven disappointing, despite the theoretical benefit of lipid peroxide removal by GPx and apparently beneficial changes in intermediate markers such as platelet aggregation, vasoconstriction, and thromboxane prostacyclin ratios following supplementation. Further studies of high-risk populations are needed, including a focus on the concerted action by combinations of selenium and vitamin E. 

There are numerous pathological conditions in which derangements in thromboxane biosynthesis are supposed to contribute to the development of the symptoms. The well-known effects of TXA2, bronchoconstriction, vasoconstriction and induction of platelet aggregation, sjuggest the possible involvement of the compound in various pulmonary and cardiovascular events. The roles of thromboxanes in some respiratory diseases as well as in certain platelet disorders have already been discussed. 

However, most pathological conditions, believed to involve derangements in the thromboxane biosynthesis - or in the thromboxane/prostacyclin balance - concern the cardiovascular system. A large number of diseases affecting this organ system have been studied in this respect, i.e. atherosclerosis, myocardial infarction, coronary artery disease with angina of various etiologies, thrombotic disorders, hemostatic defects, circulatory shock, ulcerative diseases, and so on. The possible roles of thromboxane and prostacyclin in the cardiovascular system have been discussed in several reviews, e.g. refs. 32, 33, 348-354. 

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