Thromboxane Subject

Certain structural indications of thromboxane A2 biosynthesis inhibition and hence potential therapeutic utility in arterial thrombosis prompted the synthesis of the pyridine prostanoid 544 (Scheme 165) (83TL3291). Brief metalation of 42 followed by DMF quench afforded aldehyde 541, which upon Homer-Emmons chain extension, reduction, and protection gave 542. Having served as a DMG, the bromo function was subjected to metal-halogen exchange, transmetalation (CuCN), and condensation with an iodo allene to furnish the 3,4-disubstituted pyridine 543. The latter was transformed into two derivatives 544 (with and without double bond), which were shown to be effective inhibitors of thromboxane A2. 

Smith AP, Cuthbert MF. The response of normal and asthmatic subjects to prostaglandins E2 and F2alpha by different routes, and their significance in asthma. Adv Prostaglandin Thromboxane Res 1976 1 449-59. 

In 27 postmenopausal subjects who took estradiol for 8 weeks, either alone or in combination with the progestogen norethisterone, there was an increase in plasma thromboxane beta2 concentration, possibly determined by platelet activation, which suggests an increased shortterm risk of thrombosis P-selectin expression was not affected (54). 

In four subjects given a single oral dose of aspirin 37.5 mg before and after a natural stable fish oil daily for 1 week, serum thromboxane A2 fell by 40% after aspirin alone, but by 62% after fish oil + aspirin, and leukotriene B4 rose by 19% after aspirin and fell by 69% after fish oil + aspirin serum prostacyclin fell equally in both cases (18). 

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). 

Abbreviations-. AA, arachidonic acid AMI, acute myocardial infarction AR, aspirin resistance ASA, aspirin CABG, coronary artery bypass graft surgery CAD, coronary artery disease CK-MB, creatinine kinase-MB CVA, cerebrovascular accident EPI, epinephrine HS, healthy subjects LTA, light transmittance aggregometry mm, millimolar PAR, platelet activity ratio PCI, percutaneous coronary intervention PR, platelet reactivity RPFA, rapid platelet function analyzer TXA2, thromboxane A2. 

Platelet aggregation proceeds like an avalanche because, once activated, one platelet can activate other platelets. On the injured endothelial cell a thrombus is formed, which obstructs blood flow. Ultimately, the vascular lumen is occluded by the thrombus as the latter is solidified by vasoconstriction promoted by the release of serotonin and thromboxane A2 from the aggregated platelets and by locally activated thrombin. Thrombin plays a twofold part in thrombus Luellmann, Color Atlas of Pharmacology All rights reserved. Usage subject to terms... 

Subsequently, Qureshi (169) extended his investigations to TRF (Palm Vitee) from palm oil in both animal and human models. In a double-blind crossover study involving 20 hypercholesterolaemic human subjects (serum cholesterol >294 mg/dL), Palm Vitee supplementation was found to cause a significant drop in serum TC and LDL-C. The LDL-associated apolipoprotein Apo B was also decreased by 9-11%. Moreover, Palm Vitee supplementation resulted in a significant decrease (25%) in serum thromboxane and platelet factor PF4 by 16%. Similar cholesterol-lowering effects of Palm Vitee have also been indicated in genetically hypercholesterolemic swine (170). 

Patrignani P, Filabozzi P, Patrono C Selective, cumulative inhibition of plate-let thromboxane production by low-dose aspirin in healthy subjects. J. Clin. Invest 2-1366,1982... 

The initial products derived from lipid peroxidation are subject to decomposition reactions, which may be facilitated by the presence of metals and other one-elec-tron-donating species. In particular, the lipid hydroperoxide and bicyclic endoper-oxide products are susceptible to degradation. Bicyclic endoperoxides undergo acid-catalyzed ring-scission across the endoperoxide to yield the three-carbon dial-dehyde, malondialdehyde (MDA) (Figure 5.1) [2]. MDAis also produced enzymatically from the endoperoxide-metabolizing enzyme thromboxane synthase [3, 4]. MDA is an abundant product of lipid peroxidation and reacts with DNA nucleophiles (see discussion below). 

In a randomised, placebo-controlled study in 24 healthy subjects zileuton 800 mg every 12 hours was given with naproxen 500 mg every 12 hours for 5 days. No clinically significant change was found in the pharmacokinetics of either drug. Naproxen did not affect the inhibitory effect of zileuton on leukotriene B4 levels and similarly zileuton did not affect the inhibitory effect of naproxen on thromboxane B2. The inhibition of the 5-lipoxygenase pathway by zileuton did not appear to worsen the gastrointestinal effects associated with naproxen. No special precautions would seem necessary. ... 

---