Urine 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). 

Regulation of blood flow and urine processing in the kidney Prostaglandin E (PGE), PGF, PGl (also called prostacyclin), and thromboxanes (TXA)... 

Urinary thromboxane is the end metabolite of thromboxane A2, which is a measure of platelet aggregation. Urinary levels are elevated in patients with unstable coronary disease in keeping with the known participation of platelets in the pathogenesis of CAD. It is difficult to measure, and collecting urine in acute situation is at times problematic. 

HL Hubbard, TD Eller, DE Mais, et al. Extraction of thromboxane B2 from urine using an immobilized antibody column for subsequent analysis by gas chromatography-mass spectrometry. Prostaglandins 33 149, 1987. 

C Chiabrando, A Benigni, A Piccinell, et al. Antibody-mediated extraction negative-ion chemical ionization mass spectrometric measurement of thromboxane-B2 and 2,3-dinorthromboxane B2 in human and rat urine. Anal Biochem 163 255, 1987. 

R Djurup, et al. Rapid, direct enzyme immunoassay of 11-keto-thromboxane B2 urine, validated by immunoaffinity/gas chromatography-mass spectrometry. Clin Chem 39 2470, 1993. 

The PG endoperoxide can be further processed by three metabolic routes (1) the primary prostaglandin pathway, (2) the prostacyclin pathway, and (3) the thromboxane pathway. The two major prostaglandins that are synthesized in the primary pathway are PGF2 and PGE2. The major prostacyclin is PGI2, and thromboxane A2 is the principal thromboxane formed. As mentioned earlier, all the prostaglandins turn over rapidly and their metabolic products can be found in urine and feces. 

Figure 6.8 Urinary, 2,3-dinor-thromboxane (Tx) B2 (normal < 350 pg/mg creatinine) and 2,3-dinor-6-keto-prostaglandin (PG) (normal < 220 pg/mg creatinine) in 6h urine aliquots over 2 days in a patient admitted with unstable angina who subsequently developed an acute myocardial infarction...

Fig. 6. Urine prostaglandin (PG)E2 and thromboxane (Tx)B2 levels. Results are means SEM, n = 7, and are expressed as a percentage of control.

Studies by Diczfalusy et al have shown that oxidation of prostaglandin F2a is primarily peroxisomal. This is concluded from both in vitro and in vivo studies which showed that the major urinary metabolite of prostaglandin F2a i.e. 5a, 7a-dihydroxy-ll-keto-tetranorprosta-l,16-dioic acid was virtually absent in urine from Zellweger patients. Similar studies have resolved the major role of peroxisomes in the P-oxidation of N-acetyl-LTE4 and thromboxane... 

In the thromboxane area the assay problems are even more pronounced (Fig. 2). So far, no compound has been identified, neither in the blood stream, nor in the urine which reliably reflects thromboxane production in vivo and which thus would be the obvious choice for monitoring (Fig. 2). When the thromboxane pathway was discovered, it was first assumed that the stable hydrolysis product, would be a good... 

---