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Chemical Compound Review

AG-G-03279     7-[(1S,3S,4S,5S)-3-[(3S)-3- hydroxyoct-1...

Synonyms: CTK1H0173
 
 
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Disease relevance of thromboxane A2

  • Because most trials using aspirin to reduce TxA2 production have failed to prevent preeclampsia, it is critical to determine whether eicosanoid changes occur before the onset of clinical disease or are secondary to clinical manifestations of preeclampsia [1].
  • These results suggest that renal TXA2 synthesis contributes to the regulation of renal hemodynamics in nonazotemic cirrhotic patients with ascites and avid sodium retention, but it does not seem to affect sodium balance [2].
  • We conclude that the prostanoid excess in gestational trophoblastic disease, as evidenced for the first time in this study, may originate from choriocarcinoma cells, or may be a paraneoplastic phenomenon, and we conclude also that TxA2 excess may contribute to the tumor growth and/or formation of metastases [3].
  • Thromboxane A2 (TXA2) biosynthesis is enhanced in the majority of patients with type IIa hypercholesterolemia [4].
  • We conclude that in patients with chronic renal failure, infusion of conjugated estrogens results in a significant shortening of the bleeding time together with an increase in platelet reactivity, as indicated by an increase of TxA2 and beta-TG concentration in the microvasculature [5].
 

High impact information on thromboxane A2

  • MAIN OUTCOME MEASURES: Excretion of urinary metabolites of PGI2 (PGI-M) and TxA2 (Tx-M) as measured from timed urine collections obtained prospectively before 22 weeks', between 26 and 29 weeks', and at 36 weeks' gestation [1].
  • Peptide mapping studies of in vivo phosphorylated TXA2 receptors demonstrated cGMP mediates phosphorylation of the carboxyl terminus of the TXA2 receptor [6].
  • Nanomolar concentrations of G kinase were found to catalyze the phosphorylation of platelet TXA2 receptors in vitro, but not Galphaq copurifying with the TXA2 receptors in these experiments [6].
  • These data identify TXA2 receptors as cGMP-dependent protein kinase substrates and support a novel mechanism for the inhibition of cell function by NO in which activation of G kinase inhibits signaling by G protein-coupled receptors by catalyzing their phosphorylation [6].
  • We found that MSU crystals, but not calcium pyrophosphate dihydrate (CPPD) crystals, induced COX-2, which correlated with the synthesis of prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) [7].
 

Chemical compound and disease context of thromboxane A2

 

Biological context of thromboxane A2

  • Although cysteinyl leukotrienes (cLTs) and thromboxane A2 (TXA2) have been proposed to be involved in the pathophysiology of asthma, the role of these lipid mediators in propranolol-induced bronchoconstriction (PIB) has not been evaluated in asthmatics [12].
  • This increased TXA2 biosynthesis is frequently accompanied by a stimulation of prostacyclin formation which is one of the most potent inhibitors of platelet aggregation and smooth muscle contraction [13].
  • Since HUS is also associated with platelet activation and consumption, we also studied the urinary excretion of thromboxane A2 (TxA2) metabolites [14].
  • The urinary excretion of both TxA2 hydrolysis product, TxB2, and the major beta-oxidation metabolite, 2,3-dinor-TxB2, were lower than normal in the acute phase of HUS if expressed as absolute values.(ABSTRACT TRUNCATED AT 250 WORDS)[14]
  • To elucidate the relationship between the cyclical reduction of coronary flow (CRCF) and metabolic alterations of TXA2 and PGI2, we attempted to determine the plasma levels of their stable catabolites, thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), in the coronary circulation of 69 dogs [15].
 

Anatomical context of thromboxane A2

  • The synthesis of the prostaglandins (PG), prostacyclin (PGI2), PGE2, and thromboxane A2 (TXA2), has been investigated in actively growing and contact-inhibited bovine aortic endothelial cell cultures [16].
  • 7. The results of the present study suggest that endogenously produced TxA2 enhances contractions to sumatriptan in the human isolated coronary artery [17].
  • 5. The transient contraction produced by high concentrations of TEI 7165 was not observed in cerebral arteries precontracted with 1 nM U46619, a stable analogue of thromboxane A2 (TXA2) [18].
  • 6. Compared to control vascular segments, endothelial denudation did not reduce TxA2 production (with endothelium = 2.56 +/- 1.38 vs. without endothelium = 12.32 +/- 4.94 ng TxB2 g-1 2 h-1), suggesting that the production of TxA2 is not confined to the endothelium [17].
  • These data suggest that administration of a single dose of selective TXA2 synthetase inhibitor prior to coronary ligation modulates platelet function for up to 48 hours and reduces the extent of myocardial injury, which may, in part, relate to decrease in neutrophil accumulation [19].
 

Associations of thromboxane A2 with other chemical compounds

  • They do not reduce the formation of the COX-1-derived thromboxane A2 (TXA2), however, which is both atherogenic and a potent vasoconstrictor [20].
  • The urinary excretion of 11-dehydro-TXB2, largely a reflection of platelet TXA2 production in vivo, was measured by a previously validated radioimmunoassay technique [4].
  • At early stages (24 hr) of injury, inhibition of iNOS using the selective inhibitor L-N6-(1-iminoethyl) lysine (L-NIL) at doses sufficient to reduce urinary excretion of nitrate/nitrite, reduced glomerular synthesis of the prostaglandins PGE2 and PGI2, but had no effect on that of thromboxane A2 (TxA2) [21].
  • Because aerosolized administration of antiasthmatic drugs is effective and safe, this study examined the effect of aerosolized TXA2 receptor antagonist (S-1452) on allergic bronchoconstriction in passively sensitized and mechanically ventilated guinea pigs [9].
  • The data suggest that TXA2 is released during frusemide-induced diuresis in rats, and the released TXA2 has an opposing antidiuretic effect [22].
 

Gene context of thromboxane A2

  • Messenger RNA for PHS-2, PHS-1, TXA2 synthase and cPLA2, which was assessed by reverse transcription-polymerase chain reaction (RT-PCR), was expressed in PMNs without LPS stimulation [23].
  • Despite a high TXAS level, uninduced MEG-01 cells synthesized only a small amount of thromboxane A2 (TXA2) due to limited PGHS-1 or PGHS-2 expressions [24].
  • Injection with the B1R agonist produced a hypotensive response (12+/-1.3 mm Hg), which was further accentuated by TxA2 blockade (21.7+/-4.1 mm Hg) [25].
  • For this reason, the effects of TXA2 might be exacerbated during extended therapy with COX-2 inhibitors, potentially predisposing patients to heart attack and stroke [20].
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1), thereby inhibiting platelet function via blockade of thromboxane A2 (TxA2) formation, and COX-2, the enzyme that mediates inflammatory responses [26].
 

Analytical, diagnostic and therapeutic context of thromboxane A2

References

  1. Prostacyclin and thromboxane changes predating clinical onset of preeclampsia: a multicenter prospective study. Mills, J.L., DerSimonian, R., Raymond, E., Morrow, J.D., Roberts, L.J., Clemens, J.D., Hauth, J.C., Catalano, P., Sibai, B., Curet, L.B., Levine, R.J. JAMA (1999) [Pubmed]
  2. Effects of OKY 046, a thromboxane-synthase inhibitor, on renal function in nonazotemic cirrhotic patients with ascites. Gentilini, P., Laffi, G., Meacci, E., La Villa, G., Cominelli, F., Pinzani, M., Buzzelli, G. Gastroenterology (1988) [Pubmed]
  3. Urinary excretion of degradation products of prostacyclin and thromboxane is increased in patients with gestational choriocarcinoma. Aitokallio-Tallberg, A.M., Jung, J.K., Kim, S.J., Viinikka, L.U., Ylikorkala, R.O. Cancer Res. (1991) [Pubmed]
  4. Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia. Notarbartolo, A., Davì, G., Averna, M., Barbagallo, C.M., Ganci, A., Giammarresi, C., La Placa, F.P., Patrono, C. Arterioscler. Thromb. Vasc. Biol. (1995) [Pubmed]
  5. Effect of conjugated estrogens on platelet function and prostacyclin generation in CRF. Heistinger, M., Stockenhuber, F., Schneider, B., Pabinger, I., Brenner, B., Wagner, B., Balcke, P., Lechner, K., Kyrle, P.A. Kidney Int. (1990) [Pubmed]
  6. Mechanism of platelet inhibition by nitric oxide: in vivo phosphorylation of thromboxane receptor by cyclic GMP-dependent protein kinase. Wang, G.R., Zhu, Y., Halushka, P.V., Lincoln, T.M., Mendelsohn, M.E. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  7. Monosodium urate microcrystals induce cyclooxygenase-2 in human monocytes. Pouliot, M., James, M.J., McColl, S.R., Naccache, P.H., Cleland, L.G. Blood (1998) [Pubmed]
  8. Thromboxane and prostacyclin synthesis in experimental pancreas transplantation. Changes in parenchymal and vascular prostanoids. Johnson, B.F., Thomas, G., Wiley, K.N., Greaves, M., Preston, F.E., Fox, M., Raftery, A.T. Transplantation (1993) [Pubmed]
  9. Effects of aerosol administration of a thromboxane receptor antagonist (S-1452) on experimental asthma in guinea pigs. Saito, M., Fujimura, M., Mizuhashi, K., Shintani, H., Matsuda, T. Allergy (1994) [Pubmed]
  10. Effects of thromboxane synthetase inhibitor (RS-5186) on experimentally-induced cerebral vasospasm. Takeuchi, H., Tanabe, M., Okamoto, H., Yamazaki, M. Neurol. Res. (1999) [Pubmed]
  11. Role of prostaglandins and thromboxane in the control of renal hemodynamics in experimental liver cirrhosis. Leehey, D.J., Uckerman, M.T., Rahman, M.A. J. Lab. Clin. Med. (1989) [Pubmed]
  12. Effect of leukotriene and thromboxane antagonist on propranolol-induced bronchoconstriction. Fujimura, M., Abo, M., Kamio, Y., Myou, S., Ishiura, Y., Hashimoto, T., Matsuda, T. Am. J. Respir. Crit. Care Med. (1999) [Pubmed]
  13. New trends in thromboxane and prostacyclin modulators. Dogné, J.M., de Leval, X., Delarge, J., David, J.L., Masereel, B. Current medicinal chemistry. (2000) [Pubmed]
  14. Renal prostacyclin biosynthesis is reduced in children with hemolytic-uremic syndrome in the context of systemic platelet activation. Noris, M., Benigni, A., Siegler, R., Gaspari, F., Casiraghi, F., Mancini, M.L., Remuzzi, G. Am. J. Kidney Dis. (1992) [Pubmed]
  15. Reduction of prostacyclin synthesis as a possible cause of transient flow reduction in a partially constricted canine coronary artery. Tada, M., Esumi, K., Yamagishi, M., Kuzuya, T., Matsuda, H., Abe, H., Uchida, Y., Murao, S. J. Mol. Cell. Cardiol. (1984) [Pubmed]
  16. Cultured endothelial cells increase their capacity to synthesize prostacyclin following the formation of a contact inhibited cell monolayer. Eldor, A., Vlodavsky, I., Hy-Am, E., Atzmon, R., Weksler, B.B., Raz, A., Fuks, Z. J. Cell. Physiol. (1983) [Pubmed]
  17. Augmented contraction of the human isolated coronary artery by sumatriptan: a possible role for endogenous thromboxane. Maassen VanDenBrink, A., Bax, W.A., Ferrari, M.D., Zijlstra, F.J., Bos, E., Saxena, P.R. Br. J. Pharmacol. (1996) [Pubmed]
  18. Effects of isocarbacyclin, a stable prostacyclin analogue, on monkey isolated cerebral and peripheral arteries. Kawai, Y., Ohhashi, T. Br. J. Pharmacol. (1994) [Pubmed]
  19. Reduction in myocardial neutrophil accumulation and infarct size following administration of thromboxane inhibitor U-63,557A. Wargovich, T.J., Mehta, J., Nichols, W.W., Ward, M.B., Lawson, D., Franzini, D., Conti, C.R. Am. Heart J. (1987) [Pubmed]
  20. Estrogen stimulation of COX-2-derived PGI2 confers atheroprotection. Shah, B.H. Trends Endocrinol. Metab. (2005) [Pubmed]
  21. Regulatory interactions between inducible nitric oxide synthase and eicosanoids in glomerular immune injury. Lianos, E.A., Guglielmi, K., Sharma, M. Kidney Int. (1998) [Pubmed]
  22. Implication of thromboxane in frusemide diuresis in rats. Melki, T.S., Foegh, M.L., Ramwell, P.W. Clin. Sci. (1986) [Pubmed]
  23. Induction of cytosolic phospholipase A2 and prostaglandin H2 synthase-2 by lipopolysaccharide in human polymorphonuclear leukocytes. Zaitsu, M., Hamasaki, Y., Matsuo, M., Miyazaki, M., Hayasaki, R., Muro, E., Yamamoto, S., Kobayashi, I., Ichimaru, T., Miyazaki, S. Eur. J. Haematol. (1999) [Pubmed]
  24. Differential expression of thromboxane A synthase and prostaglandin H synthase in megakaryocytic cell line. Matijevic-Aleksic, N., Sanduja, S.K., Wang, L.H., Wu, K.K. Biochim. Biophys. Acta (1995) [Pubmed]
  25. Mechanisms mediating the vasoactive effects of the B1 receptors of bradykinin. Duka, I., Duka, A., Kintsurashvili, E., Johns, C., Gavras, I., Gavras, H. Hypertension (2003) [Pubmed]
  26. Effects of meloxicam on platelet function in healthy adults: a randomized, double-blind, placebo-controlled trial. Rinder, H.M., Tracey, J.B., Souhrada, M., Wang, C., Gagnier, R.P., Wood, C.C. Journal of clinical pharmacology. (2002) [Pubmed]
  27. Thromboxane synthase inhibitor, UK 38485, prevents renal injury in the rabbit isolated perfused kidney exposed to cold ischemia. Kuzu, M.A., Köksoy, C., Alaçayir, I., Yazar, O., Kuterdem, E. Transplantation (1995) [Pubmed]
  28. Urinary excretion of prostacyclin and thromboxane degradation products in patients with ovarian malignancy: effect of cytostatic treatment. Aitokallio-Tallberg, A., Viinikka, L., Ylikorkala, O. Br. J. Cancer (1989) [Pubmed]
  29. Beneficial effects of iloprost cardioplegia in ischemic arrest in isolated working rat heart. Feng, J., Wu, G., Tang, S., Chahine, R., Lamontagne, D. Prostaglandins Leukot. Essent. Fatty Acids (1996) [Pubmed]
  30. Pharmacological studies on the TXA2 synthetase inhibitor (E)-3-[p-(1H-imidazol-1-ylmethyl)phenyl]-2-propenoic acid (OKY-046). Hiraku, S., Taniguchi, K., Wakitani, K., Omawari, N., Kira, H., Miyamoto, T., Okegawa, T., Kawasaki, A., Ujiie, A. Jpn. J. Pharmacol. (1986) [Pubmed]
 
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