Showing papers by "Garret A. FitzGerald published in 1992"
TL;DR: It is suggested that platelets inhibit clot lysis at therapeutic concentrations of t-PA as a consequence of clot retraction and decreased access of fibrinolytic proteins.
110 citations
TL;DR: Two human 12-lipoxygenase enzyme (arachidonate:oxygen 12-oxidoreductase, EC 1.13.11.31)-related genes were characterized from 13 distinct clones isolated from three genomic bacteriophage and cosmid libraries, indicating a highly related gene family.
Abstract: Two human 12-lipoxygenase enzyme (arachidonate:oxygen 12-oxidoreductase, EC 1.13.11.31)-related genes were characterized from 13 distinct clones isolated from three genomic bacteriophage and cosmid libraries. A complete gene (12-lipoxygenase gene 1) spanning approximately 17 kilobases and consisting of 14 exons with sequence matching the cloned platelet/human erythroleukemia (HEL) cell cDNA sequence was identified. Several consensus sites for transcription factors and two potential transcription initiation sites within the 5' flanking region, encompassing the putative promoter region, were identified. A segment of a second, probable pseudogene (12-lipoxygenase gene 2), which displays approximately 85% identity to gene 1 within exon sequences, was also characterized. The presence of two 12-lipoxygenase genes was also substantiated by Southern blot analysis of total human genomic DNA. Exon-intron boundaries for the 12-lipoxygenase genes were located in the identical corresponding positions to the previously cloned human 5-lipoxygenase and rabbit 15-lipoxygenase genes, indicating a highly related gene family. Three lipoxygenase genes (12-lipoxygenase genes 1 and 2, 15-lipoxygenase) were localized to human chromosome 17, whereas the most unrelated lipoxygenase (5-lipoxygenase) was mapped to chromosome 10 by PCR analysis of a human-hamster somatic hybrid DNA panel. 12-Lipoxygenase gene 1 expression could be detected in human erythroleukemia cells, platelets, and human umbilical vein endothelial cells with certainty by reverse transcription-PCR analysis. There was no detectable 12-lipoxygenase gene 2 expression in several tissues and cell lines.
92 citations
TL;DR: The effects of this eicosanoid on renal tissues in vitro and of pharmacological manipulation of TxA2 synthesis and action in vivo suggest that such interventions will provide new drugs for the treatment of human kidney disease.
91 citations
TL;DR: In this paper, a controlled-release formulation containing 75 mg of aspirin, designed to release 10 mg per hour, was developed to inhibit prostaglandin G/H synthase in platelets in the prehepatic circulation.
Abstract: Background. The antithrombotic efficacy of aspirin is attributed to its inhibition of the enzyme prostaglandin G/H synthase, which is necessary for the formation of thromboxane A2 in platelets. Thromboxane A2 is a potent vasoconstrictor and platelet agonist. However, the formation of prostacyclin by vascular endothelium also requires prostaglandin G/H synthase, and prostacyclin exerts opposite effects on platelet function and vascular tone. We wanted to see whether controlled-release aspirin would affect the formation of thromboxane A2 but not prostacyclin by reducing the aspirin concentration that reaches the posthepatic circulation. Methods. A controlled-release formulation containing 75 mg of aspirin, designed to release 10 mg per hour, was developed to inhibit prostaglandin G/H synthase in platelets in the prehepatic circulation. The effects of the controlled-release preparation on plasma levels of aspirin and salicylate, serum levels of thromboxane B2, and urinary dinor metabolites of prosta...
51 citations
TL;DR: The n-3 fatty acids are highly unsaturated fatty acids that are prominent constituents of marine oils as discussed by the authors, which originate in plankton and extend up the food chain from krill to fish, and then may be ingested by man.
24 citations
TL;DR: At plasma levels that exert a potent antiplatelet effect, iloprost did not alter the pharmacokinetics of t-PA in men, and prostacyclin analogues may prove useful as an adjunct to plasminogen activators, particularly in patients at high risk for thrombotic reocclusion.
Abstract: BACKGROUNDCoronary reocclusion complicates the thrombolytic therapy of acute myocardial infarction despite the routine use of aspirin. This is consistent with experimental studies demonstrating that multiple agonists, in addition to thromboxane A2, mediate the platelet activation underlying reocclusion. Consequently, a more potent antiplatelet therapy with a broader spectrum of activity than aspirin may be required in this setting. Prostacyclin and its more stable analogue, iloprost, inhibit platelet aggregation to all known agonists and exert an additional effect over aspirin alone. Experiments in animal models have demonstrated, however, that iloprost increases the clearance of tissue-type plasminogen activator (t-PA) and impairs thrombolysis in vivo. This study examines whether a similar interaction occurs in humans.METHODS AND RESULTSTwelve patients with acute myocardial infarction received t-PA intravenously, 60 mg in the first hour and a maintenance infusion of 13.3 mg/hr for 3 hours. Patients were ...
21 citations
TL;DR: The stimulation of platelets, activation of the coagulation cascade, release of platelet-derived vasoconstrictors, and endothelial dysfunction all contribute to the thrombotic vascular occlusion that results in myocardial infarction.
5 citations
TL;DR: Interest in arachidonic acid has been fostered by the biologically active compounds into which it may be converted; the variety of these compounds has led to the introduction by Corey of the term “eicosanoid” as a generic title.
Abstract: Arachidonic acid (C20:5;n-6) is a polyunsaturated 20 carbon fatty acid that contains 4 double bonds, at the 5, 8, 11 and 14 positions and is the most abundant fatty acid in the phospholipid component of cell membranes. Interest in arachidonic acid has been fostered by the biologically active compounds into which it may be converted; the variety of these compounds has led to the introduction by Corey of the term “eicosanoid” as a generic title.
5 citations
01 Jan 1992
TL;DR: The effect of a novel inhibitor of thromboxane synthase, DP1904, on the baseline and allergen stimulated release of eicosanoids into the bronchoalveolar lavage fluid of sheep was determined.
Abstract: We determined the effect of a novel inhibitor of thromboxane synthase, DP1904, on the baseline and allergen stimulated release of eicosanoids into the bronchoalveolar lavage fluid of sheep. DP1904 was effective in reducing the baseline and allergen stimulated production of TXB2. Inhibition of thromboxane synthase was associated with an increase in other prostaglandin endoperoxide metabolites, PGE2 and PGD2. Diversion of endoperoxide metabolism occurs in sheep lung tissue in vivo.
3 citations