Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0850803 (anaphylaxis)
 8,092 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 5-lipoxygenase pathway for the oxidative metabolism of unsaturated fatty acids was first recognized less than 10 years ago with the definition of 5-S hydroxy eicosatetraenoic acid (5-HETE) as a product, and its potential biological relevance to inflammation was suggested solely by the modest chemotactic activity of this compound. Major interest in this pathway did not occur until 5 years later when leukotriene B4 (LTB4) was first described, and the slow-reacting substance of anaphylaxis (SRS-A) was chemically defined as three additional leukotriene products of tis pathway: leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4). The possibility that the inhibition of the generation of leukotriene compounds might have a significant effect in limiting a variety of inflammatory disorders was suggested by the extensive pro-inflammatory effects demonstrated by these substances, the demonstration that many inflammatory cells generate leukotrienes, and the finding that the leukotrienes can be detected in complex biological fluids in vivo. Although there is a potential for inhibiting the biological activities of each leukotriene at the receptor level, the present paper will focus completely on the approach of limiting leukotriene synthesis and biological activities through the provision of alternative substrate fatty acids.
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PMID:Pharmacological modulation of leukotriene and platelet activating factor biosynthesis and activities by alternative dietary fatty acids. 265 75

A new series of acrylamide derivatives (7-10) were synthesized. Antiallergic activity of these compounds was evaluated and their structure-activity relationships were examined. Compound 10d, N-[4-(4-diphenylmethyl-1-piperazinyl)butyl]-3-(3-pyridyl)acrylamid e, showed antiallergic activity equivalent or superior to that of ketotifen in the rat passive cutaneous anaphylaxis (PCA) test by oral administration. Compound 10d, unlike ketotifen, had more potent in vitro 5-lipoxygenase inhibitory activity than caffeic acid, whereas its in vitro antihistamine activity was weaker than that of ketotifen. In addition, its inhibitory activity against histamine release from rat mast cells was approximately two-thirds as potent as that of disodium cromoglycate (DSCG). Compound 10d is a promising agent for treating a variety of allergic diseases.
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PMID:Acrylamide derivatives as antiallergic agents. I. Synthesis and structure-activity relationships of N-[(4-substituted 1-piperazinyl)alkyl]-3-(aryl and heteroaryl)acrylamides. 272 Aug 41

A new series of 3-heteroarylacrylamides 2 and 4 was prepared and the inhibitory activities against the rat passive cutaneous anaphylaxis (PCA) reaction and the enzyme 5-lipoxygenase (5-LO) were tested. Most of the compounds exhibited an anti-PCA activity superior to or equivalent to ketotifen and had a 5-LO inhibitory activity. The 3-heteroarylacrylamide derivatives including 3-(3-pyridyl)acrylamides represent a new structural class of compound that exhibits not only an in vivo anti-PCA activity but also an in vitro 5-LO inhibitory activity.
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PMID:Acrylamide derivatives as antiallergic agents. III. Synthesis and structure-activity relationships of N-[4-(4-diphenylmethyl-1-piperazinyl)butyl]- and N-[4-(4-diphenylmethylene-1-piperidyl)butyl]-3-heteroarylacry lamides. 275 77

Synthesis of the cardioactive peptidoleukotrienes depends on the activity of 5-lipoxygenase. It is unclear whether inhibition of endogenous leukotriene biosynthesis can alter vasoconstriction and negative inotropic effects associated with inflammatory states in the heart. In an attempt to study this problem, two 5-lipoxygenase inhibitors, the novel compound RG 6866, N-methyl-4-benzyloxyphenyl acetohydroxamic acid, and AA 861 have been examined in Langendorff-perfused guinea pig hearts undergoing cardiac anaphylaxis and compared to indomethacin and LY 171883, a cyclooxygenase inhibitor and a leukotriene antagonist, respectively. In paced hearts perfused at constant pressure, RG 6866 had no apparent direct effects, infused intracardially at 20 micrograms/min, about 3 mumol/l. LY 171883, but not RG 6866 or indomethacin, antagonized coronary vasoconstriction by exogenous leukotriene D4. When hearts were challenged with antigen (ovalbumin 1 mg i.c.) in the presence of antihistamines, a significant reduction in coronary flow occurred within 30 s which was maximal at 2-3 min, -48 +/- 3%, and persisted for at least 10 min. An initial positive intropic effect was followed by a 25% fall in developed pressure. Both 5-lipoxygenase inhibitors blocked effects of antigen challenge on coronary flow: RG 6866, -4 +/- 3%, AA 861, -11 +/- 3%; reduction at 2 min. The late negative inotropic effect was also blocked. The combined 5-lipoxygenase inhibitor/leukotriene antagonist, RG 5901, and the leukotriene antagonist, LY 171883, were also effective, but not indometacin. These results provide further evidence for the contribution of leukotrienes to cardiac anaphylaxis. More importantly, these findings suggest that 5-lipoxygenase inhibitors can be beneficial in situations where endogenous leukotrienes produce coronary vasoconstriction and myocardial depression.
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PMID:Effects of 5-lipoxygenase inhibition on cardiac anaphylaxis in isolated guinea pig hearts. 281 96

Inbred hyper-reactive rats, actively sensitized to OVA, were anesthetized, cannulated, and ventilated with room air. Tracheal instillation of Ag (OVA) resulted in an elevation of airways pressure (14.4 +/- 0.6 cm H2O). Measurement of biliary peptide leukotriene levels before and after Ag challenge using reverse phase HPLC and RIA techniques showed significant elevations in leukotriene (LT) levels, the amounts released being LTC4 (3.65 +/- 0.78), LTD4 (2.8 +/- 1.11), and N-Ac LTE4 (3.87 +/- 1.15) expressed as ng/100 g of body weight, n = 13. Identification of these metabolites were confirmed by HPLC/RIA techniques and LTC4 was further characterized by UV spectroscopy and its enzymatic conversion by gamma-glutamyl transpeptidase to LTD4. [3H]LTC4 (16 ng) administration by tracheal instillation resulted in a 31.4 +/- 4.3% recovery of radioactivity through the bile over 4 h (n = 3) with the major identified metabolite being N-Ac LTE4. [3H]LTC4 (16 ng) plus synthetic LTC4 (5 micrograms) showed a 30.8 +/- 3.1% recovery through the bile after tracheal instillation (3-h collection, n = 4) with significant amounts of LTC4 as well as N-Ac LTE4 present. [3H]LTC4 administration by the portal vein resulted in a 37.4 +/- 8.8% biliary recovery over 60 min (n = 6), the metabolites present in the bile being LTC4, LTD4, LTE4, and N-Ac LTE4. Pretreatment with the 5-lipoxygenase inhibitor L-656,224 (15 mg/kg, 3.5 h pre-p.o.) before Ag challenge resulted in a significant inhibition (greater than 90%, p less than 0.05) of biliary leukotriene levels in this model. Our study demonstrates that peptide leukotrienes are produced in the anesthetized rat after pulmonary anaphylaxis and that biliary leukotriene measurement is suitable for showing the biochemical efficacy of leukotriene inhibitors in vivo. In vivo tracer experiments suggest that the biliary metabolic profile of the peptide leukotrienes is dependent on the site and levels of release as well as the efficiency of the vascular clearance of the various metabolites.
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PMID:The in vivo production of peptide leukotrienes after pulmonary anaphylaxis in the rat. 284 89

In studies of the role of leukotrienes in inflammatory reactions, the induction of rat reversed passive Arthus pleurisy (a type III allergic reaction) was employed. Increases of exudate volume, vascular permeability, and migration of inflammatory cells in the pleural cavity were observed. The vascular permeability was enhanced biphasically during 0-30 min (early response) and during 3-6 h (late response) after induction of the pleurisy. The infiltration of inflammatory cells, mainly polymorphonuclear leukocytes, into the cavity increased and reached a maximum 6 h after the pleurisy was induced. Leukotriene B4 (LTB4), 5-monohydroxyeicosatetraenoic acid (5-HETE), and slow-reacting substance of anaphylaxis (SRS-A), consisting of LTC4, LTD4 and LTE4, were detected in the exudate by reversed-phase high-performance liquid chromatography during the early response. The contents of LTC4 reached a maximum 10 min after the challenge, followed by a rapid decrease within 1 h. The rise and decay of LTC4 correlated with the increase in vascular permeability during the early phase. AA-861, a 5-lipoxygenase inhibitor, given intrapleurally inhibited the increase in vascular permeability, cell migration, and generation of leukotrienes during the early phase of the pleurisy. These results indicate that products of the 5-lipoxygenase pathway, such as LTC4 and LTB4, may play an important role as chemical mediators in the inflammatory reaction.
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PMID:Role of leukotrienes in rat reversed passive Arthus pleurisy and the effect of AA-861, a 5-lipoxygenase inhibitor. 300 Sep 49

The changes in arterial plasma concentrations of immunoreactive leukotriene B (LTB) were compared after antigen challenge of two groups of sensitized, mepyramine-treated, and mechanically ventilated guinea pigs, one fed a diet enriched with fish oil and the other a control diet enriched with beef tallow. The lung tissue of animals fed a fish oil-enriched diet (FFD) for 9 to 10 wk incorporated eicosapentaenoic acid (EPA) and docosahexaenoic acid to constitute 8 to 9% of total fatty acid content, whereas these alternative fatty acids constituted less than 1% of the total fatty acid content of the lung tissue of animals on a beef tallow-supplemented diet (BFD). The maximum increase after antigen challenge in immunoreactive LTB4 from 0.16 +/- 0.04 ng/ml to 0.84 +/- 0.25 ng/ml in BFD animals and from 0.47 +/- 0.11 to 5.1 +/- 1.4 ng/ml immunoreactive LTB (LTB4 and LTB5) in FFD animals was significant (p less than 0.02) for each. Furthermore, the increase in total immunoreactive LTB in mepyramine-treated FFD animals was significantly greater than the increase in LTB4 in mepyramine-treated BFD guinea pigs at 2 to 8 min after antigen challenge (p less than 0.05). Resolution of arterial plasma immunoreactive LTB from pooled samples by reverse-phase high-performance liquid chromatography demonstrated that the sum of LTB4 and LTB5 in FFD animals exceeded that of LTB4 in BFD animals and that the quantity of LTB4 in the FFD animals was at least as great as that in the BFD animals during anaphylaxis. The products eluting at the retention times of LTB4 and LTB5 exhibited the chemotactic activity of their respective synthetic standards. The combination of indomethacin and mepyramine markedly augmented the antigen-induced increase in arterial plasma immunoreactive LTB4 concentrations in BFD animals, but had no effect on immunoreactive LTB levels in FFD animals. Limited in vivo measurements showing a lesser increase of plasma immunoreactive thromboxane B2 in the FFD relative to the BFD animals during anaphylaxis and ex vivo measurements showing a decreased LTB4-stimulated (cyclooxygenase product-dependent) contractile response of pulmonary parenchymal strips from the FFD relative to the BFD animals provide evidence for blockade in the cyclooxygenase pathway in the FFD animals. The measurements of arterial plasma LTB indicate that indomethacin treatment alone, which inhibits cyclooxygenase activity, and FFD treatment each augment the metabolism of arachidonic acid by the 5-lipoxygenase pathway in animals pretreated with mepyramine.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Enhancement of plasma levels of biologically active leukotriene B compounds during anaphylaxis in guinea pigs pretreated by indomethacin or by a fish oil-enriched diet. 300 14

We examined changes in the levels of eicosanoids in blood and pulmonary lymph of anesthetized sheep undergoing acute anaphylaxis. Within 1-3 min of intravenous antigenic challenge of previously sensitized sheep, there were approximately 7-30-fold elevations in mean arterial plasma levels of thromboxane B2 and 6-ketoprostaglandin F1 alpha, respectively, as measured by RIA. Negligible changes in levels of these cyclooxygenase products were found in both nonsensitized sheep and in sensitized sheep treated with indomethacin before antigenic challenge. In contrast, no changes in levels of sulfidopeptide leukotrienes (SPLT) in pulmonary lymph were detectable by RIA during anaphylaxis in sensitized or nonsensitized sheep, but levels of SPLT in indomethacin-treated sensitized sheep increased more than fivefold above levels in lymph from both other groups of animals. The immunoreactive SPLT in lymph from indomethacin-treated sheep was accounted for as LTE4, as demonstrated by mobility on HPLC and absorbance at 280 nm. These results support the possibility that certain undesirable effects of nonsteroidal antiinflammatory drugs, such as cardiopulmonary reactions in aspirin-sensitive individuals, and impaired renal and cardiac function during therapy with these drugs, may be related in part to augmented synthesis of the 5-lipoxygenase pathway products, especially those of the sulfidopeptide class. Increased LT production could also limit the antiinflammatory effectiveness of these drugs in many disease states.
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PMID:Cyclooxygenase blockade elevates leukotriene E4 production during acute anaphylaxis in sheep. 301 47

Three major lines of evidence support a role of eicosanoids and PAF in shock. Formation of each of the cyclooxygenase metabolites of arachidonate is enhanced at some point during the shock; these metabolites include PGE2, PGF2 alpha, PGI2, and TXA2. Enhanced formation of 5-HETE and the cysteinyl-LTs provides evidence for activation of the 5-lipoxygenase pathway of arachidonate metabolism, and preliminary biochemical evidence suggests that formation of PAF in anaphylactic and endotoxic shock is also enhanced. Second, TXA2, cysteinyl-leukotrienes, and, to an even greater extent, PAF are able to produce shock and death in intact animals. Third, pharmacological studies show that selective antagonists or synthesis inhibitors modify the course of the shock. While any of these lines of evidence may not by itself provide proof for a cause-effect relationship, the data taken together strongly suggest that vasoactive lipids might be involved in fundamental processes in the pathophysiology of shock. However, the role of vasoactive lipids might vary in different shock paradigms, change at various time points during the evolution of the shock, and depend on the species studied. Moreover, while the majority of the reports tend to focus on a specific substance, the metabolism of all of the eicosanoids mentioned, as well as PAF and probably other arachidonate metabolites (e.g. 15-lipoxygenase products such as lipoxins), changes during shock states. This fact probably causes most of the discrepancies in studies using specific antagonists or synthesis inhibitors to modify the state of shock. Thus, while blockade of one mediator might provide some protection, it might not be sufficient to halt or reverse the main course of the pathophysiological process. For example, the increase in vascular permeability, a fundamental phenomenon in trauma, anaphylaxis, or endotoxemia, might be mediated by PAF, LTs, PGs, peptides (e.g. kinins, substance P, CGRP) and amines (e.g. histamine in some species). Attempting to reverse such a complex phenomenon by blocking one specific factor might not be productive unless the specific substance played a key role in generation of the other factors. It seems, however, that while interactions between PGs, LTs, and PAF do occur (31, 32, 70), none of the shock states are crucially dependent on one class of the vasoactive lipids. Therefore, the therapeutic strategy should be based on multiple sites of action, either by drug combinations or multiple actions of a specific drug.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Prostaglandins, leukotrienes, and platelet-activating factor in shock. 303 39

The release of slow reacting substance of anaphylaxis (SRS-A) by anti-immunoglobulin E(IgE; epsilon)-antibody mediated passive peritoneal anaphylaxis (PPA) in rats was investigated immunopharmacologically. A significant amount of SRS-A was released by anti-epsilon-antibody in the peritoneal cavity of rats passively sensitized with IgE. The amount of SRS-A released by anti-epsilon-antibody was about one third less than that released in an anti-gamma-antibody and IgG2a system. The release of SRS-A was initiated at 2 min and reached its maximum 5 to 10 min after the injection of anti-epsilon-antibody. Disodium cromoglycate, tranilast and ketotifen inhibited the release of both SRS-A and histamine caused by anti-epsilon-antibody mediated PPA. Glucocorticoids (hydrocortisone, prednisolone and dexamethasone) also inhibited the release of both mediators. rho-Bromophenacyl bromide inhibited the release of both mediators. AA-861, a potent 5-lipoxygenase inhibitor, inhibited the release of SRS-A but not histamine. Indomethacin slightly enhanced the release of SRS-A and inhibited the release of histamine. Cytarabine resulted in leucopenia and inhibited the release of histamine but not SRS-A during PPA. Dextran sulfate reduced the number of glass adherent peritoneal cells and inhibited the release of SRS-A but not histamine. These results suggest the suitability of anti-epsilon-antibody mediated rat PPA for investigating the effect of anti-allergic agents on the release of SRS-A.
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PMID:Pharmacological studies on the release of slow reacting substance of anaphylaxis during anti-immunoglobulin E antibody mediated passive peritoneal anaphylaxis in rats. 310 86


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