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)

Leukotrienes are potent inflammatory mediators synthesized from arachidonic acid (AA) predominately by cells of myeloid origin. The synthesis of these lipids is believed to be dependent not only on the expression of the enzyme 5-lipoxygenase (5-LO), which catalyzes the first steps in the synthesis of leukotrienes, but also on expression of a nuclear membrane protein termed the 5-LO-activating protein (FLAP). To study the relationship of these two proteins in mediating the production of leukotrienes in vivo and to determine whether the membrane protein FLAP has additional functions in various inflammatory processes, we have generated a mouse line deficient in this protein. FLAP-deficient mice develop normally and are healthy. However, an array of assays comparing inflammatory reactions in FLAP-deficient mice and in normal controls revealed that FLAP plays a role in a subset of these reactions. Although examination of DTH and IgE-mediated passive anaphylaxis showed no difference between wild-type and FLAP-deficient animals, mice without FLAP possessed a blunted inflammatory response to topical AA and had increased resistance to platelet-activating factor-induced shock compared to controls. Also, edema associated with Zymosan A-induced peritonitis was markedly reduced in animals lacking FLAP. To determine whether these differences relate solely to a deficit in leukotriene production, or whether they reflect an additional role for FLAP in inflammation, we compared the FLAP-deficient mice to 5-LO-deficient animals. Evaluation of mice lacking FLAP and 5-LO indicated that production of leukotrienes during inflammatory responses is dependent upon the availability of FLAP and did not support additional functions for FLAP beyond its role in leukotriene production.
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PMID:Role of the 5-lipoxygenase-activating protein (FLAP) in murine acute inflammatory responses. 909 80

A novel series of trimethylhydroquinone derivatives was synthesized and evaluated for their anti-lipid peroxidation activity in rat liver microsomes, inhibition of rat basophilic leukemia-1 (RBL-1) cell 5-lipoxygenase and 48 h homologous passive cutaneous anaphylaxis (PCA) activity in rats. 4-[4-[4-(Diphenylmethyl)-1-piperazinyl]-butoxy]-2,3,6-trimethyl phenol (9c) exhibited the ability to inhibit Fe(3+)-ADP induced NADPH dependent lipid peroxidation (IC50 = 5.3 x 10(-7) M), 5-lipoxygenase ((IC50 = 3.5 x 10(-7) M) and PCA reaction (57% inhibition at 100 mg/kg p.o.).
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PMID:Synthesis of trimethylhydroquinone derivatives as anti-allergic agents with anti-oxidative actions. 1007 52

We were interested in RCS (rabbit aorta contracting substance) and SRS-A (slow reacting substance of anaphylaxis) and their involvement in human bronchial asthma. When we started our anti-asthmatic drug research in the 1970's. We synthesized a lot of chemical compounds and eventually discovered that AA-861 inhibited the generation of SRS-A from the lung tissue of actively sensitized guinea pigs. AA-861 was found to be a potent 5-lipoxygenase inhibitor. This compound reduced experimental allergic asthma in guinea pigs, but it is easily metabolized in the body. More recently, we found a novel compound, AA-2414 (seratrodast), which is not metabolized in the body. AA-2414 proved to be not a 5-lipoxygenase inhibitor, but a thromboxane A2 (TXA2) receptor antagonist. Seratrodast is the first receptor antagonist that is being developed as an anti-asthmatic drug. Seratrodast inhibits both immediate-, late asthmatic responses in guinea pigs, and also reduces airway hyperresponsiveness in dogs. The anti-asthmatic action of seratrodast in animal models indicates that the drug should be of use in the treatment of human asthmatics. In clinical studies, seratrodast showed a marked effect to improve clinical parameters in bronchial asthma. It is also reported that seratrodast is free from harmful aftereffects. Clinical trials are under way in the US.
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PMID:[Thromboxane A2 antagonist--discovery of seratrodast]. 1037 98

Novel benzimidazole derivatives were synthesized and their pharmacological activities were examined. These compounds showed a good suppressive action on histamine release from rat peritoneal mast cells produced by antigen-antibody reaction, an antagonistic action on guinea pig ileum contraction caused by histamine, an inhibitory action on 5-lipoxygenase in rat basophilic leukemia-1 (RBL-1) cells, and a preventive action on NADPH dependent lipid peroxidation induced by Fe3+-ADP in rat liver microsomes. In addition, 1-[2-[2-(4-Hydroxy-2,3,5-trimethylphenoxy)ethoxy]-ethyl]-2-(4-meth yl-1-homopiperazino)-1H-benzimidazole difumarate (BOM1006) exhibited a dose dependent suppressive action on 48 h homologous passive cutaneous anaphylaxis (PCA) reaction in rats orally administered the drug.
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PMID:Synthesis and biological activities of novel antiallergic agents with 5-lipoxygenase inhibiting action. 1072 60

Symmetrical bis(quinolylmethoxyphenyl)alkylcarboxylic acids were investigated as inhibitors of leukotriene biosynthesis and 4, 4-bis(4-(2-quinolylmethoxy)phenyl)pentanoic acid sodium salt (47.Na) met our design parameters for a drug candidate (ABT-080). This compound was readily synthesized in three steps from commercially available diphenolic acid. Against intact human neutrophils, 47.Na inhibited ionophore-stimulated LTB(4) formation with an IC(50) = 20 nM. In zymosan-stimulated mouse peritoneal macrophages producing both LTC(4) and PGE(2), 47.Na showed 9000-fold selectivity for inhibition of LTC(4) (IC(50) = 0.16 nM) over PGE(2) (IC(50) = 1500 nM). Preliminary pharmacokinetic evaluation in rat and cynomolgus monkey demonstrated good oral bioavailability and elimination half-lives of 9 and 5 h, respectively. Pharmacological evaluation of leukotriene inhibition with oral dosing was demonstrated in a rat pleural inflammation model (ED(50) = 3 mg/kg) and a rat peritoneal passive anaphylaxis model (LTB(4), ED(50) = 2.5 mg/kg; LTE(4), ED(50) = 1.0 mg/kg). In a model of airway constriction induced by antigen challenge in actively sensitized guinea pigs, 47.Na dosed orally blocked bronchoconstriction with an ED(50) = 0.4 mg/kg, the most potent activity we have observed for any leukotriene inhibitor in this model. The mode of inhibitory action of 47.Na occurs at the stage of 5-lipoxygenase biosynthesis as it blocks both leukotriene pathways leading to LTB(4) and LTC(4) but not PGH(2) biosynthesis. However, 47.Na does not inhibit 5-lipoxygenase catalysis in a broken cell enzyme assay; therefore it is likely that 47.Na acts as a FLAP inhibitor.
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PMID:Symmetrical bis(heteroarylmethoxyphenyl)alkylcarboxylic acids as inhibitors of leukotriene biosynthesis. 1096 51

Leukotriene C(4) synthase (LTC(4)S), the terminal 5-lipoxygenase pathway enzyme that is responsible for the biosynthesis of cysteinyl leukotrienes, has been deleted by targeted gene disruption to define its tissue distribution and integrated pathway function in vitro and in vivo. The LTC(4)S (-/-) mice developed normally and were fertile. LTC(4)S activity, assessed by conjugation of leukotriene (LT) A(4) methyl ester with glutathione, was absent from tongue, spleen, and brain and > or = 90% reduced in lung, stomach, and colon of the LTC(4)S (-/-) mice. Bone marrow-derived mast cells (BMMC) from the LTC(4)S (-/-) mice provided no LTC(4) in response to IgE-dependent activation. Exocytosis and the generation of prostaglandin D(2), LTB(4), and 5-hydroxyeicosatetraenoic acid by BMMC from LTC(4)S (-/-) mice and LTC(4)S (+/+) mice were similar, whereas the degraded product of LTA(4), 6-trans-LTB(4), was doubled in BMMC from LTC(4)S (-/-) mice because of lack of utilization. The zymosan-elicited intraperitoneal extravasation of plasma protein and the IgE-mediated passive cutaneous anaphylaxis in the ear were significantly diminished in the LTC(4)S (-/-) mice. These observations indicate that LTC(4)S, but not microsomal or cytosolic glutathione S-transferases, is the major LTC(4)-producing enzyme in tissues and that its integrated function includes mediation of increased vascular permeability in either innate or adaptive immune host inflammatory responses.
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PMID:Attenuated zymosan-induced peritoneal vascular permeability and IgE-dependent passive cutaneous anaphylaxis in mice lacking leukotriene C4 synthase. 1131 40

Leukotrienes (LTs) have been known in the field of immunology since the 1930s. At that time they were referred to as the slow reacting substance of anaphylaxis. However, they were not characterised until the 1980s, when they were noted to be formed during the breakdown of arachidonic acid (AA) by the enzyme 5-lipoxygenase (5-LO). There are five types of LT: LTA(4), LTB(4), LTC(4), LTD(4) and LTE(4). LTs are so called because the molecules were originally isolated from leukocytes and their carbon backbones contain 3 double bonds in series (a trion). This structural information provided the key to the oxidative pathway of lipometabolism, known as the 5-LO pathway. LTs are classified as inflammatory mediators. They are produced by a number of cell types, particularly mast cells, eosinophils, basophils, macrophages and monocytes. With the identification disorders associated with inflammatory pathways, such as asthma, allergic rhinitis and paranasal sinusitis, the LTs have been implicated in the pathogenesis of these conditions and have become targets for therapeutic modulation. In this review we will look at the biological effects of LTs, how they are formed, their role in asthma patients, the first therapeutic use of LT inhibitors and finally LTs with reference to the paranasal sinus areas.
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PMID:The role of leukotriene inhibitors in allergic rhinitis and paranasal sinusitis. 1177 31

The antiallergic effects of ardisiaquinone A, a potent 5-lipoxygenase inhibitor, were examined. Pretreatment with ardisiaquinone A (0.1-10 microM) significantly inhibited compound 48/80-induced production of cysteinyl-leukotrienes (cys-LTs; LTC4, LTD4 and LTE4) in rat peritoneal mast cells, but not histamine release. The IC50 value was 5.56 microM. Pre-administration with ardisiaquinone A (0.1-1 mg/kg, s.c.) dose-dependently inhibited rat homologous passive cutaneous anaphylaxis (PCA) and the maximal inhibitory ratio was 22.3 +/- 3.9% at the dose of 1 mg/kg. Ardisiaquinone A (1-5 mg/kg, s.c.) dose-dependently prevented the allergen-induced increase of tracheal pressure in ovalbumin-sensitized guinea pigs, especially during the late phase. In conclusion, the findings of this study show that 5-lipoxygenase inhibitor ardisiaquinone A partially attenuates the allergen-induced increases of vascular permeability and tracheal pressure via the inhibition of cys-LTs production in mast cells.
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PMID:Antiallergic effect of ardisiaquinone A, a potent 5-lipoxygenase inhibitor. 1182 21

Non steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used for inflammation therapy. The major drawback in using the NSAIDs is in their tendency to cause gastrointestinal toxicity. Since the roles of arachidonic acid (A.A) metabolites, as leukotrienes (Lts), prostaglandins (PGs) and thromboxanes (TXA(2)) as mediators of the inflammatory reaction were clarified, much effort has been made to develop inhibitors of the production of these chemical mediators as anti-inflammatory agents. These mediators also play important roles in some inflammatory or allergic diseases, acting either alone or in combination and inhibitors of 5-lipoxygenase (5-LOX) and/or cyclooxygenase isoforms 1,2 (COX-1,2) may be useful for the treatment of asthma, psoriasis and rheumatoid arthritis. Leukotrienes, the products of 5-LOX metabolism have been associated with immediate hypersensitivity reactions, anaphylaxis and asthma. In addition, active oxygen species (AOS) including superoxide anion (O(2)(-)), hydrogen peroxide, hydroxyl radical and ferric radical, mediate cell damage in a variety of pathophysiological conditions and are responsible for oxidative injury of enzymes, lipid membranes and DNA in living cells and tissues. Prostaglandins and leukotrienes in the arachidonate pathway linked with lipid peroxidation may amplify the oxidative damage. Nitric oxide (NO) plays also a role as an effector in inflammation, since PG and NO thought to be important in maintaining mucosal integrity. Dual or selective inhibitors, specific receptor antagonists, AOS scavengers, and NO donors have been under development for therapeutic application. Several classes of inhibitors have been identified and at least 12 major chemical series are known to affect PGs production directly. In this review, we account on our research work concerning NSAIDs combined with a reference of the recent literature.
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PMID:Non steroidal anti-inflammatory and anti-allergy agents. 1186 Mar 51

Arachidonic acid metabolism via 5-lipoxygenase gives rise to a group of biologically active lipids known as leukotrienes: leukotriene B(4), which is a potent activator of leukocyte chemotaxis, and cysteinyl leukotrienes (leukotriene C(4), D(4)and E(4)) which account for the spasmogenic activity previously described as slow-reacting substance of anaphylaxis. The biological actions of leukotrienes and the observations that leukotrienes are synthesised in the lung following antigen provocation and are elevated in asthma, stimulated considerable activity in the pharmaceutical industry to find drugs that modulate the synthesis or actions of leukotrienes. Three cysteinyl leukotriene antagonists (zafirlukast [Accolate], montelukast [Singulair] and pranlukast) and one 5-lipoxygenase inhibitor (zileuton) have received regulatory approval for the treatment of asthma. The clinical data obtained from using these drugs are generally consistent and complimentary. As a class the leukotriene modulators produce a rapid improvement in lung function after the first oral dose. Lung function improvements are maintained on chronic administration and are associated with reductions in a variety of asthma symptom scores. All of the available data are consistent with the hypothesis that all the leukotriene modulators exert their clinical benefit primarily through interference with cysteinyl leukotrienes. There are no compelling clinical data for an additional contribution by leukotriene B(4)in human asthma. In other respiratory conditions such as COPD, which are characterised by pronounced neutrophil infiltration, it may be that the chemotactic properties of leukotriene B(4)are more important and therefore evaluation of 5-lipoxygenase inhibitors in this condition is warranted. The introduction of the leukotriene modulators into clinical practice is the culmination of over 60 years of research since the initial discovery of the slow-reacting substances. The leukotriene modulators, and in particular the cysteinyl leukotriene antagonists, provide respiratory physicians with an oral therapeutic option and have set an efficacy standard which new oral anti-inflammatory approaches will have to beat.
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PMID:Leukotrienes in respiratory disease. 1205 25


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