The Antiallergic Agent Amoxanox Suppresses SRS-A Generation by Inhibiting Lipoxygenase

Saijo, Taketoshi; Makino, Haruhiko; Tamura, Shozo; Kuriki, Hisashi; Ashida, Yuzuru; Terao, Shinji; Maki, Yoshitaka

doi:10.1159/000233978

Cited by 17 publications

(6 citation statements)

References 27 publications

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“…3, A and B, amlexanox was able to repress the release of both FGF-1:␤-gal and p40 Syn-1 in response to temperature stress. The inhibition of FGF-1:␤-gal and p40 Syn-1 release was dependent upon the concentration of amlexanox and was within the concentration range that exhibits pharmacologic effects as an anti-allergic and anti-inflammatory agent (27)(28)(29). Similar amlexanox concentrations were also able to inhibit the release of FGF-1 from FGF-1 NIH 3T3 cell transfectants in vitro (Fig.…”

Section: And B)mentioning

confidence: 68%

S100A13 Is Involved in the Regulation of Fibroblast Growth Factor-1 and p40 Synaptotagmin-1 Release in Vitro

Carreira

LaVallee²,

Tarantini

et al. 1998

Journal of Biological Chemistry

116

112

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We have previously characterized the release of the signal peptide sequence-less fibroblast growth factor (FGF) prototype, FGF-1, in vitro as a stress-induced pathway in which FGF-1 is released as a latent homodimer with the p40 extravesicular domain of p65 synaptotagmin (Syn)-1. To determine the biologic relevance of the FGF-1 release pathway in vivo, we sought to resolve and characterize from ovine brain a purified fraction that contained both FGF-1 and p40 Syn-1 and report that the brain-derived FGF-1:p40 Syn-1 aggregate is associated with the calcium-binding protein, S100A13. Since S100A13 binds the anti-inflammatory compound amlexanox and FGF-1 is involved in inflammation, we examined the effects of amlexanox on the release of FGF-1 and p40 Syn-1 in response to stress in vitro. We report that while amlexanox was able to repress the heat shock-induced release of FGF-1 and p40 Syn-1 in a concentration-dependent manner, it had no effect on the constitutive release of p40 Syn-1 from p40 Syn-1 NIH 3T3 cell transfectants. These data suggest the following: (i) FGF-1 is associated with Syn-1 and S100A13 in vivo; (ii) S100A13 may be involved in the regulation of FGF-1 and p40 Syn-1 release in response to temperature stress in vitro; and (iii) the FGF-1 release pathway may be accessible to pharmacologic regulation.

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Section: And B)mentioning

confidence: 68%

S100A13 Is Involved in the Regulation of Fibroblast Growth Factor-1 and p40 Synaptotagmin-1 Release in Vitro

Carreira

LaVallee²,

Tarantini

et al. 1998

Journal of Biological Chemistry

116

112

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“…Macrophages were ob tained from the peritoneal cavity and purified according to a minor modification of a procedure described previously [9]. Their purity was more than 90%.…”

Section: Purification O F Rat Peritoneal Mast Cells and Rat Resident mentioning

confidence: 99%

“…Chemical structure of O amlexanox. [7][8][9], In particular, this drug strongly inhibits IgEmediated histamine release from rat mast cells; its IC50 value is 0.4 x 10'8 M [8]. In the study reported here, we investigated the effects of amlexanox on the cAMP content of rat peritoneal mast cells to clarify the mechanism by which amlexanox inhibits hista mine release from rat peritoneal mast cells.…”

Section: Introductionmentioning

confidence: 97%

Mechanism of Action of an Antiallergic Agent, Amlexanox (AA-673), in Inhibiting Histamine Release from Mast Cells

Makino

Saijo

Ashida

et al. 1987

Int Arch Allergy Immunol

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100

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Amlexanox markedly inhibits histamine release from rat mast cells. To clarify the mechanism of this inhibition, we investigated the effect of amlexanox on cAMP content, which, when increased, inhibits histamine release in rat peritoneal mast cells. At concentrations of 10^––8––10^––6M, amlexanox or isoproterenol increased the cAMP content of mast cells over that of control cells about 2-fold. When the mast cells were incubated with 10^––8, 10^––7 and 10^––6M of amlexanox combined with 10^––7M isoproterenol, the cAMP contents were synergistically increased 15-, 60- and 88-fold, respectively. 3-Isobutyl-1-methylxanthine (IBMX) at 10^––6––10^––4M increased the cAMP content 1.7––3.8-fold, and a combination of 10^––4M IBMX and 10^––7M isoproterenol synergistically increased the cAMP content 41-fold. A combination of amlexanox and IBMX synergistically increased the cAMP content 19-fold. The increase in cAMP content, when amlexanox and isoproterenol were combined, was transient; it peaked at 0.5 min after the drugs were administered, then decreased to 20–30% of the peak value about 2 min later. Pretreatment of mast cells with amlexanox reduced the effect of the combination of amlexanox and isoproterenol, indicating tachyphylaxis; pretreatment with IBMX had no such effect. The cAMP content of macrophages was also increased by amlexanox, but when combined with isoproterenol or PGE₂, the effect was additive. Amlexanox inhibited cAMP phosphodiesterase in rat mast cells; its IC₅₀ value was 1.4 × 10^––⁵M, and its inhibitory activity was half that of IBMX. These results suggest that amlexanox inhibits histamine release by augmenting the cAMP content in mast cells, and that this augmentation is caused by enhancing the cAMP generation and, additively, by inhibiting cAMP phosphodiesterase.

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“…Amlexanox (AA-673) was developed as an agent to inhibit mediator release from the mast cell. It influences hista mine release and SRS-A generation by inhib iting the lipooxygenase pathway [3,4]. This distinguishes AA-673 from disodium cromoglycate (DSCG) -another inhibitor of me diator release.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of me diator release is the main therapeutic ap proach in handling ocular anaphylactic con dition. Amlexanox (AA-673) 0.25% ophthal mic solution is a newly developed ocular anti-allergic drug which has been reported to inhibit histamine release [3][4][5], and also slow-reacting substance of anaphylaxis (SRS-A), mainly by affecting the lipooxygenase pathway [5], This study was designed to investigate the dynamics of AA-673 in ana phylactic conjunctiva and to evaluate the direct effect on the major mediator of ana phylaxis, histamine, utilizing an in vivo model of ocular anaphylaxis. …”

Section: Introductionmentioning

confidence: 99%

Pharmacodynamics of Amlexanox (AA-673) in Normal and Anaphylactic Rat Conjunctiva and Its Effect on Histamine Concentration

Rankov

Sasaki²,

Fukuda³

1990

Ophthalmic Res

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The pharmacodynamics of Amlexanox (AA-673), an azoxanthone derivative recently developed as an ocular anti-allergic drug, were studied in normal and anaphylactic rat conjunctiva. Ocular anaphylaxis was induced by topical application of dithiothreitol and antigen challenge (egg albumin). The drug concentration was measured at 5, 30, 60 and 120 min after instillation of AA-673 0.25% ophthalmic solution. Histamine concentrations in the pretreated and untreated anaphylactic conjunctiva were compared. In both groups the drug concentration decreased exponentially with time, showing a marked delay in the anaphylactic group. There was a significant difference in histamine values between the pretreated and untreated groups.

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The Antiallergic Agent Amoxanox Suppresses SRS-A Generation by Inhibiting Lipoxygenase

Cited by 17 publications

References 27 publications

S100A13 Is Involved in the Regulation of Fibroblast Growth Factor-1 and p40 Synaptotagmin-1 Release in Vitro

S100A13 Is Involved in the Regulation of Fibroblast Growth Factor-1 and p40 Synaptotagmin-1 Release in Vitro

Mechanism of Action of an Antiallergic Agent, Amlexanox (AA-673), in Inhibiting Histamine Release from Mast Cells

Pharmacodynamics of Amlexanox (AA-673) in Normal and Anaphylactic Rat Conjunctiva and Its Effect on Histamine Concentration

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