Effect of a novel 5-lipoxygenase inhibitor, E6080 on bronchospasm, airway cellular infiltration and leukotriene production in guinea pigs

Tsunoda, Hajime; Katayama, Satoshi; Sakuma, Y.; Tanaka, Shigeru; Tsukidate, Kazuo; Abe, S.; Yamatsu, Isao; Katayama, Kouichi

doi:10.1016/0952-3278(91)90066-e

Cited by 8 publications

(9 citation statements)

References 26 publications

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“…Data from in vivo studies suggest that E6080 is a potent 5-lipoxygenasc inhibitor, as already reported [12][13][14], In this in vitro study, it was confirmed that E6080 inhibited the Ag-induced LT release from passively sensitized guinea-pig and human lung fragments and from human basophils, as well as the calcium ionophore A23187-induced LT release from human PMNs and the LTC4 release from rat alveolar macrophages, exposed to phagocytotic stimulation with silica particles.…”

Section: Discussionsupporting

confidence: 65%

“…human platelet 12-lipoxygcnase, soybean 15-lipoxygenase and sheep seminal vesicle cyclooxygenase, were more than 10 pM (data not shown). Furthermore, an important metabolite of the 5-lipoxygenase pathway is LTB4 which is a powerful chemotactic and chemokinetic agent [10,11], It has been reported that E6080 inhibited airway infiltration of neutrophils and eosinophils 6 h after Ag inhalation in passively sensitized guinea-pigs [12]. In the present studies, E6080 inhibited LTB4 generation from human lung fragments and human PMNs.…”

Section: Discussionsupporting

confidence: 50%

“…Data from in vivo studies suggest that E6080 is a potent 5-lipoxygenase inhibitor, as already reported [12][13][14]. In this study, we confirmed the in vitro effects of a newly de veloped 5-lipoxygenase inhibitor, E6080 [6-hydroxy-2-(4-sulfamoylbenzylamino)-4,5,7-trimethylbenzothiazole hy drochloride], on LT release and compared them with those of AA861 [2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-l, 4-benzoquinone], a specific and potent 5-lipoxygenase inhibitor [15,16].…”

Section: Introductionsupporting

confidence: 51%

“…If this is the case, selective inhibition of LT formation or selective antagonism of the action of these mediators would be expected to have bene ficial effects in asthmatic patients. It is conceivable that 5-lipoxygenase inhibitors would be more beneficial for asth matic patients than LT antagonists since 5-lipoxygenase inhibitors could inhibit the generation of both types of LTs (LTB4 and cysteinyl-LTs) [12], whereas LT receptor antag onists could antagonize cysteinyl-LTs, but not LTB4, at the same time.…”

Section: Introductionmentioning

confidence: 99%

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Effects of the New 5-Lipoxygenase Inhibitor E6080 on Leukotriene Release in vitro

Sakuma¹,

Katayama²,

Tsunoda³

et al. 1992

Int Arch Allergy Immunol

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Fundamental studies were conducted to examine the release of histamine and leukotriene (LT) C₄ from lung fragments of guinea pigs and the effects of E6080 on the release of LTB₄ and LTC₄ from lung fragments or inflammatory cells. The release of histamine and LTs showed large interindividual variations and a marked dependence on experimental conditions. Addition of 10 mML-cysteine significantly increased LTC₄ release compared with that in its absence (about 1.7 times, in terms of mean value). E6080 inhibited antigen-stimulated LTB₄ and LTQ release from passively sensitized human (IC₅₀: LTB₄ 0.08 µM, LTC₄ 0.2 µM) and guinea-pig lung fragments (IC₅₀: LTQ 1.1 µM). The LTB₄ and LTQ releases from healthy human polymorphonuclear leukocytes (calcium ionophore A23187) and from allergic patients’ leukocytes (basophils, antigen) were inhibited by E6080 with IC₅₀ values of below 1.0 µM Furthermore, the LTQ release from rat alveolar macrophages (silica particles) was inhibited by E6080 with an IC₅₀ of 0.2 µM The potent inhibition by E6080 might be a result of the inhibition of 5-lipoxygenase, since 5-lipoxygenase in rat basophilic leukemia cell was inhibited by E6080 with an IC₅₀ of 0.2 µM The results confirm the potent inhibitory effects of E6080 on the release of LTs.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionsupporting

confidence: 50%

Section: Introductionsupporting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

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Effects of the New 5-Lipoxygenase Inhibitor E6080 on Leukotriene Release in vitro

Sakuma¹,

Katayama²,

Tsunoda³

et al. 1992

Int Arch Allergy Immunol

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“…In this study, the effects of a newly synthesized and orally active 5-lipoxygcnase inhibitor, 6-hydroxy-2-(4-sulfamoylbcnzylamino)-4,5,7-trimethylbenzothiazolc hydro chloride (E6080) [14][15][16][17], were determined on IgE-mcdiated reactions in rhesus monkey models in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of IgE-Mediated Leukotriene Generation and Bronchoconstriction in Primates with a New 5-Lipoxygenase Inhibitor, E6080

Katayama

Sakuma²,

Abe³

et al. 1993

Int Arch Allergy Immunol

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The inhibitory effects of a novel compound, 6-hydroxy-2-(4-sulfamoylbenzyl-amino)-4,5,7-trimethylbenzothiazole hydrochloride (E6080) on IgE-mediated reactions in vitro and in vivo were determined in rhesus monkeys. E6080 inhibited both antigen- and anti-human IgE-induced leukotriene C₄ generations from lung fragments at similar concentrations: the IC₅₀s of E6080were 1.11 and 0.96 μM, respectively. AA861 also inhibited both leukotriene C₄ generations with IC₅₀s of 0.79 and 0.76 μM, respectively. All 9 monkeys demonstrating positive cutaneous reactivity against Ascaris antigen at < 10^––⁷ g protein/0.1 ml showed reproducible bronchoconstriction upon aerosolized antigen challenge, but 5 monkeys demonstrating weak or no reactivity to the antigen at levels > 10^––5 g protein/0.1 ml showed no significant bronchoconstriction. The high responder monkeys showed a marked increase in lung resistance (R_L 335.3 ± 85.3%, n = 11) and a decrease in dynamic lung compliance (67.7 ± 4.2%, n = 11) after antigen challenge following pretreatment with diphenhydramine. These pulmonary changes lasted for more than 30 min. E6080 at oral doses of 3 and 10 mg/kg showed dose-dependent inhibition of both pulmonary changes. Ten milligrams per kilogram of E6080, administered 1.5 h prior to antigen challenge, significantly inhibited the changes in both parameters, while 3 mg/kg showed significant inhibition of only the R_L change. These results demonstrate that E6080 inhibited immunologically stimulated leukotriene production in the lung, resulting in inhibition of the antigen-induced airway response in primates.

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Effect of a Novel 5-Lipoxygenase Inhibitor, E6080 on the Eicosanoid Production of Human Peritoneal Cells

Pruimboom

Dijk

Zijlstra

et al. 1993

Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation and Radiation Injury

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Effect of a novel 5-lipoxygenase inhibitor, E6080 on bronchospasm, airway cellular infiltration and leukotriene production in guinea pigs

Cited by 8 publications

References 26 publications

Effects of the New 5-Lipoxygenase Inhibitor E6080 on Leukotriene Release in vitro

Effects of the New 5-Lipoxygenase Inhibitor E6080 on Leukotriene Release in vitro

Inhibition of IgE-Mediated Leukotriene Generation and Bronchoconstriction in Primates with a New 5-Lipoxygenase Inhibitor, E6080

Effect of a Novel 5-Lipoxygenase Inhibitor, E6080 on the Eicosanoid Production of Human Peritoneal Cells

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