Hisashi Kuriki

Pharmacological profile of AA-861, A 5-lipoxygenase inhibitor

AA-861, a selective 5-lipoxygenase inhibitor, suppressed A23187-induced formations of 5-HETE and LTB4 in rat peritoneal macrophages. Immunologically-stimulated generation of SRS-A was also inhibited in guinea pig lung and rat peritoneal cavity. AA-861 had no effects on histamine release from rat mast cells or passive cutaneous anaphylaxis in rats. Essentially no antagonistic activity to LTD4 or histamine was observed. This compound exerted an obvious inhibition of allergic bronchoconstriction in guinea pigs and a moderate reduction of carrageenin-induced paw edema and pleurisy in rats. These findings suggest that SRS-A plays an important role in asthmatic and inflammatory reactions.

Mechanism of action of an antiallergic agent, amlexanox (AA-673), in inhibiting histamine release from mast cells: acceleration of cAMP generation and inhibition of phosphodiesterase

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(-6)M, 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(-6) M of amlexanox combined with 10(-7) M isoproterenol, the cAMP contents were synergistically increased 15-, 60- and 88-fold, respectively. 3-Isobutyl-1-methylxanthine (IBMX) at 10(-6)-10(-4) M increased the cAMP content 1.7-3.8-fold, and a combination of 10(-4) M IBMX and 10(-7) M 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 X 10(-5) M, and its inhibitory activity was half that of IBMX.(ABSTRACT TRUNCATED AT 250 WORDS)

A novel anti-asthmatic quinone derivative, AA-2414 with a potent antagonistic activity against a variety of spasmogenic prostanoids

The anti-asthmatic activity of AA-2414 [(+/-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptano ic acid] has been studied in vivo and in vitro. Experimental allergic asthma was inhibited by orally administered AA-2414 in a dose-dependent manner. AA-2414, 0.08-1.25 mg/kg (p.o.), inhibited the bronchconstriction in guinea pigs induced by a prostaglandin endoperoxide analogue (U-46619), leukotriene D4 (LTD4), and platelet activating factor (PAF) with a long duration of action. The compound did not inhibit histamine-induced bronchoconstriction. AA-2414 reduced the induction of pulmonary inflation caused by LTD4 aerosol inhalation. AA-2414 competitively inhibited the contractile response to U-46619 in guinea pig tracheal and parenchymal strips and dog saphenous vein strips with pA2 values of 7.69, 8.29 and 6.79, respectively. Furthermore, the contractile responses of guinea pig tracheal strip to PGD2, 9 alpha, 11 beta-PGF2 and PGF2 alpha were inhibited with pA2 values of 7.20, 7.79 and 5.71, respectively. These results suggest that AA-2414, a quinone derivative, is a novel, potent and orally active antagonist of a variety of spasmogenic prostanoids.

Mechanism of the Action of Amoxanox (AA-673), an Orally Active Antiallergic Agent

Amoxanox inhibited immunologically stimulated and LTD4-induced bronchoconstriction in laboratory animals. Amoxanox, like DSCG, inhibited rat IgE-mediated PCA and histamine release from rat peritoneal mast cells, and suppressed immunologically stimulated or calcium ionophore A23187-induced SRS-A generation in rat peritoneal cavity and guinea pig lung fragments. This compound also reduced the contractile response of guinea pig lung parenchymal and ileal strips to LTD4, but did not significantly affect the response of the ileum to either histamine or acetylcholine. Therefore, the antiallergic action of amoxanox seems to be associated with inhibition of chemical mediator release and antagonistic activity on SRS-A.

Role of Leukotrienes in Rat Reversed Passive Arthus Pleurisy and the Effect of AA-861, a 5-Lipoxygenase Inhibitor

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.

Selective β-adrenoceptor activities of tetrahydronaphthalene derivatives

Abstract Alpha - and beta -adrenoceptor activities of a group of tetralin derivatives prepared as fixed analogs of isoproterenol, adrenaline and noradrenaline were evaluated in vitro assays. All of the present compounds showed strong direct β-stimulating activity fairly selective for tracheal muscle. Activity of a trans isomer about the C(1)-C(2) bond was ten times higher than that of the cis isomer. None of the compounds tested had any practical α-adrenoceptor activity. Structure-activity interrelationships between the present series of compounds and some known adrenergic agonists are discussed.

Inhibition by amoxanox (AA-673) of the immunologically, leukotriene D4- or platelet-activating factor-stimulated bronchoconstriction in guinea pigs and rats.

We studied the effects of amoxanox (AA-673) on allergic asthma and spasmogen-induced bronchoconstriction in guinea pigs and rats. Amoxanox given orally or parenterally inhibited allergic asthma mediated by IgE, IgG1, or heterologous IgG in guinea pigs and by IgE in rats. This compound also reduced leukotriene D4- and platelet-activating factor-induced bronchoconstriction in guinea pigs, strongly suggesting an antagonistic activity against slow reacting substance of anaphylaxis (SRS-A). Histamine- or acetylcholine-induced bronchoconstriction was not significantly affected by amoxanox. These antiasthmatic effects of amoxanox seem to be associated with an inhibition of the release of chemical mediators such as histamine and SRS-A and with an antagonism against SRS-A.

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

Amoxanox has potent antiallergic activity because it inhibits the release of chemical mediators such as histamine and leukotrienes. We studied the in vitro effect of amoxanox on arachidonic acid metabolism, including the lipoxygenase and cyclooxygenase pathways. Amoxanox inhibited calcium ionophore A23187-induced formation of 5-HETE, LTB4, SRS-A (LTC4, LTD4 and LTE4), and 12-HETE in rat peritoneal resident monocytes. These results indicate that amoxanox inhibits 5- and 12-lipoxygenases. The compound, however, did not affect the formation of TXB2 or 6-keto-PGF1 alpha in guinea pig lung fragments and PGE2 or PGF2 alpha in bovine seminal vesicles, suggesting that it did not inhibit cyclooxygenase. These results show that the antiallergic action of amoxanox is associated, at least in part, with the reduction of leukotrienes due to the inhibition of lipoxygenases.

The effect of inhaled leukotriene D4, histamine, or antigen on central and peripheral airways of guinea pigs: analysis of bronchograms with an interactive image analysis system

The effect on guinea pig airways of the inhalation of leukotrienes, histamine or antigen was investigated by measuring changes in lung volume and analyzing the airway area on bronchograms with the Zeiss interactive image analysis system (IBAS). LTC4, LTD4, LTE4 and histamine inhaled through an ultrasonic nebulizer caused inflation of the lung: LTD4 was the most potent of the leukotrienes and was 100 times more potent than histamine on a molar basis. The results of analyses of areas of large and small bronchi and bronchioles on the bronchograms indicated that LTD4 selectively decreased the area of the peripheral airways. Inhalation of an antigen in actively sensitized animals resulted in inflation of the lung and in a selective decrease in the area of the peripheral airways. Anaphylactic bronchoconstriction provoked by antigen inhalation was clearly inhibited by AA-861, a 5-lipoxygenase inhibitor but not significantly by mepyramine, an antihistamine. These observations indicate that LTD4 is a potent constrictor of the peripheral airways in guinea pigs and that the anaphylactic bronchoconstriction provoked by antigen inhalation could be mediated by LTD4 in actively sensitized guinea pigs.

Interaction of the Antiallergic Agent AA-344 with Biogenic Amines and Prostaglandins in Production of Cyclic AMP in Rat Mast Cells

AA-344, which has been evidenced to inhibit selectively IgE-mediated allergic reactions, exhibited an inhibitory effect on cyclic AMP phosphodiesterase (PDase) in the homogenates of purified rat peritoneal mast cells (RMC). AA-344 showed synergistic effects with epinephrine, isoproterenol or prostaglandin E2 and F2 alpha in increasing cyclic AMP level in RMC: the combinations caused an increase in cyclic AMP 30-160 times as much as that caused by the respective agent alone. In the latter effect, AA-344 was at least 1,000 times as potent as theophylline. On the other hand, histamine or serotonin with or without AA-344 had no effect on the RMC cyclic AMP. These results obtained in vitro suggest that AA-344 may exert antiallergic action by increasing cyclic AMP via an interaction with epinephrine or prostaglandins which might be endogenously involved in regulation of a function of RMC in allergic reactions.