AbstractThe experimental asthma caused by IgE antibody in rats was inhibited by HSR-6071 (6-(1-pyrrolidinyl)-N-(1H-tetrazol-5-yl)-2-pyrazinecarboxamide) (0.01-0.1 mg kg−1 i.v.) in a dose-dependent manner. The inhibitory activity of HSR-6071 was more potent than those of disodium cromoglycate and ketotifen, and equipotent with amlexanox. The bronchoconstriction mediated by IgE or IgG antibody in guinea-pigs was also prevented by HSR-6071 (0.3, 1 and 3 mg kg−1 i.v.), amlexanox (3, 10 and 30 mg kg−1 i.v.) and ketotifen (0.1 mg kg−1 i.v.) but not by disodium cromoglycate (10 mg kg−1 i.v.). HSR-6071 was more potent than amlexanox, but less potent than ketotifen. HSR-6071 suppressed antigen-induced histamine and SRS-A release from minced lung tissues of guinea-pigs sensitized passively with rabbit anti-EA serum and was a more potent inhibitor of the release of SRS-A than of histamine. On the other hand, histamine- or acetylcholine-induced bronchoconstriction in guinea-pigs was scarcely affected by HSR-6071 at doses sufficient to inhibit the experimental asthma, but LTD4-induced bronchoconstriction was dramatically inhibited. These results indicate that the inhibitory action on experimental allergic asthma of HSR-6071 may be due to suppression of antigen-induced histamine and SRS-A release from lung tissues and to antagonism of SRS-A action. In addition, HSR-6071 inhibited cyclic AMP phosphodiesterase activity and produced relaxation of the guinea-pig isolated trachea. These pharmacological actions may contribute to the production of the anti-allergic action of HSR-6071.

01 Jan 1990·The Japanese Journal of Pharmacology

Potent inhibitory activity of HSR-6071, a new antiallergic agent, on Passive Cutaneous Anaphylaxis(PCA).

Article

Author: Eiichi Makino ; Hiromi Takahashi ; Hideo Kato ; Tetsuo Ohashi ; Yasuo Ito ; Hiroshi Azuma ; Hiroichi Nagai ; Akihide Koda

Antiallergic effects of 6-(1-pyrrolidinyl)-N-(1H-tetrazol-5-yl)-2-pyrazinecarboxamide (HSR-6071), a newly synthesized agent, were investigated. The 48-hr homologous passive cutaneous anaphylaxis (PCA) in rats was inhibited in a dose-dependent manner by i.v. and p.o. administration of the agent (ED50 = 0.0096 mg/kg and 0.18 mg/kg, respectively). The IgE-mediated histamine release from rat peritoneal exudate cells was inhibited by HSR-6071, with an IC50 of 4.6 x 10(-10) M. Regarding the non-immunological histamine release, HSR-6071 inhibited compound 48/80-induced, but not A23187-induced and spontaneous histamine release. On the other hand, an increase in vascular permeability induced by histamine, serotonin and bradykinin was unaffected by HSR-6071 in doses sufficient to inhibit PCA. In addition, the contractile responses of isolated guinea pig ileum to histamine, acetylcholine and serotonin were also unaffected by the agent even in a high concentration of 10(-4) M. These results indicate that HSR-6071 possesses a potent antiallergic activity and that the inhibition of PCA by HSR-6071 may be due to the suppression of chemical mediators release from mast cells.

01 Jan 1989·Iyo Kizai Kenkyujo hokoku. Reports of the Institute for Medical and Dental Engineering, Tokyo Medical and Dental University

[Problems on the determination of intracellular free calcium concentration when measured by fura-2/AM in mast cells].

Article

Author: Ohashi, T ; Azuma, H

When rat peritoneal mast cells which had been loaded with fluorescent Ca2+ indicator fura-2/AM were exposed to compound 48/80, fura-2 fluorescence was increased in the presence of 1mM extracellular Ca2+, but remained unchanged in the Ca2(+)-eliminated medium. Only in the presence of 1mM extracellular Ca2+, both fura-2 fluorescence and histamine release were increased in response to compound 48/80, depending on the concentration of the stimulant. Both of these responses were attenuated in the same degree by such release inhibitors as disodium cromoglycate and HSR-6071. Fluorescent microscopic observation of fura-2/AM-loaded mast cells revealed that fura-2 fluorescence was densely localized in the granules and the nucleus, but less in the cytoplasm. All these results strongly suggest that increase in the fura-2 fluorescence might not result from the increase in cytoplasmic free Ca2+ concentration, but from binding of fura-2, which had been released together with chemical mediators from granules following stimulation, to extracellular Ca2+. Therefore, it seems likely that the fura-2/AM loading method is inadequate to investigate whether or not the increase in cytoplasmic free Ca2+ concentration triggers release of chemical mediators from mast cells.

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 1	-	Abbott Laboratories	-
Asthma	Phase 1	JP	Hokuriku Seiyaku Co., Ltd.	-

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