Effects of Quinotolast, a New Orally Active Antiallergic Drug, on Experimental Allergic Models

Abstract

ABSTRACT-The effects of a new antiallergic drug, quinotolast [sodium 5-(4-oxo-1-phenoxy-4H quinolizine-3-carboxamido)tetrazolate monohydrate], were studied and compared with those of tranilast, amlexanox, pemirolast, repirinast and disodium cromoglycate (DSCG) in experimental allergic models. Quinotolast potently inhibited such type I allergic reactions as passive cutaneous anaphylaxis (PCA) and anaphylactic bronchoconstriction in rats by both intravenous and oral dosing. All of these effects were stronger than those of the reference drugs tested. Quinotolast inhibited histamine release from rat peritoneal cells, but it had no antagonistic effect on histamine-, serotonin-, platelet activating factor or bradykinin-induced cutaneous reactions in rats. Moreover, it was clearly demonstrated that quinotolast and DSCG had a cross tachyphylaxis to inhibit PCA in rats, suggesting that these drugs, at least in part, share the same mechanism of action. Furthermore, quinotolast potently inhibited PCA in guinea pigs in which DSCG and other reference drugs showed poor inhibitory activity. Quinotolast also showed stronger inhibi tory effects on histamine and peptide leukotrienes release from guinea pig lung fragments or mouse cultured mast cells than the other drugs tested. Thus, the effect of quinotolast on type I allergic reaction would seem to be based on an inhibition of mediator release from inflammatory cells including mast cells. The results suggest that quinotolast will be beneficial in the treatment of type I allergy-related diseases.

Evidence questioning cromolyn's effectiveness and selectivity as a ‘mast cell stabilizer' in mice

“…10 Clinical studies showed that inhalation of cromolyn by subjects with allergic asthma blocked allergen-induced bronchospasm, presumably by inhibiting the release of mediators from mast cells, 11 an idea that was supported by the drug’s ability to inhibit the degranulation of rat peritoneal mast cells in response to challenge with IgE and specific antigen in vitro . 12–15 For this reason, cromolyn is often characterized clinically as a “mast cell stabilizer”, 16 and this drug is now used for the treatment of other diseases thought to involve mast cell activation, including allergic rhinitis, allergic conjunctivitis, and mastocytosis. 17 …”

Inhibition of Histamine and Eicosanoid Release from Dispersed Human Lung Cells In Vitro by Quinotolast

“…At concentrations from 0.02 to 10 pg/ml, this drug shows "anti-allergic" effects in standard in vitro tests with rats, guinea pigs and mice (1). After the oral administration of quinotolast of 0.32-3.2 mg/kg to rats and 1 mg/kg to guinea pigs, the time to reach the maximum plasma concentrations, 0.07-0.5…”

“…Quinotolast has been recently developed as an orally active anti-allergic drug (1). At concentrations from 0.02 to 10 pg/ml, this drug shows "anti-allergic" effects in standard in vitro tests with rats, guinea pigs and mice (1).…”

“…It was observed that the oral administration of 0.01 mg/kg to rats and 3.2 mg/kg to guinea pigs were effective doses of quinotolast for the inhibition of the PCA reaction (1). In humans, the maximum plasma concentration was 0.2 pg/ml after the oral administration of a clinically active dose, 5 mg, twice a day (19).…”

“…An understanding of the biochemistry of this mediator release is required for the rational development of future drug therapies for human hypersensitivity reactions. Quinotolast [sodium 5-(4-oxo-1-phenoxy-4H-quinolizine-3-carboxamido) tetrazolate monohydrate] is a new orally active anti-allergic drug that prevents the release of histamine from rat mast cells and the release of leukotrienes from guinea pig lung (1). However, it is generally accepted that mast cells from different species, and even those from different tissues within a given species, are functionally heterogeneous (2).…”