Yoshimichi Okayama (1,#), Jun Hiroi (2), Laurie C. -K. Lau (1) and Martin K. Church (1)
(1) Immunopharmacology Group, University Medicine, Centre Block, Southampton General Hospital, Southampton S016 6YD, U.K.
(2) Pharmacological Research Laboratories, Product Development Research Division, Fujisawa Pharmaceutical Co., Ltd., Osaka 532, Japan
(#) Present address: The First Department of Internal Medicine, Gunma University School of Medicine, 3-39 Showa-machi, Maebashi 371, Japan
Abstract: We have examined the effects of a new anti-allergic drug, quinotolast [sodium 5-(4-oxo-1-phenoxy- 4H-quinolizine- 3-carboxamido)tetrazolate monohydrate], in inhibiting the release of histamine and the generation of leukotriene (LT) C4 and prostaglandin (PG) D2 from dispersed human lung cells and compared this with those of its active metabolite in the rat, hydroxy quinotolast, and reference drugs, tranilast and sodium cromoglycate (SCG). Quinotolast in the concentration range of 1-100 microg/ml inhibited histamine and LTC4 release in a concentration-dependent manner. The inhibitory effect of quinotolast on histamine release from dispersed lung cells was largely independent of the preincubation period, no tachyphylaxis being observed. Hydroxy quinotolast and tranilast showed a weak inhibition of histamine release only when the drugs were added to the cells simultaneously with anti-IgE challenge. Quinotolast, 100 microg/ml, and SCG, 1 mM, significantly inhibited PGD2 and LTC4 release. Quinotolast inhibited PGD2 release by 100% and LTC4 release by 54%, whereas SCG inhibited PGD2 release by 33% and LTC4 release by 100%. No cross-tachyphylaxs between quinotolast and SCG was observed. The results demonstrated that quinotolast showed a significant inhibition of inflammatory mediators from human dispersed lung cells, suggesting that quinotolast is a good candidate for a clinical anti-allergic drug.
Keywords: Quinotolast, Dispersed human lung cell, Histamine, Eicosanoid, Hydroxy quinotolast