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

Abstract

ABSTRACT-Wehave 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 ttg/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 pg/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-tachyphylaxis 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.

Identification of PPA1 inhibitor candidates for potential repurposing in cancer medicine

“…Devazapide and tarazepide were successful in preclinical analyses and reached clinical stage, 71,72 while quinotolast progressed to regulatory approval for clinical use in some countries. 73,74 Our MD analyses revealed that the PPA1-ligand complexes exhibited stable behavior with these ligands, as indicated by consistent RMSD backbone and Rg values. The RMSF results exhibited similar fluctuations for all ligands, with the exception of tarazepide displaying greater fluctuation between residues 100−120.…”

“…Our in silico investigation revealed three potential repurposing ligands: devazepide, quinotolast, and tarazepide. Devazapide and tarazepide were successful in preclinical analyses and reached clinical stage, 71,72 while quinotolast progressed to regulatory approval for clinical use in some countries 73,74 . Our MD analyses revealed that the PPA1‐ligand complexes exhibited stable behavior with these ligands, as indicated by consistent RMSD backbone and Rg values.…”