REV 2871 (CHBZ): A novel inhibitor of histamine release

Abstract

CHBZ is a novel, non-disodium cromoglycate (DSCG)-like, antiallergic drug in vitro. Whereas DSCG loses antisecretory activity with increasing time of preincubation with rat mast cells (RMC) before antigen challenge, and does not inhibit non-immunologically mediated release from human leukocytes, CHBZ exerts long-lived inhibition of both types of release from both types of cells. CHBZ is taken up by RMC in a saturable and time-dependent manner. It is enzymatically converted inside RMC to a DSCG-like metabolite, REV 3579, which, because of its ionic character, accumulates inside the cell. CHBZ, presumably through the action of the REV 3579 generated intracellularly, may mediate long-lived phosphorylation of the same 78 K protein which is transiently phosphorylated upon exposure of RMC to DSCG.

Mechanism of action of the nonlipophilic antiallergic drug eclazolast (REV 2871) in the inhibition of mediator release in a mast cell model

“…These phosphorylations occur intracellularly. An intracellular target is in accordance with the finding that eclazolast resides intracellularly, and most likely concentrates into the cytosol [1].…”

“…Eclazolast has been extensively investigated in human basophils [5,22] and rat mast cells [1]. The compound can be classified as a prodrug, it rapidly penetrates into cells and is subsequently hydrolysed, forming the anionic carboxylic acid.…”

“…48, 1999 Mechanism of action of the nonlipophilic antiallergic drug eclazolast (REV 2871) in the inhibition of mediator release 573 nor has it been found in activated cells (data not shown). Coutts et al [1] reported that in rat mast cells, eclazolast induces a minimal increase in 32 P phosphorylation of an 78 KDa protein.…”

“…Previous studies demonstrated that inhibition of exocytosis by lipophilic antiallergic drugs correlated with inhibition of Ca 2+ influx through SOC channels, and distortion of cellular membranes [1,4,17]. Therefore, the effects of eclazolast were compared with known membrane disturbing drugs like astemizole, meclozine and oxatomide in model membranes.…”

“…1) is an antiallergic drug which exerts extended inhibition of IgE-mediated histamine release from mast cells [1]. The inhibition of mediator release by antiallergic drugs has been associated with lipophilic properties of the drugs and distortion of membrane structures [2][3][4].…”