In vitro studies on the mechanism of action of a new antiallergic, Ro 21-7634

Abstract

The effects of Ro 21-7634 and disodium cromoglycate (cromoglycate) on the in vitro release of mediators of anaphylaxis from rat peritoneal cells and guinea pig lung tissue were compared. Ro 21-7634 was 25 fold more potent than cromoglycate as an inhibitor of antigen-induced histamine release from passively sensitized (IgE) rat peritoneal cells. Ro 21-7634 was also the more potent inhibitor of both compound 48/80- and concanavalin A-induced histamine release from rat peritoneal cells. The two drugs shared the common properties of producing the same maximal level of inhibition in each of the above releasing systems and exhibiting a time and concentration dependent loss of inhibitory activity when added to the cells prior to the releasing agent. Neither drug inhibited ionophore A23187-or ionophore X537A-induced histamine release from these cells. Ro 21-7634 inhibited antigen-induced (IgG1) histamine and SRS-A release from actively sensitized guinea pig lung fragments, whereas cromoglycate did not. The results indicate that Ro 21-7634 and cromoglycate act through a common mechanism to inhibit allergic mediator release and that Ro 21-7634 is the more potent inhibitor.

Immunopharmacological Studies on TBX, a New Antiallergic Drug (2) Inhibitory Effects on Histamine Release from Peritoneal Mast Cells and Lung Fragments of Rats

“…In contrast, all the drugs displayed little or no inhibition of A23187-induced histamine release. Our results are in agree ment with those reported by many investiga tors (31)(32)(33)(34)(35). However, there are a few papers demonstrating that DSCG inhibits A23187 induced histamine release from rat mast cells (36,37).…”

Mechanism of the Action of Amoxanox (AA-673), an Orally Active Antiallergic Agent

“…DSCG inhibits histamine release, but not SRS-A generation in guinea pig lung fragments [20,21,36,37] and does not exert antagonistic activity against SRS-A [20,21], This compound suppressed the IgEbut not the lgG-mediated bronchoconstriction [20,[38][39][40][41]. These results are consistent with our ob servations in the present and previous [1] studies.…”

Ro 21-7634, a new antiallergic agent with potent oral activity

“…However, the action of Ketotifen is probably due to an antihistamine or antiserotonin activity rather than inhibition of mediator release [4,10]. Such an explanation of activity in the PCA test is also probably true for Oxatomide [5,10], as well as chlorpheniramine, a known antihistaminic [14], and cyproheptadine, a serotonin and histamine antagonist [14]. Cromoglycate was essentially inactive after oral administration, but antiallergic activity could be demonstrated with intravenous use.…”

“…The oral potency of Ro 21 7634 was greater than the other compounds tested except for Ketotifen. However, the action of Ketotifen is probably due to an antihistamine or antiserotonin activity rather than inhibition of mediator release [4,10]. Such an explanation of activity in the PCA test is also probably true for Oxatomide [5,10], as well as chlorpheniramine, a known antihistaminic [14], and cyproheptadine, a serotonin and histamine antagonist [14].…”

“…This is also suggested by the observation in vitro that Ro 21-7634 has no direct bronchial smooth muscle relaxation activity when assayed on guinea pig tracheal tissue (data not shown). The question of the mechanism of action of Ro 21-7634 is examined more thoroughly in the accompanying manuscript [10]. Other test systems in which Ro 21-7634 was inactive at doses far in excess of those required for therapeutic activity included: central nervous system depression (mouse), intestinal motility (mouse), gastric secretion (rat), immunosuppression or immunoenhancement (mouse), antibacterial or antiviral activity (mouse), analgesic activity (mouse), and antiinflammatory activity (rat).…”