Pharmacologic Profile of a New Antiallergic Compound PRD-92-Ea

Abstract

PRD-92-Ea [5,5-Dimethyl-11-oxo-5H, HH-(2) benzopyrano (4,3-g) (1) benzopyran-9-carboxylic acid ethanolamine], was an active antiallergic compound in rat and monkey experimental models of immediate hypersensitivity. It inhibited, in a dose-dependent manner, the rat PCA reaction after both intravenous and oral administration. It also inhibited the degranulation of rat peritoneal mast cells after antigenic challenge. PRD-92-Ea was also active in preventing bronchoconstriction in Ascaris-sensitive Rhesus monkeys after intravenous, topical and oral administration. Using chopped monkey tissues, it was found that PRD-92-Ea prevented histamine release from the respiratory mast cells, but not from the cutaneous mast cells. No reason for this dichotomy of effect is known. PRD-92-Ea showed antagonistic activity against the allergic mediators released from mast cells. In order of decreasing potency it was active against SRS-A (monkey lung), PGF_2α, PGE₂, serotonin, bradykinin and histamine. Apart from its antiallergic effects PRD-92-Ea had no other significant pharmacological activity.

The Difference in Effect of Predosing with Antiallergic Compounds between the Rat PCA Model and the Monkey Asthma Model

“…We have no explanation for these findings but they demonstrate that the mast cells of the rat behave differently under the influence of these new drugs to the mast cells of the monkey. In nonhuman primates DSCG and PRD-92-Ea are either not effective [3,7] or much less effective [1] in preventing skin mast cells from degranulating after antigen challenge, while the respiratory mast cells are fully sensitive. In the rat these com pounds do not separate the mast cells into sensitive and nonsensitive populations and rat mast cells do demonstrate tachyphylaxis and cross-reacting tachyphylaxis, whereas the sensitive mast cells in the monkey as shown in the present study do not exhibit tachyphylaxis when predosed with DSCG or PRD-92-Ea.…”

“…The production of antiovalbumin reaginic ser um and the method for testing of compounds af ter intravenous administration in the rat passive cutaneous anaphylaxis (PCA) test have been de scribed previously [3].…”

“…The monkey asthma model procedure has been described fully in a previous paper [3] except that the method of bronchial challenge was modified as follows:…”

“…complicated by the finding of cross-reacting tachyphylaxis where predosing with chemi cally distinct compounds, a phenoanthroline salt [2] and a nitroindanedionc [6], inhibit ed the effectiveness of a subsequent dose of DSCG and vice versa. The present work was undertaken to see if the phenomenon of tachyphylaxis would be present in a species other than the rat and whether cross-react ing tachyphylaxis also extended to PRD-92-Ea, a member of another distinct chemical group but having a similar pharmacological profile [3] to DSCG and other new antial lergic compounds of this type.…”

Anti-Allergy Properties of PRD-92 E_a in Guinea Pig and Rat

“…PRD-92 Ea (5,5-dimethyl-ll-oxo-5H, 11 H-(2)benzopy rano(4,3-g)( 1 )benzopyran-9" carboxylic acid ethanolamine) resembles disodium cromoglycate (DSCG) in being an inhibitor of mediator secretion from activat ed rat peritoneal mast cells and from chop ped monkey lung mast cells [5]. This com pound has the additional property of being well absorbed following oral administration in rat and monkey [4,5,10] and in man [6].…”