Late phase bronchoconstriction and eosinophilia as well as methacholine hyperresponsiveness in Ascaris-sensitive rhesus monkeys were reversed by oral administration of U-83836E.
We used the Ascaris-sensitive primate model to assess the effect of oral doses of the 2-aminochroman (U-83836E) lazaroid on the antigen-induced late phase (24 h) bronchoconstriction (LPBC), eosinophilia and methacholine hyperreactivity. Following establishment of consistent lung resistance measurements and bronchoalveolar lavage eosinophilia in 4 Ascaris reactor primates, we determined the baseline aerosol mecholyl provocative challenge for 50% increase (PC50 in mg/ml) in these animals. Twenty-four hours following antigen challenge, we again determined the PC50 (mg/ml). In all 4 animals, there was a statistically significant decrease in PC50 (5.4- to 32-fold, n = 5-7; p < 0.029). Bronchoconstriction at 24 h increased in all 4 (49-86% over saline aerosol, p < 0.05). Eosinophilia increased from 21 to an average of 33% of total cells (p < 0.05 compared to saline). Repeating the antigen challenge in the presence of oral doses of 10 mg/kg U-83836E 18 and 3 h before and 6 h after challenge resulted in 53-70% inhibition of LPBC, 53-81% inhibition of eosinophilia (p < 0.05 compared to Ascaris) and return of the mecholyl PC50 (mg/ml) to before antigen levels (p = NS) thus blocking increased hyperreactivity. These results indicate U-83836E, like steroids, would be an effective drug for asthma and lung inflammation.
Johnson
H G
HG
Upjohn Company, Kalamazoo, MI 49001-0199.
Stout
B K
BK
D000818:Animals; D001200:Ascaris / Q000276:immunology; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects*; D002839:Chromans / Q000494:pharmacology*; D004802:Eosinophilia / Q000188:drug therapy*; D005260:Female; D008253:Macaca mulatta; D016210:Methacholine Chloride / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*
D002839:Chromans; D010879:Piperazines; D016210:Methacholine Chloride; C066382:U 78517F