Activity of a novel hydroquinone inhibitor of leukotriene synthesis (U-66,858) in the rhesus monkey Ascaris reactor.
The IgE-mediated hypersensitivity to Ascaris antigen in reactor rhesus primates was used to assess the pharmacologic profile of U-66,858 (1-acetoxy-2-n-butyl-4-methoxy-naphthalene). When the compound was given by the oral route, it showed dose-related inhibition of resistance (RL) and compliance (Cdyn) changes. When the compound was given by the aerosol route, it showed dose independent inhibition. In 15 animals, aerosols (52 +/- 32 to 53 +/- 10% for RL, p = 0.05 and 45 +/- 19 to 28 +/- 19% Cdyn inhibitions, p = 0.05) for 5.0-0.1% aerosol. By the oral route, inhibition was seen at 1-4 h following administration. In 5 animals, oral doses of 10 and 5 mg/kg inhibited (RL by 98 +/- 2 to 78 +/- 1.5%, p = 0.01 and Cdyn by 75 +/- 17 to 60.9 +/- 9.1%, p = 0.05) by 10 and 5 mg/kg U-66,858, respectively. The in vivo demonstration of inhibition of pulmonary bronchoconstriction by this compound, in a model known to be leukotriene sensitive, coupled with its potent in vitro inhibition of 5-lipoxygenase enzymes, suggests this compound may be of use in 5-lypoxygenase-mediated models of asthma.
Johnson
H G
HG
Hypersensitivity Diseases Research, Upjohn Company, Kalamazoo, Mich.
Stout
B K
BK
D000280:Administration, Inhalation; D000284:Administration, Oral; D000336:Aerosols; D000818:Animals; D000947:Antigens, Helminth / Q000008:administration & dosage*; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D001200:Ascaris / Q000276:immunology*; D001986:Bronchial Spasm / Q000201:enzymology* / Q000276:immunology; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006873:Hydroquinones / Q000008:administration & dosage* / Q000494:pharmacology; D007442:Intubation, Intratracheal; D016859:Lipoxygenase Inhibitors; D008253:Macaca mulatta; D008297:Male; D009284:Naphthols / Q000008:administration & dosage* / Q000494:pharmacology
D000336:Aerosols; D000947:Antigens, Helminth; D006873:Hydroquinones; D016859:Lipoxygenase Inhibitors; D009284:Naphthols; C057769:bunaprolast; D001091:Arachidonate Lipoxygenases