Effects of a selective phosphodiesterase IV inhibitor (CDP-840) in a leukotriene-dependent non-human primate model of allergic asthma.
The activity of CDP-840, a novel, selective phosphodiesterase IV inhibitor was determined in a leukotriene-dependent non-human primate model of allergic asthma. Measurements of specific airway resistance (sRaw) were recorded in a dual chamber plethysmograph for 1 h and 3-5 h after challenge of allergic conscious squirrel monkeys with an aerosol of ascaris antigen. Orally administered CDP-840 (10 mg/kg; 1 h before challenge) produced partial inhibition (41 and 45%, respectively) of both the acute (1 h post antigen) response and the late (3-5 h post antigen) response to antigen but failed to alter the response to an aerosol of leukotriene D4. In a second series of experiments, intravenous CDP-840 (5 mg/kg; 30 min before challenge) showed improved potency, producing 82% inhibition of the early and 51% inhibition of the late phase response. CDP-840 was inactive when tested intravenously at 1 mg/kg and was inactive against the 3-5 h response when administered after the early phase response (5 mg/kg; i.v. 60 min post antigen challenge). The novel phosphodiesterase IV inhibitor CDP-840 selectively inhibited antigen-induced bronchoconstriction in conscious squirrel monkeys. This effect appears to be independent of any direct bronchodilator action. It is concluded that the activity of CDP-840 in this model may be due to an inhibitory effect on mediator (e.g., leukotriene) release.
Jones
T R
TR
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, QC, Canada.
McAuliffe
M
M
McFarlane
C S
CS
Piechuta
H
H
Macdonald
D
D
Rodger
I W
IW
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D000947:Antigens, Helminth / Q000494:pharmacology; D001200:Ascaris / Q000737:chemistry; D001249:Asthma / Q000139:chemically induced / Q000517:prevention & control*; D016084:Bronchoconstriction / Q000187:drug effects*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015289:Leukotrienes / Q000494:pharmacology; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012453:Saimiri; D012882:Skin Tests; D013997:Time Factors
D000947:Antigens, Helminth; D015289:Leukotrienes; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; C102660:CDP 840; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4