Antiasthmatic effects of a leukotriene biosynthesis inhibitor (MK-0591) in allergic dogs.
Peptidoleukotrienes may be important mediators of human bronchial asthma. Accordingly, the effects of a selective leukotriene (LT) biosynthesis inhibitor (MK-0591) were assessed in allergic dogs characterized by acute bronchoconstriction and subsequent airway hyperresponsiveness induced by inhaled ragweed allergen. Peak acute increases in airway resistance (Rrs) induced by ragweed were associated with increased bronchoalveolar lavage histamine concentration, and neither parameter was inhibited by MK-0591 (8 micrograms.kg-1.min-1 i.v.). However, the duration of the bronchoconstriction was significantly decreased by MK-0591, with a reduction in the area under the curve of 40% (P < 0.05). Associated with the acute bronchoconstriction in placebo-treated animals was a fivefold increase in urinary LTE4 excretion (as seen with allergic asthmatic patients), which was reduced to < 10% of basal values by MK-0591. Similarly, whole blood LTB4 biosynthesis was abolished in the MK-0591-treated animals. Bronchial hyperresponsiveness preallergen (measured as the percent concentration of acetylecholine required to increase Rrs by 5 cmH2O.l-1.s) tended to improve with MK-0591 (0.41 +/- 0.15 vs. 0.23 +/- 0.05%). Five hours after allergen inhalation, the percent concentration declined substantially in the placebo group (0.07 +/- 0.02%; P < 0.01), revealing an increased airway responsiveness that was significantly blunted by MK-0591 (0.26 +/- 0.07%; P < 0.001). These data suggest that selective inhibition of LT biosynthesis by novel compounds such as MK-0591 may modify the airway changes associated with bronchial hyperresponsiveness, as well as offer symptomatic relief in asthma.
Becker
A B
AB
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe Claire, Quebec, Canada.
Black
C
C
Lilley
M K
MK
Bajwa
K
K
Ford-Hutchinson
A W
AW
Simons
F E
FE
Tagari
P
P
D058927:5-Lipoxygenase-Activating Proteins; D000403:Airway Resistance / Q000502:physiology; D000485:Allergens / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004285:Dogs; D006632:Histamine / Q000378:metabolism; D007211:Indoles / Q000627:therapeutic use*; D020024:Leukotriene Antagonists; D007975:Leukotriene B4 / Q000096:biosynthesis; D017999:Leukotriene E4 / Q000096:biosynthesis / Q000652:urine; D015289:Leukotrienes / Q000096:biosynthesis; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011804:Quinolines / Q000627:therapeutic use*; D012130:Respiratory Hypersensitivity / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D000485:Allergens; D002352:Carrier Proteins; D007211:Indoles; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D008565:Membrane Proteins; D011804:Quinolines; C078266:MK 0591; D007975:Leukotriene B4; D017999:Leukotriene E4; D006632:Histamine