title: Effect of a leukotriene antagonist, LY171883, on cold air-induced bronchoconstriction in asthmatics.
abstract: Isocapnic hyperpnea (ISH) of cold air induces bronchoconstriction in many asthmatic subjects. Although this response is well described, it is unclear whether this bronchoconstriction is related to the release of bronchoactive mediators. We examined whether pretreatment with LY171883, a competitive antagonist of leukotriene D4 activity via LTD4 receptors, reduced the bronchospastic response to cold air ISH in asthmatics using a randomized, double-blind, two-phase crossover design. In 20 subjects, 2 wk of treatment with either LY171883 600 mg twice a day or placebo did not result in a change in FEV1 (3.45 +/- 0.21 L placebo versus 3.59 +/- 0.20 L LY171883; p greater than 0.05). Nineteen subjects underwent cold-air ISH; LY171883 increased the geometric mean respiratory heat loss required to reduce the FEV1 by 20% (PD20RHE) from 1.00 kcal/min with placebo to 1.24 kcal/min with LY171883 (p less than 0.05). A similar difference was noted when responses were expressed as a function of minute ventilation. LY171883 produced greater shifts in the PD20RHE in more reactive subjects (r = 0.69, p less than 0.002). Among 11 different symptom scores recorded by 18 subjects, there was a significant decrease in daytime chest tightness with LY171883 (p less than 0.03). The increase in PD20RHE while the subjects received LY171883 is consistent with the hypothesis that LTD4 becomes available during cold-air ISH and may mediate bronchoconstriction. The small magnitude of the effect on the PD20RHE may be due to the role of other mediators in cold-air-induced bronchoconstriction or, alternatively, to an inadequate blockade of LTD4 effects.
authors.affiliation: Department of Medicine, Beth Israel Hospital, Boston, Massachusetts.
authors.forename: E
authors.initials: E
authors.lastname: Israel
authors.forename: E F
authors.initials: EF
authors.lastname: Juniper
authors.forename: J T
authors.initials: JT
authors.lastname: Callaghan
authors.forename: P N
authors.initials: PN
authors.lastname: Mathur
authors.forename: M M
authors.initials: MM
authors.lastname: Morris
authors.forename: A R
authors.initials: AR
authors.lastname: Dowell
authors.forename: G G
authors.initials: GG
authors.lastname: Enas
authors.forename: F E
authors.initials: FE
authors.lastname: Hargreave
authors.forename: J M
authors.initials: JM
authors.lastname: Drazen
mesh_terms: D000098:Acetophenones; D001249:Asthma / Q000150:complications*; D001833:Body Temperature Regulation / Q000187:drug effects; D001986:Bronchial Spasm / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D003080:Cold Temperature; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D020024:Leukotriene Antagonists; D008297:Male; D011897:Random Allocation; D012119:Respiration; D013777:Tetrazoles
chemical_list: D000098:Acetophenones; D020024:Leukotriene Antagonists; D013777:Tetrazoles; C044660:LY 171883