Prevention of exercise-induced bronchoconstriction by inhaled low-molecular-weight heparin

Because many biological actions of heparin including the antiallergic activ ity are molecular weight dependent, we hypothesized that low-molecular-weig ht heparin (LMWH) may have greater potency in attenuating exercise-induced bronchoconstriction (EIB). Therefore, in the present investigation we studi ed the effects of inhaled LMWH, enoxaparin, and unfractionated heparin on E IB in subjects with asthma. Thirteen asthmatic subjects performed a standar dized exercise challenge on a treadmill to document the presence of EIB. Th e workload was increased until 85% of predicted maximal heart rate was achi eved, and the exercise was sustained at that workload for 10 min. EIB was a ssessed by measuring FEV1 before and immediately after the exercise. On fiv e different experiment days the subjects were pretreated with 4 mi of aeros olized heparin (80,000 units = 7.5 mg/kg), placebo, or 3 different doses of enoxaparin (0.5 mg/kg, 1 mg/kg, 2 mg/kg) in a double-blind, randomized, cr ossover design, and exercise challenge was performed 45 min later. Bronchia l provocation with methacholine was also performed in five subjects on two additional days after pretreatment with either placebo or inhaled enoxapari n (2 mg/kg), and venous blood was obtained for analysis of plasma antifacto r Xa. Postexercise, the maximal decreases in FEV1 (mean +/- SE) were 30 +/- 4% and 29 +/- 5% on control and placebo days. The exercise-induced decreas es in FEV1 were inhibited by 31% with heparin (Delta FEV1 20 +/- 4%); and b y 28%, 38%, and 48% by enoxaparin at doses of 0.5 mg/kg (Delta FEV1 = 21 1: 5%), 1 mg/kg (Delta FEV1 = 18 +/- 5%), and 2 mg/kg (Delta FEV1 = 15 +/- 3% ), respectively (p < 0.05). The inhibitory effect of 0.5 mg/kg dose of enox aparin was comparable to heparin (7.5 mg/kg), whereas 2 mg/kg dose of enoxa parin was the most potent. Inhaled enoxaparin failed to modify the bronchoc onstrictor response to methacholine, and did not change the plasma antifact or Xa activity. These data demonstrate that inhaled enoxaparin prevents EIB in a dose-dependent manner; and its antiasthmatic activity is independent of its effect on plasma antifactor Xa activity.