J Garrigo | PubMed Health

PubMed1996

Time course of the protective effect of inhaled heparin on exercise-induced asthma.

We have previously shown that heparin attenuates allergic bronchoconstriction in sheep, inhibits anti-IgE mediated histamine release in isolated mast cells, and prevents the bronchoconstrictor response in subjects with exercise-induced asthma (EIA). The purpose of the present study was to determine the pharmacokinetics of anti-asthmatic activity of inhaled heparin in EIA and compare it with cromolyn sodium, a mast cell stabilizing agent with established efficacy in EIA. Nine subjects with a history of EIA were studied on 10 different experiment days. After obtaining baseline pulmonary functions on day 1, subjects performed a standardized exercise challenge to document the presence of EIA. While monitoring minute ventilation and heart rate, exercise challenge was performed on a treadmill with increasing workload, until 85% of predicted maximum heart rate was achieved. The subjects then continued the exercise at that workload for 10 min. EIA was assessed by measurements of specific airway conductance (SGaw) before and after exercise. On experiment days 2-10, the exercise challenge was performed after the subjects inhaled 4 ml of either heparin (20,000 u/ml), cromolyn (20 mg), or placebo solutions with increasing pretreatment intervals of 15 min, 1 h, 3 h, or 6 h in a single-blind, randomized fashion. Maximum decreases in SGaw (mean +/- SE) at 3 to 5 min after exercise on control (39 +/- 2.1%) and placebo (37 +/- 2.6%) days were reproducible. Heparin and cromolyn had no effect on baseline SGaw but attenuated the EIA in a time-dependent fashion. Heparin inhibited the bronchoconstrictor responses to exercise by 58%, 78%, and 67% (p < 0.05) when nebulized 15 min, 1 h and 3 h, respectively, before exercise; cromolyn attenuated the responses by 37%, 46%, and 41%, respectively, (p < 0.05). Although heparin offered greater protection than cromolyn (at 1 to 3 h), both agents were ineffective when administered 6 h before exercise. These data demonstrate that inhaled heparin prevents EIA for up to 3 h and is more effective than cromolyn.

Administration, Inhalation↗

PubMed1993

Preventing bronchoconstriction in exercise-induced asthma with inhaled heparin.

BACKGROUND: We have previously reported that inhaled heparin prevents allergic bronchoconstriction in sheep and inhibits the anti-IgE-mediated release of histamine from mast cells in vitro. Since the release of such mediators has been implicated in exercise-induced asthma, we investigated whether inhaled heparin could also attenuate the bronchoconstrictor response in this disease. METHODS: On five days we studied 12 subjects with a history of exercise-induced asthma. On day 1 they underwent a standardized exercise challenge on a treadmill to document the presence of exercise-induced asthma. Minute ventilation was estimated with a calibrated respiratory inductive plethysmograph. The workload was increased until the heart rate reached 85 percent of the predicted maximal value, and was sustained for 10 minutes. The magnitude of bronchoconstriction was assessed by measuring specific airway conductance before and after the exercise. On day 2 the partial-thromboplastin time was measured in plasma obtained before and after the subjects inhaled a nebulized solution of heparin (1000 U per kilogram of body weight). On days 3 through 5 the subjects were pretreated with 4 ml of inhaled heparin (1000 U per kilogram), cromolyn sodium (20 mg), or placebo according to a single-blind, randomized, crossover design and underwent exercise challenge 45 minutes later. To exclude the possibility that heparin had any direct effect on airway smooth muscle, bronchial provocation with histamine was induced in five subjects on two further days after pretreatment with either heparin or placebo. RESULTS: Inhaled heparin and cromolyn sodium had no effect on specific airway conductance at base line, but did attenuate the exercise-induced decreases in this variable: the mean (+/- SE) maximal decrease five minutes after exercise was 9 +/- 5 percent after pretreatment with heparin, as compared with 22 +/- 5 percent after pretreatment with cromolyn and 35 +/- 2 percent after pretreatment with placebo. Heparin did not change the partial-thromboplastin time and did not modify the bronchoconstrictor response to histamine. CONCLUSIONS: Inhaled heparin prevents exercise-induced asthma without influencing histamine-induced bronchoconstriction. This non-anticoagulant action of heparin is more likely to be related to a modulation of mediator release than to a direct effect on smooth muscle.

Administration, Inhalation↗