Ignacio Danta

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.

Inhibition of antigen-induced bronchoconstriction by a new calcium antagonist, gallopamil: Comparison with cromolyn sodium

We have previously demonstrated partial attenuation of antigen-induced bronchoconstriction by aerosolized verapamil (Chest 1985;88:176-80). In the present investigation, we studied the effect of a new calcium antagonist, gallopamil, on allergic bronchial reactivity and compared it to that of cromolyn sodium. Nine asymptomatic subjects with ragweed hypersensitivity and a history of bronchial asthma were studied on 4 different days, without and after pretreatments with aerosolized placebo, gallopamil (10 mg), or cromolyn sodium (20 mg) solution, in a single-blind, randomized, crossover design. Bronchial reactivity was measured as the cumulative provocative dose of ragweed antigen in breath units (PD35) that caused a 35% decrease in specific airway conductance (SGaw). Baseline SGaw was comparable on control, placebo-, gallopamil- and cromolyn sodium-treatment days. The airway deposition dose of gallopamil and cromolyn sodium was calculated at 1.05 mg and 2.1 mg, respectively. Neither cromolyn sodium nor gallopamil had a significant effect on mean SGaw. Mean +/- PD35 on control and placebo-treatment days was 0.54 +/- 0.95 and 0.23 +/- 0.17 breath units, respectively. Aerosolized gallopamil and cromolyn sodium increased the mean PD35 to 56 +/- 41 and 24 +/- 35 breath units, respectively (p less than 0.05). Gallopamil completely inhibited the antigen-induced bronchoconstriction in six (67%) subjects, whereas cromolyn sodium was totally effective in two of the nine (22%) subjects. These results demonstrate that aerosolized gallopamil inhibits allergic bronchial reactivity with efficacy comparable or better than cromolyn sodium.

Relationship between deposition of and responsiveness to inhaled methacholine in normal and asymptomatic subjects

The purpose of this study was to determine if the intersubject variability in airway responsiveness to methacholine is a function of the methacholine mass deposited in the airways and if methacholine hyperresponsiveness in asymptomatic subjects with asthma is related to increased methacholine deposition. Ten normal and 10 age-matched asymptomatic subjects with asthma inhaled, with a standardized single breath maneuver, a dry aerosol (mass median aerodynamic diameter, 1.5 micron; geometric SD, 2.1) generated from solutions of methacholine at concentrations ranging from 0.078 mg/ml to 80 mg/ml in buffered saline, mixed with a fixed concentration of the fluorescent tracer quinine. The mass of methacholine deposited was calculated from the fluorescence of the inspired and expired aerosol trapped on an absolute filter before inspiration and during expiration. Specific airway conductance (SGaw) was measured before and after the inhalation of increasing concentration of methacholine, and the provocative deposited mass corresponding to a 35% decrease in SGaw was calculated. Baseline aerosol deposition (quinine-labeled buffered saline) ranged from 63% to 94% and was similar in normal subjects (mean 85%) and asymptomatic subjects with asthma (mean 84%). There was a correlation between the decrease in SGaw and methacholine mass deposited at first dose in the normal subjects (p less than 0.001) but not in asymptomatic subjects with asthma. Mean provocative methacholine mass corresponding to a 35% decrease in SGaw was 86 micrograms (range 2 to 157 micrograms) in asymptomatic subjects with asthma and 1361 micrograms (range 157 to 3434 micrograms) in normal subjects (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Prolonged bronchial obstruction after a single antigen challenge in ragweed asthma

Some patients with allergic asthma exhibit late-phase responses to inhalation challenge with specific antigen. However, the duration of these responses is difficult to determine because of diurnal variations in airway function, a common phenomenon in patients with asthma. We therefore examined the pattern and duration of pulmonary function in six asymptomatic patients with a history of ragweed asthma and a documented late-phase response after specific and nonspecific bronchial challenge and compared them to responses after control challenge with normal saline. On 3 different days, specific airway conductance (SGaw) and gas distribution by the single breath nitrogen test were measured before (9:00 A.M.) and hourly for 24 hours after inhalation challenge with either normal saline, ragweed extract, or histamine at concentrations sufficient to decrease SGaw immediately by 35% or more. The fluctuations in SGaw after saline and histamine were considerable but failed to follow a typical diurnal or biphasic pattern. There was no difference in mean SGaw between the histamine and saline challenges from 1 to 24 hours after inhalation. In contrast, ragweed challenge produced a typical late-phase response followed by partial recovery of mean SGaw. However, mean SGaw remained subsequently lower than after saline challenge throughout the remaining observation period with fluctuations about this lower level. Gas distribution demonstrated marked intra- and intersubject variations and was therefore not different among the three challenges at any time of measurement. These observations suggest that a single specific but not nonspecific bronchial challenge causes prolonged airflow obstruction in subjects with allergic asthma that lasts 24 hours or longer, independent of variations in baseline airway function.

Modification of Histamine- and Methacholine-Induced Bronchoconstriction by Calcium Antagonist Gallopamil in Asthmatics

We studied the comparative modification of histamine- and methacholine-induced bronchoconstriction by a calcium antagonist, gallopamil, in 8 subjects with bronchial asthma. Dose-response curves to aerosolized methacholine or histamine were performed, without and following pretreatment with inhaled gallopamil (10 mg), on 6 different experiment days to determine the cumulative provocative dose (PD50) of each agonist in breath units which caused a 50% decrease in specific airway conductance (SGaw). Baseline values of SGaw were similar on different experiment days and gallopamil had no significant effect on SGaw. PD50 values for histamine on control and placebo days were 6.8 +/- 2.8 and 5.2 +/- 2.8 breath units (mean +/- SE), respectively. Pretreatment with gallopamil increased histamine PD50 to 19.8 +/- 7.5 breath units, which was significantly greater than on control and placebo days (p < 0.01). PD50 values for methacholine on control and placebo days were 9.5 +/- 5.6 and 8.8 +/- 5.8 breath units, respectively. Gallopamil pretreatment had no significant effect on methacholine-induced bronchoconstriction; methacholine PD50 increased to 13.4 +/- 5.5 breath units (p = NS). The mean dose ratio (ratio of PD50 for the agonist in the presence and absence of gallopamil) for histamine was 6.9, which was 3.7-fold higher than the dose ratio of 1.9 methacholine in the same subjects. These data suggest that gallopamil causes greater inhibition of histamine- versus methacholine-induced bronchoconstriction. This suggests that calcium influx in airway smooth muscle through voltage-dependent channels primarily occurs in response to histamine and not to methacholine.