Effects of nedocromil sodium on the bronchomotor response to sulfur dioxide in asthmatic patients.

It is known that cromolym sodium and nedocromil sodium share similar antiallergic properties. This study examined whether nedocromil sodium, a pyranoquinoline dicarboxylic acid, could inhibit sulfur dioxide (SO2) bronchoconstriction in a dose-dependent manner in 10 men with mild asthma. Previous studies have shown that cromolyn sodium produces such inhibition in allergic monkeys and asthmatic subjects. Subjects in this double-blind, placebo-controlled study were nonsmoking men between the ages of 23 and 40 years (mean age, 30.7 years). The study took place over 5 days within a 3-week period. On the first of 5 days, each subject had a history taken and physical examination, SO2 baseline test, laboratory testing, and a methacoline dose-response test. On each of 4 test days, the subjects received pretreatment with either placebo or a 2, 4, or 8 mg dose of nedocromil sodium in a randomized, double-blind sequence, followed after 30 minutes by an SO2 dose-response test. Results showed that maximum bronchoconstriction response to SO2 was significantly attenuated (p < 0.01) by all three doses of nedocromil sodium, with small differences noted between dose levels. We concluded that nedocromil sodium inhibited SO2-induced bronchospasm at dose levels as low as 2 mg.

SO2-induced enhancement of inhalative allergic sensitization: inhibition by anti-inflammatory treatment.

Epidemiological studies have shown a relationship between air pollution and allergic airway disease. In a previous study we have found that exposure to SO2 enhances allergic sensitization to inhaled ovalbumin (OA) in the guinea pig. We have now investigated the influence of pre-treatment with anti-inflammatory drugs on SO2-induced enhancement of allergic sensitization in this model. Four groups of 6 guinea pigs each were exposed to 5 ppm SO2 on 5 consecutive days over 8 h per day with intermittent inhalation of OA, while the air-control group was exposed to clean air and OA. During the period of SO2 exposure and sensitization three experimental groups were treated with indomethacin (group I), methylprednisolone (group M) and nebulized nedocromil sodium (group N), while the control group remained untreated. Guinea pigs were investigated for sensitization to OA by specific bronchial provocation tests using body plethysmographic measurement of compressed air (CA) and by measurement of specific antibody response in serum. While in the SO2-exposed control group 5 of 6 animals reacted to specific bronchial provocation testing (CA median 0.15 ml, range 0-0.175 ml), only 1 animal was sensitized in group M (CA 0 ml, 0-0.125, p < 0.05), whereas no bronchial reactions were seen in groups I and N (CA 0 ml, 0-0.05, p < 0.025). Specific IgG antibody titres increased in the control group (median 43 EU-->85 EU), but not in the treatment groups (medians group I 35 EU-->35 EU, group M 30-->35 EU, group N 64-->50 EU).(ABSTRACT TRUNCATED AT 250 WORDS)

Nonadrenergic bronchodilation induced by high concentrations of sulfur dioxide.

SO2 is an environmental pollutant known to elicit bronchospasm in susceptible subjects. We observed that brief exposure of artificially bronchoconstricted cats to high concentrations of SO2 induces a bronchodilator response. This study assessed the characteristics of this response and examined various mechanisms that might underlie it. Cats were anesthetized with diallylbarbital-urethan, and airway smooth muscle tone, measured by lung resistance and dynamic lung compliance, was elevated with a continuous infusion of 5-hydroxytryptamine. Administration of 10 breaths of SO2 via a tracheostomy induced concentration-dependent bronchodilation in the range 100-1,000 parts/million. Only infrequently was bronchoconstriction observed before bronchodilation. SO2-induced bronchodilator responses were unaffected by pretreatment with intravenous atropine or propranolol, establishing them as nonadrenergic noncholinergic (NANC) in origin. Neither the ganglionic blocking agent hexamethonium nor the nerve toxin tetrodotoxin influenced the SO2-induced bronchodilation, thus excluding a role for central or local autonomic reflexes in the response. Efforts to modulate the response by pretreatment with the cyclooxygenase inhibitor indomethacin or the mediator release inhibitor cromolyn sodium also were unsuccessful. Administration of acidic aerosols failed to mimic the SO2-induced bronchodilator response. Although the mechanism whereby SO2 induces bronchodilation under these experimental conditions remains unclear, release of a NANC inhibitory transmitter from a neural, epithelial, or other cellular source via a mechanism insensitive to both tetrodotoxin and cromolyn is a distinct possibility. An intrinsic NANC inhibitory system may exist in feline airways functioning as a local regulator of bronchomotor tone and possibly serving to override responses to strong, potentially asphyxial bronchoconstrictive stimuli.

Effect of metaproterenol sulfate on mild asthmatics' response to sulfur dioxide exposure and exercise.

Twenty asthmatic volunteers, most with mild disease, underwent dose-response studies with sulfur dioxide (SO2) under three pretreatment conditions: (1) drug (metaproterenol sulfate in aerosolized saline solution), (2) placebo (aerosolized saline only), and (3) no pretreatment. Sulfur dioxide exposure concentrations were 0.0, 0.3, and 0.6 ppm. Experimental conditions were presented in random order at 1-wk intervals. Exposures lasted 10 min with heavy continuous exercise. Lung function was measured at baseline, after pretreatment (immediately pre-exposure), immediately post-exposure, and during a 2-hr follow-up. Subjects could elect to take bronchodilators during follow-up. Symptoms were monitored before, during, and for 1 wk after exposure. With no pretreatment, subjects exhibited typical exercise-induced bronchospasm at 0.0 ppm, slightly increased responses at 0.3 ppm, and more marked increases at 0.6 ppm. Seven subjects took bronchodilator after 0.6-ppm exposures, compared to 2 at lower concentrations. Within 30 min post-exposure, most subjects' symptoms and lung function had returned to near pre-exposure levels. A similar sequence was observed when subjects received placebo. Drug pretreatment improved lung function relative to baseline, prevented bronchoconstrictive responses at 0.0 and 0.3 ppm, and greatly mitigated responses at 0.6 ppm. Thus, typical bronchodilator usage by asthmatics is likely to reduce their response to ambient SO2 pollution.

Acute transient SO2-induced airway hyperreactivity: effects of nedocromil sodium.

The effect of nedocromil sodium given as an aerosol on the immediate lung hyperreactivity and lung inflammation caused by a 2-h exposure to 400 ppm SO2 has been studied in dogs. Exposure to SO2 caused an immediate increase in bronchial responsiveness to histamine aerosol that lasted for approximately 2 h. The total number of cells recovered by bronchial lavage increased postexposure. Initially this increase was caused by epithelial cells (0.25 and 1 h) and later by neutrophils (1, 2, 3, and 4 h). There was no significant change in the numbers of lymphocytes, macrophages, eosinophils, goblet cells, or mast cells in the lavages. Nedocromil sodium (approximately 8 mg) given as a nebulized aerosol before and after SO2 exposure prevented the increase in lung reactivity and attenuated the increase in the total number of cells (epithelial cells and neutrophils) in the lung lavages for the 4 h after exposure. Nedocromil sodium did not affect the reactivity of normal dogs to histamine aerosol. Nedocromil sodium appears to act as an anti-inflammatory agent in this model of lung inflammation, preventing an increase in lung reactivity and reducing cell infiltration. The mechanism of action of nedocromil sodium in this model is unknown.

Interaction of cromolyn and a muscarinic antagonist in inhibiting bronchial reactivity to sulfur dioxide and to eucapnic hyperpnea alone.

To determine whether the combination of an agent thought to inhibit mediator release (cromolyn) and an agent that inhibits parasympathetic pathways inhibits sulfur dioxide-induced bronchoconstriction more than either agent alone, we measured the bronchomotor response of 9 asthmatic subjects to inhalation of sulfur dioxide after treatment with cromolyn sodium (200 mg by spinhaler), with atropine sulfate (2.0 mg by nebulizer), and with the 2 drugs given together. Then, to determine whether the combination of cromolyn and a parasympathetic antagonist would similarly inhibit bronchoconstriction provoked by a different nonallergic stimulus, we measured the bronchomotor response of another group of asthmatic subjects to eucapnic hyperpnea of dry air at room temperature after treatment with cromolyn (200 mg), with ipratropium bromide (100 and 200 micrograms by metered-dose inhaler), and with cromolyn (200 mg) and ipratropium bromide (200 micrograms) given together. In both studies, we found that the combination treatment provided greater protection than that obtained with either agent alone. The concentration of sulfur dioxide required to cause bronchoconstriction was significantly greater after treatment with the combination of cromolyn and atropine (2.58 ppm, geometric mean) than after cromolyn alone (0.84 ppm), after atropine alone (0.78 ppm), or after placebo (0.43 ppm). Similarly, the rate of ventilation with dry air required to cause bronchoconstriction was significantly greater after treatment with the combination of cromolyn and ipratropium (106 +/- 22 L/min, mean +/- SD) than after cromolyn alone (65 +/- 19 L/min), after 200 micrograms of ipratropium alone (64 +/- 13 L/min), or after placebo (43 +/- 10 L/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of bronchial irritant receptors in asthma.

Sulphur dioxide inhaled at low concentration had no detectable effect on forced expiratory volume in one second in non-asthmatic atopic controls, but it induced asthma and increased bronchial reactivity in nine symptomless atopic and non-atopic asthmatic patients. This increased reactivity was inhibited by sodium cromoglycate (SCG) and partly inhibited by atropine. This suggests that SCG, in addition to its ability to stabilise mast cells, may also act on bronchial irritant receptors or directly on smooth muscle in asthmatic patients.

Effect of oil mists on the irritancy of sulfur dioxide. II. Motor oil.

This study examines the effect of sub-micrometer aerosols of motor oil on the irritant potency of sulfur dioxide. The increase in pulmonary flow resistance in guinea pigs was used as the bioassay of irritant response. When administered simultaneously, both unused and used motor oil protected against the irritant response to sulfur dioxide. This protective effect was lost when the oils had been previously reacted with sulfur dioxide. The additives used in the motor oil provided an equivalent protection when dissolved in a mineral oil which alone did not protect. Pre-exposure to motor oil did not provide protection. Sulfur dioxide and motor oil given together as a pre-exposure provided protection against further exposure to sulfur dioxide.