A multicenter evaluation of the clinical benefits of cromolyn sodium aerosol by metered-dose inhaler in the treatment of asthma

The efficacy and safety of cromolyn sodium by metered-dose inhaler (MDI) (1 mg per actuation) was evaluated with a double-blind, placebo-controlled, parallel-study design. Subjects with asthma, aged 8 to 58 years, whose asthma was well controlled taking cromolyn sodium capsules by Spinhaler turboinhaler, plus beta 2-agonists, entered the study after being maintained with cromolyn sodium capsules for a minimum of 4 weeks. The investigation began with a 2-week control interval with cromolyn sodium capsules followed by a 4-week single-blind period with placebo capsules. Subjects whose asthma significantly worsened while they were receiving placebo therapy were then randomized to a 10-week double-blind phase in which they received either active cromolyn sodium or placebo by MDI. Efficacy variables included diary data, physician evaluation, and spirometry. Comparisons were made between baseline period scores and each assessment variable over time. Of 155 subjects entered, 93 qualified for the double-blind, randomized phase. Eighty-three subjects completed the study and were analyzed. At baseline there existed no significant differences between the active-treatment and placebo-treatment groups. Significant differences (p less than 0.05) in favor of the cromolyn sodium-treatment group, however, were noted at all time points for daily diary symptoms (cough, breathlessness, and overall asthma severity), physician's assessments at each clinic visit, physician's and patient's overall final assessments, FEV1 at each clinic visit, and FVC and peak expiratory flow rate at the final visit. Concomitant bronchodilator medication use was less in the cromolyn sodium-treatment group. Cromolyn sodium by MDI is highly effective for (1) controlling asthmatic symptoms, (2) improving lung functions, and (3) decreasing the need for concomitant bronchodilators.     

A controlled study on the effect of treatment with cromolyn sodium pressurized aerosol on bronchial reactivity in patients with asthma

The effect of cromolyn sodium (CS) pressurized aerosol on bronchial hyperreactivity was assessed by comparison with placebo in a double-blind crossover study of 14 adult patients with clinically stable asthma. The trial was performed in a cold climate during the pollen-free winter months and the patient's risk of exposure to clinically relevant allergens was judged to be low. The dose was two puffs, each of 1 mg CS or placebo, four times daily over two successive 4-week periods, the order of treatment being decided by random allocation. No significant difference between treatments was observed in bronchial reactivity to histamine, determined as PC15. There was no difference between treatments with regard to symptoms, which were slight, or daily peak expiratory flow recordings, which showed minimal circadian variation. The results suggest that, although prolonged treatment with CS may decrease bronchial reactivity by reducing airway inflammation secondary to the assault of allergic stimuli, the drug probably has little or no effect on the basal bronchial reactivity in asthma.     

The preventive effect and duration of action of nedocromil sodium and cromolyn sodium on exercise-induced asthma (EIA) in adults

Nedocromil sodium, 4 mg, from a metered-dose inhaler, cromolyn sodium, (cr) 20 mg, from a Spinhaler, and placebo (pl) were compared in their efficacy and duration of action in preventing exercise-induced asthma. Twelve patients with asthma performed treadmill exercise tests 20 minutes, 2 hours, and 4 hours after a single dose of drug in a double-blind, crossover trial. Both active drugs were significantly better than pl at 20 minutes. Two hours after drug administration, only cr was significantly different from pl. The direct comparison between nedocromil and cr demonstrated no significant difference on FEV1, and the only significant difference was with forced expiratory flow between 25% and 75% of vital capacity at 2 hours. It is concluded that at these clinically recommended doses, both drugs are equally effective in preventing exercise-induced asthma with cr possibly having a somewhat longer duration of action.     

Comparison of sodium cromoglycate pressurized aerosol and powder in the treatment of asthma

The effect of a pressurized aerosol formulation of sodium cromoglycate divided in doses of 8 mg a day was compared with that of a standard sodium cromoglycate powder (80 mg a day) in a double blind crossover trial lasting 16 weeks. No significant differences between the two formulations were detected in terms of patients' asthma severity and lung function, recorded monthly at the clinic and daily by the patients. The pressurized aerosol in a much smaller dose appears to be as effective a method as standard cromoglycate, and an alternative method of inhaling sodium cromoglycate for patients who prefer an aerosol to a dry powder formulation.     

Levocabastine versus cromolyn sodium in the treatment of pollen-induced conjunctivitis

Thirty patients with allergic conjunctivitis, caused by Parietaria or grass pollens, participated in a double-blind parallel study comparing levocabastine to cromolyn sodium, both given as eye drops. Symptom and sign scores were recorded during a 4-week period. The patients received only these drugs during the time of observation. The evaluation of the clinical signs and symptoms by the clinicians and by the patients revealed a significant improvement of conjunctivitis in all patients. The intergroup comparison was equal in the two groups treated respectively with levocabastine and cromolyn. Therefore, levocabastine and cromolyn are effective in the treatment of pollen-induced allergic conjunctivitis.     

Effects of nedocromil sodium, cromolyn sodium, and a placebo in exercise-induced asthma.

The incidence and severity of exercise-induced asthma were determined in nineteen asthmatic patients who performed eight minutes of exercise following four treatments administered in a random order. The treatments were nedocromil sodium, cromolyn sodium, placebo, and no treatment. It was concluded that nedocromil sodium (8 mg) and cromolyn sodium (4 mg) provide equal protection against exercise-induced asthma.     

Topical cromolyn (disodium cromoglycate) solution in the treatment of young children with atopic dermatitis

A double-blind, randomized-group comparative trial was conducted to assess the therapeutic effect of cromolyn solution on atopic dermatitis in young children (less than 3 yr old). Topically applied cromolyn solution was found to be very effective, improving dermatitis, itching and sleep disturbance, with no untoward effects.     

Comparison between sodium cromoglycate (MDI: metered-dose inhaler) and beclomethasone dipropionate (MDI) in treatment of adult patients with mild to moderate bronchial asthma A double-blind, double-dummy randomized, parallel-group study

This study compared the efficacy and tolerability of sodium cromoglycate (SC) and beclomethasone dipropionate (BDP) in adult patients with bronchial asthma inadequately treated with bronchodilators alone. The study was a double-blind, randomized, double-dummy, parallel-group study. Patients with mild to moderate symptomatic asthma, inadequately treated with bronchodilators only, were, after a 2–week run-in (base-line) period, randomized to 8 weeks of treatment with either SC 10 mg four times daily or BDP 100 μg four times daily. Salbutamol metered-dose inhaler was given as relief medication. A total of 37 patients were randomized for treatment, 19 patients in the SC group and 18 patients in the BD group. Efficacy and safety were determined by daily record card data: morning and evening peak-expiratory-flow rates (PEER), daytime and nighttime asthma symptom scores, and rescue salbutamol use. At clinic visits, FEV₁ and FVC were measured, as were the physician's and the patient's assessment of the medication at the end of the study. The safety and tolerability of the trial medication were assessed by monitoring adverse events throughout the study. A clinically and statistically significant improvement of the asthma in FEV₁, symptom scores, rescue medication, and global opinion of efficacy was observed, and both groups provided equivalent efficacy. The morning PEFR as well as the evening PEFR for both groups improved, but was statistically significant only for the BDP group (M-PEFR). Both drugs were well tolerated with only a few minor adverse events. This trial shows that SC and BDP are equally effective anti-inflammatory treatments for mild to moderate bronchial asthma in adults.     

Nedocromil sodium and cromolyn (sodium cromoglycate) selectively inhibit antibody-dependent granulocyte-mediated cytotoxicity

Nedocromil sodium and cromolyn (sodium cromoglycate) are prophylactic agents in asthma which were initially found to be inhibitors of mast cell activation. Recent evidence has suggested that their effects on granulocyte-mediated reactions may contribute to their therapeutic effects. Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF) enhance the activity of granulocytes in antibody-dependent cell-mediated cytotoxicity (ADCC). Preincubation of purified neutrophils or eosinophils with nedocromil sodium or cromolyn partially inhibited their ability to mediate ADCC when stimulated by GM-CSF or TNF. Preincubation with nedocromil sodium did not alter the ability of neutrophils to produce superoxide or release lysozyme in response to soluble or phagocytic stimuli, and GM-CSF-enhanced superoxide production triggered by chemotactic peptide was not altered in such drug-treated neutrophils. After nedocromil sodium treatment, neutrophils showed no consistent changes in TNF-stimulated adherence to either plastic culture wells or umbilical vein endothelium. These findings demonstrate that nedocromil sodium and cromolyn directly and selectively affect the function of granulocytes in vitro. While drug-treated granulocytes were impaired in immune-directed cytotoxicity stimulated by GM-CSF or TNF, activation of other granulocyte functions by the same stimuli was intact.     

The effect of thymoxamine and cromolyn sodium on postexercise bronchoconstriction in asthma.

Of the 22 patients with extrinsic bronchial asthma, 13 patients developed post-exercise bronchoconstriction after treadmill exercise, whereas in 9 patients treadmill exercise had no effect on the ventilatory capacity. No statistical difference in the resting lung volumes and CO transfer factor was found between the two groups. A significant inhibition of postexercise bronchoconstriction was observed in 12 of 13 patients following thymoxamine or cromolyn sodium inhalation. Inhibition of postexercise bronchoconstriction by alpha blockade with thymoxamine suggests that increased alpha adrenergic activity in the presence of diminished beta receptor responsiveness to catecholamines, norepinephrine released during exercise could have a marked alpha agonistic effect giving rise to bronchoconstriction. It has been suggested that cromolyn sodium has a cyclic phosphodiesterase inhibiting action. This might increase levels of AMP and restore the beta receptor responsiveness to catecholamines.     

The relative merits of cromolyn sodium and high-dose theophylline therapy in childhood asthma

The use of cromolyn sodium (SCG) and high-dose theophylline (HDT) in the treatment of chronic perennial asthma in children is reviewed. It is noted that the regimens are only suitable for children with persistent symptoms uncontrolled by simpler forms of treatment. The methods of administration and dosage based on pharmacologic data are considered, and the potential importance of long-acting theophylline and nebulized cromolyn preparations is noted. Short-term studies have confirmed the efficacy of both drugs, and a comparative study showed little difference between them. Long-term studies of SCG have demonstrated its value to some 66% of children without serious side effects. No formal long-term studies have been carried out on HDT. Side effects from theophylline can often be eliminated by careful control of blood levels. From published evidence, neither SCG nor HDT is effective in steroid-dependent asthmatic children, and they contribute little, if anything, to management in such cases. The difference in cost of the drugs is small when all factors are considered, and either regimen is justified by the saving in medical expenses when used for carefully selected patients.     

Evaluation of procaterol and albuterol (salbutamol) aerosol in the treatment of asthma.

Procaterol aerosol (10 micrograms/inhalation) was compared to albuterol (salbutamol) aerosol (100 micrograms/inhalation), two inhalations t.i.d. or q.i.d., in 333 outpatients with reversible bronchial airway obstruction over a 12-week period in a double-blind randomized and parallel study. Predose and postdose pulmonary function tests (PFTs) were performed initially and after 2, 4, 8, and 12 weeks of therapy. Patients maintained a daily diary of asthma symptom scores. A significantly higher percentage of patients receiving procaterol (59%) continued therapy on a t.i.d. schedule rather than a q.i.d. schedule compared with patients receiving albuterol (48%, P less than .05). Pulmonary function tests indicated similar improvement in both groups. Clinically significant improvement in mean FEV1 was maintained for four to seven hours postdose for procaterol and for three to six hours for albuterol. Adverse experiences were reported in 15% of procaterol-treated patients and 17% of albuterol-treated patients. Headache and tremor were most frequent, with no significant differences in frequencies between groups. Both procaterol and albuterol were highly effective in improving pulmonary function and controlling symptoms of asthma; both were well tolerated. Procaterol had a longer duration of action, and more patients were controlled on a t.i.d. dosage regimen.     

Clinical, physiologic, and psychologic comparison of treatment by cromolyn or theophylline in childhood asthma

Treatment of chronic perennial childhood asthma with cromolyn sodium (CS) or long-acting theophylline (LAT) was compared in 13 children by a double-blind, cross-over trial in which each drug was administered for 4 wk. LAT was administered twice daily in individual doses to elicit adequate blood levels (mean 14.0 +/- 1.6 SEM, micrograms per milliliters). Powdered CS was administered by inhalation in a dose of 20 mg four times daily. The patients were followed by means of a daily symptom and drug consumption diary and twice daily peak flow measurements. A series of psychologic studies were performed in the third week of each month. Exercise and histamine bronchial provocation tests were performed at the end of each month. There were no significant differences between the month in which CS was taken and the month in which LAT was taken in terms of diary scores, peak flow rates, additional drug consumption, or in bronchial reactivity to exercise or histamine at the end of each month. The results of psychologic tests reflecting visual-spatial planning were significantly better for the four children receiving CS with lower IQ scores (87 to 105) but not for the nine children with higher IQ scores (111 to 134). The possibility that the psychologic performance of children with lower intelligence may be adversely affected by theophylline requires further evaluation.     

Evaluation of the addition of cromolyn sodium to bronchodilator maintenance therapy in the long-term management of asthma

Three hundred ninety-seven patients, aged 5 to 63 years, took part in a year-long international multicenter, double-blind, placebo-controlled trial. The patients, whose asthma was considered not adequately controlled, were divided into two groups according to their principal medication at entry (group A, oral and/or inhaled beta 2-bronchodilators; group B, methylxanthines, with or without beta 2-agonists) and randomly allocated to additional treatment with cromolyn sodium (metered-dose inhaler, 2 mg, four times a day, or capsules, 20 mg, four times a day) or matching placebo. A 2-month baseline preceded 10 to 12 months of treatment. After 4 to 8 weeks of treatment, patients were encouraged to reduce bronchodilator usage. Patients used diary cards to record asthma severity, sleep difficulty, morning and evening peak expiratory flow rates, days of disruption of normal activity, use of test treatments, and concomitant medication. Significant differences favoring cromolyn sodium (p less than 0.05 and better) were observed for most of the treatment period in respect to (1) asthma severity, (2) morning and evening peak expiratory flow rates, and (3) days of disruption of normal activity. Patients receiving cromolyn sodium experienced fewer exacerbations and tended to use less concomitant medication than patients receiving placebo. Patients' opinions of treatment significantly favored cromolyn sodium. These results demonstrate the value of the addition of cromolyn sodium to existing therapy in the long-term management of asthma and endorse its use as a first-line treatment.