Comparison of the protective effects of cromolyn sodium and nedocromil sodium in the treatment of exercise-induced asthma in children Fernando M. de Benedictis, MD, Gianluca Tuteri, MD, Albert0 Bertotto, MD, Lucia Bruni, and Renato Vaccaro, MD Pen&a, iculy Seventeen children with asthma were studied in a double-blind, crossover, placebo-controlled study designed to compare the efficacy of cromolyn sodium with that of nedocromil sodium in preventing exercise-induced asthma. All drugs were delivered through a metered-dose inhaler (cromolyn sodium 10 mg; nedocromil sodium 4 mg; placebo, two puffs). Nedocromil sodium and cromolyn sodium provided signijicant, comparable protection from exercise-induced asthma, and both drugs were better than placebo. We conclude that nedocromil sodium and cromohm sodium administered by a pressurized aerosol provide equal protection against exercise-induced asthma in children. (JALLERGY CLIN IMMNOL 1994;94:684-8.) Key words: Exercise-induced asthma, cromolyn sodium, nedocromil sodium, children Cromolyn sodium (SCG) and nedocromil so- dium (NCS) are commonly used in the manage- ment of asthma. NCS exhibits a considerable protective effect on the mucosal mast cells both in vivo and in vitro, whereas SCG has little effect.‘, ’ Because of its protective action on mast cells, NCS has been considered more protective than SCG in the treatment of exercise-induced asthma (ETA).’ SCG and NCS for preventing EIA have been compared in some studies in aduIts,3,4 but to date there is only one report on children.’ No com- parative data are available on the effects of these two drugs at specific postexercise time points in children with asthma. Our study therefore com- pared the efficacy of NCS and SCG, both admin- istered by metered-dose inhaler (MDI), in pre- venting EIA in children. METHODS The study had a double-blind, randomized, cross- over, placebo-controlled design. Seventeen subjects (11 From Clinica Pediatrica, University of Perugia, Perugia, Italy. Received for publication Aug. 24, 1993; revised Apr. 1, 1994; accepted for publication Apr. 5, 1994. Reprint requests: Fernando M. de Benedictis, MD, Clinica Pediatrica, Policlinico Monteluce, 06123 Perugia, Italy. Copyright 0 1994 by Mosby-Year Book, Inc. 0091-6749/94$3.00 + 0 l/1/56599 Abbreviations used EIA: Exercise-induced asthma FEV,: Forced expiratory volume in 1 second MDI: Metered-dose inhaler NCS: Nedocromil sodium SCG: Cromolyn sodium male, 6 female) aged 7 to 15 years (mean 10.2 * 2.2 years) were recruited. All patients attended the Pedi- atric Asthma Clinic at Perugia General Hospital and had asthma as defined by the American Thoracic Soci- ety.6 All subjects had previously demonstrated a consis- tent drop in forced expiratory volume in 1 second (FEV,) of at least 15% from baseline after a 6-minute standard treadmill exercise screening test. They were being treated with different antiasthmatic regimens, such as sustained-release theophylline, p-agonists, SCG, ‘NCS, and inhaled steroids; no patients were undergoing therapy with oral steroids. Sustained-re- lease theophylline was withheld for 24 hours and other drugs were withheld for 12 hours before each exercise test. None of the subjects had a history of respiratory infection in the 4 weeks before the trial. Informed consent was obtained from patients and their parents, and the protocol was approved by the hospital ethics committee. The screening test consisted of steady-state running for 6 minutes on a treadmill inclined to produce a heart 664
Transcript
Comparison of the protective effects of cromolyn sodium and nedocromil sodium in the treatment of exercise-induced asthma in children
Fernando M. de Benedictis, MD, Gianluca Tuteri, MD, Albert0 Bertotto, MD, Lucia Bruni, and Renato Vaccaro, MD Pen&a, iculy
Seventeen children with asthma were studied in a double-blind, crossover, placebo-controlled study designed to compare the efficacy of cromolyn sodium with that of nedocromil sodium in preventing exercise-induced asthma. All drugs were delivered through a metered-dose inhaler (cromolyn sodium 10 mg; nedocromil sodium 4 mg; placebo, two puffs). Nedocromil sodium and cromolyn sodium provided signijicant, comparable protection from exercise-induced asthma, and both drugs were better than placebo. We conclude that nedocromil sodium and cromohm sodium administered by a pressurized aerosol provide equal protection against exercise-induced asthma in children. (JALLERGY CLIN IMMNOL 1994;94:684-8.)
Key words: Exercise-induced asthma, cromolyn sodium, nedocromil sodium, children
Cromolyn sodium (SCG) and nedocromil so- dium (NCS) are commonly used in the manage- ment of asthma. NCS exhibits a considerable protective effect on the mucosal mast cells both in vivo and in vitro, whereas SCG has little effect.‘, ’ Because of its protective action on mast cells, NCS has been considered more protective than SCG in the treatment of exercise-induced asthma (ETA).’
SCG and NCS for preventing EIA have been compared in some studies in aduIts,3, 4 but to date there is only one report on children.’ No com- parative data are available on the effects of these two drugs at specific postexercise time points in children with asthma. Our study therefore com- pared the efficacy of NCS and SCG, both admin- istered by metered-dose inhaler (MDI), in pre- venting EIA in children.
METHODS The study had a double-blind, randomized, cross-
male, 6 female) aged 7 to 15 years (mean 10.2 * 2.2 years) were recruited. All patients attended the Pedi- atric Asthma Clinic at Perugia General Hospital and had asthma as defined by the American Thoracic Soci- ety.6 All subjects had previously demonstrated a consis- tent drop in forced expiratory volume in 1 second (FEV,) of at least 15% from baseline after a 6-minute standard treadmill exercise screening test. They were being treated with different antiasthmatic regimens, such as sustained-release theophylline, p-agonists, SCG, ‘NCS, and inhaled steroids; no patients were undergoing therapy with oral steroids. Sustained-re- lease theophylline was withheld for 24 hours and other drugs were withheld for 12 hours before each exercise test. None of the subjects had a history of respiratory infection in the 4 weeks before the trial. Informed consent was obtained from patients and their parents, and the protocol was approved by the hospital ethics committee.
The screening test consisted of steady-state running for 6 minutes on a treadmill inclined to produce a heart
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rate of at least 85% of the maximum predicted for age7 After screening, in random, blinded order and on three separate days, each patient was tested with different treatments inhaled by MDI: SCG (5 mg twice), NCS (2 mg twice), or placebo (two puffs). The drugs were administered by a trained physician, and all the patients were skilled in the: use of MDIs. The “closed lip” technique was used. For two patients a spacer device was added to the MD1 to improve compliance. The patients performed the exercise test 20 minutes after inhalation of each drug. Each patient always performed tests at the same time of the day, and all four tests were completed within 10 days.
Room temperature and relative humidity were moni- tored in a climate chamber. Differences of 1” C in temperature and 5 mg H,O/L of air in humidity on the test days of each patient were considered acceptable.* Room temperatures ranged from 21” to 23” C, and relative humidity ranged from 48% to 58% on the different study days.
Pulmonary function was measured with a turbine spirometer (Pocket Spirometer I; Micro Medical Lim- ited, Rochester, Kent, United Kingdom) according to accepted standards.” ” Predicted normal values for spirometry were obtained from the study of Knudson et al.” All children were already familiar with the spirom- eter. Measurements were performed before drug inha- lation (baseline value), before every exercise test (pre- exercise value), and then 3, 5, 10, 15, and 30 minutes after the end of exercise. Heart rate was also measured before and immediately after the exercise. The exercise test was performed only if the baseline FEV, was greater than 70% of the mean predicted for the child’s height and if the baseline FEV, varied less than 10% from the values on previous test days. The maximum percentage drop in FEV, and the percentage of pro- tection of FEVr were calculated from the results of the pulmonary function tests:
Maximum % drop in FEV, = Preexercise FEV, - Lowest postexercise FEV,
Preexercise FEV,
% Protection = T PI
where Ps is the percentage drop in FEV, at the screen- ing test and Pr is the percentage drop in FEV, after each treatment.
Complete protection was considered to have been obtained if the percentage drop in FEV, was within the normal range (< lO%).” Clinical protection was con- sidered to have been obtained if the percentage fall after receiving the active drug was half or less of the percentage drop after receiving placebo.13
Analysis of variance was used for repeated measures and Student’s t test, including the Bonferroni adjust- ment, was used for paired data. Differences were con- sidered significant at ap value of less than 0.05.
TABLE I. Maximum percentage drops in FEV, after exercise
RESULTS The mean predrug baselines FEV, were 1.82 L
(103% of predicted), 1.84 L (105%) and 1.83 L (105%) for SCG, NCS, and placebo, respectively, with no statistically significant differences in these values. None of the treatments caused significant changes in FEV, before the exercise test (1.81 L, 1.84 L, and 1.82 L, respectively for SCG, NCS, and placebo). No statistically significant differ- ences emerged in preexercise values in the three groups.
The mean maximum percentage drops in FEV, (+- standard deviation) in the screening test, after placebo, after SCG, and after NCS were 31.1% 1 13.8%,27.4% +- 17.3%, 14.0% ? 14.6%, 14.4% ? ll.l%, respectively (Table I). Both SCG and NCS were significantly more protective than placebo (SCG,p < 0.0001; NC&p < 0.001) but there was no significant difference between SCG and NCS. Complete protection was provided to 53% (9 of 17) 53% (9 of 17), and 12% (2 of 17) of subjects by SCG, NCS, and placebo, respectively. Only 35% of patients (6 of 17) received complete protection from both active drugs (Table II).
The protection percentages were 59.6% 5 28.1%, 56.3% & 29.3%, and 23.8% & 26.6% for SCG, NCS, and placebo, respectively. A protec- tion value greater than 50% (clinical protection) was obtained in 59% of patients treated with SCG
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Time
0 3 5 10 15 30
0
-25
SCG-NCS vs.plscabo:’ p < O,OOl;*‘p < 0,Ol
- SCG - NCS -f- Placebo + Screening
FIG. 1. Percentage drop in FEV, in response to exercise after administration of SCG, NCS, placebo, and no therapy (screening). At all times studied, both SCG and NCS showed significant differences from placebo but not from each other.
Mean 23.8 59.6 56.3 Standard deviation 26.6 28.1 29.3
(10/17), in 70% treated with NCS (12/17), and in 6% who received placebo (l/17). Both SCG and NCS were significantly better than placebo, but there was no statistically significant difference between the active drugs.
Percentage changes from preexercise levels at each of the time points after challenge were also compared. At each time after the exercise chal-
lenge, the percentage drop in FEV, with SCG and NCS was significantly lower than with placebo. No statistically significant difference was seen be- tween SCG and NCS at any postexercise time (Fig. 1).
DISCUSSION
NCS, a new, nonbronchodilating, antiasthmatic drug, is said to be better than SCG in some in vivo and in vitro studies.‘, 2 It has been reported effective in inhibiting EIA in adults,3s 4* I4 adoles- cents,” and children.‘6“8 Surprisingly, only a few studies have compared the protective effects of NCS and SCG in the treatment of EIA.3W5, l4 Furthermore, the method of inhalation and the doses used in each study were quite different, making comparison difficult.
Our study shows that SCG (10 mg) and NCS (4 mg) inhaled through an MD1 give comparable protection against EIA and that both drugs are more. effective than placebo. Morton et a1.3 re- ported that the percentage of adults completely protected from EIA was higher after treatment with NCS (62.5%) than after treatment with SCG (25%). Because SCG was administered at a low dosage, however, these results may have been distorted.3
The percentages of patients with complete pro- tection from EIA in our study were 53% (9 of 17) for NCS and 53% (9 of 17) for SCG, which is lower than reported by Novembre et a1.19 in chil-
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dren (73% for NCS, 47% for SCG). These au- thors, however, selected a 15% drop in FEV, as a cutoff for complete protection, as opposed to our choice of less than 10%. Because the pharmaco- logic protection from EIA is related to severity of EIA after no medication,3 the relative low level of protection in our study when compared with those seen in other studies3* lp could also be explained by the severity of EIA in our patients. In fact, most of our patients had moderate or severe EIA at the screening test. In addition, because the NCS dose of 4 mg by MD1 lies near the top of the dose-response curve,14 it is unlikely that better protection could have been obtained by increasing the dose of the drug.
The inhibitory effect of SCG on EIA is dose related, whether given by nebulization” or MDI.2’ A 20 mg dose of SCG aerosol provided the same protection as 12 mg of nebulized solution, whereas 20 mg delivered by a Spinhaler (Fisons Corp., Rochester, N.Y.) protected better than 1 mg given by MDI.Z2 The 2 mg dose that is ordinarily prescribed in some countries appears to be suboptimal for many patients; in our view, a 10 mg aerosol dose of SCG should be recommended for preventing EIA.
When recommended clinical doses are admin- istered by MDI, both in children5 and in adults,4 SCG and NCS are equally effective in preventing EIA. Two of our children used a spacer device for a better compliance in inhalation, but this tech- nique did not modify the results obtained with a simple MDI.’
The effects of NCS and SCG were also similar when the percentage drop in FEV, was observed at each time point after the challenge. When the values obtained after treatment with both active drugs were compared with those recorded after placebo administration, a significant improvement was found at each postexercise time point. K(inig et a1.4 evaluated the duration of EIA in adults after preexercise treatment with SCG and NCS by measuring the area under the curve for the per- centage drop in FEV,; no significant difference between SCG and NCS was found at any point in time. The longer duration of EIA after treatment with SCG compared with NCS described by Mor- ton et aL3 may be explained by the nonequivalent dosages.
A statistically significant effect of a drug on EIA does not necessarily indicate that the effect is clinically important. We therefore also evalu- ated the protection percentage against EIA as an index of good clinical control. This analysis
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yielded the same results as the analysis of the percentage drop in FEV, itself.
The phenomenon of poor concordance between the FEV, drops after screening and placebo that occurred in some of our patients is well known and can make estimates of real protection from EIA difficult at times. In this study, however we used the smallest drop in FEV, as baseline whether regardless screening or placebo, and the results were not altered significantly.
We conclude that SCG (10 mg) and NCS (4 mg) administered by a pressurized aerosol provide equal protection against EIA in children. Further studies are needed to clarify whether there are differences in the duration of action in inhibiting EIA between these two antiasthmatic drugs.
We thank Dr. Geraldine Anne Boyd for her valuable help.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Eady RP, Greenwood B, Jackson DM, Orr TS, Wells E. The effect of nedocromil sodium and sodium cromoglycate on antigen-induced bronchoconstriction in the Ascar& sensitive monkey. Br J Pharmacol 1985;85:323-5. Leung KB, Flint KC, Brostoff J, Hudspith BN, Johnson NM, Pearce FL. A comparison of nedocromil sodium and sodium cromoglycate on human lung mast cells obtained by bronchoalveolar lavage and by dispersion of lung frag- ments. Eur J Respir Dis 1986;69(Suppl 147):223-6. Morton AR, Ogle SL, Fitch KD. Effects of nedocromil sodium, cromolyn sodium, and a placebo in exercise- induced asthma. Ann Allergy 1992;68:143-8. Ktinig P, Hordvik NI, Kreutz C. The preventive effect and duration of action of nedocromil sodium and cromolyn sodium on exercise-induced asthma (EIA) in adults. J ALLERGY CLIN IMMUNOL 1987;79:64-8. Comis A, Valletta EA, Sette L, Andreoli A, Boner AL. Comparison of nedocromil sodium and sodium cromogly- cate administered by pressurized aerosol, with and without a spacer device in exercise-induced asthma in children. Eur Respir J 1993;6:523-6. American Thoracic Society. Chronic bronchitis, asthma, and pulmonary emphysema. Am Rev Respir Dis 1962;85: 762-8. Eggleston PA, Rosenthal RR, Anderson SA, et al. Guide- lines for the methodology of exercise challenge testing of asthma. J ALLERGY CLIN IMMUNOL 1979;64:642-6. Anderson SD, Schoeffel RE, Follet R, Perry CP, Daviskas E, Kendall M. Sensitivity to heat and water loss at rest and during exercise in asthmatic patients. Eur J Respir Dis 1982;63:459-63. Taussig LM, Chernick V, Wood R, Farrell P, Mellins RB. Standardization of lung function testing in children. J Pediatr 1980;97:668-76. American Thoracic Society. Statement: Snowbird work- shop on standardization of spirometry. Am Rev Respir Dis 1979;119:831-8. Knudson RJ, Slatin RC, Lebowitz MD, et al. The maximal expiratory flow-volume curve: normal standards, variabil-
666 de Benedictis et al. J ALLERGY CLIN IMMUNOL
OCTOBER 1994
ity, and effects of age. Am Rev Respir Dis 1976;113:587- 600.
12. Silverman M, Anderson SD. Standardization of exercise tests in asthmatic children. Arch Dis Child 1972;47:882-7.
13. Silverman M, Konig P, Godfrey S. The use of serial exercise tests to assess the efficacy and duration of action of drugs for asthma. Thorax 1973;28:574-8.
14. Albazzaz MK, Neale MG, Pate1 KR. Dose-response study of nebulized nedocromil sodium in exercise induced asthma. Thorax 1989;44:816-9.
15. Debelic M. Nedocromil sodium and exercise induced asthma in adolescents. Eur J Respir Dis 1986;69(Suppl 147):266-7.
16. Chudry N, Correa F, Silverman M. Nedocromil sodium and exercise induced asthma. Arch Dis Child 1987;62: 412-4.
17. Henriksen JM. Effect of nedocromil sodium on exercise- induced bronchoconstriction in children. Allergy 1988;43: 449-53.
18. Boner AL, Vallone G, Bennati D. Nedocromil sodium in exercise-induced bronchoconstriction in children. Ann Al- lergy 1989;62:38-41.
19. Novembre E, Veneruso G, Frongia G, Lombardi E, Tucci F, Vierucci A. Inhibition of exercise-induced asthma by nedocromil sodium and cromoglycate in children [Ab- stract]. J ALLERGY CLIN IMMUNOL 1993;91(Suppl):168.
20. Pate1 KR, Berkin KE, Kerr JW, Dose-response study of sodium cromoglycate in exercise-induced asthma. Thorax 1982;37:663-6.
21. Tullett WM, Tan KM, Wall RT, Pate1 KR. Dose-response effect of sodium cromoglycate pressurized aerosol in ex- ercise induced asthma. Thorax 1985;40:41-4.
22. Bar-Yishay E, Gur I, Levy M, Volozny D, Godfrey S. Duration of action of sodium cromoglycate on exercise induced asthma: comparison of 2 formulations. Arch Dis Child 1983:58:624-7.
