BRIEF COMMUNICATION

A controlled study of disodium cromoglycate in the treatment of bronchial asthma Manuel Lopez, M.D., Francis C. Lowell, M.D., and William Franklin, M.D., Boston, Mass.

Disodium cromoglycate, a chromone derivative, has been shown by others to prevent or diminish the asthmatic attack in&wed by allergenic exposure and to diminish or relieve the symptoms of asthma in a nnmher of controlled clinical trials. A double- blind crossoz)er study with 87 trials was carried out: Ir, 17 trials the drug wdp identi- fied ccs helpful, in 4 the placebo WM regarded as helpful, and there was no opinion in 6. This is strong evidence that disodinm cromoglyeate is effective in relieving symptoms in asthma (p = <Q.OI). More extensive clinical trials are reqwired to assess the clinical usefulness of the medication.

D isodium cromoglycate* is an odorless, white, hydrated crystalline pow- der moderately soluble in water but practically insoluble in alcohol.

This compound has been shown in suitable subjects to decrease the asthma attack induced by experimental exposure to an inhaled allergen.l? 2 It is not a bronchodilator, antihistaminic, or anti-inflammatory drug, and its action is distinct from that of corticosteroids. For clinical use the medication is admin- istered as a fine powder inhaled from a special dispenser.

Immunologic studies in animals have shown : (1) inhibition of wheal and flare response in monkeys when injected with allergen into skin sites passively sensitized with human skin-sensitizing antibody; (2) inhibition of anaphylaxis in marmosets with small doses of the drug given intravenously shortly before antigen challenge; and (3) substantial inhibition of homologous PCA reaction with reagin-like antibody obtained from rats sensitive to a parasite (Nippo-

From the Department of Medicine, Harvard Medical School, and the Allergy Unit, De- partment of Medicine, Massachusetts General Hospital.

Supported by United States Public Health Service Grant No. AI 02638. Received for publication Aug. 29, 1968. “Intal, Fison Pharmaceuticals, Ltd.

118

strongylus brasiliensis) when the drug was given intravenously shortly baforc: administration of antigen. 3s 4 Disodium cromoglycate did not protect sensitixetl guinea pigs against bronchospasm induced with aerosol or intravenous atlmin- istration of the antigen.2s 3 Other immunologic studies in animals have shown no interference with the normal immune reactions of the atopic or reaginic typtb.

Controlled clinical trials have been carried out in adults by Howell ant1 Rltounyan,j Kennedy,G Moran and associates,7 and Grant and associates’ and in children by Smith and DeveyQ in England. The first three studies and that b>- Smith and Devey indicated that the drug was effective in diminishing the (IX,- quency and severity of asthma; whereas in a study by Kidner and associates.‘” an effect was less certain, and that by Grant and associates failed to show a~!> difference between the drug and a placebo. The criteria for a drug eflrct in the studies describing a favorable effect included both subjective and object ivt responses of the patients; whereas in the study by Grant and associates tile single criterion adopted was a change in FEV, a criterion which ne~~crthcl~~ss gave a highly significant difference in favor of the drug in one of tilt, studicxr: cited.lO

A recent controlled clinical trialI in this eoontry indirated iI Favoral~ir effect of disodium cromoglycate on asthma.

A controlled clinical trial of disodium cromoplycatc in asthma is thcl i;uh,jwt of this report.

MATERIALS AND METHODS

Patients were selected from the Allergy Clinic of the Massachusetts Genet*al Hospital and the private practice of t,he authors. Twenty-seven trials WVI(‘V completed in 25 patients, 16 men and 11 women, ranging in age from 25 to 6-t years. All had perennial asthma defined as reversible obstructive pulmonar> disease associated with eosinophilia and had been followed for periods euccetlia~ 6 months. All required some medication for the control of symptoms, and 1,; required daily doses of steroids for maintenance of relative well-being. Skin tcisti; by both the scratch and intracutaneous methods gave intense reactions IO otl~’ or more extracts of environmental airborne allergens in 14, react,ions ol’ int cl’- mediate intensity in 8, and no significant reactions in 5. At the beginning ot‘ the trial, patients selected were clinically stable asthmatic persons requiring liitl(x or no steroids. Later, patients on larger doses of steroids were also included. “211 patients were fully informed about the nature of the study.

A double-blind trial was set up as follows: Two preparations, one containing 20 mg. of disodium cromoglycate with isoproterenol and the other lactose ilnd isoproterenol in capsules identical in taste and color, were labeled A and B in random fashion. Each patient received a 2 week supply with instructions to take one capsule 4 times daily, a total daily dose of 80 mg. of the drug. The preparations were dispensed from a specially designed inhaler which perforatect the capsule and dispersed the contents in the airstream. Pat,ients were instrwtd to inhale repeatedly until the capsule was emptied. Each patient received :I :! week supply of preparation A and at the end of this trial, a 2 week supply of preparation B.

120 Lopez, Lowell, and Franklin J. Allergy August, 1969

Each patient kept a daily record of duration and severity of symptoms and medication and was seen weekly, at which time expirogra.ms were done. The notes kept by the patients and the physician were reviewed with the patient at the end of each completed trial, and an opinion regarding the efficacy of preparations A and B was recorded before the code was broken.

X-ray of the chest and laboratory tests, including hemoglobin, hematocrit, red cell count, white cell count, differential count, sedimentation rate, urine pI1, specific gravity, albumin, sugar and sediment, blood direct and indirect bilirubin, SGOT, and protein, including electrophoresis, were performed at the beginning and at the end of the study.

RESULTS

Although expirograms were done at each visit, these were usually not help- ful in assessing the patients’ responses and are therefore not presented. The reason for this is probably our policy of maintaining patients at or near maxi- mum ventilatory values with appropriate medication. Thus the effect of the drug was discernable chiefly in terms of greater exercise capacity, less interruption of sleep, and lessened requirement for bronchodilator medication. The trials were too short to permit use of a change in steroid requirement as an indicator of drug effect. We depended, therefore, on the double-blind experimental design to assure objectivity in what was, in effect, a subjective report of the drug’s effect. The results of 27 trials are as follows: (1) opinion favored placebo in 4 trials; (2) opinion favored drug in 17 trials; (3) no opinion in 6 trials.

For purposes of analysis, one may exclude the 6 trials in which no opinion as to the relative merits of the two preparations was expressed. In the 21 remaining trials in which an opinion was expressed, the drug was correctly identified in 17 and incorrectly in 4. By chi square analysis the p value for this result is highly significant (p = <O.Ol). This is strong evidence that disodium cromoglycate is effective in relieving symptoms in asthma. Most of those correctly identifying the drug reacted intensely by scratch test, some only by intracutaneous tests, and one failed to react to any of the extracts tested by either method.

No toxic effects or changes in the biochemical and hematological measure- ments attributable to the drug were recognized during the study.

DISCUSSION

Although this study provides strong evidence that disodium cromoglycate is effective in relieving the symptoms of asthma, striking responses were not frequent, and in some trials there was some hesitation before arrival at an opinion regarding effect,iveness. Thus the effect of disodium cromoglycate given in this manner appears to be a limited one.

In general, the intensity of skin reactivity did not seem to influence the outcome of the trials. A 41-year-old steroid-dependent woman, who exhibited no skin reactions on testing, appeared to derive unquestioned benefit from the drug. She underwent two trials, correctly and unhesitatingly identified the drug in both, and has been managed very successfully while continuing to take

Controlled study of disodium cronaoglywlP It! t

the drug over a period of more than a year, durin, D which time her steroid requirement has gradually fallen. The apparent effectiveness of tht> drug in both patients with and without skin reactivity has interesting implications. if indeed, as the experimental work indicates, the drug’s action is to inhibit tXlc consequences of t.he allergic reaction, then a common pathway in the pat ho- genesis of asthma would appear to bc present in both patients lacking skin reactivity as well as in the patients having specific allergic c~aasc~s i’o~ l!je a.sthIlEl.

Our espcrience in giving disodium cromoglpcate over periods of man ths EI;IS been limited to patients requiring relatively large manitenance doses of sterc)iiIs. With disodium cromoglycate it was possible in one paGent, as mcwtiouetl, I o rcducr~ the maintenance requirement of prednisone from 20 mg per rla,~ lo 7.5 mg. and simultaneously to lessen the frequency of relapses. In ihis at~tl another patient there was a striking increase in exercise tolerance. llowcx\c>r. extensive clinical trials will be required to assess the clinical usct’11111~s c>t’ &sodium cromoglycate in the management of asthmatic patients.

REFERENCES

1. Altounyq R. E. C.: Inhibition of experimental asthma by a new compound, disotlium nromoglycate, Intal, Acta allergol. 22: 487, 1967.

2. Pepgs, J., Hargreave, F. E., Chan, M., and McCarthy, D. C.; eromoglycate on allergen-inhalation tests, Lane& 2: 137, 1968.

Inhibitory effect of disodium

3. Car, J. S. G.: Disodium cromoglycate (FPL 670) (Intal) : A specific inhibitor of reaginic antibody-antigen mechanisms, Nature 216: 13281,1967.

4. Lopez, M., and Bloch, K. J.: In preparation. 5. Howell, J. B. L., and Altounyan, R. E. C.: A double-blind trial of disodium cromogly

cate in the treatment of allergic bronchial asthma, Lancet 2: 539, 1967. 6. Kennedy, M. C. S.: Disodium cromoglycate in asthma, Lancet, 2: 838, 1967. (Letter to

t,he Editor.) 7. Moran, F., Bankier, J. D. H., and Boyd, G.: Disodium cromoglycate in the trpatment of

allergic bronchial asthma, Lancet 2: 137, 1968. 8. Grant, I. W. B., Chanel, S., and Drever, J. C.:

2: 673, 1967. (Letters to the Editor.) Disodium cromoglycate in asthma, Lancet

9. Smith, M. J., and Devey, G. F.: Clinical trial of disodium cromoglycate in t.he treatment of asthma in children, Brit. M. J. 1: 340, 1968.

10. Kidner, P. H., Pride, N. B., Meisner, P., and Pearson, R. S. B.: I&odium cromog]yp&

in the treatment of bronchial asthma, Lancet 2: t&!j, 1968. 11. Chen J. L., Moore, N., Norman, P. S., and Van Metre, T. E.: Disodium cromoglycate, a

near compound for the prevention of exacerb’ations of asthma, J. ALLERQY 43: $39, 1969.