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Sodium Cromoglycate (Cromolyn Sodium): A Review of its Mode of Action, Pharmacology, Therapeutic Efficacy and Use

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Summary

Synopsis

Sodium cromoglycate (cromolyn sodium; FPL 670)2 is a synthetic bischromone derivative advocated for use in the prophylaxis and adjunctive management of bronchial asthma. It is not intended for the treatment of acute attacks. Sodium cromoglycate does not possess direct anti-inflammatory or bronchodilator properties, but when inhaled prior to antigen bronchial challenge in asthmatic subjects it inhibits at least partially, the development of an allergic bronchial reaction.

Sodium cromoglycate is believed to act by stabilisation of mast cell membranes, thereby inhibiting the release of pharmacological mediators of anaphylaxis when the cells are triggered in a selective manner. In experimental studies in allergic subjects, sodium cromoglycate has been shown to inhibit the development of both immediate and late antigen-induced asthmatic reactions; in contrast, corticosteroids whether given orally or by inhalation, inhibit only the late response.

Numerous short-term controlled therapeutic trials have demonstrated the superiority over placebo of prophylactically administered sodium cromoglycate in children and adults with bronchial asthma. Most long-term trials have not been placebo controlled, but in the few that have, sodium cromoglycate has controlled symptoms over a long period when used in conjunction with conventional antiasthmatic therapy. Allowing for those responding to placebo, about 50% of patients given sodium cromoglycate have been adequately controlled by the drug.

The degree of symptomatic improvement in asthma symptoms has varied considerably between studies and individuals, and objective evidence of improvement has sometimes been minimal or absent in patients who improved subjectively. These variations may be related to trial design and to the varied clinical characteristics of the study population. Prophylactic sodium cromoglycate is of considerable benefit to a few patients and of some benefit to many.

Young patients, who, between moderate to severe attacks of asthma are relatively free from symptoms, often respond. There is a tendency towards a more frequent response in patients with strong evidence of allergy in whom allergy is a dominant causative factor in their asthma, and in patients in whom the drug produces considerable amelioration of post-exercise airways obstruction, but there is still no clear indication of how to select those who will benefit most from treatment. The absence of demonstrable allergy does not preclude a favourable response, just as its presence does not ensure one.

Sodium cromoglycate therapy may permit a gradual and careful reduction in maintenance dosages of corticosteroids or their complete withdrawal in a few patients.

Side-effects have generally been infrequent, mild and transient; local irritation of the throat and trachea having been reported most frequently. Skin rash has occurred rarely. In long-term studies in man there has been no evidence of sodium cromoglycate having caused radiological changes in the lungs, or any renal, hepatic or haematological abnormalities.

Pharmacological Studies

Studies in experimental animals have shown sodium cromoglycate to have no direct bronchodilator action and no anti-inflammatory or steroid-like properties. It does not antagonise the effects of histamine, SRS-A (slow reacting substance of anaphylaxis), serotonin, bradykinin, acetylcholine or prostaglandins F and E1. Sodium cromoglycate is, however, capable of inhibiting certain anaphylactic reactions in animals and bronchial reactions to inhaled antigens in man, provided it is administered before antigen challenge. Little or no inhibition of the allergic response occurs if the drug is given after antigen challenge.

The mode of action of sodium cromoglycate in bronchial asthma is believed to involve the temporary stabilisation of mast cell membranes, although its precise effect at a cellular level remains to be established. The drug does not affect either the ability of antibodies to sensitise mast cells or the interaction of antigens with cell-fixed antibodies, but probably acts at a stage subsequent to this to prevent the release of pharmacological mediators of anaphylaxis when the cells are triggered in a selective manner. Studies in various experimental models have shown that the common feature of sodium cromoglycate activity is the mast cell rather than any specific antibody type. In the rat, sodium cromoglycate was found to inhibit mast cell disruption and the release of histamine mediated by both reaginic (IgE) and non-reaginic (IgGa) antibodies, but the release of SRS-A from sensitised leucocytes was not affected. Similarly, in chopped human lung tissue passively sensitised with human reaginic serum, sodium cromoglycate inhibited the release of both histamine and the SRS-A after challenge with the appropriate antigen, but it had no appreciable effect on the release of histamine from actively sensitised human leucocytes.

Other studies have demonstrated that sodium cromoglycate can also inhibit mast cell degranulation and the release of histamine caused by non-antigenic stimuli such as phospholipase A, compound 48/80 and dextran. The inhibition of both immunologically and non-immunologically-induced mediator release is best explained on the basis of stabilisation of mast cell membranes.

An additional finding that sodium cromoglycate inhibits bronchial constriction induced in man by α-adrenergic receptor stimulation in the presence of β-adrenergic receptor blockade, suggests that the drug may also interact with adrenergic mechanisms, or that it may stabilise mast cells to the effect of α-adrenergic receptor stimulation. Although conclusive evidence for such an effect is lacking, this finding is of interest in view of the possibility that an impairment of adrenergic control mechanisms is associated with smooth muscle hyper-reactivity in asthma. A reduction in the degree of hypersensitivity to histamine has been observed in some patients, usually after prolonged sodium cromoglycate administration, and this raises the possibility that the drug may also have a direct action on bronchial smooth muscle. However, this effect may be a consequence of the drug’s antiallergic action and an overall improvement in lung function rather than a direct smooth muscle stabilising effect.

Experimental studies in man

Experimental studies in allergic subjects have shown that the inhalation of sodium cromoglycate prior to antigen challenge inhibits, at least partially, the development of immediate (type I) IgE-mediated allergic bronchial reactions. This protective effect was evident with inhalations of the drug at both 1 minute and 1 hour before antigen challenge, but when inhaled at 1, 6 and 15 minutes after antigen challenge it became progressively less effective. In most studies, complete or partial inhibition of immediate bronchial reactions (as assessed by changes in bronchial response measurements) have been reported in the majority of patients, and controlled studies have demonstrated the superiority of sodium cromoglycate over placebo. However, in 1 study it was reported that sodium cromoglycate effectively inhibited the antigen-induced asthmatic reaction in only 2 of 13 patients. The reason for the drug’s reduced efficacy in this study is not clear, but may have been related to differences in the method and duration of bronchial response measurements, the method of administration, and the antigens utilised for bronchial challenge. Also the degree and duration of protection provided by sodium cromoglycate depends on the degree of bronchial sensitivity to specific antigen challenge, and this varies in individual patients.

In addition to suppressing immediate bronchial reactions to antigen challenge, sodium cromoglycate has also been shown to inhibit the development of late reactions, including both type III late obstructive reactions in non-atopic individuals and late obstructive reactions which are not type III in nature in atopic subjects. For example, in patients with allergic pulmonary aspergillosis or dual reactions to inhalations of house dust, prior inhalation of sodium cromoglycate inhibited the development of both the immediate and late asthmatic responses. In these patients the protective effect of the drug on the late reaction was evidently due to the suppression of the introductory type I reaction. However, in patients with asthma and/or alveolitis due to avian sensitivity, sodium cromoglycate inhibited the development of type III late asthmatic and febrile reactions even when no introductory type I trigger reaction took place. This suggests that the blocking effect on type III late asthmatic responses may not necessarily be due to the inhibition of the preceding type I trigger reaction, although as yet, evidence for a direct effect on type III allergic mechanisms is lacking. In comparisons of the effects of sodium cromoglycate with corticosteroids given either orally (prednisolone) or by inhalation (beclomethasone dipropionate), it has been shown that whereas sodium cromoglycate inhibits both immediate and late antigen-induced asthmatic reactions, corticosteroids inhibit only the late response and have little or no effect on the immediate reaction.

Pharmacokinetic studies in man have shown that sodium cromoglycate is very poorly absorbed from the gastro-intestinal tract when given orally. After inhalation of the drug in powder form, less than 10% of the inhaled dose reaches the lungs, the remainder being deposited in the mouth and oropharynx and then swallowed. The amount which actually reaches the lungs is dependent to some extent on the degree of airways obstruction present, since in patients with low inspiratory flow rates, less drug is absorbed. Once sodium cromoglycate has reached the lungs it is rapidly absorbed and excreted unchanged in the urine and bile. Clearance from the lung is rapid, as approximately 97% of the inhaled dose is cleared at a rate corresponding to a half-life of 0.6 hours; the remainder is cleared at a slower rate corresponding to a half life of 1.5 hours.

Therapeutic Trials

A large number of placebo-controlled short-term studies have demonstrated the superiority of sodium cromoglycate over placebo in patients with asthma of varying severity and aetiology. Most of these studies have relied largely on subjective assessment of the therapeutic efficacy of the drug. Some degree of improvement has been reported in 34 to 100% of asthmatic patients during short-term treatment. Subjective improvement based on changes in the frequency and severity of symptoms such as wheeze, chest tightness, breathlessness, inability to sleep, cough and the number of asthmatic attacks has often not been closely correlated with changes in pulmonary function measured by spirometry performed at each weekly or fortnightly visit to the clinic. However, subjective improvement has more consistently correlated with other objective criteria such as the reduced need for concomitant therapy.

In most of the therapeutic trials of sodium cromoglycate in asthma which were published before 1970, 0.1 mg of isoprenaline was included with each 20 mg dose of sodium cromoglycate to prevent the occasional transient bronchospasm resulting from the inhalation of a dry powder. As well conducted long-term trials have indicated that the added isoprenaline is of little therapeutic advantage, findings of trials using sodium cromoglycate alone or with isoprenaline have been discussed together.

Design of Trials

All short-term therapeutic trials of sodium cromoglycate in asthma have to a greater or lesser degree based their assessment on the symptomatic changes recorded in daily diaries by the patients themselves. This has generally been supplemented by independent clinical assessment and less frequently by physiological measurements of lung function. There have been considerable differences between studies in the method of scoring individual subjective symptoms and of determining and expressing the efficacy of treatment. Comparison of results obtained in different studies is complicated by the lack of an accepted universal method of grading asthma and of objective terms to define it, and by the differing criteria for the extent of improvement, the differing composition and characteristics of the study population, the varying thoroughness of testing for allergic factors, the different standard routine medication and principles of altering its dosage and the lack of data on the extent of reversibility of airways obstruction. Also, the design of some trials was inadequate, there being no ‘run-in’ period nor an allowance for any ‘carry-over’ effect.

Symptomatic Improvement

Studies which presented results for individual patients have provided most useful information on the therapeutic efficacy of sodium cromoglycate and have indicated a wide variation in the degree of symptomatic and objective improvement. Symptom scores have improved by 1 to 100% in adults and have varied similarly in children. In the few trials in adults in which the daily change in the severity of the individual symptoms could be calculated the change was seldom marked. More commonly, changes in subjective criteria have been expressed as the average or mean for the group. Wheeze, chest tightness, breathlessness and the number and severity of attacks of asthma were most often reduced to a statistically significant degree during sodium cromoglycate therapy compared with the placebo period. In other studies, analysis of patient and/or physician preference data indicated an advantage for sodium cromoglycate over placebo.

Very favourable results in grass pollen asthma have been reported by some investigators, but others have found sodium cromoglycate to be of less value. The variability in findings may result from failing to allow for the ‘carry-over’ between treatment periods and to monitor the atmospheric pollen count.

Studies in children, which have given results in individual patients, have reported a greater or lesser degree of improvement during treatment with sodium cromoglycate in about 60 to 80% of cases. As in adults, the extent of improvement has varied considerably between individuals.

Several studies in children and in adults have recorded a reduction in the usage of aerosol bronchodilators during sodium cromoglycate compared with placebo periods. There has often been a close correlation between subjective improvement and reduced aerosol bronchodilator usage. There is no clear trend for the use of aerosol bronchodilators to be reduced more frequently in studies using sodium cromoglycate plus isoprenaline.

Lung Function Studies

About half of the studies reporting subjective improvement have also found some clear improvement in physiological measurements of lung function. This may be due to the infrequency of the measurements and to inappropriate tests. In the study showing perhaps the most convincing improvement in lung function during treatment with sodium cromoglycate, peak expiratory flow rate was measured twice daily. An improvement in peak expiratory flow rate occurred in all patients who improved subjectively. However, whilst frequent measurement of lung function is more likely to give a reliable indication of the changes in airways obstruction, statistically significant improvement in lung function during prophylactic treatment with sodium cromoglycate has been reported in several studies in which measurements of lung function were performed at intervals of 1 to 4 weeks.

The most commonly used index of airways obstruction, the FEV, has increased by an average of 7 to 27% in different studies. In the only short-term study which interposed short periods of corticosteroid treatment during treatment with either sodium cromoglycate or placebo the mean increase ascribable to sodium cromoglycate was less than 10%. An average increase of 23% after salbutamol inhalation indicated the potential for prompt improvement. Generally, in studies giving individual results there has been a trend for the lung function to improve to some degree in many of the patients who improved subjectively, but those who experienced the greatest alleviation of symptoms did not necessarily show the greatest increase in dynamic lung volumes.

Several reasons have been suggested for the lack of improvement in objective measurements of lung function in some patients who improve subjectively. Invoked most frequently, has been the possibility that a reduction in hyperinflation occurs in the absence of any appreciable increase in dynamic lung volumes, thus resulting in subexpiration. However, the relative frequency of this phenomenon in patients treated with sodium cromoglycate remains unknown, as few studies have measured static lung volumes as well as spirometric and other tests of lung function. Lack of correlation between subjective and objective criteria is probably related to many factors including the frequency of physiological measurements of lung function, the extent of initial airways obstruction and of irreversible changes, the differing bronchial reactivity in individuals and the simultaneous reduction of dosage of corticosteroids in some studies but not in others. There has been a trend for dynamic lung volumes to increase to a greater extent in patients whose lung function was less than 59% of predicted normal during placebo, which was more apparent in children than in adults. Included among these patients are probably those with labile asthma in whom the fixed component of airways resistance is small. Such patients tend to respond well to sodium cromoglycate.

Long-Term Trials

Although more valuable information concerning the therapeutic efficacy of antiasthmatic medication can be derived from long-term studies, such studies of sodium cromoglycate have generally been uncontrolled and rather poorly designed. The possible response to placebo, even after prolonged treatment, is evident from a well-designed study in which 40% of the patients on placebo were still adequately controlled at 16 weeks with a standard panel of drugs which had failed to control symptoms before the trial began. This trial, the best designed and conducted long-term trial of sodium cromoglycate in selected adult asthmatics to date, showed that fewer patients on sodium cromoglycate deteriorated than those on placebo. Patients were allocated at random to receive sodium cromoglycate plus isoprenaline, sodium cromoglycate alone, isoprenaline or placebo and to one of two dosage schedules. Patients were withdrawn from the trial if their treatment regimen failed to adequately control their symptoms. By 52 weeks treatment failure had occurred in 20% given sodium cromoglycate plus isoprenaline, in 30% on sodium cromoglycate alone, in 75% on isoprenaline and 84% given placebo. There was little difference in the failure rate between patients allocated the full dose of a sodium cromoglycate-containing regimen and those on the reducing dose. Although a multiple regression analysis was performed incorporating a wide range of pre-treatment clinical factors, because of the large number of variables involved there were too few patients in each treatment group to enable definite statistical conclusions. In all other medium- or long-term trials in adults, a placebo either has not been included or has not been allocated at random. In open long-term trials, the proportion of adult asthmatics showing some degree of objective improvement has ranged from 52 to 100%.

In a 1 year withdrawal-type trial of sodium cromoglycate in asthmatic children, 71% given sodium cromoglycate plus isoprenaline were still well controlled at the end of the trial, whereas 76% of the placebo group had withdrawn because of inadequate control of symptoms. Allowing for the response in the placebo group, this study indicates that about 50% of patients with asthma benefit from regular treatment with sodium cromoglycate and generally, is supportive of the numerous short-term trials.

In two well-designed long-term open trials in severely affected asthmatic children, sodium cromoglycate improved the patient’s ability to exercise and to play games, and produced a reduction in the frequency of asthmatic attacks, in hospital admissions and in school absenteeism and a decreased need for concomitant medication when compared with the year before treatment with the drug. In one of these studies sodium cromoglycate had a marked effect on the seasonal pattern of asthma.

Dosage of sodium cromoglycate has been adjusted in some studies although few have given results in relation to the different dosage levels.

Exercise-Induced Asthma

Single-dose studies, both uncontrolled and single- or double-blind, have demonstrated that sodium cromoglycate can ameliorate post-exercise airways obstruction if given a short time before exercise.

Exercise tests performed in known responders and nonresponders to sodium cromoglycate have suggested that those children in whom the drug causes considerable amelioration of exercise-induced asthma may also benefit from its continued administration. However, the possible correlation between amelioration of exercise-induced asthma and overall clinical usefulness has yet to be established.

Corticosteroid-Sparing Effect

Numerous short-term studies have reported that the maintenance dosage of corticosteroids can be reduced during sodium cromoglycate therapy, but results of such studies are of doubtful value and long-term studies are necessary to determine the extent of any reduction in systemic corticosteroids and whether this can be maintained over a period of several months. Although the change in corticosteroid requirements has often been employed as an objective-measure of the therapeutic efficacy of sodium cromoglycate, few studies have been adequately designed to determine the change in corticosteroid requirements. A few relatively well-designed trials have shown that prophylactic treatment with sodium cromoglycate enables a careful gradual reduction and sometimes withdrawal of systemic steroids, but that this reduction is less dramatic than that reported in many short-term studies.

The extent to which it has been possible to reduce maintenance corticosteroid requirements has varied greatly between individuals; due in part to widely differing initial corticosteroid dosages and duration of treatment, differing criteria for ‘successful’ reduction of dosage and the failure to establish that the dosage of corticosteroids received at the beginning of sodium cromoglycate therapy was the lowest necessary to control symptoms. In the best designed trial of the ‘steroid-sparing’ effects of sodium cromoglycate, a 12-week double-blind trial followed by a 6 to 12 month follow-up period indicated that a significant reduction in corticosteroid requirements or a change in the format of administration was possible in about half of the 34 children. During the follow-up period, a further reduction of 25% in corticosteroid requirements occurred in 5 of 13 patients in whom a reduction of less than 50% was possible during the double-blind phase.

It is important that any reduction of systemic corticosteroids should be attempted only when the patient’s asthma is well controlled on the usual dosage of steroid and with full doses of adjuvant therapy, that special care be taken after steroid withdrawal until the HPA axis has recovered, and that severe exacerbations of asthma be treated promptly by a large increase in dosage of corticosteroids.

Selection of Patients for Cromoglycate Therapy

Despite numerous therapeutic trials involving many hundreds of asthmatic children and adults there is still no clear indication of how to select those patients who will show objective and subjective improvement during sodium cromoglycate therapy. Generally, young patients with strong evidence of allergy and those who have a high lability index and in whom sodium cromoglycate produces a considerable amelioration in post-exercise bronchoconstriction, seem to respond favourably to the drug. However, the apparent absence of any or all of these factors does not necessarily preclude a good response, just as their presence does not ensure one. Why some asthmatic patients with some or all of the features associated with a favourable response fail to improve is unknown.

Side-effects have generally been infrequent, mild and transient and largely confined to occasional irritation of the throat and trachea resulting from the inhalation of dry powder.

Dosage is usually one capsule inhaled at intervals of 6 hours. In an occasional patient, dosage can be reduced to one capsule every 8 to 12 hours once an adequate response has been obtained. In other patients it may be necessary to double the usual dosage to achieve an adequate response. Other asthma therapy should be continued until clinical improvement permits a progressive reduction in dosage.

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Manuscript reviewed by: E.S.K. Assem, Department of Pharmacology, University College London, England; D.M. Aviado, Department of Pharmacology, University of Pennsylvania, School of Medicine, Philadelphia, USA; A.B.X. Breslin, Specialist: Chest Diseases, Repatriation General Hospital, Concord, Sydney, Australia; L.H. Capel, Consultant Physician, Royal National Throat, Nose and Ear Hospital, London, England; H. Chai, Director, Hospital Services, Children’s Asthma Research Institute and Hospital, Denver, Colorado, USA; I. Engstrom, Pediatric Department, Karolinska Sjukhuset, Stockholm, Sweden; K.D. Fitch, Medical Consultant, Department of Physical Education, University of Western Australia, Nedlands, Perth, Australia; R.M. Ford, Specialist: Allergic Disorders, Adelaide, Australia; J.D. Gökemeyer, Academisch Ziekenhuis Groningen, The Netherlands; I.W.B. Grant, Respiratory Unit, Northern General Hospital, Edinburgh, Scotland; J.B.L. Howell, Faculty of Medicine, Southampton General Hospital, Southampton, England; J.H. Lee, Honorary Thoracic physician, Royal Prince Alfred Hospital, Sydney, Australia; J.B. Mackay, Chest Department, Wellington Hospital, Wellington, New Zealand; A.R. Morton, Department of Physical Education, University of Western Australia, Nedlands, Perth, Australia; N.G.M. Orie, Academisch Ziekenhuis Groningen, Kliniek Voor Inwendige Ziekten, The Netherlands; K.N.V. Palmer, Department of Medicine, University of Aberdeen, Aberdeen, Scotland; J. Pepys, Department of Clinical Immunology, Cardiothoracic Institute, Brompton, London, England; P.D. Phelan, Clinical Research Unit, Royal Children’s Hospital, Melbourne, Australia; A.S. Rebuck, Cardio-Respiratory Unit, McMaster University Medical Centre, Hamilton, Ontario, Canada; H. Shioda, The Sagamihara National Hospital, Kanagawa-ken, Japan; H. Tanimoto, Department of Respiratory Disease, Toranomon Hospital, Tokyo, Japan; G. Taylor, Department of Bacteriology and Virology, Immunology Laboratories, University of Manchester, Manchester, England; K. de Vries, Academisch Ziekenhuis Groningen, The Netherlands; Y. Yamamura, 3rd Department of Internal Medicine, Osaka University Hospital, Osaka, Japan.

See subject index in each issue for further indexing terms.

‘Aarane’ (Syntex); ‘Inostral’, ‘Intal’, ‘Lomudal’, ‘Rynacrom’, FPL670 (Fisons).

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Brogden, R.N., Speight, T.M. & Avery, G.S. Sodium Cromoglycate (Cromolyn Sodium): A Review of its Mode of Action, Pharmacology, Therapeutic Efficacy and Use. Drugs 7, 164–282 (1974). https://doi.org/10.2165/00003495-197407030-00002

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