R. N. Brogden, T. Speight, G. Avery
2012
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Influential Citations
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Drugs
Abstract
SummarySynopsisSodium 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 StudiesStudies 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 F2α 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 manExperimental 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 correspondi