Cromolyn Sodium

233:327-37 40 Morris HG. Drug-induced desensitization of beta adrenergic receptors. J Allergy Clin Immunol 1980; 65:83-86 41 Svedmyr NL, Larsson SA, Theringer GK: Development of 'resistance' in beta adrenergic receptors of asthmatic patients. Chest 1976; 69:479-83 42 Jenne JW. Wither beta-adrenergic tachyphylaxis? J Allergy Clin Immunol 1982; 70:413-16 43 Wilson JD, Sutherland DC, Thomas AC. Has the change to betaagonists combined with oral theophylline increased cases of fatal asthma? Lancet 1981; 1:1235-7 44 Patel AK, Skatvud JB, Thomsen JH. Cardiac arrhythmias due to oral aminophylline in patients with chronic obstructive pulmonary disease. Chest 1981; 80:661-5 45 Duh AK, Desoyza ND, Au Wy, et al. The effect of aminophylline on cardiac rhythm in advanced chronic obstructive pulmonary disease: correlation with serum theophylline levels. Eur J Respir Dis 1983; 64:264-70 46 Kelly H~ Menendez R, McWilliams B. Lack of significant cardiac toxicity from chronic theophylline and beta-adrenergic therapy. Am Rev Respir Dis 1983; 127(2):130 47 Stableforth D. Death from asthma. Thorax 1983; 38:801-5 48 VincentNJ, KnudsonR, Leith DE, MacldemP1; MeadJ. Factors influencing pulmonary resistance. J Appl Physiol 1970; 29: 236-43 49 Reid L. Basic aspects of bronchial anatomy-and further knowledge of pulmonary neuroanatomy. Scand J Respir Dis 1979; (suppl 103):13-17 50 Reed CEo Abnormal autonomic mechanisms in asthma. J Allergy Clin Immunoll974; 53:34-41 51 De Vries K. Protective effect of inhaled SCH 1000 on bronchoconstriction induced by serotonin, histamine, acetylcholine and propranolol. Postgrad Med J 1975; 51:(suppl 7):106 52 Ruffin RE, Fitzgerald JD, Rebuck AS. A comparison of the bronchodilator activity of seH 1000 and salbutamol. J Allergy Clin Immunoll977; 59:136-41 53 Chan CS, Brown IG, Kelly CA, Dent AG, Zimmerman P~ Bronchodilator responses to nebulized ipratropium bromide and salbutamol singly and in combination in chronic bronchitis. Br J Clin Pharmacoll984; 17:103-5 54 Davis A, Vickerson F, Worsley G, Mindorff C, Kazim F, Levison H. Determination of the dose response relationship for nebulized ipratropium bromide. J Pediatr (in press) 55 Barnes PJ, Basbaum CB, Nadel]A. Autoradiographic localization of autonomic receptors in airway smooth muscle. Am Rev Respir Dis 1983; 127:758-62 56 Colebatch HJH, Olsen CR, Nadel JA. Effect of histamine, serotonin and acetylcholine on peripheral airways. J Appl Physiol 1966; 21:217-26 57 Robertson C, Smith F, Levison H. Emergency management of asthma: frequent low dose nebulized salbutamol. Pediatr Res 1984; 18(pt 2):396A 58 Shim CS, Williams MH. Bronchodilator response to oral aminophylline and terbutaline versus aerosol albuterol in patients with chronic obstructive pulmonary disease. Am J Med 1983; 75:697-701 59 Barclay J, Whiting B, Meredith PA, et al. Theophyllinesalbutamol interaction:' bronchodilator response to salbutamol at maximally effective plasma theophylline concentrations. Br J Coo Pharmacoll981; 11:203-8 60 Barclay J, Whiting B, Addis GJ. The influence on maximal response to salbutamol in severe chronic obstructive pulmonary disease. Eur J Clin Pharmacoll982; 22:389-93 61 Smith jA, Weber R~ Nelson H. Theophylline and aerosolized terbutaline in the treatment of bronchial asthma. Chest 1980; 78:816-18 62 Rachelefsky GS, Katz RM, Mickey MR, et al. Metaproterenol

lIS

and theophylline in asthmatic children. Ann Allergy 1980; 45: 207-12 63 Shenfield GM. Combination bronchodilator therapy. Drugs 1982; 24:414-39

Cromolyn Sodium· 1. Leonard Bernstein, M.D. t

£"'1romolyn sodium has been available for the treatment of asthma in the United States for over ten years, but general appreciation of its pharmacologic action and rationale for use in various forms of asthma has been a gradual process. Indeed, only recently does this drug appear to be on the threshold of acceptance by the majority of physicians in the United States for the total management of asthma. The purposes of this article are to review the development of this drug, summarize current experimental and clinical data about its probable mode(s) of action, and discuss current recommendations on how the drug should be used to obtain optimal efficacy in the management of asthma.

'-.J

DRUG DEVELOPMENT

Cromolyn sodium was derived from khellin, a natural drug extracted from Ammi visnaga, an Eastern Mediterranean herb. Since cromones were the active constituents of khellin, various analogs containing these moieties were prepared and studied. The first phase-one human study of one of these biscromolyn derivatives (cromolyn sodium) was conducted by DJ: Roger Altounyan, who himselfsuffered from asthma. He demonstrated that prior inhalation of this drug attenuated his own asthmatic symptoms induced by allergen challenge in the laboratory. 1 Since it had been previously determined that this drug was neither a bronchodilator nor an antagonist of other anaphylactic mediators, it was postulated that the drug was a unique antiallergic agent. This hypothesis was confirmed by subsequent animal experiments which demonstrated that prior administration of the drug inhibited allergen-induced histamine release. i These early experiments suggested that the acute antiallergic effects of cromolyn sodium were due to its ability to stabilize mast cell membranes. PHARMACOKINETICS

Conventional pharmacokinetics of this drug were difficult to assess, because it is eliminated rapidly from the serum, and its distribution and elimination phases are almost identical. 3 Oral absorption of cromolyn sodium is minimal, and it is not approved for use by this route. Until recently, only the powdered form of cromolyn was available. This is inhaled through a special apparatus, or Spinhaler, which is activated by a Venturi effect. Because dispersion of powders into respirable particulates as small as 3..., is difficult, this apparatus was designed to operate at high inspiratory flow rates, ranging between 40 and 100 Umin. When the apparatus is used properly, it is claimed that 50 percent .of respirable *From the Division of Immunology, Department of Medicine, The University of Cincinnati Medical Center, Cincinnati. , tClinica1 Professor of Medicine and Environmental Health Sciences; Co-director, Allergy Research Laboratory and Allergy Train ... ing Program. Dr. Bematein, University of Cincinnati, 8464 Reprint re~:

Winton ROOd, Cincinnati 45231

particles 6"", or smaller in diameter will be inhaled. After deposition in the airways, it is estimated that about 8 to 10 percent of drug is absorbed. Recent development of a sensitive cromolyn radioimmunoassay has provided new data about its absorption from the lung. After inhalation of the contents of a 2O-mgcromolyn sodium capsule by asthmatic volunteers, peak plasma levels ofl to 36 nglml were observed 5 to 30 minutes after the inhalation. The mean percentage of cromolyn sodium absorbed by asthmatic patients was estimated to be in the range of 1 to 15. Higher inspiratory flow rates associated with a lo-second breath-holding technique favored the optimal deposition and absorption of drug, whereas poor inhalation techniques resulted in lower plasma drug levels. The duration of action is usually considered to be 4 to 6 hours, but at least 1 study showed a longer"carryover" effect. 4 It should be emphasized that cromolyn sodium exerts its experimental and clinical effects according to classic pharmacologic dose-response kinetics. Under laboratorycontrolled conditions, the inhibitory dose-response effect has been demonstrated for allergen-induced, exercise-induced, and sulfur dioxide-induced varieties of bronchospasm. ~7 MODES OF AcnON

The precise pharmacologic activity of cromolyn sodium

has not been fully elucidated. The chief effect in animal

experimental models is inhibition of mediators released in response to IgE antibody allergen interactions. 8 What should also be emphasized is that it also inhibits mediator release induced by nonimmunologic stimuli such as dextran, compound 48180, and phospholipase A. However, the effects of cromolyn sodium in animal models may vary from species to species. Because of this wide Variability in animal models, much of what is currently known about the pharmacologic mechanisms of cromolyn sodium is derived directly from human studies. From the clinical point of view, the paramount therapeutic effect of cromolyn sodium is its unique ability to suppress both immediate- and late-onset asthmatic responses after bronchoprovocation by a variety ofallergens. 9 These effects have been documented not only by improvement of pulmonary function tests, but also by marked inhibition of mediator release as measured by sensitive plasma assays.JD This suppressive effect on release of neutrophil chemotactic factor of anaphylaxis (NCF-A) can be demonstrated more readily because this mediator has a much longer plasma half-life than histamine. Cromolyn sodium also prevents the impairment of mucociliary transport induced by specific bronchial challenge." Several investigators have reported that protective effects of cromolyn sodium in patients naturally exposed to aeroallergens during a pollinating season were similar to those occurring after controlled allergen provocation in the laboratory. 11 Cromolyn sodium also ameliorates exercise-induced asthma in a major subset of asthmatic patients with exercise-induced asthma." Nonimmunologic mediator release of both histamine and NCF-A may occur in up to 70 percent of patients with exerciseinduced asthma, and it is postulated that the prophylactic effects ofcromolyn sodium administered before exercise may occur because of its ability to inhibit release of these mediators in such patients. 14 How cromolyn sodium acts at the cellular level is not

completely understood. The fact that it stabilizes the mast cell membrane during the antigen-dependent and activation stages of mast cell mediator release is documented, but how this occurs has not been conclusively explained. The most promising hypothesis is that the drug affects membranous and/or cytosolic events that are involved in ••calcium gating. "15 One suggestion is that it could accomplish this simply by virtue of its hydrophilic effect. A more attractive explanation of its effect on calcium regulation is the fact that it enhances phosphorylation of a cytoplasmic large molecular weight (78,000 daltons) protein which may be a putative blocker of calcium transport. 18 New clinical evidence indicates that cromolyn sodium may modulate several types of reflex-induced asthma. Current proposed mechanisms for the drug's inhibitory effect on exercise-induced asthma are somewhat controversial, but there is a plausible likelihood that two different mechanisms may be involved. As previously mentioned, the prophylactic effect of cromolyn sodium in some asthmatic subjects may be ascribed to interference with nonimmunologic mediator release, as indexed by plasma measurements of histamine and NCF-A. However; other investigators have reported that challenge by the isocapnic hyperventilation, frigid-air technique did not cause release of NCF-A in allergic asthmatic patients who later on the same day demonstrated significant plasma increases of this mediator after bronchial challenge with specific allergen. 17 Thiswas interpreted as evidence that the protective effect of cromolyn on cold air or equivalent challenges did not depend entirely on its ability to block mediator release from mast cells. Although direct experimental evidence for non-mast cell activity of cromolyn sodium is still lacking, an alternative pathway is suggested by animal experiments in which the drug suppresses excitatory activity of afferent, nonmyelinated, vagal ··C" fiber endings provoked by 5-hydroxytryptamine. 18 A dose-dependent protective effect of cromolyn sodium on reflex-mediated asthma induced by sulfur dioxide has been demonstrated independently in several laboratories. 1,19 In this system the inhibitory dose of cromolyn sodium is about twice that required for protection against allergen-induced bronchoconstriction. However, at this dose the effect of cromolyn sodium is superior to that of atropine. Differences of dose responses required for comparable protection after sulfur dioxide- and allergen-induced bronchospasm suggest that the pharmacologic effects of sodium cromolyn may have different pathways. In this respect, the effects of cromolyn sodium on the sulfur dioxide system appear to be similar to the responses of certain subpopulations of asthmatic subjects after exercise and/or hyperventilation. It is also noteworthy that cromolyn sodium exerts protective effects on several types of industrial agents (toluene diisocyanate, western red cedar, colophony) which are thought to induce asthma via reflex pathways. 10 One of the most interesting developments in understanding the pharmacology of cromolyn sodium is its possible effect on nonspecific bronchial hyperreactivity which correlates highly with clinical severity of asthma. 5 Thus, patients with dual asthmatic responses are much more sensitive to histamine challenge than patients exhibiting only an immediate-onset asthmatic reaction. 11 Several short- and longterm clinical trials of allergic asthma clearly demonstrated that pretreatment with cromolyn sodium prevented the rise CHEST / 87 /1 / JANUARY, 1985 / Supplement

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FICURE 1. Inhibitory effectsofcromolynsodiumupon mastcelland reflex pathways ofasthma. Adaptedfrom Richard 1M. Humoral and neural modes of action of sodium cromoglycate. International Conference on Bronchial Hyperreactivity. Oxford: The Medicine PublishingFoundation, 1982:26.

of histamine sensitivity during the pollen season. One negative study was conducted during the nonpollinating months of pollen-allergic asthmatic patients. 13 Clinical investigations about the possible protective effects of cromolyn sodium on methacholine-induced hyperreactivity are mixed and much less impressive. Cromolyn sodium's depressor effect on histamine hyperreactivity may partially account for its down regulation of late-onset asthmatic reactions. The delayedonset asthmatic reaction is associated with a pronounced inflammatory response, persistence of inflammatory mediators, and an increase of bronchial liability. Inasmuch as cromolyn sodium reduces both histamine hyperreactivity and the late (inflammatory) phase of asthma, it is postulated that these phenomena may be causally related. Why methacholine sensitivity is not inhibited by cromolyn in most patients is not clear, but presumably could be explained by different anatomic reflex pathways of these chemical agonists. It may be helpful to summarize how cromolyn sodium may affect the major operational components of asthma. As shown in Figure 1, a wide spectrum of environmental stimuliallergic, nonallergic, or re8ex-may evoke the physiologic state of bronchial hyperreactivity which is an essential predeterminant of the asthmatic response. Some external or internal stimuli exert their effects through peripheral and CNS reflex pathways, while other exogenous substances (allergic or nonallergic) may cause direct activation and release of mast cell mediators. These mediators cause profound effects in various effector systems, some of which amplify the final asthmatic response by augmentation of mast cell degranulation and further stimulation of re8ex efferent pathways. The weight of current experimental data now suggests that cromolyn sodium not only prevents mediator release from intraluminal and submucosal mast cells, but also attenuates certain types of reflex-induced bronchoconstriction. CLINICAL STUDIES

The first clinical evidence that cromolyn sodium was 708

effective for prophylaxis of asthma was demonstrated by a double-blind clinical study conducted by Howell and AItounyan." Some of the early studies were difficult to interpret, because the drug was originally formulated with isoproterenol. Later, after this flaw was corrected, comparable efficacy was observed by other investigators using preparations without isoproterenol. Some of these studies also showed objective changes of pulmonary function tests. Cromolyn sodium was approved for general medical use in the United States after a number of short-term, double-blind clinical investigations indicated that the drug was effective. The largest clinical study in the United States was sponsored by the American Academy of Allergy and Immunology. 4 This was a short-term, double-blind, crossover study of252 asthmatic patients. Drug-treated patients reported significant improvement of asthmatic symptoms and reduced requirements for other medications during the treatment. Adverse effects were minimal. At about the same time, a similar cooperative trial by the British Medical Research Council reported comparable results." Long-term clinical effectiveness was also demonstrated by several well-controlled investigations which revealed successful clinical responses in about 65 percent of both adult and pediatric asthmatic patients. 'Ireatment failures tended to surface in the first month of treatment in the patients whose clinical courses deteriorated rapidly just prior to the institution of cromolyn therapy. In contrast to its use as a first-line preventive agent in the United Kingdom and elsewhere, cromolyn sodium did not gain wide acceptance for the treatment of asthma in the United States.- This was due partially to coincidental progress in delineating the pharmacokinetics of theophylline and introduction of several effective, long-acting theophylline preparations. Moreover, cromolyn sodium was often held in reserve for a subset of refractory asthmatic patients, most of whom were steroid-dependent. Clinical efficacy in this group of patients was never claimed to be outstanding and it was readily apparent that this standard of medical practice AdvanceIln Dlagnoeis & 1hNdment of Asthma

could not be compared directly with how the drug was being used elsewhere in the world. A number of other myths also emerged about cromolyn sodium therapy: (1) it is only effective in allergic asthma; (2) it is only effective in children; (3) it is not dose-dependent; (4) it is less effective than theophylline; (5) its primary use is as a steroid sparing agent; (6) objective pulmonary function changes cannot be demonstrated after cromolyn sodium therapy; (1) long-term use of a powdered drug could have deleterious intrapulmonary and immunologic side effects. Critical analysisofearly and recent clinical trials lend no substantive support for any of these unfounded early clinical notions. Nevertheless, they have persisted in some circles, and at least until the present have relegated cromolyn sodium to the status ofa second-line drug in the United States. The questions of the efficacyof cromolyn sodium vis-a-vis theophylline and possible serious adverse effects of the drug should be addressed further, Direct clinical comparison of cromolyn sodium with bronchodilators was not thought to be relevant in the early clinical trials of the drug because preclinical pharmacologic experiments revealed minimal direct bronchodilator effects. It was therefore assumed that the effects of a prophylactic drug-ie, cromolyn sodiumcould not be compared reliably or directly with short-acting smooth muscle bronchodilators. However; when sustainedacting theophylline formulations evolved as the treatment of choice in the United States, it became evident that direct comparative trials of cromolyn sodium and theophylline as first-line drugs would, in fact, have considerable impact on clinicians who used these drugs without objective evidence of their relative effectiveness. At least 5 controlled, comparative therapeutic trials of cromolyn and theophylline have revealed almost identical profiles of overall clinical efficacy during respective study periods.":" These studies focused attention on the issue of first choice of drugs in the office treatment of asthma-ie, should theophylline or cromolyn sodium be the initial drug? Of course the clinical staging and severity of asthma must be taken into account, but assuming that this question is posed for patients matched with respect to stage and severity, these recent clinical studies make a strong case for cromolyn sodium in terms of: (1) better risk! benefit ratio; (2) fewer adverse effects; and (3) the advantage of decreasing nonspecific bronchial hyperreactivity or the inflammatory component associated with late-onset asthmatic reactions. The chiefdisadvantages ofcromolyn sodium use are patient noncompliance and improper use of the drug. However; noncompliance can usually be resolved by good patient education given by concerned physicians and pulmonary technicians. The recent availability of nebulized solutions ofcromolyn sodium containing 20 mg/2 ml may increase the possibility of using the drug in younger children and older patients who have difficulty with the Spinhaler apparatus. Concerning possible adverse effects induced by cromolyn sodium, there is very little evidence to support earlier fears about serious side effects. A prospective study of 375 asthmatic patients revealed that the overall incidence of adverse reactions was 2 percent. 33 Dermatitis occurred in 5 patients, myositis in 2, and gastroenteritis in 1. Most of the side effects were classified as minor. These included symptoms of irritation of the throat, hoarseness, dryness of the mouth, acute

cough, and the sensation of chest tightness or bronchospasm occurring immediately after inhaling the powder. The latter symptoms could usually be prevented by several preliminary inhalations ofa PI-agonistdrug. Nausea, vomiting, facial rash and/or urticaria have also been reported. Nasal congestion occurring several weeks after beginning cromolyn sodium therapy may be noted. A few cases of pulmonary infiltration and eosinophilia associated with cromolyn sodium have also been described. Immunologic studies in a few of these patients showed increased binding of radioactive cromolyn .by IgG, positive cromolyn-induced lymphocyte proliferation, and production of migratory inhibitory factor in one patient with pulmonary infiltrates and in 5 other patients with subacute or acute reactions to cromolyn. However; these immunologic reactions were not found in the recent prospective study. CURRENT RECOMMENDATIONS

Based on all availableefficacydata and a critical assessment of the benefit/risk ratio, it now becomes increasingly apparent that cromolyn sodium should be considered as a first-line drug in the treatment of asthma. The general rationale for this conclusion is based on the following attributes of this drug: (1) it has been demonstrated to be a useful prophylactic and baseline drug for treatment of mild, moderate, and severe asthmatic patients. In particular, its overall efficacyis at least as good as theophylline without the threat of longterm toxicity; (2) long-term efficacy of the drug has been proved by subjective and physiologic improvement; (3)prospective investigations have revealed minimal adverse or hypersensitivity reactions; (4) cromolyn sodium has been shown to be effective in both allergic and nonallergic asthma; (5) there is documented evidence that cromolyn sodium attentuates many varieties of reflex bronchoconstriction, some forms of airways hyperreactivity, and bronchial lability. Recent bronchoalveolar lavage (BAL) studies in asthmatic patients have provided additional evidence for the antiinflammatory effects of cromolyn sodium by demonstrating a marked decrease in BALeosinophils in treatment responder patients," (6) it may be a useful agent for prevention of obstruction in both small and large airways. Lack of proper instruction about the administration of cromolyn is probably the most common reason for poor patient compliance. It is therefore essential that the initial and long-term management of Spinhaler or nebulized cromolyn be supervised carefully. If results are equivocal, the total trial period should be extended from eight to 12 weeks, and the dose should be doubled during the last six weeks. There is general consensus that the effects of the drug are optimized if it is given for 1 week before allergen exposure (eg, one of the pollen seasons),30 minutes before a known allergen (eg, dog, cat, or laboratory animals), or 15 minutes prior to exercise. Long-term use of cromolyn sodium should be considered for patients with reflexmediated asthma, patients with dual and! or late asthmatic responses after controlled bronchial challenges, and especially for those patients who begin to show unusual airwayshyperreactivity and bronchial lability. In my experience, cromolyn may be especially useful for patients with a cough variant syndrome. Presumably this effect could be mediated by attenuation of irritant receptors. Nebulized aqueous solutions of cromolyn sodium have CHEST I 87 I 1 I JANUARY, 1986 I SUpplenw1t

718

recently been approved by the Food and Drug Administration. These are especially usefulfor youngchildren or those

14 Lee TH, Nagakura 1: Cromwell 0, Brown MJ, Causon R, Kay AB. Neutrophil chemotactic activity and histamine in atopic and nonatopic subjects after exercise-induced asthma. Am Rev Respir Dis 1984; 129:409-12 15 Mazurek N, Berger G, Pecht I. A binding site on mast cells and basophils for the anti-allergic drug cromolyn. Nature 1980; 286:722-3 16 Theoharides rc, Sieghart W, Greengard ~ Douglas ww. Antiallergic drug cromolyn may inhibit histamine secretion by regulating phosphorylation of a mast cell protein. Science 1980; 207:80-82 17 Deal EC Jr, Wasserman SI, Soter NA, Ingram RH Jr, McFadden ER Jr. Evaluation of role played by mediators of immediate hypersensitivity in exercise-induced asthma. J Clin Invest 1980;

SUMMARY

18 Richards 1M. Humoral and neural modes of action of sodium cromoglycate. International Conference Bronchial on Hyperreactivity. Oxford: The Medicine Publishing Foundation, 1982:29 19 Sheppard D, Saisho A, Nadel ]A, Boushey HA. Exercise increases sulfur-dioxide-induced bronchoconstriction in asth... matic subjects. Am Rev Respir Dis 1981; 123:486-91 20 Pepys J. The role of industrial agents in the etiology of asthma. Adv Asthma Allergy Pulm Dis 1976; 3:1-8 21 Cockcroft DW, Ruffin RE, Dolovich], Hargreave FE. Allergeninduced increase in non-allergic bronchial reactivity. Clin Allergy 1977; 7:503-13 22 Dickson ~ Cole M. Severe asthma in children-a IO-year followup. In: Pepys J, Edwards AM, eds. The mast cell-its role in health and disease. Tunbridge Wells, England: Pitman Medical Publishing Co, 1979:343-52 23 Ryo Ung Yun ICB, Townley RG. Cromolyn therapy in patients with bronchial asthma. ]AMA 1976; 236:927-30 24 Howell JBL, Altounyan REC. A double-blind trial of disodium cromoglycate in the treatment of allergic bronchial asthma. Lancet 1967; 2:539-42 25 Brompton HospitaVMedical Research Council Collaborative lHal. Long-term study of disodium cromoglycate in treatment of severe extrinsic or intrinsic bronchial asthma in adults. Br Med J 1972; 4:383-8 26 Bernstein IL. Cromolyn sodium in the treatment of asthma: changing concepts. J Allergy Clin Immunoll981; 68:247-53 27 Buckley JM, Pearlman DS, Avner SE. Theophylline sparing effects of cromolyn sodium in allergic asthmatic patients. In: Proceedings of the American Academy of Pediatrics Annual Meeting, Oct 25-30, 1980 28 Edmunds AI: Carswell F, Robinson ~ Hughes AO. Controlled trial of cromoglycate and slow-release aminophylline in perennial childhood asthma. Br Med J 1980; 281:842 29 Hambleton G, Weinberger M, Taylor J, Cavanaugh M, Ginchansky E, Godfrey S, et ale Comparison of cromoglycate (cromolyn) and theophylline in controlling symptoms of chronic asthma: a collaborative study. Lancet 1977; 1:381-5 30 MacDonald TH. Monitoring response to bronchodilator therapy in asthma in childhood. J Int Med Res 1979; 7:87-92 31 Newth CJL, Newth C~ Thrner JAE Comparison of nebulised sodium cromoglycate and oral theophylline in controlling symptoms of chronic asthma in pre-school children: a double blind study. Aust NZ J Med 1982; 12:232-8 32 Selcow JE, Mendelson L, Rosen J~ A comparison of cromolyn and bronchodilators in patients with mild to moderately severe asthma in an office practice. Ann Allergy 1983; 50:13-18 33 Settipane GA, Klein DE, Boyd GK. Adverse reactions to cromolyn. JAMA 1979; 241:811-13 34 Diaz ~ Galleguillos FR, Gonzalez MC, Kay AB. Bronchoalveolar lavage in asthma: the effect of disodium cromoglycate on leucocyte counts, immunoglobulins and complement [Abstract]. J

patients who are unable to tolerate the powder because of an unusually sensitive cough reflex. as Recently, we have been using nebulized aqueous cromolyn sodium for patients with these problems and also for patients who have unusual degrees of bronchial lability and airways hyperreactivity. Thus far, this experience reveals that aerosol inhalation of aqueous cromolyn sodium in steroid-dependent patients is an especially useful method of reducing bronchial irritability in some of these patients. This type of clinical improvement often makes it possible to institute a successful steroid-tapering program. Cromolyn sodium is a valuable agent in the pharmacologic management of asthma. In addition to its established effects of inhibiting mediator release, it now appears that it is a useful drug for diminishing the effects of reflex-mediated asthma, nonspecific bronchial hyperreactivity, and diurnal swings of bronchial lability. Because of these unique prophylactic properties, the availability of a nebulized aqueous solution delivery system and recent clinical reports showing that its efficacy is comparable to theophylline, cromolyn sodium should be reconsidered as a first-line antiasthmatic drug in the United States. REFERENCES 1 Altounyan REC. Inhibition of experimental asthma by a new compound-disodium cromoglycate (Intal). Allergy 1967; 22: 487-51 2 Sheard ~ Blair AMJN. Disodium cromoglycate: activity in three in vitro models of the immediate hypersensitivity reaction in lung. Int Arch Allergy Appl Immunol1970; 38:217-24 3 COX JSG, Beach JE, Blair AM, Clarke AJ, King J, Lee TB, et al. Disodium cromoglycate (Intal). Adv Drug Res 1970; 5:115-96 4 Bernstein IL, Siegel SC, Brandon ML, Brown EB, Evans RR Feinberg AR, et al. A controlled study of cromolyn sodium sponsored by the Drug Committee of the American Academy of Allergy and Immunology. J Allergy Clin Immunol 1972; 50:

235-45 5 Altounyan REC. Review of clinical activity and mode of action of

sodium cromoglycate. Clin Allergy 1980; 10:481-9 6 Patel KR, Berkin KE, Kerr JW Dose-response study of sodium cromoglycate in exercise-induced asthma. Thorax 1982; 37 :663-6 7 Harris MG, Parkes PEG, LessofMH, OrrTSC. Role of bronchial irritant receptors in asthma: a collaborative study. Lancet 1981; 1:5-7 8 Orr TSC, Cox JSG. Disodium cromoglycate, an inhibitor of mast cell degranulation and histamine release induced by phospholipase A. Nature 1969; 233:197-8 9 Pepys J, Hargreave FE, Chan M, McCarthy DS. Inhibitory effects of disodium cromoglycate on allergen inhalation tests. Lancet 1968; 2:134-7 10 Atkins PC, Norman ME, Zweiman B. Antigen-induced neutrophil chemotactic activity in man: correlation with bronchospasm and inhibition by disodium cromoglycate. J Allergy Clin Immunol 1978; 62:149-55 11 Wanner A. The role of mucociliary dysfunction in bronchial asthma. Am J Med 1979; 67:477-85 12 Engstrom I. Evaluation of LomudaI treatment in children. Scan J Respir Dis 1977; 101(suppl):49-56 13 Ben-Dov I, Bar-Yishay E. Godfrey S. Heterogeneity in the response of asthmatic patients to pre-exercise treatment with cromolyn sodium. Am Rev Respir Dis 1983; 127:113-16

72S

65:659-65

Allergy Clin Immunoll984; 73:117 35 Prenner BM, Hyte MK, U ryniak TJ. The efficacy of 1% cromolyn sodium nebulizer solution in the treatment of young asthmatic children. Ann Allergy 1982; 48:254-5

The Use of Corticosteroids in the Treatment of Asthma Sheldon L. Spector, M.D., F.C.C.P.*

corticosteroids were first introduced for the treatment of asthma, they were hailed as miracle drugs. As experience was extended, so was the appreciation of the myriad side effects. Advances in our understanding of the physiologic properties of oral agents has led to the discovery of methods for avoiding adverse effects. Additionally, new compounds and improved delivery by the aerosol route have mitigated side effects. Even with the new knowledge gained, systemic corticosteroids remain one of the most misunderstood medications utilized in the treatment of asthma and other pulmonary diseases. Physicians have been criticized for failure to use the drugs in patients dying during an attack of asthma, 1 yet their utilization during status asthmaticus has been questioned repeatedly. 2.3 "~Then

~"

POSTULATED MODE OF AcnON

Corticosteroids have several immunologic and anti-inflammatory actions." Among the reasons postulated for corticosteroid effectiveness in obstructive lung disease are: (1) inhibition of synthesis or release of chemical mediators; (2) inhibition of cholinergic mechanisms (both probably act through changes in cyclic AMP and/or cyclic GMP); (3) a direct effect of corticosteroids on smooth muscle relaxation; (4) enhanced restoration of the effect of p-adrenergic bronchodilators; and (5) alteration of immune mechanisms and/or mediators of inflammation such as arachidonic acid." One of the most important actions of corticosteroids is their effect on metabolites of arachidonic acid. Macroeortin" and lipomodulin7 are newly synthesized in the presence of corticosteroids. By inhibiting phosphodiesterase ~, they prevent the formation of leukotrienes, prostaglandins, thromboxanes, and other metabolites of arachidonic acid. Corticosteroids influence the migration and function of leukocytes. Neutrophils, which are normally marginated on the endothelium of capillary and other vessels throughout the body, including the lungs, reenter the circulation, whereas monocytes, eosinophils, and lymphocytes, particularly thymus-derived lymphocytes, disappear from the circulation. Although large daily doses of corticosteroids added to in vitro preparations might inhibit mononuclear leukocyte chemotaxis, phagocytosis, and killing, the high concentrations required to show these effects do not result from treatment within the usual dosage range for asthma or COPD. In fact, when we studied monocyte cellular function in asthmatic patients receiving alternate-day steroid therapy, we found no significant alteration in monocyte chemotaxis, bacterial killing, or phagocytosis. 8 Corticosteroids interfere with lymphocyte proliferation, which may explain their suppressive effect on delayed-type *Clinical Professor of Medicine, University of California at Los Angeles.

Reprint requests: Dr. Spector, 11645 Wilshire Blvd, Los Angeles

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hypersensitivity measurements such as tuberculin reactivity. However; in humans, unlike other species which are more steroid sensitive, the usual doses of corticosteroids do not interfere with antibody production." Although dose and timing of corticosteroid administration is important, steroids alter delayed-type hypersensitivity skin tests, but do not interfere with immediate (IgE-mediated) skin test reactivity.lo Even though tuberculin reactivity, for example, might be altered by steroids, the test should nevertheless be performed, since valuable information might be gained from a positive test. Additionally, small dose, alternate day steroids have a minimal inhibitory capacity. Corticosteroids and catecholamines act synergistically to potentiate cyclic AMP action and to replenish p-receptors in cells. The action has been demonstrated in various clinical studies'r" and with the use of various in vitro techniques. 13.l" Table 1 summarizes the most important postulated mechanisms of action for corticosteroids. USE IN STATUS ASTHMATICUS

Although there is general agreement that corticosteroids are beneficial in the management of chronic asthma, their use in the management of status asthmaticus has been challenged. In a randomized, double-blind study of 38 young patients in status asthmaticus, McFadden and eo-workers" administered either 0.25, 0.50, or 1.0 g of hydrocortisone hemisucciante or placebo intravenously (IV), followed by isoproterenol, given at hourly intervals for a minimum of 6 hours. Results showed no statistical differences in any physiologic or clinical variable studied. The authors concluded that hydrocortisone provided no specific benefit during the 6-hour period of observation. Furthermore, Luksza" stated that steroids are ineffective once severe asthma is established and may have contributed to the epidemic of asthma deaths in the mid-l960s, possibly by enhancing the cardiotoxicity of Isoprenaline (isoproterenol). Kattan et al' studied 19 children in status asthmaticus who had not received corticosteroids prior to hospitalization. Patients were randomized into 2 groups, each of which received albuterol inhalations and IV aminophylline. Additionally, one group received 7 mWkg of hydrocortisone IV

Table I-Propoaed Meclaanilma of Action of Cor1icOBteroida Direct relaxation of bronchial smooth muscle Inhibition of synthesis and release of chemical mediators including histamine and arachidonic acid products Stimulation oflipomodulin and/or macrocortin, which are inhibitors of phosphodiesterase A Decrease in late-phase inflammatory response Stimulation of cAMP Altered vascular permeability and vasoconstriction Inhibition of cholinergic mechanisms Inhibition of cyclic guanosine monophosphate StabiIization of lysosomes Influence on the migration and function of leukocytes Neutrophils reenter the circulation Monocytes, eosinophils, and lymphocytes leave the circulation Improved mucociliary clearance and decreased mucous formation Enhanced response to catecholamines Increased synthesis and restoration of p-adrenergic receptors

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