Summary

Drugs 37 (Suppl. 1): 123-126 (1989)

0012-6667/89/0100-0123/$2.00/0 © ADiS Press Limited All rights reserved.

Clinical Pharmacology of Nedocromil Sodium

K.M.S. Rocchiccioli and P.A. Riley Fisons pic, Pharmaceutical Division, Loughborough, Leicestershire, United Kingdom

In attempts to define the clinical pharmacological activity of inhaled nedocromil sod­ium, various challenge systems, ranging from specific antigen challenge to provocation with chemical irritants such as sulphur dioxide, have been used. A single dose (4mg) of nedocromil sodium taken before antigen challenge prevented both early and late asthmatic responses, whereas the same dose taken shortly after the early response delayed onset of the late reaction but did not affect its magnitude. Exercise-induced asthma was inhibited by pretreatment with nedocromil sodium, as were the bronchoconstrictor responses to hyperventilation of cold dry air and inhalation of ultrasonically nebulised distilled water ('fog'). Mast cells lying in the surface mucosa of the lung are thought to be less stable in asthmatic subjects and may be implicated in the mechanism of response to these 3 types of physical insult. However, in addition to the marked protective action on isolated mu­cosal mast cells which has been reported from preclinical studies, nedocromil sodium was also effective against bronchoconstriction induced by sulphur dioxide in hyper-responsive asthmatic and atopic subjects. The response to sulphur dioxide, in which axon reflexes are thought to be involved, is less likely to have an immunological mechanism and it is clear that in this type of situation the effect of nedocromil sodium can be more readily differentiated from that of sodium cromoglycate. The increased potency and wider scope of activity described for nedocromil sodium suggests a therapeutic advantage for this new compound in chronic inflammatory allergic lung disorders.

As the results presented at this meeting have demonstrated, a great deal of preclinical work on nedocromil sodium has been carried out in a num­ber of different cellular and animal models, and it is clear that it is not possible to use anyone model to profile this drug satisfactorily. This problem ap­plies equally to the field of clinical pharmacology, and more than one type of challenge study has been required to build up the profile of nedocromil sod­ium. So far, a total of 52 studies involving 554 patients have been completed, in which the agents for challenge included antigen, exercise, cold air, fog, adenosine, sulphur dioxide, metabisulphite,

neurokinins, bradykinin, toluene di-isocyanate and citric acid.

1. Effect on the Late Asthmatic Reaction

Nedocromil sodium is known to be effective in preventing the immediate response of asthmatic patients to antigen challenge (Lowhagen et al. in press; Y oungchaiyud & Lee 1986). The late reac­tion to antigen in dual asthmatic responders is of particular importance, however, because of its re­lationship to the development of secondary bron­chial hyper-reactivity.

Clinical Pharmacology of Nedocromil Sodium

A double-blind study was therefore carried out by Crimi et al. (in press) in a group of 12 asthmatic patients who were known to be dual responders to house dust mite, to examine the effects of nedocromil sodium and placebo administered half an hour before, and I hour after, antigen challenge. The immediate reaction was monitored for 60 minutes and the late reaction for up to 7 hours after challenge. Administration of placebo did not prevent the occurrence of a marked early reaction, followed by a late reaction after 4 to 6 hours. Ne­docromil sodium 4mg given before antigen abol­ished the immediate reaction and also significantly attenuated the late reaction. When administered I hour after the early reaction, nedocromil sodium did not significantly affect the magnitude of the late reaction but appeared to delay its onset. This activity could be important in the development of bronchial hyper-reactivity.

2. Effect on Cold Air-Induced Bronchoconstriction

It has been accepted for some time that hyper­ventilation of cold, dry air induces bronchocon­striction in asthmatic and atopic subjects, and this effect may represent one of the underlying mech­anisms of exercise-induced asthma (Anderson 1985), which is known to be inhibited in a dose­related manner by the action of nedocromil sod­ium (Bundgaard et al. 1988; Henriksen 1988; Shaw & Kay 1985).

In a double-blind, placebo, crossover study by Juniper et al. (1987), nedocromil sodium (I mg, 2mg and 4mg) and sodium cromoglycate (lOmg) were compared with placebo, each treatment being ad­ministered 20 minutes before challenge with cold air. PDIO and FEV 1 measurements demonstrated the occurrence of a marked bronchoconstrictor re­sponse, which was significantly inhibited after all of the drug treatments compared with the response after placebo. In this study, nedocromil sodium showed only a slight trend towards a dose-related response, and there was no difference in efficacy between the 2 drugs.

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3. Effect on Bronchoconstriction Induced by Hypotonic Solution

Inhalation of ultrasonically nebulised hypotonic solutions, or ' fog' challenge, also causes broncho­constriction in asthmatic subjects. The mechanism is not fully elucidated, although the release of pre­formed mediators from superficial lung mucosal mast cell populations in response to local changes in osmotic pressure has been implicated. Robuschi and colleagues (1987) studied the effect of nedocromil sodium on ' fog' -induced bronchocon­striction in 12 asthmatic subjects. Each patient underwent 3 successive challenges of increasing duration (30, 60 and 120 seconds) at intervals of 4 minutes, and lung function measurements were checked at I-minute intervals to establish the max­imum bronchoconstriction occurring after each challenge. A double-blind placebo crossover trial in which nedocromil sodium (4mg) was given by in­halation 30 minutes before the first challenge, showed that the response to ' fog', which had in­creased with the duration of exposure, was almost completely inhibited by pretreatment with nedo­cromil sodium.

4. Effect on Adenosine Monophosphate­Induced Bronchoconstriction

Adenosine monophosphate (AMP) is a natur­ally occurring purine nucleotide which has been implicated in the pathogenesis of asthma (Mann et al. 1985). Altounyan et al. (1986a) examined the effect of pretreatment with nedocromil sodium and sodium cromoglycate on AMP-induced broncho­constriction in a group of 10 atopic, non-asthmatic subjects. Increasing concentrations of AMP were first inhaled by each subject to determine a PD40 dose. This dose was used for subsequent AMP challenges, and nebulised solutions of nedocromil sodium or sodium cromoglycate (at concentrations of 1,0.1, om and 0.001%) were administered 10 minutes before challenge and the effects compared with placebo. Both drugs gave significant protec­tion (p < 0.05 or better) against AMP-induced bronchoconstriction, and nedocromil sodium was

Clinical Pharmacology of Nedocromil Sodium

found to be significantly more effective than sodium cromoglycate at each concentration used (p < 0.001 at 1%; p < 0.05 at 0.001 to 0.1%).

5. Effect on Sulphur Dioxide-Induced Bronchoconstriction

Inhalation of sulphur dioxide (S02) at low con­centrations is also known to cause bronchocon­striction in asthmatic and atopic individuals. Altounyan (l986b) compared the efficacy and dur­ation of action of nedocromil sodium (4mg) and sodium cromoglycate (lOmg) against S02-induced bronchoconstriction in a group of 6 atopic, non­asthmatic subjects. In a single-blind study, test compounds or matched placebo were inhaled from a pressurised aerosol at 0.5, 2 or 4 hours before inhalation of S02. The protection provided by sod­ium cromoglycate was relatively slight, and statis­tical significance was seen only at 30 minutes after S02 inhalation. Nedocromil sodium, in contrast, gave significantly more protection than placebo (p < 0.001) for up to 4 hours and was significantly (p < 0.01) more effective than sodium cromogly­cate throughout.

S02 challenge has not been favoured by many investigators, because of the expensive and cum­bersome apparatus required for analysis. However,

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sodium metabisulphite has recently been shown to offer a more practical alternative, since S02 is gen­erated during nebulisation of this compound. Dixon and Ind (1988) found that asthmatic and atopic non-asthmatic subjects, unlike normal controls, showed a dose-related reduction in specific airways conductance in response to the inhalation of ne­bulised sodium metabisulphite. The response could be blocked in part by the anticholinergic action of oxitropium bromide, whereas pretreatment with nedocromil sodium (4mg by inhalation) led to complete inhibition. When this same dose of nedocromil sodium was matched against sodium cromoglycate lOmg, it again gave total protection, whereas that afforded by sodium cromoglycate, al­though significant (p < 0.05), was only partial.

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The potent HI-histamine antagonist, terfena­dine, had no effect on bronchoconstriction caused by metabisulphite, suggesting that the response does not involve mast cells. In animals, S02 is known to stimulate afferent fibres in the airways (Roberts et al. 1983), and it seems likely that afferent nerv­ous pathways may be involved in the response of asthmatic and atopic subjects to inhaled metabi­sulphite. If so, these results suggest that nedocromil sodium is more effective than sodium cromogly­cate at blocking afferent activity in the lung.

A divergence in the activity of nedocromil

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Protective effect of sodium cromoglycate (%)

Fig. 1. Comparison of the protective effect of nedocromil sodium with that of sodium cromoglycate in a group of atopiC volunteers on (a) antigen bronchial challenge (b) 'fog ' bronchial challenge and (e) sulphur dioxide bronchial challenge.

Clinical Pharmacology of Nedocromil Sodium

sodium and sodium cromoglycate, first noticed by Roger Altounyan during the course of his studies in a group of atopic volunteers, was expressed by him in figure I. The 3 graphs show the relative degree of protection obtained from the 2 com­pounds in different challenge situations and illus­trate the shift from a roughly equal distribution about the line of identity after antigen challenge, towards a clear preference for nedocromil sodium after S02 challenge. When the intermediate situa­tion of 'fog' challenge is considered, it can be seen that the superiority ofnedocromil sodium becomes obvious as the part played by chemical irritants or non-immunological factors assumes greater im­portance.

6. Conclusions

These early impressions of the actlvlty of nedocromil sodium in bronchial challenge tests have found support among the many studies which have been subsequently carried out, and a few of these have been mentioned in this brief review. To summarise, nedocromil sodium has been found to be highly effective in inhibiting the bronchocon­stricti on produced in response to a variety of non­specific bronchial challenge agents, both physical and chemical in origin, in addition to its activity against specific allergen challenge. It also atten­uated a delayed reaction to antigen challenge, which may have important implications in the develop­ment of bronchial hyper-reactivity. Finally, nedo­cromil sodium has been shown to be more effec­tive than sodium cromoglycate against adenosine and S02 challenge, in which neural involvement is thought to playa more prominent role. The evi­dence of increased potency and possibly additional mechanisms of activity seen in clinical pharma­cological studies with nedocromil sodium comple­ments the findings of preclinical laboratory exper-

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iments and suggests that this compound should have therapeutic advantages over sodium cromo­glycate in clinical practice.

References

Altounyan REC, Lee TB, Rocchiccioli KMS, Shaw CL. A com­parison of the inhibitory effects of nedocromil sodium and sodium cromoglycate on adenosine monophosphate-induced bronchoconstriction in atopic subjects. European Journal of Respiratory Diseases 69 (Suppl. 147): 277-279, 1986a

Altounyan REC, Cole M, Lee TB. Inhibition of sulphur dioxide­induced bronchoconstriction by nedocromil sodium and sod­ium cromoglycate in non-asthmatic, atopic subjects. European Journal of Respiratory Diseases 69 (Suppl. 147): 274-276, 1986b

Anderson SD. Issues in exercise-induced asthma. Journal of Allergy and Clinical Immunology 76: 763-772, 1985

Bundgaard A, Enehjelm SD, Schmidt A. A comparative study of the effects of two different doses of nedocromil sodium and placebo given by pressurised aerosol in exercise-induced bronchoconstriction. Allergy 43: 493-496, 1988

Crimi E, Brusasco v, Crimi P. Effect of nedocromil sodium on the late asthmatic reaction to bronchial antigen challenge. Journal of Allergy and Clinical Immunology, in press

Dixon CMS, Ind PW. Metabisulfite induced bronchoconstriction: mechanisms. American Review of Respiratory Disease 137: 238, 1988

Henriksen JM. Effect of nedocromil sodium on exercise-induced bronchoconstriction in children. Allergy 43: 449-453, 1988

Juniper EF, Kline PA, Morris MM, Hargreave FE. Airway con­striction by isocapnic hyperventilation of cold, dry air: com­parison of magnitude and duration of protection by nedo­cromil sodium and sodium cromogiycate. Clinical Allergy 17: 523-528, 1987

Lowhagen 0, Balder B, Rak S. Nedocromil sodium in bronchial antigen challenge. Clinical Allergy, in press

Mann JS, Cushley MJ, Holgate ST. Adenosine-induced broncho­constriction in asthma. American Review of Respiratory Disease 132: 1-6, 1985

Roberts AM, Hahn HL, Schulz HD, Nadel JA, Coleridge HM, et al. Afferent C-fibres are responsible for the reflex airway con­striction and secretion evoked by pulmonary administration of sulphur dioxide in dogs. Physiologist 25: 226, 1983

Robuschi M, Vaghi A, Simone P, Bianco S. Prevention of fog­induced bronchospasm by nedocromil sodium. Clinical Allergy 17: 69-74,1987

Shaw RJ, Kay AB. Nedocromil, a mucosal and connective tissue mast cell stabilizer, inhibits exercise-induced asthma. British Journal of Diseases of the Chest 79: 385-389, 1985

Youngchaiyud P, Lee TB. Effect of nedocromil sodium on the immediate response to antigen challenge in asthmatic patients. Clinical Allergy 16: 129-134, 1986

Author's address: Dr K. Rocchiccio/i, Fisons pic, Pharmaceutical Division, Bakewell Road, Loughborough, Leics. LEI I ORH (United Kingdom).