Scot. med. J., 1977, 22: 234
THE THERAPEUTIC USE OF SODIUM CROMOGLYCATE BP James W. Kerr Western Infirmary and Knightswood Hospital, Glasgow
1958 Altounyan observed that a deriva-
tive of Khellin inhibited the asthmatic Iresponse to an inhaled allergen. This observN
ation led to the development of sodium cromoglycate (Intal) and its introduction for the treatment of allergic bronchial asthma (Howell & Altounyan, 1967). Sodium cromoglycate (SCG), which does not have a bronchodilator, anti-inflammatory or antihistamine effect, has proved a significant advance in the management of patients with asthma and is now being used in several other conditions where there is Type I allergy or an allergic component is considered likely. Pharmacology Effect on sensitised mast cell. Sodium cromoglycate is effective in extrinsic asthma or allergic rhinitis where a Type I hypersensitivity mediated by IgE is present. It has been shown to inhibit the degranulation of mast cells sensitised with IgE antibody on challenge with the appropriate antigen and thus prevent the release of histamine and SRS-A. The circulating antigen links with the membranebound antibody but the next stage in the AgjAb reaction is inhibited, probably due to a stabilisation of the mast cell membrane preventing degranulation and amine release. This action on mast cells appears to be highly specific and the release of active amines by an IgG antibody-antigen reaction in a complement-dependent system is not inhibited. Using chopped human lung passively sensitised with IgE antibody SCG inhibits the release of histamine and SRS-A on challenge with the appropriate antigen (Sheard & Blair, 1970). Pepys et al. (1968) showed that SCG could inhibit the fall in ventilation in man following bronchial antigen challenge for both Type I and Type III hypersensitivity. The prevention of the Type III response was dependent on blocking the Type I response by the prior administration of SCG. Patients sensitive to house dust or the house dust mite on bronchial challenge with house dust extract have an
immediate fall in Forced Expiratory Volume one second (FEV\), recovering within 1 hour. Six hours later 50 per cent of these subjects have a late fall in ventilation. This delayed fall in ventilation is not typical of a Type III hypersensitivity, there being no pyrexia, leucocytosis or precipitating antibody to house dust in the serum of these patients. Sodium cromoglycate inhaled before the first challenge with house dust antigen inhibits the immediate fall in FEV \ and has a significant effect in inhibiting the late reaction. This contrasts with the effect of prednisolone which only inhibits the late reaction in these patients (Booij-Noord et al., 1971). Exercise- induced asthma. In many patients with asthma vigorous exercise over several minutes leads to a decrease followed by an increase in airways resistance usually measured as a fall in FEV r- The incidence of this phenomenon varies considerably (14-90 per cent) probably being dependent on a number of factors such as the intensity and form of the exercise, age and patient selection. Several reports have shown that SCG in a single dose, given a short time before exercise can inhibit the post-exercise rise in airways resistance (Davies, 1968; Silverman & Turner-Warwick, 1972) and a similar prophylaxis of asthma induced by hyperventilation has been reported (Clarke, 1971). Because of the limited duration of the protective effect of SCG in exercise-induced bronchospasm, the booster dose should be given within 1 hour of exercise. Also, the timing of daily medication with SCG is important if optimum results are to be obtained. Histamine hypersensitivity and alpha-adrenergic receptor activity in asthma. The effect of SCG on exercise-induced asthma and the benefit in some patients with intrinsic asthma and no evidence of Type I hypersensitivity, has led to investigation of the effect of this drug on bronchial reactivity as measured by the effect of histamine (Kerr et al., 1970) and alpha-adrenergic stimulation in the presence
The Therapeutic use of Sodium Cromoglycate UP
of beta-receptor blockade (Marcelle, 1970). In both situations SCG has a protective effect inhibiting bronchial constriction. Nevertheless opinion is divided whether SCG has an effect on the membrane of bronchial smooth muscle in addition to the specific effect on mast cells. Pharmacokinetics Not more than 1 per cent of sodium cromoglycate is absorbed from the gastrointestinal tract. The drug is therefore administered in a Spinhaler designed so that SCG powder is inhaled into the airways with each full inspiration (Fig. I). Each capsule contains 20 mg. SCG and with a Spinhaler 90 per cent enters the body, most of which is unabsorbed. A significant amount enters the large airways but only 3.2 per cent is taken up by the lungs. Sodium cromoglycate is not metabolised and is excreted unchanged in the bile and urine. It is marketed in 2 forms, each capsule containing 20 mg. of SCG. The compound formula also contains 0.1 mg. isoprenaline sulphate which was included to combat any transient bronchospasm due to the inhalation
of a dry powder. The inclusion of isoprenaline made it more difficult to make a true evaluation of SCG in asthma in the early trials, and it was only later that longer term trials showed the added isoprenaline was of little therapeutic advantage (Patel et al., 1971; Brompton Hospital/MRC collaborative trial, 19i2). When the value of SCG has been established the SCG compound may reduce the amount of medication prescribed for a patient. Bronchial asthma The pharmacology of SCG suggested that this drug would be most effective in preventing attacks of asthma. It should not be used in status asthmaticus or in severe acute bronchospasm where the patient is unable to use the Spinhaler effectively. Sodium cromoglycate may be introduced as the patient recovers from the acute phase of an asthmatic attack when, for example, prednisolone is being tapered off and stopped, or during a more persistent but chronic phase of bronchospasm not adequately controlled by a simple bronchodilator, or asthma sufficiently trouble-
The spinhaler is opened and the capsule inserted in the propeller. The Sleeve which is shown herewith a window is pushed down and upwards to puncture two holes in the capsule. The spinhaler is then ready for use. It is held in the mouth and the powder is usually emptied from the capsule after three or four full inhalations. 235
Kerr
some to interfere with the patient's daily routine. Most younger patients with asthma and evidence of an allergic component identified by skin testing or bronchial challenge and measurement of serum IgE levels benefit from SCG. This contrasts with the result in patients with intrinsic asthma. Here the onset of the bronchospasm is usually later in life, and, although episodic at onset, usually becomes continuous. A bronchial infection is often associated with the start of intrinsic asthma. There is usually no evidence of a Type I hypersensitivity and the response to SCG can be disappointing. In intrinsic asthma the presence of a sputum eosinophilia or the inhibition of exercise-induced bronchospasm with 20 mg. of SCG before exertion suggests a good clinical response may be achieved. Patients start treatment with 20 mg. 4 times daily from the Spinhaler and it helps to supervise the initial use of the apparatus. The subjective improvement is associated with less wheeze and tightness in the chest and a reduction in the number of more severe attacks. Exercise tolerance is improved and there is a reduction in the need for bronchodilator drugs (Morrison Smith & Devey, 1968). In patients established on oral steroids some reduction in dosage can often be achieved and a few patients can stop them. The objective improvement is shown by increased FEV l and PEFR, and the static lung volumes move towards predicted as pulmonary hyperinflation diminishes (Robertson et al., 1969). The relationship of SCG to the use of inhalation steroids has still to be fully evaluated. Side effects Side effects with SCG have been remarkably infrequent. Local irritation of the mouth and throat can arise and the occasional facial or urticarial rash. There have been 2 reports of severe bronchospasm produced by SCG (Muller & Kowalski, 1975; Paterson et al., 1976). Allergic rhinitis The beneficial effect of sodium cromoglycate in allergic asthma has led to the use of SCG in patients with allergic rhinitis. Experimental studies have shown that sodium cromoglycate applied to the nasal mucosa as a micronised powder or as a 2 per cent aqueous solution 236
inhibits the reaction of the nasal mucosa on challenge with specific allergen, usually house dust or grass pollen extracts (Taylor & Shivalkar, 1971; Jenssen, 1973). The protection of the nasal mucosa appears to persist for at least 4 hours after 1 mg. of SCG. Trials to assess the benefit of SCG in patients with seasonal hay fever are difficult to assess because of the varying intensity of symptoms that can occur spontaneously due to fluctuating levels of atmospheric pollen. Changing concentrations of atmospheric pollen can easily eliminate differences between a placebo and active period of treatment. The results of hay fever trials are therefore less clear cut than the non-seasonal experimental investigations already mentioned. Sodium cromoglycate can be applied to the nasal mucosa either in powder form, 10 mg. being insufflated into each nostril 4 times daily, or as a 2 per cent solution sprayed into each nostril 6 times daily (31.2 mg.jday). There is no significant difference in the clinical response or in the incidence of side effects with either preparation, although it has been suggested that the liquid preparation is more effective where there is marked nasal obstruction (Halopainen et al., 1975; Manners, 1975). Over a dozen controlled trials have been reported and in most sodium cromoglycate has been shown to be superior to placebo in controlling symptoms of rhinitis and nasal obstruction during the pollen season with a reduction in the need for antihistamines (Engstrom et al., 1971; Holopainen et al., 1975). Perennial rhinitis
Histological studies of the nasal mucosa biopsies have shown that patients with perennial rhinitis have diminished numbers of mast cells which are degranulating, associated with an increased number of eosinophils (Brain et al., 1974). Following therapy with SCG there is an increase in the number of mast cells without evidence of degranulation and a decreased eosinophilia. Controlled trials using a 2 per cent solution of sodium cromoglycate have shown a significant reduction in sneezing, nasal obstruction, catarrh and eosinophilia after 4 weeks' therapy. A few patients complain of nasal irritation both with active treatment and placebo (Girard & Bertrand,
The Therapeutic use of Sodium Cromoglycate BP
1975). Patients with an eosinophilia in the nasal discharge appear to do best, but in all trials some patients showed no benefit from SCG, and the drug's effect is prophylactic rather than curative. Vernal keratoconjunctivitis Vernal conjunctivitis is an intractable condition which develops in a proportion of patients with atopy, although sometimes there is no atopic history. In 1972 Easty et al. reported that a controlled trial of disodium cromoglycate applied topically reduced the amount of mucous discharge and the severity of eye itching. Objectively there was no change in the cobblestone papillae but the degree of inflammatory hyperaemia was reduced and punctate keratopathy improved. This report and further studies have culminated in 2 per cent SCG being made available as Opticrom. The prophylactic regular use of the eye drops 4 times daily allows corticosteroids to be used intermittently and reduces the risk of corticosteroid damage to the eye (Rice & Jones, 1973). Ulcerative colitis Histological examination of the rectal mucosa in patients with ulcerative colitis often shows an increased number of plasma cells, eosinophils and degranulated mast cells. Further, Wright and Truelove showed that one out of 5 patients with ulcerative colitis could expect a sustained real improvement in symptoms when on a milk-free diet. These observations suggested that SCG given orally might be of value in ulcerative colitis. Recently there have been reports of the use of SCG in ulcerative colitis and proctitis. Heatley et al. (1975) gave 300 mg. SCG daily together with 200 mg. in an enema using a double blind crossover technique, and 14 of 26 patients seemed to have some benefit. Mani et al. (1976) used 2 g. per day of oral SCG for 6 months in 12 patients with extensive ulcerative colitis and found an improvement in general wellbeing, and in histological and sigmoidoscopic appearances. The use of sodium cromoglycate in ulcerative colitis requires further evaluation, and meantime sulphasalazine and corticosteroid enemata remain first choice for treatment. A case of life-long diarrhoea due to systemic mastocytosis in
which SCG has restored a normal bowel movement pattern over 6 months has been reported (Dolovich et al., 1974). Food allergy Allergic reactions to food may present as urticaria in adults or as colicky abdominal pain and diarrhoea in children. Most reports of the use of SCG in these situations have included only a few patients, each being used as his own control. Shiner et al. (1975) investigated 2 infants with allergy to cow's milk proteins and suggest the use of SCG. There have been additional reports that 50 mg. SCG given 4 times daily orally allow cow's milk to be reintroduced and tolerated (Freier & Berger, 1973; Kingsley, 1974; Kuzemko & Simpson, 1975). Conclusion Sodium cromoglycate BP has an established place in the treatment of allergic asthma. Its specificity in Type I hypersensitivity has made it of considerable value in the investigation of a number of conditions in which the cause is unknown, but an IgE allergic component is suspected. Its exact mode of action has still to be elucidated and will undoubtedly lead to a better understanding of the conditions in which it is of therapeutic value. REFERENCES Booij-Noord, H., Orie, N. G. M., de Vries, K. (1971). Immediate and late bronchial obstructive reactions to inhalation of house dust and protective effects of disodium cromoglycate and prednisolone. Journal of Allergy, 48, 344 Brain, D. J., Singh, K. P., Trotter, C. M., Viner, A. S. (1974). Sodium cromoglycate 2 per cent solution in perennial rhinitis: a clinical and histological study. Journal ofLaryngology and Otology, 88, 1001 Brompton Hospital/Medical Research Council Collaborative Trial (1972). Long-term study of disodium cromoglycate in treatment of severe extrinsic and intrinsic bronchial asthma in adults. British Medical Journal, 4, 383 Clarke, P. S. (1971). Effect of disodium cromoglycate on exacerbations of asthma produced by hyperventilation. British Medical Journal, 1, 317 Davies, S. E. (1968). Effect of disodium cromoglycate on exercise induced asthma. British Medical Journal, 3, 593 Dolovich, J., Punthakee, N. D., MacMillan, A. B., Osbaldeston, G. J. (1974). Systemic mastocytosis: control of lifelong diarrhoea by ingested disodium cromoglycate, Canadian Medical Association Journal, 3, 684 237
Kerr
Easty, D. L., Rice, N. S. C., Jones, B. R. (1972). Clinical trial of topical disodium cromoglycate in vernal kerato conjunctivitis. Clinical Allergy, 2, 99 Engstrom, I., Oberger, E., Blychert, A., Kraepelin, S. (1971). Disodium cromoglycate in the treatment of seasonal allergic rhinoconjunctivitis in children. Annals of Allergy, 29, 505 Freier, S., Berger, H. (1973). Disodium cromoglycate in gastro-intestinal protein intolerance. Lancet, 1, 913 Girard, J. P., Bertrand, J. (1975). Study of 2 per cent solution of sodium cromoglycate in perennial rhinitis assessed by subjective and objective parameters. Clinical Allergy,S, 301 Halopainen, E., Viner, T., Backman, A., Salo, 0., Hannuksela, M., Malmberg, H. (1975). Clinical trial of a 2 per cent solution of DSCG in perennial rhinitis. Acta Allergologica, 30, 216 Heatley, R. V., Caleraft, B. J., Rhodes, J., Owen, E., Evans, B. K. (1975). Disodium cromoglycate in the treatment of chronic proctitis. Gut, 16, 559 Howell, J. B. L., Altounyan, R. E. C. (1967). A double blind trial of disodium cromoglycate in the treatment of allergic bronchial asthma. Lancet, 2, 539 Jenssen, A. O. (1973). Measurement of resistance to air flow in the nose in a trial with sodium crornoglycate (BP) solution in allergen-induced nasal stenosis. Clinical Allergy, 3, 277 Kerr, J. W., Govindaraj, M., Patel, K. R. (1970). Effect of alpha-receptor blocking drugs and disodium crornoglycate on histamine hypersensitivity in bronchial asthma. British Medical Journal, 2, 139 Kingsley, P. J. (1974). Oral sodium cromoglycate in gastrointestinal allergy. Lancet, 2, 1011 Kuzemko, J. A., Simpson, K. R. (1975). Treatment of allergy to cow's milk. Lancet, 1, 337 Mani, V., Green, F. N. Y., Lloyd, G., Fox, H., Turnberg, L. A. (1976). Treatment of ulcerative colitis with oral disodium cromoglycate, Lancet, 1, 439
238
Manners, B. T. B. (1975). A comparison of sodium cromoglycate nasal solution and powder in hay fever. British Journal of Clinical Practice, 29, 153 Marcelle, R. (1970). Activite du DSCG sur la bronchomotricite de l'homme in vitro. Respiration, 27 (Suppl.), 369 Morrison Smith, J., Devey, G. F. (1968). Clinical trial of disodium cromoglycate in treatment of asthma in children. British Medical Journal, 2, 340 Miiller, J., Kowalski, J. (1975). Unusual side effects during disodium crornoglycate (In tal) therapy in a case of bronchial asthma (case report). Pneumonologie, 151, 323 Patel, K. R., Kerr, J. W., Wade, I. M. (1971). The effect of disodium cromoglycate on pulmonary function in extrinsic bronchial asthma over 12 months. Clinical Allergy, 1, 199 Paterson, I. C., Grant, I. W. B., Crompton, G. K. (1976). Severe broncho-constriction provoked by sodium cromoglycate. British Medical Journal, 2, 916 Pepys, J., Hargreave, F. E., Chan, Moira, McCarthy, D. S. (1968). Inhibitory effects of disodium crornoglycate on allergen inhalation tests. Lancet, 2, 134 Rice, N. S. C., Jones, B. R. (1973). Vernal keratoconjunctivitis: an allergic disease of the eyes of children. Clinical Allergy, 3 (Supp!.), 629 Robertson, D. G., Epstein, S. W., Warrell, D. A. (1969). Trial of disodium cromoglycate in bronchial asthma. British Medical Journal, 1, 552 Sheard, P., Blair, A. N. J. N. (1970). Disodium cromoglycate. Activity in 3 in vitro models of the immediate hypersensitivity reactions in lung. International Archives of Allergy and Applied Immunology, 38, 217 Shiner, Margot, Ballard, Janet, Smith, Marguerite, M. (1975). The small intestinal mucosa in cow's milk allergy. Lancet, 1, 136 Silverman, M., Turner-Warwick, Margaret (1972). Exercise induced asthma. Response to disodium cromoglycate in skin-test positive and skin-test negative subjects. Clinical Allergy, 2, 137 Taylor, G., Shivalkar, P. R. (1971). Disodium cromoglycate: Laboratory studies and clinical trial in allergic rhinitis. Clinical Allergy, 1, 189
THE THERAPEUTIC USE OF SODIUM CROMOGLYCATE BP James W. Kerr Western Infirmary and Knightswood Hospital, Glasgow
1958 Altounyan observed that a deriva-
tive of Khellin inhibited the asthmatic Iresponse to an inhaled allergen. This observN
ation led to the development of sodium cromoglycate (Intal) and its introduction for the treatment of allergic bronchial asthma (Howell & Altounyan, 1967). Sodium cromoglycate (SCG), which does not have a bronchodilator, anti-inflammatory or antihistamine effect, has proved a significant advance in the management of patients with asthma and is now being used in several other conditions where there is Type I allergy or an allergic component is considered likely. Pharmacology Effect on sensitised mast cell. Sodium cromoglycate is effective in extrinsic asthma or allergic rhinitis where a Type I hypersensitivity mediated by IgE is present. It has been shown to inhibit the degranulation of mast cells sensitised with IgE antibody on challenge with the appropriate antigen and thus prevent the release of histamine and SRS-A. The circulating antigen links with the membranebound antibody but the next stage in the AgjAb reaction is inhibited, probably due to a stabilisation of the mast cell membrane preventing degranulation and amine release. This action on mast cells appears to be highly specific and the release of active amines by an IgG antibody-antigen reaction in a complement-dependent system is not inhibited. Using chopped human lung passively sensitised with IgE antibody SCG inhibits the release of histamine and SRS-A on challenge with the appropriate antigen (Sheard & Blair, 1970). Pepys et al. (1968) showed that SCG could inhibit the fall in ventilation in man following bronchial antigen challenge for both Type I and Type III hypersensitivity. The prevention of the Type III response was dependent on blocking the Type I response by the prior administration of SCG. Patients sensitive to house dust or the house dust mite on bronchial challenge with house dust extract have an
immediate fall in Forced Expiratory Volume one second (FEV\), recovering within 1 hour. Six hours later 50 per cent of these subjects have a late fall in ventilation. This delayed fall in ventilation is not typical of a Type III hypersensitivity, there being no pyrexia, leucocytosis or precipitating antibody to house dust in the serum of these patients. Sodium cromoglycate inhaled before the first challenge with house dust antigen inhibits the immediate fall in FEV \ and has a significant effect in inhibiting the late reaction. This contrasts with the effect of prednisolone which only inhibits the late reaction in these patients (Booij-Noord et al., 1971). Exercise- induced asthma. In many patients with asthma vigorous exercise over several minutes leads to a decrease followed by an increase in airways resistance usually measured as a fall in FEV r- The incidence of this phenomenon varies considerably (14-90 per cent) probably being dependent on a number of factors such as the intensity and form of the exercise, age and patient selection. Several reports have shown that SCG in a single dose, given a short time before exercise can inhibit the post-exercise rise in airways resistance (Davies, 1968; Silverman & Turner-Warwick, 1972) and a similar prophylaxis of asthma induced by hyperventilation has been reported (Clarke, 1971). Because of the limited duration of the protective effect of SCG in exercise-induced bronchospasm, the booster dose should be given within 1 hour of exercise. Also, the timing of daily medication with SCG is important if optimum results are to be obtained. Histamine hypersensitivity and alpha-adrenergic receptor activity in asthma. The effect of SCG on exercise-induced asthma and the benefit in some patients with intrinsic asthma and no evidence of Type I hypersensitivity, has led to investigation of the effect of this drug on bronchial reactivity as measured by the effect of histamine (Kerr et al., 1970) and alpha-adrenergic stimulation in the presence
The Therapeutic use of Sodium Cromoglycate UP
of beta-receptor blockade (Marcelle, 1970). In both situations SCG has a protective effect inhibiting bronchial constriction. Nevertheless opinion is divided whether SCG has an effect on the membrane of bronchial smooth muscle in addition to the specific effect on mast cells. Pharmacokinetics Not more than 1 per cent of sodium cromoglycate is absorbed from the gastrointestinal tract. The drug is therefore administered in a Spinhaler designed so that SCG powder is inhaled into the airways with each full inspiration (Fig. I). Each capsule contains 20 mg. SCG and with a Spinhaler 90 per cent enters the body, most of which is unabsorbed. A significant amount enters the large airways but only 3.2 per cent is taken up by the lungs. Sodium cromoglycate is not metabolised and is excreted unchanged in the bile and urine. It is marketed in 2 forms, each capsule containing 20 mg. of SCG. The compound formula also contains 0.1 mg. isoprenaline sulphate which was included to combat any transient bronchospasm due to the inhalation
of a dry powder. The inclusion of isoprenaline made it more difficult to make a true evaluation of SCG in asthma in the early trials, and it was only later that longer term trials showed the added isoprenaline was of little therapeutic advantage (Patel et al., 1971; Brompton Hospital/MRC collaborative trial, 19i2). When the value of SCG has been established the SCG compound may reduce the amount of medication prescribed for a patient. Bronchial asthma The pharmacology of SCG suggested that this drug would be most effective in preventing attacks of asthma. It should not be used in status asthmaticus or in severe acute bronchospasm where the patient is unable to use the Spinhaler effectively. Sodium cromoglycate may be introduced as the patient recovers from the acute phase of an asthmatic attack when, for example, prednisolone is being tapered off and stopped, or during a more persistent but chronic phase of bronchospasm not adequately controlled by a simple bronchodilator, or asthma sufficiently trouble-
The spinhaler is opened and the capsule inserted in the propeller. The Sleeve which is shown herewith a window is pushed down and upwards to puncture two holes in the capsule. The spinhaler is then ready for use. It is held in the mouth and the powder is usually emptied from the capsule after three or four full inhalations. 235
Kerr
some to interfere with the patient's daily routine. Most younger patients with asthma and evidence of an allergic component identified by skin testing or bronchial challenge and measurement of serum IgE levels benefit from SCG. This contrasts with the result in patients with intrinsic asthma. Here the onset of the bronchospasm is usually later in life, and, although episodic at onset, usually becomes continuous. A bronchial infection is often associated with the start of intrinsic asthma. There is usually no evidence of a Type I hypersensitivity and the response to SCG can be disappointing. In intrinsic asthma the presence of a sputum eosinophilia or the inhibition of exercise-induced bronchospasm with 20 mg. of SCG before exertion suggests a good clinical response may be achieved. Patients start treatment with 20 mg. 4 times daily from the Spinhaler and it helps to supervise the initial use of the apparatus. The subjective improvement is associated with less wheeze and tightness in the chest and a reduction in the number of more severe attacks. Exercise tolerance is improved and there is a reduction in the need for bronchodilator drugs (Morrison Smith & Devey, 1968). In patients established on oral steroids some reduction in dosage can often be achieved and a few patients can stop them. The objective improvement is shown by increased FEV l and PEFR, and the static lung volumes move towards predicted as pulmonary hyperinflation diminishes (Robertson et al., 1969). The relationship of SCG to the use of inhalation steroids has still to be fully evaluated. Side effects Side effects with SCG have been remarkably infrequent. Local irritation of the mouth and throat can arise and the occasional facial or urticarial rash. There have been 2 reports of severe bronchospasm produced by SCG (Muller & Kowalski, 1975; Paterson et al., 1976). Allergic rhinitis The beneficial effect of sodium cromoglycate in allergic asthma has led to the use of SCG in patients with allergic rhinitis. Experimental studies have shown that sodium cromoglycate applied to the nasal mucosa as a micronised powder or as a 2 per cent aqueous solution 236
inhibits the reaction of the nasal mucosa on challenge with specific allergen, usually house dust or grass pollen extracts (Taylor & Shivalkar, 1971; Jenssen, 1973). The protection of the nasal mucosa appears to persist for at least 4 hours after 1 mg. of SCG. Trials to assess the benefit of SCG in patients with seasonal hay fever are difficult to assess because of the varying intensity of symptoms that can occur spontaneously due to fluctuating levels of atmospheric pollen. Changing concentrations of atmospheric pollen can easily eliminate differences between a placebo and active period of treatment. The results of hay fever trials are therefore less clear cut than the non-seasonal experimental investigations already mentioned. Sodium cromoglycate can be applied to the nasal mucosa either in powder form, 10 mg. being insufflated into each nostril 4 times daily, or as a 2 per cent solution sprayed into each nostril 6 times daily (31.2 mg.jday). There is no significant difference in the clinical response or in the incidence of side effects with either preparation, although it has been suggested that the liquid preparation is more effective where there is marked nasal obstruction (Halopainen et al., 1975; Manners, 1975). Over a dozen controlled trials have been reported and in most sodium cromoglycate has been shown to be superior to placebo in controlling symptoms of rhinitis and nasal obstruction during the pollen season with a reduction in the need for antihistamines (Engstrom et al., 1971; Holopainen et al., 1975). Perennial rhinitis
Histological studies of the nasal mucosa biopsies have shown that patients with perennial rhinitis have diminished numbers of mast cells which are degranulating, associated with an increased number of eosinophils (Brain et al., 1974). Following therapy with SCG there is an increase in the number of mast cells without evidence of degranulation and a decreased eosinophilia. Controlled trials using a 2 per cent solution of sodium cromoglycate have shown a significant reduction in sneezing, nasal obstruction, catarrh and eosinophilia after 4 weeks' therapy. A few patients complain of nasal irritation both with active treatment and placebo (Girard & Bertrand,
The Therapeutic use of Sodium Cromoglycate BP
1975). Patients with an eosinophilia in the nasal discharge appear to do best, but in all trials some patients showed no benefit from SCG, and the drug's effect is prophylactic rather than curative. Vernal keratoconjunctivitis Vernal conjunctivitis is an intractable condition which develops in a proportion of patients with atopy, although sometimes there is no atopic history. In 1972 Easty et al. reported that a controlled trial of disodium cromoglycate applied topically reduced the amount of mucous discharge and the severity of eye itching. Objectively there was no change in the cobblestone papillae but the degree of inflammatory hyperaemia was reduced and punctate keratopathy improved. This report and further studies have culminated in 2 per cent SCG being made available as Opticrom. The prophylactic regular use of the eye drops 4 times daily allows corticosteroids to be used intermittently and reduces the risk of corticosteroid damage to the eye (Rice & Jones, 1973). Ulcerative colitis Histological examination of the rectal mucosa in patients with ulcerative colitis often shows an increased number of plasma cells, eosinophils and degranulated mast cells. Further, Wright and Truelove showed that one out of 5 patients with ulcerative colitis could expect a sustained real improvement in symptoms when on a milk-free diet. These observations suggested that SCG given orally might be of value in ulcerative colitis. Recently there have been reports of the use of SCG in ulcerative colitis and proctitis. Heatley et al. (1975) gave 300 mg. SCG daily together with 200 mg. in an enema using a double blind crossover technique, and 14 of 26 patients seemed to have some benefit. Mani et al. (1976) used 2 g. per day of oral SCG for 6 months in 12 patients with extensive ulcerative colitis and found an improvement in general wellbeing, and in histological and sigmoidoscopic appearances. The use of sodium cromoglycate in ulcerative colitis requires further evaluation, and meantime sulphasalazine and corticosteroid enemata remain first choice for treatment. A case of life-long diarrhoea due to systemic mastocytosis in
which SCG has restored a normal bowel movement pattern over 6 months has been reported (Dolovich et al., 1974). Food allergy Allergic reactions to food may present as urticaria in adults or as colicky abdominal pain and diarrhoea in children. Most reports of the use of SCG in these situations have included only a few patients, each being used as his own control. Shiner et al. (1975) investigated 2 infants with allergy to cow's milk proteins and suggest the use of SCG. There have been additional reports that 50 mg. SCG given 4 times daily orally allow cow's milk to be reintroduced and tolerated (Freier & Berger, 1973; Kingsley, 1974; Kuzemko & Simpson, 1975). Conclusion Sodium cromoglycate BP has an established place in the treatment of allergic asthma. Its specificity in Type I hypersensitivity has made it of considerable value in the investigation of a number of conditions in which the cause is unknown, but an IgE allergic component is suspected. Its exact mode of action has still to be elucidated and will undoubtedly lead to a better understanding of the conditions in which it is of therapeutic value. REFERENCES Booij-Noord, H., Orie, N. G. M., de Vries, K. (1971). Immediate and late bronchial obstructive reactions to inhalation of house dust and protective effects of disodium cromoglycate and prednisolone. Journal of Allergy, 48, 344 Brain, D. J., Singh, K. P., Trotter, C. M., Viner, A. S. (1974). Sodium cromoglycate 2 per cent solution in perennial rhinitis: a clinical and histological study. Journal ofLaryngology and Otology, 88, 1001 Brompton Hospital/Medical Research Council Collaborative Trial (1972). Long-term study of disodium cromoglycate in treatment of severe extrinsic and intrinsic bronchial asthma in adults. British Medical Journal, 4, 383 Clarke, P. S. (1971). Effect of disodium cromoglycate on exacerbations of asthma produced by hyperventilation. British Medical Journal, 1, 317 Davies, S. E. (1968). Effect of disodium cromoglycate on exercise induced asthma. British Medical Journal, 3, 593 Dolovich, J., Punthakee, N. D., MacMillan, A. B., Osbaldeston, G. J. (1974). Systemic mastocytosis: control of lifelong diarrhoea by ingested disodium cromoglycate, Canadian Medical Association Journal, 3, 684 237
Kerr
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