- Email: [email protected]
DISODIUM CROMOGLYCATE IN HAYFEVER
575
study of hepatic enzyme induction in man, especially in relation to drug and environmental influences. We thank Dr. K. J. Zilkha and Dr. J. D. Parkes for their help with the epileptic patients, and Dr. A. P. Mowat for valuable discussion. M. C. was in receipt of a British Council scholarship. Requests for reprints should be addressed to R. W.
trial of nasal insufflation of the drug for the relief of hayfever (grass-pollen rhinitis) symptoms in hypersensitive subjects was therefore planned after a pilot trial by one of us (P. McK.) in 1968. Methods
hayfever subjects-28 men (mean age 25 years) and (mean age 30 years)-with skin tests positive for grass-pollen extract and symptoms for at least two hayfever seasons were divided into two nearly equal groups. None was to take any drug other than chlorpheniramine and the test substance; those previously treated by hyposensitisation by grass-pollen vaccine were equally distributed between the two groups. One group was given cartridges of 10 mg. sodium cromoglycate mixed with 10 mg. lactose, the other group was given cartridges containing 20 mg. lactose. Neither those in charge of the trial nor the patients knew which was which. The trial material was explained to the patients, and all were told to insufflate one cartridge in each nostril three times daily (on rising, at noon, and at 5 P.M.), using an experimental bulb insufflator. Treatment began at the end of April, 1969, to continue until the end of August or until, as described below, the application was considered ineffective. Chlorpheniramine 4 mg. tablets were to be taken if the patient considered further help was needed. Each day the patient recorded his symptoms as none, mild, troublesome, or severe, whether symptoms disturbed the previous night’s sleep, and whether chlorpheniramine 44
REFERENCES
Conney, A. H. Pharmac. Rev. 1967, 19, 317. Platt, D. S., Cockrill, B. L. Biochem. Pharmac. 1969, 18, 429. 3. Arias, I. M., Gartner, L. M., Cohen, M., Ben Ezzer, J., Levi, A. J. Am. J. Med. 1969, 47, 395. 1. 2.
Black, M., Sherlock, S. Lancet, 1970, i, 1359. Ramboer, C., Thompson, R. P. H., Williams, R. ibid. 1968, i, 966. Breckenridge, A., Orme, M. L’E., Davies, D. S., Thorgeirsson, S. Clin. Sci. 1969, 37, 565. 7. Dent, C. E., Richens, A., Rowe, D. J. F., Stamp, T. C. B. Br. med. J. 1970, iv, 69. 8. Arias, I. M.J. clin. Invest. 1962, 41, 2233. 9. Vessel, E. S., Page, J. G. ibid. 1969, 48, 2202. 10. Kuntzman, R., Jacobson, M., Levin, W., Conney, A. H. Biochem. Pharmac. 1968, 17, 565. 11. Poland, A., Smith, D., Kuntzman, R., Jacobson, M., Conney, A. H. Clin. Pharmac. Ther. 1970, 11, 724. 12. Hänninen, O. Ann. Acad. Sci. fenn. 1968, Ser. A II (chemica), p. 142. 13. Marsh, C. A. Biochem. J. 1963, 86, 77. 14. Richens, A., Rowe, D. J. F. Br. med. J. 1970, iv, 73. 15. Thompson, R. P. H. J. clin. Path. 1969, 22, 439. 16. Werk, E. E., MacGee, J., Sholiton, L. J. J. clin. Invest. 1964, 43, 4. 5. 6.
1824. 17. Thompson, R. P. H., Eddleston, A. L. W. F., Williams. R. Lancet, 1969, i, 21. 18. Kawada, M., Yamada, K., Kagawa, Y., Mano, Y. J. Biochem. Tokyo, 1961, 50, 74. 19. Conney, A. H., Burns, J. J. Nature, 1959, 184, 363. 20. Dutton, G. J. in Glucuronic Acid (edited by G. J. Dutton); p. 186. New York, 1966. 21. Whistler, R. L., Rowell, R. M. ibid. p. 137. 22. Aarts, E. M. Biochem. Pharmac. 1965, 14, 359. 23. Mowat, A. P. J. Endocr. 1968, 42, 585. 24. Fahim, M. S., Hall, D. G., Fahim, Z. Am. J. Obstet. Gynec. 1969, 105, 124.
DISODIUM CROMOGLYCATE IN HAYFEVER L. H. CAPEL
P. MCKELVIE Rhinitis Clinic, Royal National Throat, Nose and Ear Hospital, London N.W.1 In a double-blind trial of nasal insufflation of disodium cromoglycate for hayfever (grass-pollen rhinitis) nine of twenty-two patients taking the drug were helped compared with one of nineteen who took lactose—a statistically
Summary
16
women
was
taken.
Patients
were seen every two weeks except during absence for summer holiday or work. On each attendance one of us only (L. H. C.) interviewed the patient to establish whether the patient felt certain that he was being helped or not. If it was clear to the interviewer that the patient thought he was helped, then the trial was continued. If there was any doubt about help on two successive visits or if the patient was clear on two successive visits that he or she was not helped, then the trial in that patient was stopped: such patients would usually refer to their increasing use of the chlorpheniramine tablets. When the trial was completed at the end of August, 1969, the code was broken.
Results
Judged in this way 9 of 22 patients who tooh disodium cromoglycate were helped compared witt 1 of 19 who took lactose-a statistically significan SUMMARY OF RESULTS
significant difference. Introduction
IT has been shown by Altounyan 1 and by Pepys et al. that inhalation of disodium cromoglycate can give hypersensitive subjects some protection from asthma, and by Taylor3 that it can give them some protection from rhinitis when these conditions are induced by antigen aerosol inhalation. In a doubleblind trial Weinbren et al. have shown that daily inhalation of the drug can partly relieve the symptoms of clinical asthma. Cox5 has suggested that these effects may be due in whole or in part to inhibition of release of histamine and other humoral mediators after union of antigen with the reaginic antibodies attached to cells in the sensitive tissues. A controlled
difference (P=0-02). 3 patients failed to attend. The accompanying table summarises the results. Analysis of the diary cards was inconclusive (see
below). Discussion
The trial was a double-blind assessment by clinician and patient of the patient’s opinion of his response to treatment. The patient was recorded as helped this when only opinion was clear without doubt. Patients who were " helped " were not necessarily symptom-free, but they would repeatedly insist that
576 symptoms were mild compared with the experience of previous years, that they would like the treatment " next year, and that they would be prepared to pay for it if necessary ". Comparison of scores from the cards was difficult since each patient’s assessment of severity was different and in some a degree of perennial rhinitis caused nasal stuffiness at nights: furthermore, whilst all patients started insufflations together the time of onset of the season varied from patient to patient, so some patients were using the insufflation for up to eight weeks before the usual time of starting their season. How far eye symptoms were helped is uncertain, and in theory such help would not be expected. For these reasons the diary card scores were discarded. Seen in retrospect, better trial methods might include start of treatment either just before the time when the season is expected to begin in each case, start when symptoms indicate that the season for that patient has begun, or start when grasspollen counts indicate risk of exposure, and stop when counts indicate the passing of this particular risk. Insufflation four times daily would probably be better than three times daily used in the present test. The treatment is non-specific-a therapeutic advantage which, however, adds another difficulty to assessment, since hayfever in Great Britain can arise from allergens other than grass pollens. Since the double-blind assessment significantly selected patients using the disodium cromoglycate it is reasonable to assume that they were indeed helped by it. Patients using it but not helped may have been using the insufflator inefficiently or may have been unsuitable for this form of treatment. A more efficient insufflator using standard capsules is now being tested. Application of drugs to the nasal mucous membrane by insufflation of powder would seem to be a crude method: immediately after insufflation the material is seen as clumps of powder on the mucous membrane, but within a few minutes it appears fairly evenly dispersed, presumably by ciliary action on the mucous sheet lining the nasal mucous membrane. Our study confirms a report from Finland by Holopainen et al.6that nasal insufflation of disodium cromoglycate can help patients with seasonal rhinitis. The authors of that study used diary card scores to show that 13 patients using the drug fared better on Our study average than 14 patients using lactose. showed that some patients were helped by the insufflation methods we used and some were not. Because of its great theoretical and therapeutic interest the use of disodium cromoglycate inhalation for allergens acting on the nasal mucous membrane deserves further study. We are grateful to Dr. Wallace Fox and Miss Ruth Tall for their advice and help in the planning of this study. Dr. A. S. Viner, of Fisons Pharmaceuticals Ltd., kindly supplied the capsules of disodium cromoglycate and lactose
MISDIRECTED VENTRICULO-ATRIAL CATHETER : A METHOD OF REPOSITIONING WITHOUT THORACOTOMY D. N. GRANT J. F. N. TAYLOR
Department of Neurosurgery and Thoracic Unit, Hospital for Sick Children, London W.C.1
misplaced Holter catheter was successfully repositioned without operation in a seven-month-old infant, using the Müller catheter-guide system commonly employed in the investigation of congenital heart-disease. A
Summary
Introduction
IN the treatment of hydrocephalus by ventriculoatrial shunt, the insertion of the atrial catheter into the heart, either directly or via the azygos vein, when all available neck veins have become thrombosed, is now regarded as a satisfactory technique.’ We report the case of a child in whom this method was used but the atrial catheter was mistakenly directed into the left brachiocephalic vein. Rather than subject the child to a second thoracotomy, the position of the atrial catheter was corrected by pulling it into the heart with a special catheter.
Case-report presented several days after birth with focal convulsions. He was found to have septicxmia, a cerebral abscess, and ventriculitis. The responsible organism was The child
a
Proteus.
After several weeks of intensive treatment the
cerebrospinal fluid was thought to be sterile, but ventriculography showed hydrocephalus resulting from irregular cicatrisation within the lateral ventricles. This was treated at the age of 11 weeks by ventriculo-atrial shunt using the right internal jugular vein. At the age of 22 weeks the whole valve assembly was removed because of septicxmia and replaced with a new assembly (following the method described by Nicholas et al.2), using once again the right internal jugular vein. 7 weeks later this valve became blocked and was removed. Attempts to pass a new catheter down the
and the insuffiators. REFERENCES
Altounyan, R. E. C. Acta allerg. 1962, 22, 485. Pepys, J., Hargreave, F. E., Chan, M., McCarthy, D. S. Lancet, 1968, ii, 134. 3. Taylor, G. Acta allerg. 1969, 24, 369. 4. Weinbren, I., Bound, J., Capper, L. Br.J. Dis. Chest, 1969, 63, 155. 5. Cox, J. S. G. Nature, 1967, 216, 1328. 6. Holopainen, E., Backusan, A., Salo, O. P. Lancet, 1971, i, 55. 1. 2.
Fig. 1-Chest radiograph showing misdirected ventriculo-atrial catheter.
study of hepatic enzyme induction in man, especially in relation to drug and environmental influences. We thank Dr. K. J. Zilkha and Dr. J. D. Parkes for their help with the epileptic patients, and Dr. A. P. Mowat for valuable discussion. M. C. was in receipt of a British Council scholarship. Requests for reprints should be addressed to R. W.
trial of nasal insufflation of the drug for the relief of hayfever (grass-pollen rhinitis) symptoms in hypersensitive subjects was therefore planned after a pilot trial by one of us (P. McK.) in 1968. Methods
hayfever subjects-28 men (mean age 25 years) and (mean age 30 years)-with skin tests positive for grass-pollen extract and symptoms for at least two hayfever seasons were divided into two nearly equal groups. None was to take any drug other than chlorpheniramine and the test substance; those previously treated by hyposensitisation by grass-pollen vaccine were equally distributed between the two groups. One group was given cartridges of 10 mg. sodium cromoglycate mixed with 10 mg. lactose, the other group was given cartridges containing 20 mg. lactose. Neither those in charge of the trial nor the patients knew which was which. The trial material was explained to the patients, and all were told to insufflate one cartridge in each nostril three times daily (on rising, at noon, and at 5 P.M.), using an experimental bulb insufflator. Treatment began at the end of April, 1969, to continue until the end of August or until, as described below, the application was considered ineffective. Chlorpheniramine 4 mg. tablets were to be taken if the patient considered further help was needed. Each day the patient recorded his symptoms as none, mild, troublesome, or severe, whether symptoms disturbed the previous night’s sleep, and whether chlorpheniramine 44
REFERENCES
Conney, A. H. Pharmac. Rev. 1967, 19, 317. Platt, D. S., Cockrill, B. L. Biochem. Pharmac. 1969, 18, 429. 3. Arias, I. M., Gartner, L. M., Cohen, M., Ben Ezzer, J., Levi, A. J. Am. J. Med. 1969, 47, 395. 1. 2.
Black, M., Sherlock, S. Lancet, 1970, i, 1359. Ramboer, C., Thompson, R. P. H., Williams, R. ibid. 1968, i, 966. Breckenridge, A., Orme, M. L’E., Davies, D. S., Thorgeirsson, S. Clin. Sci. 1969, 37, 565. 7. Dent, C. E., Richens, A., Rowe, D. J. F., Stamp, T. C. B. Br. med. J. 1970, iv, 69. 8. Arias, I. M.J. clin. Invest. 1962, 41, 2233. 9. Vessel, E. S., Page, J. G. ibid. 1969, 48, 2202. 10. Kuntzman, R., Jacobson, M., Levin, W., Conney, A. H. Biochem. Pharmac. 1968, 17, 565. 11. Poland, A., Smith, D., Kuntzman, R., Jacobson, M., Conney, A. H. Clin. Pharmac. Ther. 1970, 11, 724. 12. Hänninen, O. Ann. Acad. Sci. fenn. 1968, Ser. A II (chemica), p. 142. 13. Marsh, C. A. Biochem. J. 1963, 86, 77. 14. Richens, A., Rowe, D. J. F. Br. med. J. 1970, iv, 73. 15. Thompson, R. P. H. J. clin. Path. 1969, 22, 439. 16. Werk, E. E., MacGee, J., Sholiton, L. J. J. clin. Invest. 1964, 43, 4. 5. 6.
1824. 17. Thompson, R. P. H., Eddleston, A. L. W. F., Williams. R. Lancet, 1969, i, 21. 18. Kawada, M., Yamada, K., Kagawa, Y., Mano, Y. J. Biochem. Tokyo, 1961, 50, 74. 19. Conney, A. H., Burns, J. J. Nature, 1959, 184, 363. 20. Dutton, G. J. in Glucuronic Acid (edited by G. J. Dutton); p. 186. New York, 1966. 21. Whistler, R. L., Rowell, R. M. ibid. p. 137. 22. Aarts, E. M. Biochem. Pharmac. 1965, 14, 359. 23. Mowat, A. P. J. Endocr. 1968, 42, 585. 24. Fahim, M. S., Hall, D. G., Fahim, Z. Am. J. Obstet. Gynec. 1969, 105, 124.
DISODIUM CROMOGLYCATE IN HAYFEVER L. H. CAPEL
P. MCKELVIE Rhinitis Clinic, Royal National Throat, Nose and Ear Hospital, London N.W.1 In a double-blind trial of nasal insufflation of disodium cromoglycate for hayfever (grass-pollen rhinitis) nine of twenty-two patients taking the drug were helped compared with one of nineteen who took lactose—a statistically
Summary
16
women
was
taken.
Patients
were seen every two weeks except during absence for summer holiday or work. On each attendance one of us only (L. H. C.) interviewed the patient to establish whether the patient felt certain that he was being helped or not. If it was clear to the interviewer that the patient thought he was helped, then the trial was continued. If there was any doubt about help on two successive visits or if the patient was clear on two successive visits that he or she was not helped, then the trial in that patient was stopped: such patients would usually refer to their increasing use of the chlorpheniramine tablets. When the trial was completed at the end of August, 1969, the code was broken.
Results
Judged in this way 9 of 22 patients who tooh disodium cromoglycate were helped compared witt 1 of 19 who took lactose-a statistically significan SUMMARY OF RESULTS
significant difference. Introduction
IT has been shown by Altounyan 1 and by Pepys et al. that inhalation of disodium cromoglycate can give hypersensitive subjects some protection from asthma, and by Taylor3 that it can give them some protection from rhinitis when these conditions are induced by antigen aerosol inhalation. In a doubleblind trial Weinbren et al. have shown that daily inhalation of the drug can partly relieve the symptoms of clinical asthma. Cox5 has suggested that these effects may be due in whole or in part to inhibition of release of histamine and other humoral mediators after union of antigen with the reaginic antibodies attached to cells in the sensitive tissues. A controlled
difference (P=0-02). 3 patients failed to attend. The accompanying table summarises the results. Analysis of the diary cards was inconclusive (see
below). Discussion
The trial was a double-blind assessment by clinician and patient of the patient’s opinion of his response to treatment. The patient was recorded as helped this when only opinion was clear without doubt. Patients who were " helped " were not necessarily symptom-free, but they would repeatedly insist that
576 symptoms were mild compared with the experience of previous years, that they would like the treatment " next year, and that they would be prepared to pay for it if necessary ". Comparison of scores from the cards was difficult since each patient’s assessment of severity was different and in some a degree of perennial rhinitis caused nasal stuffiness at nights: furthermore, whilst all patients started insufflations together the time of onset of the season varied from patient to patient, so some patients were using the insufflation for up to eight weeks before the usual time of starting their season. How far eye symptoms were helped is uncertain, and in theory such help would not be expected. For these reasons the diary card scores were discarded. Seen in retrospect, better trial methods might include start of treatment either just before the time when the season is expected to begin in each case, start when symptoms indicate that the season for that patient has begun, or start when grasspollen counts indicate risk of exposure, and stop when counts indicate the passing of this particular risk. Insufflation four times daily would probably be better than three times daily used in the present test. The treatment is non-specific-a therapeutic advantage which, however, adds another difficulty to assessment, since hayfever in Great Britain can arise from allergens other than grass pollens. Since the double-blind assessment significantly selected patients using the disodium cromoglycate it is reasonable to assume that they were indeed helped by it. Patients using it but not helped may have been using the insufflator inefficiently or may have been unsuitable for this form of treatment. A more efficient insufflator using standard capsules is now being tested. Application of drugs to the nasal mucous membrane by insufflation of powder would seem to be a crude method: immediately after insufflation the material is seen as clumps of powder on the mucous membrane, but within a few minutes it appears fairly evenly dispersed, presumably by ciliary action on the mucous sheet lining the nasal mucous membrane. Our study confirms a report from Finland by Holopainen et al.6that nasal insufflation of disodium cromoglycate can help patients with seasonal rhinitis. The authors of that study used diary card scores to show that 13 patients using the drug fared better on Our study average than 14 patients using lactose. showed that some patients were helped by the insufflation methods we used and some were not. Because of its great theoretical and therapeutic interest the use of disodium cromoglycate inhalation for allergens acting on the nasal mucous membrane deserves further study. We are grateful to Dr. Wallace Fox and Miss Ruth Tall for their advice and help in the planning of this study. Dr. A. S. Viner, of Fisons Pharmaceuticals Ltd., kindly supplied the capsules of disodium cromoglycate and lactose
MISDIRECTED VENTRICULO-ATRIAL CATHETER : A METHOD OF REPOSITIONING WITHOUT THORACOTOMY D. N. GRANT J. F. N. TAYLOR
Department of Neurosurgery and Thoracic Unit, Hospital for Sick Children, London W.C.1
misplaced Holter catheter was successfully repositioned without operation in a seven-month-old infant, using the Müller catheter-guide system commonly employed in the investigation of congenital heart-disease. A
Summary
Introduction
IN the treatment of hydrocephalus by ventriculoatrial shunt, the insertion of the atrial catheter into the heart, either directly or via the azygos vein, when all available neck veins have become thrombosed, is now regarded as a satisfactory technique.’ We report the case of a child in whom this method was used but the atrial catheter was mistakenly directed into the left brachiocephalic vein. Rather than subject the child to a second thoracotomy, the position of the atrial catheter was corrected by pulling it into the heart with a special catheter.
Case-report presented several days after birth with focal convulsions. He was found to have septicxmia, a cerebral abscess, and ventriculitis. The responsible organism was The child
a
Proteus.
After several weeks of intensive treatment the
cerebrospinal fluid was thought to be sterile, but ventriculography showed hydrocephalus resulting from irregular cicatrisation within the lateral ventricles. This was treated at the age of 11 weeks by ventriculo-atrial shunt using the right internal jugular vein. At the age of 22 weeks the whole valve assembly was removed because of septicxmia and replaced with a new assembly (following the method described by Nicholas et al.2), using once again the right internal jugular vein. 7 weeks later this valve became blocked and was removed. Attempts to pass a new catheter down the
and the insuffiators. REFERENCES
Altounyan, R. E. C. Acta allerg. 1962, 22, 485. Pepys, J., Hargreave, F. E., Chan, M., McCarthy, D. S. Lancet, 1968, ii, 134. 3. Taylor, G. Acta allerg. 1969, 24, 369. 4. Weinbren, I., Bound, J., Capper, L. Br.J. Dis. Chest, 1969, 63, 155. 5. Cox, J. S. G. Nature, 1967, 216, 1328. 6. Holopainen, E., Backusan, A., Salo, O. P. Lancet, 1971, i, 55. 1. 2.
Fig. 1-Chest radiograph showing misdirected ventriculo-atrial catheter.