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The Cheese Reaction
540
and heparin,2O provides a precedent; and mast-cells have recently been shown to contain a protease 21 which is similar in several biochemical respects to kinin-forming enzyme. It might be well worth looking for new pharmacologically active substances in another group of tumours sometimes associated with diarrhoea-those of the dopamine-secreting ganglioneuroma-neuroblastoma group.22 For, although dopamine has many pharmacological effects, diarrhoea is not one of them.
The Cheese Reaction
,
ALTHOUGH the monoamine-oxidase inhibitors are widely used in the treatment of depression, the relation between their known actions and their clinical effects remains obscure. Structurally, they are divided into the hydrazines and non-hydrazines. Phenelzine (a hydrazine) and tranylcypromine (a non-hydrazine) have sympathomimetic actions of their own 23-25 and are chemically related to amphetamine. It is these two drugs that have been shown to produce an unusual side-effect clinically similar to the hypertensive crisis associated with phxochromocytoma. Although the syndrome can be
precipitated by amphetamine given concurrently, a more common association is the eating of cheese within two hours of the hypertensive attack. This provocation of a side-effect by food seems to be unique. AsATOOR et al. 26 suggested that the responsible constituent of cheese may be tyramine formed during its maturation (an average portion of cheddar contains as much as 20 mg. of tyramine). Because patients taking these drugs often eat cheese with impunity, there must be other precipitating variables, which may include differences in the composition of the cheese, individual idiosyncrasy, and fluctuations in the degree of amine-oxidase inhibition in the intestine and liver, affecting both absorption and degradation of the amine. Cheese and amphetamine are not always incriminated, and other dietary factors could be responsible. We have no definite evidence of what these may be, although alcohol has been suggested on a few occasions. Careful history-taking may in future identify other provoking agents. A puzzling feature of this serious reaction has been the variable incidence. It was not reported during the first three years of clinical use in the United States, and in this country experience seems to differ widely. In 1961 CLARK 27 reported the condition in 3 (10%) out of 30 patients taking tranylcypromine; and BROWN and WALDRON 28 observed the crisis in 6 (4%) out of 150 patients in their general practice. During 1963 there were more and more reports.29-33 GATES 34 saw 20 20.
Furth, J., Hagen, P., Hirsch, 824.
21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34.
E. I. Proc. Soc. exp.
Biol., N.Y. 1957, 95,
Langunoff, D., Benditt, E. P. Ann. N.Y. Acad. Sci. 1963, 103, 185. Rosenstein, B. L., Engelman, K. J. Pediat. 1963, 63, 217. Ling, G. M. Canad. psychiat. Ass. J. 1962, 7, suppl. p. 44. Day, M. D., Rand, M. J. Lancet, 1962, ii, 1283. Eble, J. N. J. Pharmacol. 1963, 140, 243. Asatoor, A. M., Levi, A. J., Milne, M. D. Lancet, 1963, ii, 733. Clark, J. A. ibid. 1961, i, 618. Brown, D. D., Waldron, D. H. Practitioner, 1962, 189, 83. Burke, C. W., Lees, F. Lancet, 1963, i, 13. Richmond, P. W., Roberts, A. H. Brit. med. J. 1963, ii, 999. Cooper, A. J., Rose, M. J. ibid. p. 747. Bethune, H. C., Burrell, R. H., Culpan, R. H. Lancet, 1963, ii, 1233. Mann, A. M., Laing, W. A. R. Canad. med. Ass. J. 1963, 89, 1115. Gates, J. C. Brit. med. J. 1963, ii, 683.
practice; and FOSTER 35 (25 cases), general BLACKWELL 36 37 (12), and ARENILLAS 38 (5) have also had considerable experience of the syndrome. Earlier in this
incidents in
issue Dr. CooPER reports 36 cases seen in three yearsan incidence of 20% among outpatients treated with
tranylcypromine. This apparent increase may be the result of familiarity with the condition and surer diagnosis. Because the main feature is the common complaint of headache, and because other symptoms are brief, the side-effects must often have failed to attract medical attention. When they did so, the paroxysmal onset and severity of the headache might have suggested a subarachnoid hxmorrhage. Even when the transient hypertension or occasional fibrillation was detected, the drug was unlikely to be incriminated, because the condition is an uncommon manifestation of drug toxicity, and it often appears after the patient has been taking only moderate doses for a long time. Moreover, the condition for which these drugs are prescribed often includes tension headaches or palpitation, and the patient’s symptoms are liable to be dismissed as expressions of anxiety or
hysteria. The serious complications of the reaction are intracerebral haemorrhage or acute cardiac failure precipitated by the sudden hypertension. They seem to be comparatively rare, but, like the syndrome itself, they may have been underestimated. For example, DORRELL,39 BLACKWELL,36 and CooPER (p. 527) each report 3 cases of
intracerebral hxmorrhage. The mechanism of the crisis has been investigated and preliminary communications appear in this issue, Several amine-oxidase inhibitors cause the cheese syndrome in animals; and there is additional evidence that the pressor substance in cheese is a member of the phenylethylamine group of amines (which includes tyramine) and that it acts on the peripheral adrenergic receptor. There is a discrepancy between clinical observations and the animal experiments which suggests that inhibitors with sympathomimetic activity may be less likely to precipitate the syndrome, except when the last dose of the drug is given, like amphetamine, at noon and cheese is eaten several hours later. two
In the United States action by the Food and Drug Administration has led to the withdrawal of tranylcypromine. In this country, the Dunlop Committee last week warned doctors of these side-effects 4°; and, as Dr. WEBER explains in a letter on p. 561, the manufacturers of tranylcypromine have for the past few months been giving a warning in their prescribing information and advising that cheese should be forbidden. Should the advice that the manufacturers and the committee are circulating fail to eliminate severe reactions, then, we feel bound to say, it would be simpler to dispense with tranylcypromine than with cheese. 35. Foster, A. R. Lancet, 1963, ii, 587. 36. Blackwell, B. ibid. 1963, i, 167. 37. Blackwell, B. ibid. 1963, ii, 849. 38. Arenillas, L. ibid. p. 587. 39. Dorrell, W. ibid. p. 300. 40. See ibid. Feb. 29, 1964, p. 506.
and heparin,2O provides a precedent; and mast-cells have recently been shown to contain a protease 21 which is similar in several biochemical respects to kinin-forming enzyme. It might be well worth looking for new pharmacologically active substances in another group of tumours sometimes associated with diarrhoea-those of the dopamine-secreting ganglioneuroma-neuroblastoma group.22 For, although dopamine has many pharmacological effects, diarrhoea is not one of them.
The Cheese Reaction
,
ALTHOUGH the monoamine-oxidase inhibitors are widely used in the treatment of depression, the relation between their known actions and their clinical effects remains obscure. Structurally, they are divided into the hydrazines and non-hydrazines. Phenelzine (a hydrazine) and tranylcypromine (a non-hydrazine) have sympathomimetic actions of their own 23-25 and are chemically related to amphetamine. It is these two drugs that have been shown to produce an unusual side-effect clinically similar to the hypertensive crisis associated with phxochromocytoma. Although the syndrome can be
precipitated by amphetamine given concurrently, a more common association is the eating of cheese within two hours of the hypertensive attack. This provocation of a side-effect by food seems to be unique. AsATOOR et al. 26 suggested that the responsible constituent of cheese may be tyramine formed during its maturation (an average portion of cheddar contains as much as 20 mg. of tyramine). Because patients taking these drugs often eat cheese with impunity, there must be other precipitating variables, which may include differences in the composition of the cheese, individual idiosyncrasy, and fluctuations in the degree of amine-oxidase inhibition in the intestine and liver, affecting both absorption and degradation of the amine. Cheese and amphetamine are not always incriminated, and other dietary factors could be responsible. We have no definite evidence of what these may be, although alcohol has been suggested on a few occasions. Careful history-taking may in future identify other provoking agents. A puzzling feature of this serious reaction has been the variable incidence. It was not reported during the first three years of clinical use in the United States, and in this country experience seems to differ widely. In 1961 CLARK 27 reported the condition in 3 (10%) out of 30 patients taking tranylcypromine; and BROWN and WALDRON 28 observed the crisis in 6 (4%) out of 150 patients in their general practice. During 1963 there were more and more reports.29-33 GATES 34 saw 20 20.
Furth, J., Hagen, P., Hirsch, 824.
21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34.
E. I. Proc. Soc. exp.
Biol., N.Y. 1957, 95,
Langunoff, D., Benditt, E. P. Ann. N.Y. Acad. Sci. 1963, 103, 185. Rosenstein, B. L., Engelman, K. J. Pediat. 1963, 63, 217. Ling, G. M. Canad. psychiat. Ass. J. 1962, 7, suppl. p. 44. Day, M. D., Rand, M. J. Lancet, 1962, ii, 1283. Eble, J. N. J. Pharmacol. 1963, 140, 243. Asatoor, A. M., Levi, A. J., Milne, M. D. Lancet, 1963, ii, 733. Clark, J. A. ibid. 1961, i, 618. Brown, D. D., Waldron, D. H. Practitioner, 1962, 189, 83. Burke, C. W., Lees, F. Lancet, 1963, i, 13. Richmond, P. W., Roberts, A. H. Brit. med. J. 1963, ii, 999. Cooper, A. J., Rose, M. J. ibid. p. 747. Bethune, H. C., Burrell, R. H., Culpan, R. H. Lancet, 1963, ii, 1233. Mann, A. M., Laing, W. A. R. Canad. med. Ass. J. 1963, 89, 1115. Gates, J. C. Brit. med. J. 1963, ii, 683.
practice; and FOSTER 35 (25 cases), general BLACKWELL 36 37 (12), and ARENILLAS 38 (5) have also had considerable experience of the syndrome. Earlier in this
incidents in
issue Dr. CooPER reports 36 cases seen in three yearsan incidence of 20% among outpatients treated with
tranylcypromine. This apparent increase may be the result of familiarity with the condition and surer diagnosis. Because the main feature is the common complaint of headache, and because other symptoms are brief, the side-effects must often have failed to attract medical attention. When they did so, the paroxysmal onset and severity of the headache might have suggested a subarachnoid hxmorrhage. Even when the transient hypertension or occasional fibrillation was detected, the drug was unlikely to be incriminated, because the condition is an uncommon manifestation of drug toxicity, and it often appears after the patient has been taking only moderate doses for a long time. Moreover, the condition for which these drugs are prescribed often includes tension headaches or palpitation, and the patient’s symptoms are liable to be dismissed as expressions of anxiety or
hysteria. The serious complications of the reaction are intracerebral haemorrhage or acute cardiac failure precipitated by the sudden hypertension. They seem to be comparatively rare, but, like the syndrome itself, they may have been underestimated. For example, DORRELL,39 BLACKWELL,36 and CooPER (p. 527) each report 3 cases of
intracerebral hxmorrhage. The mechanism of the crisis has been investigated and preliminary communications appear in this issue, Several amine-oxidase inhibitors cause the cheese syndrome in animals; and there is additional evidence that the pressor substance in cheese is a member of the phenylethylamine group of amines (which includes tyramine) and that it acts on the peripheral adrenergic receptor. There is a discrepancy between clinical observations and the animal experiments which suggests that inhibitors with sympathomimetic activity may be less likely to precipitate the syndrome, except when the last dose of the drug is given, like amphetamine, at noon and cheese is eaten several hours later. two
In the United States action by the Food and Drug Administration has led to the withdrawal of tranylcypromine. In this country, the Dunlop Committee last week warned doctors of these side-effects 4°; and, as Dr. WEBER explains in a letter on p. 561, the manufacturers of tranylcypromine have for the past few months been giving a warning in their prescribing information and advising that cheese should be forbidden. Should the advice that the manufacturers and the committee are circulating fail to eliminate severe reactions, then, we feel bound to say, it would be simpler to dispense with tranylcypromine than with cheese. 35. Foster, A. R. Lancet, 1963, ii, 587. 36. Blackwell, B. ibid. 1963, i, 167. 37. Blackwell, B. ibid. 1963, ii, 849. 38. Arenillas, L. ibid. p. 587. 39. Dorrell, W. ibid. p. 300. 40. See ibid. Feb. 29, 1964, p. 506.