973
abandonment of principle. The basis of the principle is forgotten in the rush to the barricades of the change
as
Letters to the Editor
status quo ante.
Further, any attempt to become skilled in relation to the machinery of administration and negotiation is looked upon as a betrayal of the professional stance. One can deplore attendance at committees the better for not understanding their value; it is even easier to oppose if one does not follow the logic or has failed to consider the bounds and constraints of negotiation.2 Amateurism in this field is protective. This somewhat derogatory description of a profession’s stance has been wonderfully borne out by medical behaviour. The reaction to change has been to invoke clinical freedom and its erosion as a stopping-point in negotiation. Exactly what clinical freedom is remains largely unspecified-it would seem that it is partly the right to do as one pleases with individual problems and partly the privilege to defy social regulation that could lead (at least in theory) to the resolution of inequality as seen from a viewpoint other than that of the individuals who demand self-determination. More fundamentally and dispassionately it might incorporate a basic right to dissent which is a characteristic of universities but a doubtful attribute of professions. Analysis such as I have attempted is one thing. It is in a good sociological tradition and it may lead to diagnosis, but unfortunately the link between that and therapy is tenuous. Particularly if the frame of reference of diagnosis-in this case predominantly a social one-is unfamiliar to the victims of the disorder, there is little hope of getting them even to realise that treatment is necessary. Yet there is no doubt that certain diseases are auto-destructive. One can smell suicide in the air for medicine as a profession. What then can be done? Little I think in the short term. We are in for a long winter of discontent during which skirmishes will take place along the picket lines between profession and public, and profession and politician. But during this time it is vitally necessary for the profession to take stock of its own raison d’etre to see how this can or should be modified and finally to come up with some practical proposals for meshing profession ideals with public expectations. There has been a conspicuous lack of effort to do this in the last year. The re-examination will not necessarily be pleasant: for example, it might mean that we can cling no longer to a position of privilege in
regard to status or salary, or our standing as quasi-independent contractors. Who knows? Let us only hope that the Royal Commission will provide a milieu in which a debate on the social situation of the doctor can be pursued. Personally I doubt that this is possible. Public inquiries of any kind are to government as the ink is to the squid (so said Winston Churchill); the chance that such obliterative tactics will not emerge are small but one can
only nurture optimism. We live in depressing times-socially, economically, and professionally. Let us only hope that by defining the nature of our profession and living for it, medicine can be preserved in a way that would justify its unique heritage. St Mary’s Hospital Medical School, London W2.
2
Eiseman, B. Surgery, St. Louis, 1975, 78, 401.
H. A. F. DUDLEY
METIAMIDE IN DUODENAL ULCER
SIR,-From the evidence presented (Oct. 25, p. 779) there is
doubt that metiamide is more effective than a placebo in reducing the pain of duodenal ulceration and healing the ulcer. But how severe was the pain that the 68 patients suffered? It was stated that it was so bad that "surgery was regarded as the only alternative treatment", yet from table v it is clear that the control group were taking one ’Rennie’ tablet a day or less. As a patient I would not consider that surgery was inevitable because medical treatment had failed, nor, as a surgeon, is this my threshold for advising that an operation is necessary. The patients studied probably only had minor discomfort, in no way representing severe symptoms compatible with failure of medical treatment, and the evidence is as follows. With a similar method of recording day and night pain, and using the same idea of topping up with antacid to relieve pain, no
TABLE I-MEAN NUMBER OF PAIN-FREE DAYS AND NIGHTS PER PATIENT IN THE WEEK PRECEDING TREATMENT AND EACH OF THE
SUBSEQUENT 3
WEEKS
have just completed a multicentre trial (Dr R. H. Balme, Dr D. Barnardo, Dr M.Chaput de Saintonge, Dr M. Lancaster-Smith, and Dr J. T. Wright), comparing ’Gaviscon’, Mag. Trisil. Co. B.P.C. and a placebo, taken regularly (8 tablets a day). In our trial the antacid used was Mag. Trisil. Co. B.P.C., as against rennies in the metiamide trial. One rennie tablet contains basically 680 mg prepared chalk and 80 mg magnesium carbonate. To maintain patient cooperation we deliberately did not do endoscopy, which would have been ideal. In tablei pain-free days and nights from our trial have been analysed so that they can be compared easily with the metiamide trial. In table ii extra antacid consumption has been compared for the total group (45) and then split into those who would be considered candidates for surgery, because they were all awoken from sleep four times a week or more in any one bad period of seven days, and those in whom conservative measures would be advised. The mean age of the surgical group (10) was 40.0, they had had symptoms for 7.7 years, and consumed more than 75 antacid tablets in 24 days in addition to the regular 8 per day. It will be seen from the tables that our 45 patients had much worse pain than the metiamide trial group. The antacid consumption in the "medical" group fell by half in three weeks, in a manner similar to that obtained with metiamide lg daily.
we
974 But in the surgical group therapy did not reduce the requirement for extra antacids in the third week. It must be emphasised that this antacid consumption is in addition to the regular 56 per week test tablets. This only serves to emphasise how little we know about the natural history of duodenal-ulcer pain and enables one to state that the decision to operate is entirely subjective and at present is based on no positive objective criteria. I would like to suggest that metiamide is tested on severe duodenal-ulcer patients in whom regular antacids really do fail to control symptoms and in whom, for example, there is no relief in the third week of treatment. Metiamide is undoubtedly one of the great modern advances and the best drug we have at present, so it should be tested on true surgical candidates, and it should be compared with antacids and not a placebo. The London
Hospital, Whitechapel, London E1
1BB.
RICHARD EARLAM
SIR,-Interest in metiamide in ulcer therapy is apparent.’ 2 Blocking histamine H2-receptor sites, metiamide inhibits gastricacid and pepsin secretion.3 However other cells have receptor sites-for example, the T lymphocytes seen at the end of an immunological reaction, when cytotoxicity from T cells declines4 (that is, in vivo 7 to 9 days after antigenic stimulation). Histamine can act by raising cyclic-A.M.p.4 These cells with H2-receptor sites seem to be immunoregulatory cells-that is, suppressor T cells. Through these suppressive cells, histamine could have an important regulatory function--depression of inflammatory responses, blockade of T-cell stimulation, blockade of antibody formation. Elimination of cells bearing H2-receptor sites can lead to an increase in plaque-forming cells’ and/or to a rupture of specific tolerance (elimination of tolerating T cells). Thus, long-term administration of metiamide could have side-effects on immunological regulation, with a risk of uncontrolled immunological responses; either cell-mediated (hypersensitivity, autoimmunisation, pseudolymphoma), or humoral (hypergammaglobulinaemia, paraproteinaemia, humoral autoimmunisation). Compensatory mechanisms in immune response could make this risk negligible in practice. However, it would be helpful if patients receiving long-term therapy with metiamide were followed by a close watch on their immunological functions. Data on the immune response under metiamide (or other H2-receptors blocking drugs, cimetidine, burimamide) must be examined in laboratory animals before commercial distribution of metiamide. Laboratory of Immunology, Faculté de Médecine Pitié-Salpetrière, 91 Boulevard de l’Hôpital, 75634 Paris Cedex
R. MOULIAS 13, France.
F. CONGY
AGE-DEPENDENT SENSITIVITY TO SALICYLATE
SIR,-Poisoning by salicylate is alarmingly common. For example, the third highest number of toxicity cases in the Stanford University Hospital from August, 1974, to March, 1975, was due to salicylates.6 Indeed, there is general awareness of the danger of salicylates, particularly to the young. This danger is due largely to the easy accessibility of aspirin in most households. In the U.S.A. aspirin is the most common cause of poisoning in childhood. Although the sensitivity of children to aspirin is often noted, no direct studies, to our knowledge, have been carried out to test the influence of age on salicylate toxicity. Some chance findings indicate the importance
of such studies.
1. Multicentre Trial. Lancet, 1975, ii, 779. 2. Bonfils, S., Bernin, J. J., Mignon, M., Hautefeuille, P., Corbic, M., Marteau, J. Nouv. Presse méd. 1975, 4, 2377. 3. Richardson, C. T., Bailey, B. A., Walsh, J. H., Fordtran, J. S. J. clin. Invest.
1975, 55, 536. 4. Lichtenstein, L. M., Henney, C. S. in Progress in Immunology II (edited by L. Brent and E. J. Holborow); vol. 2, p. 73. Amsterdam, 1974. 5. Shearer, G. M., Weinstein, Y., Melmon, K. L. J. Immun. 1974, 113, 597. 6. DAL Newsletter, April 1975, 1, no. 4. Stanford, California.
INITIAL WEIGHT OF RATS Influence of starting weight (mean + S.D.) of rats on sensitivity to salicylate. Groups of 6 rats each were fed laboratory-rat chow containing 1
salicylate. Adult rats do
_____________
not tolerate fairly large concentrations of salicylate in their diets. With 5-10% salicylate in their food, they died in a few days, and at 1% concentration they lived 2 to 3 weeks. A concentration of 1% is not much higher than that used in the long-term treatment of rheumatoid arthritis. We used adult rats because we needed large amounts of tissues to study several enzymes and metabolites of salicylates. Since
the levels of certain enzymes did not change with high doses of salicylates but others did, it was postulated (because of the well-known aminoaciduria effect of salicylates) that the protein turnover would be affected.’-9 We started experiments to check this point. However, to save isotopes, we started to feed younger rats with 1% salicylate in their diets. We found that very young rats (50-140 g) were much more susceptible to salicylate than somewhat older rats (215-232 g); in turn, these were more susceptible than adult rats (see figure). It is of interest that sensitivity to salicylate falls abruptly and not gradually as in an age (weight) related fashion. Similar findings were obtained with mice, except that 0-75% salicylate was given in the diet; mice are more sensitive to the drug than rats, possibly reflecting higher metabolic acti-
vity. Although much is known about the clinical manifestations of salicylate intoxication, as exemplified by the work of Done" and Levy et al.," much of this knowledge is empiric. Indeed, there has been relatively little biochemical information that would explain the many metabolic changes resulting from high concentrations of salicylate ingestion. The lowering of sensitivity to salicylate with age or weight merits further study which may have theoretical as well as practical interest. This work was supported by grant AM01855 from the National Institutes of Health. We thank Dr Sumner M. Kalman, department of pharmacology, Stanford University School of Medicine, for most valuable criticism of this brief communication and Miss M. J. Baguena for expert
help.
Department of Biochemistry, University of Kansas Medical Center, Kansas
City, Kansas 66103, U.S.A.
7. Mendelson,
MENDELSON S. GRISOLIA
J.
J., Villavicencio, P., Hood, W., Grisolia, S. Physiol. Chem and Phys. 1973, 5, 337. 8. Grisolia, S., Santos, I., Mendelson, J. Nature, 1968, 219, 1252. 9. Grisolia, S., Mendelson, J., Diederich, D. FEBS letters, 1970, 11, 140. 10. Done, A. K. Pediatrics, Springfield, 1960, 26, 800. 11. Levy, S., Tsuchiya, T., Amsel, L. P. Clin. Pharmac. Ther 1972, 13, 258
abandonment of principle. The basis of the principle is forgotten in the rush to the barricades of the change
as
Letters to the Editor
status quo ante.
Further, any attempt to become skilled in relation to the machinery of administration and negotiation is looked upon as a betrayal of the professional stance. One can deplore attendance at committees the better for not understanding their value; it is even easier to oppose if one does not follow the logic or has failed to consider the bounds and constraints of negotiation.2 Amateurism in this field is protective. This somewhat derogatory description of a profession’s stance has been wonderfully borne out by medical behaviour. The reaction to change has been to invoke clinical freedom and its erosion as a stopping-point in negotiation. Exactly what clinical freedom is remains largely unspecified-it would seem that it is partly the right to do as one pleases with individual problems and partly the privilege to defy social regulation that could lead (at least in theory) to the resolution of inequality as seen from a viewpoint other than that of the individuals who demand self-determination. More fundamentally and dispassionately it might incorporate a basic right to dissent which is a characteristic of universities but a doubtful attribute of professions. Analysis such as I have attempted is one thing. It is in a good sociological tradition and it may lead to diagnosis, but unfortunately the link between that and therapy is tenuous. Particularly if the frame of reference of diagnosis-in this case predominantly a social one-is unfamiliar to the victims of the disorder, there is little hope of getting them even to realise that treatment is necessary. Yet there is no doubt that certain diseases are auto-destructive. One can smell suicide in the air for medicine as a profession. What then can be done? Little I think in the short term. We are in for a long winter of discontent during which skirmishes will take place along the picket lines between profession and public, and profession and politician. But during this time it is vitally necessary for the profession to take stock of its own raison d’etre to see how this can or should be modified and finally to come up with some practical proposals for meshing profession ideals with public expectations. There has been a conspicuous lack of effort to do this in the last year. The re-examination will not necessarily be pleasant: for example, it might mean that we can cling no longer to a position of privilege in
regard to status or salary, or our standing as quasi-independent contractors. Who knows? Let us only hope that the Royal Commission will provide a milieu in which a debate on the social situation of the doctor can be pursued. Personally I doubt that this is possible. Public inquiries of any kind are to government as the ink is to the squid (so said Winston Churchill); the chance that such obliterative tactics will not emerge are small but one can
only nurture optimism. We live in depressing times-socially, economically, and professionally. Let us only hope that by defining the nature of our profession and living for it, medicine can be preserved in a way that would justify its unique heritage. St Mary’s Hospital Medical School, London W2.
2
Eiseman, B. Surgery, St. Louis, 1975, 78, 401.
H. A. F. DUDLEY
METIAMIDE IN DUODENAL ULCER
SIR,-From the evidence presented (Oct. 25, p. 779) there is
doubt that metiamide is more effective than a placebo in reducing the pain of duodenal ulceration and healing the ulcer. But how severe was the pain that the 68 patients suffered? It was stated that it was so bad that "surgery was regarded as the only alternative treatment", yet from table v it is clear that the control group were taking one ’Rennie’ tablet a day or less. As a patient I would not consider that surgery was inevitable because medical treatment had failed, nor, as a surgeon, is this my threshold for advising that an operation is necessary. The patients studied probably only had minor discomfort, in no way representing severe symptoms compatible with failure of medical treatment, and the evidence is as follows. With a similar method of recording day and night pain, and using the same idea of topping up with antacid to relieve pain, no
TABLE I-MEAN NUMBER OF PAIN-FREE DAYS AND NIGHTS PER PATIENT IN THE WEEK PRECEDING TREATMENT AND EACH OF THE
SUBSEQUENT 3
WEEKS
have just completed a multicentre trial (Dr R. H. Balme, Dr D. Barnardo, Dr M.Chaput de Saintonge, Dr M. Lancaster-Smith, and Dr J. T. Wright), comparing ’Gaviscon’, Mag. Trisil. Co. B.P.C. and a placebo, taken regularly (8 tablets a day). In our trial the antacid used was Mag. Trisil. Co. B.P.C., as against rennies in the metiamide trial. One rennie tablet contains basically 680 mg prepared chalk and 80 mg magnesium carbonate. To maintain patient cooperation we deliberately did not do endoscopy, which would have been ideal. In tablei pain-free days and nights from our trial have been analysed so that they can be compared easily with the metiamide trial. In table ii extra antacid consumption has been compared for the total group (45) and then split into those who would be considered candidates for surgery, because they were all awoken from sleep four times a week or more in any one bad period of seven days, and those in whom conservative measures would be advised. The mean age of the surgical group (10) was 40.0, they had had symptoms for 7.7 years, and consumed more than 75 antacid tablets in 24 days in addition to the regular 8 per day. It will be seen from the tables that our 45 patients had much worse pain than the metiamide trial group. The antacid consumption in the "medical" group fell by half in three weeks, in a manner similar to that obtained with metiamide lg daily.
we
974 But in the surgical group therapy did not reduce the requirement for extra antacids in the third week. It must be emphasised that this antacid consumption is in addition to the regular 56 per week test tablets. This only serves to emphasise how little we know about the natural history of duodenal-ulcer pain and enables one to state that the decision to operate is entirely subjective and at present is based on no positive objective criteria. I would like to suggest that metiamide is tested on severe duodenal-ulcer patients in whom regular antacids really do fail to control symptoms and in whom, for example, there is no relief in the third week of treatment. Metiamide is undoubtedly one of the great modern advances and the best drug we have at present, so it should be tested on true surgical candidates, and it should be compared with antacids and not a placebo. The London
Hospital, Whitechapel, London E1
1BB.
RICHARD EARLAM
SIR,-Interest in metiamide in ulcer therapy is apparent.’ 2 Blocking histamine H2-receptor sites, metiamide inhibits gastricacid and pepsin secretion.3 However other cells have receptor sites-for example, the T lymphocytes seen at the end of an immunological reaction, when cytotoxicity from T cells declines4 (that is, in vivo 7 to 9 days after antigenic stimulation). Histamine can act by raising cyclic-A.M.p.4 These cells with H2-receptor sites seem to be immunoregulatory cells-that is, suppressor T cells. Through these suppressive cells, histamine could have an important regulatory function--depression of inflammatory responses, blockade of T-cell stimulation, blockade of antibody formation. Elimination of cells bearing H2-receptor sites can lead to an increase in plaque-forming cells’ and/or to a rupture of specific tolerance (elimination of tolerating T cells). Thus, long-term administration of metiamide could have side-effects on immunological regulation, with a risk of uncontrolled immunological responses; either cell-mediated (hypersensitivity, autoimmunisation, pseudolymphoma), or humoral (hypergammaglobulinaemia, paraproteinaemia, humoral autoimmunisation). Compensatory mechanisms in immune response could make this risk negligible in practice. However, it would be helpful if patients receiving long-term therapy with metiamide were followed by a close watch on their immunological functions. Data on the immune response under metiamide (or other H2-receptors blocking drugs, cimetidine, burimamide) must be examined in laboratory animals before commercial distribution of metiamide. Laboratory of Immunology, Faculté de Médecine Pitié-Salpetrière, 91 Boulevard de l’Hôpital, 75634 Paris Cedex
R. MOULIAS 13, France.
F. CONGY
AGE-DEPENDENT SENSITIVITY TO SALICYLATE
SIR,-Poisoning by salicylate is alarmingly common. For example, the third highest number of toxicity cases in the Stanford University Hospital from August, 1974, to March, 1975, was due to salicylates.6 Indeed, there is general awareness of the danger of salicylates, particularly to the young. This danger is due largely to the easy accessibility of aspirin in most households. In the U.S.A. aspirin is the most common cause of poisoning in childhood. Although the sensitivity of children to aspirin is often noted, no direct studies, to our knowledge, have been carried out to test the influence of age on salicylate toxicity. Some chance findings indicate the importance
of such studies.
1. Multicentre Trial. Lancet, 1975, ii, 779. 2. Bonfils, S., Bernin, J. J., Mignon, M., Hautefeuille, P., Corbic, M., Marteau, J. Nouv. Presse méd. 1975, 4, 2377. 3. Richardson, C. T., Bailey, B. A., Walsh, J. H., Fordtran, J. S. J. clin. Invest.
1975, 55, 536. 4. Lichtenstein, L. M., Henney, C. S. in Progress in Immunology II (edited by L. Brent and E. J. Holborow); vol. 2, p. 73. Amsterdam, 1974. 5. Shearer, G. M., Weinstein, Y., Melmon, K. L. J. Immun. 1974, 113, 597. 6. DAL Newsletter, April 1975, 1, no. 4. Stanford, California.
INITIAL WEIGHT OF RATS Influence of starting weight (mean + S.D.) of rats on sensitivity to salicylate. Groups of 6 rats each were fed laboratory-rat chow containing 1
salicylate. Adult rats do
_____________
not tolerate fairly large concentrations of salicylate in their diets. With 5-10% salicylate in their food, they died in a few days, and at 1% concentration they lived 2 to 3 weeks. A concentration of 1% is not much higher than that used in the long-term treatment of rheumatoid arthritis. We used adult rats because we needed large amounts of tissues to study several enzymes and metabolites of salicylates. Since
the levels of certain enzymes did not change with high doses of salicylates but others did, it was postulated (because of the well-known aminoaciduria effect of salicylates) that the protein turnover would be affected.’-9 We started experiments to check this point. However, to save isotopes, we started to feed younger rats with 1% salicylate in their diets. We found that very young rats (50-140 g) were much more susceptible to salicylate than somewhat older rats (215-232 g); in turn, these were more susceptible than adult rats (see figure). It is of interest that sensitivity to salicylate falls abruptly and not gradually as in an age (weight) related fashion. Similar findings were obtained with mice, except that 0-75% salicylate was given in the diet; mice are more sensitive to the drug than rats, possibly reflecting higher metabolic acti-
vity. Although much is known about the clinical manifestations of salicylate intoxication, as exemplified by the work of Done" and Levy et al.," much of this knowledge is empiric. Indeed, there has been relatively little biochemical information that would explain the many metabolic changes resulting from high concentrations of salicylate ingestion. The lowering of sensitivity to salicylate with age or weight merits further study which may have theoretical as well as practical interest. This work was supported by grant AM01855 from the National Institutes of Health. We thank Dr Sumner M. Kalman, department of pharmacology, Stanford University School of Medicine, for most valuable criticism of this brief communication and Miss M. J. Baguena for expert
help.
Department of Biochemistry, University of Kansas Medical Center, Kansas
City, Kansas 66103, U.S.A.
7. Mendelson,
MENDELSON S. GRISOLIA
J.
J., Villavicencio, P., Hood, W., Grisolia, S. Physiol. Chem and Phys. 1973, 5, 337. 8. Grisolia, S., Santos, I., Mendelson, J. Nature, 1968, 219, 1252. 9. Grisolia, S., Mendelson, J., Diederich, D. FEBS letters, 1970, 11, 140. 10. Done, A. K. Pediatrics, Springfield, 1960, 26, 800. 11. Levy, S., Tsuchiya, T., Amsel, L. P. Clin. Pharmac. Ther 1972, 13, 258
