634
pheral vascular resistance, thereby improving tis18 39 This it sue perfusion.31 may do by counteractof action the catecholamines, since constricting ing not does seem to have any dimethylprednisolone rect effect upon vessel tone.4o The drug may also have a positive inotropic action on the heart-cardiac output rose in some experiments31 38-and improved coronary blood-flow38 and suppression of a cardioinhibitory factor are other possible benefits (a cardioinhibitory factor has been found in the serum of shocked cats and dogs37). Experimentally, methylprednisolone therapy can prevent or ameliorate the state of "shock lung’ 1.4At a cellular level it probably helps to stabilise lysosomal enzymes42 with the result that less enzyme is released from damaged cells.33 36 Other reputed effects are elimination of endotoxin 31 and preservation of the reticuloendothelial activity that is sometimes depressed in shock.34 For treating patients in severe shock the place of methylprednisolone is less secure. It is often given when a patient is close to death and when all else has failed; hence, failures should not count badly against it. Some critically ill patients have undoubtedly benefited. 1 31 43 In a controlled clinical trial reported from Finland,44 patients with multiple blunt injuries were randomly allocated to two groups. Both received conventional treatment for shock, but only one group
given methylprednisolone (10 mg/kgx3). Although the drug did not have an obvious effect upon the state of shock, and there were equal was
numbers of deaths in the two groups, the rate of fat embolism was much lower in those patients receiving methylprednisolone. The case for giving methylprednisolone in septic shock is somewhat stronger. In a double-blind prospective study SCHUMER45 found that patients receiving methylprednisolone in addition to standard treatment had a mortalityrate of 11.6%, which compared favourably with the rate of 38.4% in the non-steroid group. Methylprednisolone was not, however, superior to dexamethasone : a third group treated with dexamethasone had a mortality-rate of 10-4%. Methylprednisolone has been advocated for myocardial infarction, even when shock is absent. In dogs it improves coronary blood-flow38 and reduces the extent of ultimate infarction .46 47 Again the steroid has to be given very soon after the coronary
38. 39.
40. 41. 42. 43.
al. Am. J. Cardiol. 1974, 34, 677. Raflo, G. T., Jones, R. C. W., Wangensteen, S. L. Am. J. Surg. 1975, 130, 321. Altura, B. M., Altura, B. T. J. Pharmac. exp. Ther. 1974, 190, 300. Wilson, J. W. Surgery, Gynec. Obstet. 1972, 134, 675. Goldstein, I. M. Transplant Proc. 1975, 7, 21. Rosenbaum, R. W., Hayes, M. F., Matsumoto, T. Surgery, Gynec. Obstet.
Vyden, J. K., Nagasawa, K., Rabmowitz, B., et
1973, 136, 914 44. Rokkanen, P., Alho, A., Avikainen, J., et al. ibid. 1974, 138, 69. 45. Schumer, W. Ann. Surg. 1976, 184, 333. 46. Libby, P., Maroko, P. R., Blour, C. M., et al. J. clin. Invest. 1973, 52, 599. 47. Shatney, C. H., MacCarter, D. U., Lillehei, R. C. Am. J. Cardiol. 1976, 37, 572
occlusion (preferably before); an hour afterwards is too late.411 Where methylprednisolone has been tried in patients with acute myocardial infarction there is no convincing evidence of benefit. By plotting the rise in the serum-cretine-phosphokinase MORRISON et al. 49 deduced that the size of the infarcted area of myocardium had been reduced, but ROBERTS et al.s50 using the same technique concluded that the drug had made the patients worse, Clearly methylprednisolone is a powerful drug which can be given safely in high doses even to very ill patients, but its only secure clinical place is in organ transplantation.
SWEET REASON THE Canadian regulatory authorities have hitherto enjoyed a cachet for sweet reasonableness denied to their counterparts in the United States, where the exercise of human judgment based on a careful consideration of all the facts relevant to the assessment of carcinogenic hazard is, in effect, against the law. By initiating a ban on the use of saccharin, have the Canadians sacrificed their good reputation for no good reason, or are they aware of new data which contradict the epidemiological indications that saccharin does not increase the risk of bladder cancer,t-3 or of any other form of cancer,4 in man? The new information which led to last week’s precipitate ban on the use of saccharin in food in the U,S,A, and Canada is not yet available in Britain, but we understand that it has to do with the results of a two-generation study in which rats which were continuously exposed to 5% saccharin in the food acquired bladder tumours. But it was already well-known5 that, at this level of feeding of saccharin, bladder stones and tumours occur. Many toxicologists, in North America as well as in Britain, doubt the relevance of feeding studies involving such unrealistically high levels of incorporation of test substances in the diet, especially when the only type of tumour seen in excess is of the urinary bladder under conditions where stones occur. Clearly, tumours may arise non-specifically as a consequence of the prolonged presence of solid bodies in the bladder.6It is noteworthy that in none of the many animal tests so far reported has there been evidence of increased risk of tumours at any site other than the bladder. If saccharin has been banned for a compelling reason yet to be revealed, we will mourn its loss. Otherwise our mourning will be for the reputation of those responsible for its banishment.
48. Osher, J., Lang, T. W., Meerbaum, S., et al. ibid. 1976, 37, 564. 49. Morrison, J., Reduto, L., Pizzarello, R., et al. Circulation, 1976,
53, suppl.
1, p. 200. 50. Roberts, R., Demello, V. Sobel, B. E. ibid. p. 204. 1. Armstrong, B., Doll, R. Br. J. prev. soc. Med. 1974, 28, 233. 2. Armstrong, B., Doll, R. ibid. 1975, 29, 73. 3. Kessler, I. J. natn. Cancer Inst. 1970, 44, 673. 4. Armstrong, B., Lea, A. J., Adelstein, A. M., Donovan, J. W., White, G. C., Ruttle, S. Br. J. prev. soc. Med. 1976, 30, 151. 5. Lessel, B. Proceedings of Third International Congress of Food Science and Technology. Chicago, 1971. 6. Ball, J. K., Field, W. E. H., Row, F. J. C., Walters, M. Br. J. Urol. 1964, 7.
36, 225. Golberg, L.
Chem. Med. Abstr.
1967, 1, 57.
pheral vascular resistance, thereby improving tis18 39 This it sue perfusion.31 may do by counteractof action the catecholamines, since constricting ing not does seem to have any dimethylprednisolone rect effect upon vessel tone.4o The drug may also have a positive inotropic action on the heart-cardiac output rose in some experiments31 38-and improved coronary blood-flow38 and suppression of a cardioinhibitory factor are other possible benefits (a cardioinhibitory factor has been found in the serum of shocked cats and dogs37). Experimentally, methylprednisolone therapy can prevent or ameliorate the state of "shock lung’ 1.4At a cellular level it probably helps to stabilise lysosomal enzymes42 with the result that less enzyme is released from damaged cells.33 36 Other reputed effects are elimination of endotoxin 31 and preservation of the reticuloendothelial activity that is sometimes depressed in shock.34 For treating patients in severe shock the place of methylprednisolone is less secure. It is often given when a patient is close to death and when all else has failed; hence, failures should not count badly against it. Some critically ill patients have undoubtedly benefited. 1 31 43 In a controlled clinical trial reported from Finland,44 patients with multiple blunt injuries were randomly allocated to two groups. Both received conventional treatment for shock, but only one group
given methylprednisolone (10 mg/kgx3). Although the drug did not have an obvious effect upon the state of shock, and there were equal was
numbers of deaths in the two groups, the rate of fat embolism was much lower in those patients receiving methylprednisolone. The case for giving methylprednisolone in septic shock is somewhat stronger. In a double-blind prospective study SCHUMER45 found that patients receiving methylprednisolone in addition to standard treatment had a mortalityrate of 11.6%, which compared favourably with the rate of 38.4% in the non-steroid group. Methylprednisolone was not, however, superior to dexamethasone : a third group treated with dexamethasone had a mortality-rate of 10-4%. Methylprednisolone has been advocated for myocardial infarction, even when shock is absent. In dogs it improves coronary blood-flow38 and reduces the extent of ultimate infarction .46 47 Again the steroid has to be given very soon after the coronary
38. 39.
40. 41. 42. 43.
al. Am. J. Cardiol. 1974, 34, 677. Raflo, G. T., Jones, R. C. W., Wangensteen, S. L. Am. J. Surg. 1975, 130, 321. Altura, B. M., Altura, B. T. J. Pharmac. exp. Ther. 1974, 190, 300. Wilson, J. W. Surgery, Gynec. Obstet. 1972, 134, 675. Goldstein, I. M. Transplant Proc. 1975, 7, 21. Rosenbaum, R. W., Hayes, M. F., Matsumoto, T. Surgery, Gynec. Obstet.
Vyden, J. K., Nagasawa, K., Rabmowitz, B., et
1973, 136, 914 44. Rokkanen, P., Alho, A., Avikainen, J., et al. ibid. 1974, 138, 69. 45. Schumer, W. Ann. Surg. 1976, 184, 333. 46. Libby, P., Maroko, P. R., Blour, C. M., et al. J. clin. Invest. 1973, 52, 599. 47. Shatney, C. H., MacCarter, D. U., Lillehei, R. C. Am. J. Cardiol. 1976, 37, 572
occlusion (preferably before); an hour afterwards is too late.411 Where methylprednisolone has been tried in patients with acute myocardial infarction there is no convincing evidence of benefit. By plotting the rise in the serum-cretine-phosphokinase MORRISON et al. 49 deduced that the size of the infarcted area of myocardium had been reduced, but ROBERTS et al.s50 using the same technique concluded that the drug had made the patients worse, Clearly methylprednisolone is a powerful drug which can be given safely in high doses even to very ill patients, but its only secure clinical place is in organ transplantation.
SWEET REASON THE Canadian regulatory authorities have hitherto enjoyed a cachet for sweet reasonableness denied to their counterparts in the United States, where the exercise of human judgment based on a careful consideration of all the facts relevant to the assessment of carcinogenic hazard is, in effect, against the law. By initiating a ban on the use of saccharin, have the Canadians sacrificed their good reputation for no good reason, or are they aware of new data which contradict the epidemiological indications that saccharin does not increase the risk of bladder cancer,t-3 or of any other form of cancer,4 in man? The new information which led to last week’s precipitate ban on the use of saccharin in food in the U,S,A, and Canada is not yet available in Britain, but we understand that it has to do with the results of a two-generation study in which rats which were continuously exposed to 5% saccharin in the food acquired bladder tumours. But it was already well-known5 that, at this level of feeding of saccharin, bladder stones and tumours occur. Many toxicologists, in North America as well as in Britain, doubt the relevance of feeding studies involving such unrealistically high levels of incorporation of test substances in the diet, especially when the only type of tumour seen in excess is of the urinary bladder under conditions where stones occur. Clearly, tumours may arise non-specifically as a consequence of the prolonged presence of solid bodies in the bladder.6It is noteworthy that in none of the many animal tests so far reported has there been evidence of increased risk of tumours at any site other than the bladder. If saccharin has been banned for a compelling reason yet to be revealed, we will mourn its loss. Otherwise our mourning will be for the reputation of those responsible for its banishment.
48. Osher, J., Lang, T. W., Meerbaum, S., et al. ibid. 1976, 37, 564. 49. Morrison, J., Reduto, L., Pizzarello, R., et al. Circulation, 1976,
53, suppl.
1, p. 200. 50. Roberts, R., Demello, V. Sobel, B. E. ibid. p. 204. 1. Armstrong, B., Doll, R. Br. J. prev. soc. Med. 1974, 28, 233. 2. Armstrong, B., Doll, R. ibid. 1975, 29, 73. 3. Kessler, I. J. natn. Cancer Inst. 1970, 44, 673. 4. Armstrong, B., Lea, A. J., Adelstein, A. M., Donovan, J. W., White, G. C., Ruttle, S. Br. J. prev. soc. Med. 1976, 30, 151. 5. Lessel, B. Proceedings of Third International Congress of Food Science and Technology. Chicago, 1971. 6. Ball, J. K., Field, W. E. H., Row, F. J. C., Walters, M. Br. J. Urol. 1964, 7.
36, 225. Golberg, L.
Chem. Med. Abstr.
1967, 1, 57.
