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Sulphonamides and Hypoglycæmia
193
LEADING ARTICLES
THE LANCET LONDON::
SATURDAY, JAN. 28,
1956
Restriction of Antibiotics ? AMONN antibiotics, erythromycin has the particular merit that it will often work when others have failed; and from time to time we have urged our readers not to blunt this therapeutic weapon by using it for lesser purposes, but to keep it sheathed unless nothing else will save the patient’s life. The advantages of doing this are plain, but so also are the difficulties ; and the New Zealand government have decided that on this subject advice to doctors must now be reinforced by restrictions. Because a number of children have died from infections by organisms no longer vulnerable to any antibiotic, they have decreed that, from Feb. 1, New Zealand doctors shall
be able to get erythromycin only through hospitals and only for the treatment of diseases which do not respond to other remedies. This announcement by the minister of health, Mr. J. R. HANAN, will arouse interest in many other countries ; for, like the ban on heroin, the action now being taken may be regarded as an interference, by a government, with the doctor’s freedom to treat his patients in whatever way he chooses.
Looking at it bacteriologically and epidemiologically, seems everything to be said in favour of the New Zealand decision. When penicillin was first made available to civilian hospitals in 1944, in desperately small quantities, its use as a life-saver was one of the spectacular advances of our time. Those who had the hard task of allotting the scarce
there
supplies will remember the many painful decisions they had to make, and the early days of penicillin often darkened bv the need to refuse ;-,
but also the remarkable by they of the drug when it was used in the right way in the right cases. In those daysof scarcity a few skilled hands achieved excellent results, and there were no mysterious and fatal forms of enteritis and no other complications due to sensitised patients and resistant organisms. Now that antibiotics are plentiful, cannot the benefits of the lean years be restored, without their sufferings, by restricting the use of these substances, by common consent ? On purely scientific grounds, it is hard to see why such restriction should not have the desired effect, if it is wisely and firmly applied ; for, when an antibiotic is used less widely, the number of bacteria resistant to it diminishes swiftly. If the New Zealand plan is to do what is intended, the hospitals, of course, will have to be even more sparing than the general practitioners in their own use of erythromycin ; for it is hospitals, not sickrooms in the home, that are the great sources of antibiotic-resistant organisms. We hope, therefore, that Mr. HANAN has told the hospitals to go verv carefully in their own use of erythromycin. Provided this vital point is covered,there are very good reasons for keeping one or more antibiotics in reserve for use in the last resort. But how exactly should the restriction be secured ? Some doctors are notably careful in their prescription were
were
lightened
efficacy
of antibiotics, and it may be that the proportion who take thought about this has increased as more and more accounts have been published of the dangers of abusing these agents. But it is still unfortunately true that the habit of giving antibiotics unwisely and even casually is the cause of much avoidable disability to patients ; and it would be overoptimistic to suppose that the mere publication of advice is enough to ensure that a drug such as erythromycin is used only when life is in imminent danger. It would no doubt be easy to arrange for a suitably qualified group of doctors to meet from time to time to survey the antibiotics in use and to recommend that one or other should be " rested long enough to restore its full power ; but difficulty might well arise as soon as a move was made to give such recommendations the force of law. It is possible that the kind of restriction now applied in New Zealand would be found acceptable here because its pattern resembles that already adopted for the distribution of important drugs while they are still scarce, and because it does not in fact embody anything like a complete ban. On the other hand, recent happenings have made it seem likely that a regulation on the New Zealand pattern would be resented in this country. Thus, paradoxically, it looks as though a course of action which most doctors would acknowledge to be sound scientifically, and necessary for the good of patients, may be neither voluntarily adopted It is evident that, as a nor tolerated if imposed. profession, we must try to discover means of bringing to bear upon the interests of all patients, whether known to us by name or not, the kind of wise judgment and resolute action which a good doctor prides himself on giving the patient directly in his charge. The New Zealand decision should make us think again about the way in which antibiotics are being used in our own country, and we should also consider from whom, if not from a Government, doctors would accept direction on such subjects. "
Sulphonamides DURING action of
and
Hypoglycæmia
clinical trial of the
chemotherapeutic p-amino-benzene-sulphonamido-isopropyl-
a
thiodiazole, JANBON and
his associatesnoted that this substance produces a fall in the blood-sugar level which may be so profound as to lead to hypoglycsemic coma. This clinical observation was confirmed by experimental studies in rabbits and dogs.2 Oral or subcutaneous administration to dogs results in hypogiycsemia, the blood-sugar falling to as low as 40 mg. With continued per 100 ml. within five hours. chronic administration, hypoglycaemia develops and irreversible cause neurological changes similar to may those observed after prolonged insulin hypoglycaemia. The decrease in blood-sugar is proportional to the concentration of this sulphonamide in the blood ; and experimentally, hypoglycaemia is obtained with much lower doses if the sulphonamide is injected directly into an artery supplying the neck of the pancreas. After total removal of the pancreas, there is no hypoglycsemic action, but it persists if as little as a fifth of the gland is left. A study of several thiodiazole 1. Janbon, M., Chaptal, J., Vedel, A., Schaap, J. D: Montpellier méd. 1942, 21-22, 441. C.R. Soc. Biol., Paris, 1944, 138, 766. 2. Loubatières, A.
194 derivatives was then undertaken.3-5 Non-sulphonthat the (3-cells of the islets of Langerhans are amide thiodiazoles have no hypoglycaemic action, but stimulated to secrete insulin-a view compatible with several compounds of the p-amino-benzene-sulphonthe complete lack of action after total pancreatectomy. amido-thiodiazole group lower the blood-sugar in More recently, evidence has been produced that the animals. The tertiary butyl and isobutyl derivatives primary action is on the oc-cells, which are thought are the most active ; then, in decreasing order of to be the site of production of the hyperglycsemic activity, follow the butyl, amyl, isoamyl, propyl, and polypeptide known as glucagon.9 Histological studies isopropyl derivatives. The ethyl and methyl deriva- in the dog, rat, and rabbit have shown that the a-cells tives are inactive in this respect. Recently another are damaged or destroyed after administration of sulphonamide compound, sulphanilyl-n-butylurea, has these sulphonamides 1° ; and in one diabetic patient been found to have a similar effect on the blood-sugar who had received this treatment and who died in level. 67 This compound has been more fully investi- uraemic coma, no a-cells were found in the pancreas gated in man. After a dose of 2 g. a maximum concen- examined immediately after death.6 Glucagon is tration of free sulphonamide of about 7-5 mg. per considered by some to play a part in the normal 100 ml. of blood is reached in three hours, and there is a regulation of the blood-sugar level and to act in some considerable fall in the blood-sugar level, which returns respects as an antagonist of insulin. In alloxan to normal in about six hours. The hypoglycsemia diabetes the &bgr;-cells are damaged but the hypercan be corrected by giving glucose. With this back- glycaemia can be controlled by administration of either ground information, it was a natural step to ascertain p-amino-benzene-sulphonamido-thiodiazole or sulphthe effect of this substance in diabetic patients. anilyl-n- butylurea, 5which destroys the (x-cells and In one clinical trial 8 sulphanilyl-n-butylurea was presumably thus restores the equilibrium. LOUBAgiven to 82 patients with diabetes mellitus of varying TIÈRES and his colleagues 11 now suggest that the duration and severity. The sulphonamide was given sulphonamide not only damages the (X-cells but also after a preliminary period of observation, usually stimulates the formation of new -cells. But CHEN et all investigating the action of a closely allied 2-5 g. on the first day, 1-5 g. on the second, and thereafter 1 g. daily. The best results were seen in compound; sulphanilamido-cyclopropylthiazole, found elderly diabetics. In one group of 28 patients, aged that in normal rabbits it consistently caused hypo49 to 77, who had received inadequate or no previous glyesemia, although in alloxan-diabetic rabbits it treatment, all but 3 responded well to the drug without produced a conspicuous rise in blood-sugar. With the addition of insulin. The glycosuria, by which about the other compounds, a transient hyperglycaemia has 100 g. of sugar had been lost daily, disappeared within sometimes been noted before the fall in blood-sugar. a few days and at the same time the blood-sugar fell In human diabetes it has been suggested that insulin from fasting values of above 300 mg. to less than sensitivity or resistance may be associated with the 150 mg. per 100 ml. and remained below 200 mg. activity of the at-cells, but this has not yet been the The renal threshold for throughout day. glucose fully established. did not change. Treatment with sulphonamide was So far the evidence is insufficient for any definite substituted in a second group of 38 patients, aged conclusion about the pharmacological action of these 41 to 77, who had been previously stabilised on insulin. compounds. They clearly open up a new approach In 28 it was possible to continue treatment without to the study of carbohydrate metabolism and diabetes any insulin. The most favourable results were seen mellitus. The preliminary reports suggest that they in those with diabetes of recent onset: the response may be useful in the oral treatment of elderly was less satisfactory if previous treatment with insulin diabetics but not of young or acidotic patients. had been given for more than a year or two. Further Further carefully planned clinical trials may determine observations in the older patients show that the drug the place of these sulphonamide compounds in the acts gradually and has a long-lasting effect. It is management of diabetes, and we hope that the trials that either intermittent massive suggested therapy will be completed before these powerful substances or long-continued treatment with small maintenance become widely available. doses should be given. There is no evidence of the development of tolerance. Fewer observations Precocious have been reported in younger diabetics,68and the the classical IN sense immunity to an infection or results have not been so successful, even where higher toxin depends upon the presence of circulating antidoses were given. In most of the younger patients bodies. There are, however, circumstances in which the drug had little effect on blood-sugar levels, but some protection is conferred when the presence of in a few it enabled the dose of insulin to be reduced. antibodies can be excluded. Interference phenomena In the presence of acidosis there was a poor response, of this kind are seen in certain virus diseases. Of and the substance is clearly unsuitable for use in course, in the case of some viruses the presence of emergencies. Apart from occasional skin rashes few circulating antibodies can be detected and passive undesirable side-effects have been reported. As the can be transferred by serum from conimmunity sulphonamide in its acetylated form is relatively valescent patients ; but in other virus diseases the soluble in an acid pH range, there is little danger immunity appears to be due to exclusion effects, and of crystalluria. after an initial acute infection a permanent symbiosis The way in which these compounds work arouses much interest. LOUBATIÈRES235 originally suggested 9. de Duve, C. Lancet, 1953, ii, 99 ; Constam, G. R. Schweiz.
Immunity
3. Loubatières, A. Ibid, p. 830. 4. Bovet, D., Dubost, P. Ibid, p. 764. 5. Loubatières, A. Arch. int. Physiol. 1946, 54, 174. 6. Franke, H., Fuchs, J. Dtsch. med. Wschr. 1955, 80, 1449.
7. Achelis, J. D., Hardebeck, K. Ibid. p. 1452. 8. Bertram, F., Benfeldt, E., Otto, H. Ibid, p. 1455.
med. Wschr. 1955, 85, 92.
10.
Holt, C., von Holt, L., Kröner, B., Kühnau, J. Arch. exp. Path. Pharmakol. 1955, 224, 66, 78. Loubatières, A., Bouyard, P., de Lados, C. F. C.R. Acad. Sci., Paris, 1955, 241, 515. 12. Chen, K. K., Anderson, R. C., Maze, N. Proc. Soc. exp. Biol., N.Y. 1946, 63, 483. 11.
von
LEADING ARTICLES
THE LANCET LONDON::
SATURDAY, JAN. 28,
1956
Restriction of Antibiotics ? AMONN antibiotics, erythromycin has the particular merit that it will often work when others have failed; and from time to time we have urged our readers not to blunt this therapeutic weapon by using it for lesser purposes, but to keep it sheathed unless nothing else will save the patient’s life. The advantages of doing this are plain, but so also are the difficulties ; and the New Zealand government have decided that on this subject advice to doctors must now be reinforced by restrictions. Because a number of children have died from infections by organisms no longer vulnerable to any antibiotic, they have decreed that, from Feb. 1, New Zealand doctors shall
be able to get erythromycin only through hospitals and only for the treatment of diseases which do not respond to other remedies. This announcement by the minister of health, Mr. J. R. HANAN, will arouse interest in many other countries ; for, like the ban on heroin, the action now being taken may be regarded as an interference, by a government, with the doctor’s freedom to treat his patients in whatever way he chooses.
Looking at it bacteriologically and epidemiologically, seems everything to be said in favour of the New Zealand decision. When penicillin was first made available to civilian hospitals in 1944, in desperately small quantities, its use as a life-saver was one of the spectacular advances of our time. Those who had the hard task of allotting the scarce
there
supplies will remember the many painful decisions they had to make, and the early days of penicillin often darkened bv the need to refuse ;-,
but also the remarkable by they of the drug when it was used in the right way in the right cases. In those daysof scarcity a few skilled hands achieved excellent results, and there were no mysterious and fatal forms of enteritis and no other complications due to sensitised patients and resistant organisms. Now that antibiotics are plentiful, cannot the benefits of the lean years be restored, without their sufferings, by restricting the use of these substances, by common consent ? On purely scientific grounds, it is hard to see why such restriction should not have the desired effect, if it is wisely and firmly applied ; for, when an antibiotic is used less widely, the number of bacteria resistant to it diminishes swiftly. If the New Zealand plan is to do what is intended, the hospitals, of course, will have to be even more sparing than the general practitioners in their own use of erythromycin ; for it is hospitals, not sickrooms in the home, that are the great sources of antibiotic-resistant organisms. We hope, therefore, that Mr. HANAN has told the hospitals to go verv carefully in their own use of erythromycin. Provided this vital point is covered,there are very good reasons for keeping one or more antibiotics in reserve for use in the last resort. But how exactly should the restriction be secured ? Some doctors are notably careful in their prescription were
were
lightened
efficacy
of antibiotics, and it may be that the proportion who take thought about this has increased as more and more accounts have been published of the dangers of abusing these agents. But it is still unfortunately true that the habit of giving antibiotics unwisely and even casually is the cause of much avoidable disability to patients ; and it would be overoptimistic to suppose that the mere publication of advice is enough to ensure that a drug such as erythromycin is used only when life is in imminent danger. It would no doubt be easy to arrange for a suitably qualified group of doctors to meet from time to time to survey the antibiotics in use and to recommend that one or other should be " rested long enough to restore its full power ; but difficulty might well arise as soon as a move was made to give such recommendations the force of law. It is possible that the kind of restriction now applied in New Zealand would be found acceptable here because its pattern resembles that already adopted for the distribution of important drugs while they are still scarce, and because it does not in fact embody anything like a complete ban. On the other hand, recent happenings have made it seem likely that a regulation on the New Zealand pattern would be resented in this country. Thus, paradoxically, it looks as though a course of action which most doctors would acknowledge to be sound scientifically, and necessary for the good of patients, may be neither voluntarily adopted It is evident that, as a nor tolerated if imposed. profession, we must try to discover means of bringing to bear upon the interests of all patients, whether known to us by name or not, the kind of wise judgment and resolute action which a good doctor prides himself on giving the patient directly in his charge. The New Zealand decision should make us think again about the way in which antibiotics are being used in our own country, and we should also consider from whom, if not from a Government, doctors would accept direction on such subjects. "
Sulphonamides DURING action of
and
Hypoglycæmia
clinical trial of the
chemotherapeutic p-amino-benzene-sulphonamido-isopropyl-
a
thiodiazole, JANBON and
his associatesnoted that this substance produces a fall in the blood-sugar level which may be so profound as to lead to hypoglycsemic coma. This clinical observation was confirmed by experimental studies in rabbits and dogs.2 Oral or subcutaneous administration to dogs results in hypogiycsemia, the blood-sugar falling to as low as 40 mg. With continued per 100 ml. within five hours. chronic administration, hypoglycaemia develops and irreversible cause neurological changes similar to may those observed after prolonged insulin hypoglycaemia. The decrease in blood-sugar is proportional to the concentration of this sulphonamide in the blood ; and experimentally, hypoglycaemia is obtained with much lower doses if the sulphonamide is injected directly into an artery supplying the neck of the pancreas. After total removal of the pancreas, there is no hypoglycsemic action, but it persists if as little as a fifth of the gland is left. A study of several thiodiazole 1. Janbon, M., Chaptal, J., Vedel, A., Schaap, J. D: Montpellier méd. 1942, 21-22, 441. C.R. Soc. Biol., Paris, 1944, 138, 766. 2. Loubatières, A.
194 derivatives was then undertaken.3-5 Non-sulphonthat the (3-cells of the islets of Langerhans are amide thiodiazoles have no hypoglycaemic action, but stimulated to secrete insulin-a view compatible with several compounds of the p-amino-benzene-sulphonthe complete lack of action after total pancreatectomy. amido-thiodiazole group lower the blood-sugar in More recently, evidence has been produced that the animals. The tertiary butyl and isobutyl derivatives primary action is on the oc-cells, which are thought are the most active ; then, in decreasing order of to be the site of production of the hyperglycsemic activity, follow the butyl, amyl, isoamyl, propyl, and polypeptide known as glucagon.9 Histological studies isopropyl derivatives. The ethyl and methyl deriva- in the dog, rat, and rabbit have shown that the a-cells tives are inactive in this respect. Recently another are damaged or destroyed after administration of sulphonamide compound, sulphanilyl-n-butylurea, has these sulphonamides 1° ; and in one diabetic patient been found to have a similar effect on the blood-sugar who had received this treatment and who died in level. 67 This compound has been more fully investi- uraemic coma, no a-cells were found in the pancreas gated in man. After a dose of 2 g. a maximum concen- examined immediately after death.6 Glucagon is tration of free sulphonamide of about 7-5 mg. per considered by some to play a part in the normal 100 ml. of blood is reached in three hours, and there is a regulation of the blood-sugar level and to act in some considerable fall in the blood-sugar level, which returns respects as an antagonist of insulin. In alloxan to normal in about six hours. The hypoglycsemia diabetes the &bgr;-cells are damaged but the hypercan be corrected by giving glucose. With this back- glycaemia can be controlled by administration of either ground information, it was a natural step to ascertain p-amino-benzene-sulphonamido-thiodiazole or sulphthe effect of this substance in diabetic patients. anilyl-n- butylurea, 5which destroys the (x-cells and In one clinical trial 8 sulphanilyl-n-butylurea was presumably thus restores the equilibrium. LOUBAgiven to 82 patients with diabetes mellitus of varying TIÈRES and his colleagues 11 now suggest that the duration and severity. The sulphonamide was given sulphonamide not only damages the (X-cells but also after a preliminary period of observation, usually stimulates the formation of new -cells. But CHEN et all investigating the action of a closely allied 2-5 g. on the first day, 1-5 g. on the second, and thereafter 1 g. daily. The best results were seen in compound; sulphanilamido-cyclopropylthiazole, found elderly diabetics. In one group of 28 patients, aged that in normal rabbits it consistently caused hypo49 to 77, who had received inadequate or no previous glyesemia, although in alloxan-diabetic rabbits it treatment, all but 3 responded well to the drug without produced a conspicuous rise in blood-sugar. With the addition of insulin. The glycosuria, by which about the other compounds, a transient hyperglycaemia has 100 g. of sugar had been lost daily, disappeared within sometimes been noted before the fall in blood-sugar. a few days and at the same time the blood-sugar fell In human diabetes it has been suggested that insulin from fasting values of above 300 mg. to less than sensitivity or resistance may be associated with the 150 mg. per 100 ml. and remained below 200 mg. activity of the at-cells, but this has not yet been the The renal threshold for throughout day. glucose fully established. did not change. Treatment with sulphonamide was So far the evidence is insufficient for any definite substituted in a second group of 38 patients, aged conclusion about the pharmacological action of these 41 to 77, who had been previously stabilised on insulin. compounds. They clearly open up a new approach In 28 it was possible to continue treatment without to the study of carbohydrate metabolism and diabetes any insulin. The most favourable results were seen mellitus. The preliminary reports suggest that they in those with diabetes of recent onset: the response may be useful in the oral treatment of elderly was less satisfactory if previous treatment with insulin diabetics but not of young or acidotic patients. had been given for more than a year or two. Further Further carefully planned clinical trials may determine observations in the older patients show that the drug the place of these sulphonamide compounds in the acts gradually and has a long-lasting effect. It is management of diabetes, and we hope that the trials that either intermittent massive suggested therapy will be completed before these powerful substances or long-continued treatment with small maintenance become widely available. doses should be given. There is no evidence of the development of tolerance. Fewer observations Precocious have been reported in younger diabetics,68and the the classical IN sense immunity to an infection or results have not been so successful, even where higher toxin depends upon the presence of circulating antidoses were given. In most of the younger patients bodies. There are, however, circumstances in which the drug had little effect on blood-sugar levels, but some protection is conferred when the presence of in a few it enabled the dose of insulin to be reduced. antibodies can be excluded. Interference phenomena In the presence of acidosis there was a poor response, of this kind are seen in certain virus diseases. Of and the substance is clearly unsuitable for use in course, in the case of some viruses the presence of emergencies. Apart from occasional skin rashes few circulating antibodies can be detected and passive undesirable side-effects have been reported. As the can be transferred by serum from conimmunity sulphonamide in its acetylated form is relatively valescent patients ; but in other virus diseases the soluble in an acid pH range, there is little danger immunity appears to be due to exclusion effects, and of crystalluria. after an initial acute infection a permanent symbiosis The way in which these compounds work arouses much interest. LOUBATIÈRES235 originally suggested 9. de Duve, C. Lancet, 1953, ii, 99 ; Constam, G. R. Schweiz.
Immunity
3. Loubatières, A. Ibid, p. 830. 4. Bovet, D., Dubost, P. Ibid, p. 764. 5. Loubatières, A. Arch. int. Physiol. 1946, 54, 174. 6. Franke, H., Fuchs, J. Dtsch. med. Wschr. 1955, 80, 1449.
7. Achelis, J. D., Hardebeck, K. Ibid. p. 1452. 8. Bertram, F., Benfeldt, E., Otto, H. Ibid, p. 1455.
med. Wschr. 1955, 85, 92.
10.
Holt, C., von Holt, L., Kröner, B., Kühnau, J. Arch. exp. Path. Pharmakol. 1955, 224, 66, 78. Loubatières, A., Bouyard, P., de Lados, C. F. C.R. Acad. Sci., Paris, 1955, 241, 515. 12. Chen, K. K., Anderson, R. C., Maze, N. Proc. Soc. exp. Biol., N.Y. 1946, 63, 483. 11.
von