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Oral Diuretics
1005
LEADING ARTICLES
THE LANCET
expected. Instead, on the advice of the Medical Research Council, the Minister (whose state-
poliomyelitis
is
in the House of Commons is summarised on p. 1025) chose the other main possibility-namely, to import American vaccine and omit the safety test in this country. This is regarded as an emergency measure and is intended to be purely temporary. Leaving political considerations aside, the immediate medical advantages of this choice should outweigh the disadvantages. Vast experience with the manufacture and testing of Salk vaccine has been built up in the U.S.A., and today there is a very low probability of inducing poliomyelitis from injection of vaccine which has passed the American safety tests,3 while on the other hand a substantial proportion of those who receive the vaccine should be protected from paralytic disease this summer. But the Medical Research Council have described three degrees of safety; British-made and British-tested vaccine is in the highest category of safety, while American-made vaccine untested in this country is in the lowest; and doctors and parents can hardly be blamed if they have difficulty in deciding whether to advise or to agree to inoculations of vaccine which is declared to be not the safest. Furthermore, if cases of paralytic poliomyelitis arise in association with injections of so-called " untested " vaccine-a situation which is likely on chance grounds alone-adverse publicity could prejudice future vaccination in this country. The Government, in accordance with the Council’s advice, propose to restore check tests by the Council at the earliest possible moment; and they look forward to the time when they can dispense with the need for any vaccine containing the Mahoney strain. Whatever differences of opinion there may be about the wisdom of the Minister’s choice, at least everyone can heartily welcome this prospect. ment
LONDON
10
MAY
1958
Poliomyelitis Vaccine and Safety Tests MOST discussions on safety tests for poliomyelitis vaccine soon return to the tragedy of 1955 when over 200 people acquired poliomyelitis following the use of Cutter vaccine. This tragedy led directly to important changes in the manufacture and testing of vaccinei which have resulted in a much safer and more reliable product. Nevertheless, no biological product of this kind can be absolutely safe; and since the safety tests measure a sample of each batch of vaccine they give a guarantee of a particular degree of safety, but not of absolute safety. The Medical Research Council in this country decided that this degree of safety could be increased by substituting the relatively avirulent type-1 Brunenders strain for the more virulent Mahoney strain used in the American and Canadian (Salk) vaccine, so that if an occasional virus particle should escape the virus inactivation procedure it would be much less likely to be a paralytogenic particle. British vaccine also differs from the North American vaccine in that exhaustive safety tests are carried out on all batches by the manufacturer and independently by the Department of Biological Standards of the Medical Research Council; at the moment American vaccine is exhaustively tested by the manufacturer only, and the National Institutes of Health in the U. S.A. are not obliged to test each batch exhaustively. Last September the Minister of Health announced that the Government would offer poliomyelitis vaccine this year to children under 15 and to expectant mothers. Since the two British firms manufacturing vaccine could not produce the required amounts in time it was decided as a temporary measure to import American vaccine, provided that tests by the manufacturer and by the Department of Biological Standards in this country showed the vaccine to be satisfactory. The manufacture of poliomyelitis vaccine is an extremely difficult process, and the testing procedure is so rigorous that it is not uncommon for large batches to prove unsatisfactory and for occasional batches to be rejected. It now appears that insufficient allowance had been made for losses of this kind when the vaccine was ordered,2and a series of most unlucky accidents led to the supply of vaccine falling far below what had been expected, while at the same time the demand proved greater than was anticipated. The Minister of Health has been sharply criticised for not having foreseen this situation. After it arose there were two main courses open to him. He could order new supplies of vaccine and subject them to safety tests in this country; but the safety tests would probably be made, not concurrently with the manufacturers’ safety tests, but afterwards, entailing a delay of two or three months, and the vaccine would not be ready before August when the peak incidence of 1. Technical Committee 64, 104. 2. See
on
Poliomyelitis Vaccine. Amer. J. Hyg. 1956,
Lancet, May 3, 1958, p. 972.
Oral Diuretics DIURETIC agents were discussed two years ago by the Royal Society of Medicine 4; and last month the use of diuretics in cardiac failure was the subject of a symposium at the annual meeting of the Cardiac Society in Leeds. In the first of these discussions the limitations of oral diuretics, especially of acetazolamide (’ Diamox ’), were deservedly stressed; in the second it was apparent that an effective oral diuretic was just round the corner, if not already here. In diuretic therapy we shall doubtless continue to rely heavily on the organic mercurials given by injection; these we owe to the happy chance that diuresis during ’Novasurol’ antisyphilitic treatment of a non-oedematous patient impinged on the prepared mind of ALFRED V OGL. The quest for an oral diuretic has gone on without benefit of any comparable serendipity, and is only now beginning to promise real We have for some years had oral diuretic success. agents less potent than mercurials but potent enough to control early congestive failure in conjunction with digitalis and a low-salt diet; only recently have we gained in chlorothiazide an agent of comparable diuretic potency to mercurials given by injection. 3. Smadel, J. E. Bull. N.Y. Acad. Med. 1957, 33, 385. 4. Proc. R. Soc. Med. 1956, 5. Vogl, A. Amer. Heart J.
49, 623. 1950, 39, 881.
1006
To relieve cardiac oedema or pulmonary congestion, it is necessary to reduce the sodium content of the body; an increased excretion of water alone, or of an anion unaccompanied by sodium, is in this context irrelevant. In theory the ideal diuretic would increase the amount of sodium filtered by the glomeruli, or diminish directly the amount of sodium reabsorbed by the tubules; in practice the most effective agents at present are those which act primarily by diminishing chloride reabsorption, the increased output of chloride being then accompanied by natriuresis. When the general treatment of a cardiac invalid with rest and digitalis is effective, the glomerular filtration-rate (G.F.R.) increases and oedema may be prevented or diminished, so comparatively ineffective diuretic agents may appear to have worked efficiently. The diuretic action of theophylline drugs depends mainly on an increase in G.F.R., and some patients who have become resistant to mercurials may respond once again when aminophylline in a dose of up to 0-5 g. is given intravenously two hours after the mercurial injection.6 VOGLadvocates the use of oral theophylline preparations as an adjuvant to diuretic therapy. Decreased reabsorption of sodium can be directly effected by inducing an osmotic diuresis or by inhibiting the production of aldosterone, which is often increased in oedematous patients.8 Interest in urea as an oral osmotic diuretic has recently been revived 9; but large doses are needed, and the incidence of anorexia and nausea is fairly high. The production of aldosterone can be inhibited by amphenone, but the toxic effects of this drug preclude its therapeutic use. Several drugs act mainly by depressing anion reabsorption. The carbonic anhydrase inhibitors, which depress bicarbonate reabsorption, are of little value in the treatment of oedema, for they quickly lose their effect as the plasma-bicarbonate level falls, and with it the amount of bicarbonate filtered into the nephron; there is also a tendency to a greater loss of potassium than with mercurial diuretics.6 Since the amount of chloride entering the nephron is normally about three times as great as the amount of bicarbonate,6 there is a greater potentiality of effectiveness for drugs which depress the reabsorption of chloride rather than of bicarbonate. Three groups of drugs have been tested fairly extensively as oral chloruretic agents. These are the oral organic mercurials; the aminouracil compounds; and substituted benzothiodiazine (chlorothiazide). Oral mercurials, such as chlormerodrin (’ Merchloran ’), may cause diarrhoea, whether because they inhibit fluid absorption in the bowel as well as in the nephron or because the intestinal epithelium is highly susceptible to mercurial toxicity; and we agree with the view of GOODMAN and GILMAN 11: "
The oral administration of mercurial diuretics obviates the at the price of gastro-intestinal irritation,
necessity of injection 6. 7. 8. 9. 10.
Milne, M. D. Proc. R. Soc. Med. 1956, 49, 625. Vogl, A. Diuretic Therapy. Baltimore, 1953. Wolff, H. P., Koczorek, K. R., Buchborn, E. Lancet, 1957, ii, 63. Papp, C., Shirley Smith, K. Brit. med. J. 1957, ii, 906. Renold, A. E., Crabbé, J., Hernando-Avendano, L., Nelson, D. H., Ross, E. J., Emerson, K., Thorn, G. W. New Engl. J. Med. 1957, 256,
11.
Goodman, L. S., Gilman, A. peutics. New York, 1955.
16.
The
Pharmacological Basis of Thera-
total dosage of mercury, greater danger of systemic mercury poisoning, and a more delayed and less complete diuretic response. The route is ineffective when a rapid mobilisation of oedema fluid is desired in an acutely ill individual."
higher
Their final comment applies, we believe, with equal force to the aminouracil compounds. While these have some diuretic potency, the incidence of side-effects is high, especially with aminometradine (’ Mictine ’); the frequency of side-effects is distinctly lower with amisometradine (’ Rolicton ’), and this drug was found to be of some value in preventing recurrence of oedema which had been got rid of by mercurials.122 The aminouracil compounds quickly lose their effect, and do not really stand comparison with organic mercurials.13 Chlorothiazide is in a quite different category of effectiveness from the oral mercurials and the aminouracil drugs. In potency it is comparable to the mercurials given by injection, and may even produce diuresis in patients who have become resistant to mercurial diuretics.14 15 Favourable clinical reports on its effectiveness in generalised oedema have appeared both in America 14 16 17 and in this country.14 18 It does seem that we now have a potent oral diuretic that not only can control oedema but also, for good measure, has some hypotensive action.19 If our satisfaction at this should appear a little half-hearted, it is because we foresee possible abuse of a drug which, though convenient and potent, is also expensive and not devoid of side-effects. Gastrointestinal side-effects seem to be uncommon, but potassium depletion has been observed 14 15;this can be controlled by giving daily supplements of 2-6 g. of potassium chloride.15 One patient had an erythematous rash which disappeared when the drug was stopped.17 Hypochlorxmia has been observed in patients taking chlorothiazide,13 but should be controllable by ammonium or potassium chloride. The cost is also of some importance. According to a pricing bureau the basic cost to the N.H.S. of three injections of mersalyl is Is. 5d., whereas the basic cost of 8 g. of chlorothiazide is 9s. 102 d. ; the cost of a week’s treatment of oedema is thus more than six times as great with present oral treatment. No doubt the need to give injections carries substantial overheads above the basic cost; but at least the diuretic has been given, and there is no box of tablets to constitute a problem of domestic pharmacognosy or of self-medication in the next minor illness. Chlorothiazide certainly represents a great advance in diuretic treatment. May we hope that it will become cheaper; that it will not replace the well-tried mercurials until we know more of its side-effects; and, above all, that it will not be used to treat every patient with hypertension, or who complains of breathlessness or swelling of the ankles. 12.
Wener, J., Friedman, R., Schucher, R. Canad. med. Ass. J. 1958, 78,
200. 13. Ford, R. V., Rochelle, J. B., Handley, C. A., Meyer, J. H., Spurr, C. L. J. Amer. med. Ass. 1958, 166, 129. 14. Goodkind, M. J., Harvey, R. J., Richards, D. W. Amer. J. med. Sci. 15. 16. 17. 18. 19.
1958, 235, 164. Bayliss, R. I. S., Marrack, D., Pirkis, J., Rees, J. R., Zilva, J. Lancet, Jan. 18, 1958, p. 120. Laragh, J. H., Heinemann, H. O., Demartini, F. E. J. Amer. med. Ass. 1958, 166, 145. Schreiner, G. E., Bloomer, H. A. New Engl. J. Med. 1957, 257, 1016. Slater, J. D. H., Nabarro, J. D. N. Lancet, Jan. 18, 1958, p. 124. Wilkins, R. W. New Engl. J. Med. 1957, 257, 1026.
LEADING ARTICLES
THE LANCET
expected. Instead, on the advice of the Medical Research Council, the Minister (whose state-
poliomyelitis
is
in the House of Commons is summarised on p. 1025) chose the other main possibility-namely, to import American vaccine and omit the safety test in this country. This is regarded as an emergency measure and is intended to be purely temporary. Leaving political considerations aside, the immediate medical advantages of this choice should outweigh the disadvantages. Vast experience with the manufacture and testing of Salk vaccine has been built up in the U.S.A., and today there is a very low probability of inducing poliomyelitis from injection of vaccine which has passed the American safety tests,3 while on the other hand a substantial proportion of those who receive the vaccine should be protected from paralytic disease this summer. But the Medical Research Council have described three degrees of safety; British-made and British-tested vaccine is in the highest category of safety, while American-made vaccine untested in this country is in the lowest; and doctors and parents can hardly be blamed if they have difficulty in deciding whether to advise or to agree to inoculations of vaccine which is declared to be not the safest. Furthermore, if cases of paralytic poliomyelitis arise in association with injections of so-called " untested " vaccine-a situation which is likely on chance grounds alone-adverse publicity could prejudice future vaccination in this country. The Government, in accordance with the Council’s advice, propose to restore check tests by the Council at the earliest possible moment; and they look forward to the time when they can dispense with the need for any vaccine containing the Mahoney strain. Whatever differences of opinion there may be about the wisdom of the Minister’s choice, at least everyone can heartily welcome this prospect. ment
LONDON
10
MAY
1958
Poliomyelitis Vaccine and Safety Tests MOST discussions on safety tests for poliomyelitis vaccine soon return to the tragedy of 1955 when over 200 people acquired poliomyelitis following the use of Cutter vaccine. This tragedy led directly to important changes in the manufacture and testing of vaccinei which have resulted in a much safer and more reliable product. Nevertheless, no biological product of this kind can be absolutely safe; and since the safety tests measure a sample of each batch of vaccine they give a guarantee of a particular degree of safety, but not of absolute safety. The Medical Research Council in this country decided that this degree of safety could be increased by substituting the relatively avirulent type-1 Brunenders strain for the more virulent Mahoney strain used in the American and Canadian (Salk) vaccine, so that if an occasional virus particle should escape the virus inactivation procedure it would be much less likely to be a paralytogenic particle. British vaccine also differs from the North American vaccine in that exhaustive safety tests are carried out on all batches by the manufacturer and independently by the Department of Biological Standards of the Medical Research Council; at the moment American vaccine is exhaustively tested by the manufacturer only, and the National Institutes of Health in the U. S.A. are not obliged to test each batch exhaustively. Last September the Minister of Health announced that the Government would offer poliomyelitis vaccine this year to children under 15 and to expectant mothers. Since the two British firms manufacturing vaccine could not produce the required amounts in time it was decided as a temporary measure to import American vaccine, provided that tests by the manufacturer and by the Department of Biological Standards in this country showed the vaccine to be satisfactory. The manufacture of poliomyelitis vaccine is an extremely difficult process, and the testing procedure is so rigorous that it is not uncommon for large batches to prove unsatisfactory and for occasional batches to be rejected. It now appears that insufficient allowance had been made for losses of this kind when the vaccine was ordered,2and a series of most unlucky accidents led to the supply of vaccine falling far below what had been expected, while at the same time the demand proved greater than was anticipated. The Minister of Health has been sharply criticised for not having foreseen this situation. After it arose there were two main courses open to him. He could order new supplies of vaccine and subject them to safety tests in this country; but the safety tests would probably be made, not concurrently with the manufacturers’ safety tests, but afterwards, entailing a delay of two or three months, and the vaccine would not be ready before August when the peak incidence of 1. Technical Committee 64, 104. 2. See
on
Poliomyelitis Vaccine. Amer. J. Hyg. 1956,
Lancet, May 3, 1958, p. 972.
Oral Diuretics DIURETIC agents were discussed two years ago by the Royal Society of Medicine 4; and last month the use of diuretics in cardiac failure was the subject of a symposium at the annual meeting of the Cardiac Society in Leeds. In the first of these discussions the limitations of oral diuretics, especially of acetazolamide (’ Diamox ’), were deservedly stressed; in the second it was apparent that an effective oral diuretic was just round the corner, if not already here. In diuretic therapy we shall doubtless continue to rely heavily on the organic mercurials given by injection; these we owe to the happy chance that diuresis during ’Novasurol’ antisyphilitic treatment of a non-oedematous patient impinged on the prepared mind of ALFRED V OGL. The quest for an oral diuretic has gone on without benefit of any comparable serendipity, and is only now beginning to promise real We have for some years had oral diuretic success. agents less potent than mercurials but potent enough to control early congestive failure in conjunction with digitalis and a low-salt diet; only recently have we gained in chlorothiazide an agent of comparable diuretic potency to mercurials given by injection. 3. Smadel, J. E. Bull. N.Y. Acad. Med. 1957, 33, 385. 4. Proc. R. Soc. Med. 1956, 5. Vogl, A. Amer. Heart J.
49, 623. 1950, 39, 881.
1006
To relieve cardiac oedema or pulmonary congestion, it is necessary to reduce the sodium content of the body; an increased excretion of water alone, or of an anion unaccompanied by sodium, is in this context irrelevant. In theory the ideal diuretic would increase the amount of sodium filtered by the glomeruli, or diminish directly the amount of sodium reabsorbed by the tubules; in practice the most effective agents at present are those which act primarily by diminishing chloride reabsorption, the increased output of chloride being then accompanied by natriuresis. When the general treatment of a cardiac invalid with rest and digitalis is effective, the glomerular filtration-rate (G.F.R.) increases and oedema may be prevented or diminished, so comparatively ineffective diuretic agents may appear to have worked efficiently. The diuretic action of theophylline drugs depends mainly on an increase in G.F.R., and some patients who have become resistant to mercurials may respond once again when aminophylline in a dose of up to 0-5 g. is given intravenously two hours after the mercurial injection.6 VOGLadvocates the use of oral theophylline preparations as an adjuvant to diuretic therapy. Decreased reabsorption of sodium can be directly effected by inducing an osmotic diuresis or by inhibiting the production of aldosterone, which is often increased in oedematous patients.8 Interest in urea as an oral osmotic diuretic has recently been revived 9; but large doses are needed, and the incidence of anorexia and nausea is fairly high. The production of aldosterone can be inhibited by amphenone, but the toxic effects of this drug preclude its therapeutic use. Several drugs act mainly by depressing anion reabsorption. The carbonic anhydrase inhibitors, which depress bicarbonate reabsorption, are of little value in the treatment of oedema, for they quickly lose their effect as the plasma-bicarbonate level falls, and with it the amount of bicarbonate filtered into the nephron; there is also a tendency to a greater loss of potassium than with mercurial diuretics.6 Since the amount of chloride entering the nephron is normally about three times as great as the amount of bicarbonate,6 there is a greater potentiality of effectiveness for drugs which depress the reabsorption of chloride rather than of bicarbonate. Three groups of drugs have been tested fairly extensively as oral chloruretic agents. These are the oral organic mercurials; the aminouracil compounds; and substituted benzothiodiazine (chlorothiazide). Oral mercurials, such as chlormerodrin (’ Merchloran ’), may cause diarrhoea, whether because they inhibit fluid absorption in the bowel as well as in the nephron or because the intestinal epithelium is highly susceptible to mercurial toxicity; and we agree with the view of GOODMAN and GILMAN 11: "
The oral administration of mercurial diuretics obviates the at the price of gastro-intestinal irritation,
necessity of injection 6. 7. 8. 9. 10.
Milne, M. D. Proc. R. Soc. Med. 1956, 49, 625. Vogl, A. Diuretic Therapy. Baltimore, 1953. Wolff, H. P., Koczorek, K. R., Buchborn, E. Lancet, 1957, ii, 63. Papp, C., Shirley Smith, K. Brit. med. J. 1957, ii, 906. Renold, A. E., Crabbé, J., Hernando-Avendano, L., Nelson, D. H., Ross, E. J., Emerson, K., Thorn, G. W. New Engl. J. Med. 1957, 256,
11.
Goodman, L. S., Gilman, A. peutics. New York, 1955.
16.
The
Pharmacological Basis of Thera-
total dosage of mercury, greater danger of systemic mercury poisoning, and a more delayed and less complete diuretic response. The route is ineffective when a rapid mobilisation of oedema fluid is desired in an acutely ill individual."
higher
Their final comment applies, we believe, with equal force to the aminouracil compounds. While these have some diuretic potency, the incidence of side-effects is high, especially with aminometradine (’ Mictine ’); the frequency of side-effects is distinctly lower with amisometradine (’ Rolicton ’), and this drug was found to be of some value in preventing recurrence of oedema which had been got rid of by mercurials.122 The aminouracil compounds quickly lose their effect, and do not really stand comparison with organic mercurials.13 Chlorothiazide is in a quite different category of effectiveness from the oral mercurials and the aminouracil drugs. In potency it is comparable to the mercurials given by injection, and may even produce diuresis in patients who have become resistant to mercurial diuretics.14 15 Favourable clinical reports on its effectiveness in generalised oedema have appeared both in America 14 16 17 and in this country.14 18 It does seem that we now have a potent oral diuretic that not only can control oedema but also, for good measure, has some hypotensive action.19 If our satisfaction at this should appear a little half-hearted, it is because we foresee possible abuse of a drug which, though convenient and potent, is also expensive and not devoid of side-effects. Gastrointestinal side-effects seem to be uncommon, but potassium depletion has been observed 14 15;this can be controlled by giving daily supplements of 2-6 g. of potassium chloride.15 One patient had an erythematous rash which disappeared when the drug was stopped.17 Hypochlorxmia has been observed in patients taking chlorothiazide,13 but should be controllable by ammonium or potassium chloride. The cost is also of some importance. According to a pricing bureau the basic cost to the N.H.S. of three injections of mersalyl is Is. 5d., whereas the basic cost of 8 g. of chlorothiazide is 9s. 102 d. ; the cost of a week’s treatment of oedema is thus more than six times as great with present oral treatment. No doubt the need to give injections carries substantial overheads above the basic cost; but at least the diuretic has been given, and there is no box of tablets to constitute a problem of domestic pharmacognosy or of self-medication in the next minor illness. Chlorothiazide certainly represents a great advance in diuretic treatment. May we hope that it will become cheaper; that it will not replace the well-tried mercurials until we know more of its side-effects; and, above all, that it will not be used to treat every patient with hypertension, or who complains of breathlessness or swelling of the ankles. 12.
Wener, J., Friedman, R., Schucher, R. Canad. med. Ass. J. 1958, 78,
200. 13. Ford, R. V., Rochelle, J. B., Handley, C. A., Meyer, J. H., Spurr, C. L. J. Amer. med. Ass. 1958, 166, 129. 14. Goodkind, M. J., Harvey, R. J., Richards, D. W. Amer. J. med. Sci. 15. 16. 17. 18. 19.
1958, 235, 164. Bayliss, R. I. S., Marrack, D., Pirkis, J., Rees, J. R., Zilva, J. Lancet, Jan. 18, 1958, p. 120. Laragh, J. H., Heinemann, H. O., Demartini, F. E. J. Amer. med. Ass. 1958, 166, 145. Schreiner, G. E., Bloomer, H. A. New Engl. J. Med. 1957, 257, 1016. Slater, J. D. H., Nabarro, J. D. N. Lancet, Jan. 18, 1958, p. 124. Wilkins, R. W. New Engl. J. Med. 1957, 257, 1026.