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Thiacetazone in Tuberculosis
LEADING ARTICLES
817
At the Rome conference a further report from this centre confirmed that the results of using streptomycin and a high dose of isoniazid twice weekly under supervision are remarkably good, if the bacilli are sensitive to these
THE LANCET
drugs.
Another approach has been adopted by the East African and British Medical Research Councils. Six years ago they began investigating thiacetazone, a drug first used seventeen years ago but almost entirely Thiacetazone in Tuberculosis abandoned after reports of serious toxicity. The early TREATMENT of pulmonary tuberculosis with streptoinvestigations in East Africa were promising,3 and more mycin, isoniazid, and p-aminosalicylic acid (P.A.S.) is extensive studies were begun. Theresults have just usually thought to be almost 100% effective if the been published.4 Three regimens of isoniazid and bacilli are sensitive to these drugs. But some physicians thiacetazone were tried in patients in hospital with have claimed that this, or any other, chemotherapy will advanced and bacilli sensitive to tuberculosis fail in some patients who are too old or too ill, or have isoniazid. pulmonary Isoniazid and thiacetazone were given in the too extensive disease or too low resistance. If this view doses: 300 mg. with 150 mg.; is right, the failures that occur are due to factors following single daily 200 mg. with 150 mg.; and 300 mg. with 100 mg. The outside the physician’s control. But if it is true that results were compared with those from the " standard " failure is not attributable to inadequacy of the drugs regimen of 100 mg. isoniazid and 5 g. sodium P.A.S. themselves, then it must be attributable to inadequacy twice daily. With this standard treatment the proof the physician or the patient. And this may not be portion of patients assessed at the end of a year as having easy for the physician to accept. a favourable bacteriological status was 78%-a figure A report to the International Tuberculosis Conference similar to that obtained in many other trials with this in Rome last month strongly suggests that it must, in combination. The results with a isoniazid-thiacetazone fact, be accepted. Two of the technical committees of regimen, using high doses of both drugs were as good the International Union against Tuberculosis carried (83%). But with only 200 mg. of isoniazid the results out a large cooperative investigation of the causes were less good (62%); and with the lower dose of of failure of chemotherapy. The investigation, which thiacetazone they were even poorer (48%). A similar involved 29 hospital centres in 21 countries and 5 was undertaken in outpatients, who reference laboratories, was coordinated from London investigation received 200 mg. isoniazid and 150 mg. thiacetazone in and Paris. 652 patients were studied. The prescribed two equal doses in the day. Results were less good than treatment consisted of daily streptomycin, isoniazid, with the isoniazid-P.A.s. regimen. The size of the and P.A.S. for six months followed by isoniazid and P.A.S. individual dose of thiacetazone seems to be critical. for another 6 months. Only 372 had the drugs strictly Toxic effects of thiacetazone were not a serious according to the protocol, and not all these were followed problem. With the most effective regimen-a single daily for the whole period. The treatment could be said to dose of 150 mg. with 300 mg. isoniazid-only 7% of the have failed in only 7 (2%)-4 who died and 3 in whom patients had toxic symptoms, compared with 4% of the bacteriological evidence suggested failure before some isoniazid-P.A.S. group. The major toxic effect that had change in treatment was made. Unfortunately, about previously prevented wider use of thiacetazone was liver 15% of the patients were lost to observation; hence damage. One very malnourished patient treated with some other failures may have occurred without being thiacetazone in the East African trial died of acute recorded. Nevertheless, the results were impressive. necrosis of the liver; but no other serious liver damage Of the 290 who continued the treatment for the whole was observed. Moreover, thiacetazone has been used year, none had a persistently positive sputum at the centres in East Africa for several in certain routinely end of it. The only factor shown to have an important years without serious toxicity being reported. Nevereffect on the results was the sensitivity of the pre- theless the previous reports of toxicity cannot be entirely treatment cultures to the drugs used. more experience should be gained in other and ignored; Unfortunately, this highly effective regimen is not countries before recommending that thiacetazone universally applicable. Not all patients can be persuaded replace P.A.S. as a companion drug for isoniazid. The to follow it even for a year; and two years’ chemotherapy Medical Research Council Tuberculosis Research Unit is now widely regarded as the minimum for most types is already carrying out in various parts of the world a of the disease. Moreover, the regimen is expensive and controlled study of its side-effects. calls for efficient organisation and personnel. For most The promising results from supervised intermittent patients in the world it is at present unattainable; for treatment with streptomycin and isoniazid and single money, staff, and organising skill are all insufficient. daily dose treatment with thiacetazone and isoniazid Much research is, therefore, being directed towards are important advances and will no doubt be followed by finding less expensive and less difficult treatment. The further improvements. But we are still a long way from interim results of one such attempt have been reported 2. Hinshaw, H. C., McDermott, W. Amer. Rev. Tuberc. 1950, 61, 145. from the Tuberculosis Chemotherapy Centre in Madras.l 3. East African/British Medical Research Council, Thiacetazone/DiphenylLONDON
1. Tuberculosis
19
OCTOBER
Chemotherapy Centre,
1963
Madras. Lancet, 1963,
i,
1078.
thiourea Investigation. Tubercle, Lond. 1960, 41, 399. African/British Medical Research Council. ibid. 1963, 44, 301.
4. East
818
the ideal treatment for tuberculosis. This would require a combination of drugs that would be 100% effective even if some of the patients had bacilli resistant to one The treatment would have to be or more of them. cheap, easy to give, non-toxic, tolerable, and not too protracted. Such an ideal may not be attainable. While casting around for the ideal, we should not neglect to make the best use of the highly effective drugs that we already have. In many countries it is at present impossible to use these drugs to the fullest advantage: in others, including our own, it can be done. Not to use them efficaciously in such favourable circumstances would be
inexcusably negligent. Halothane
Jaundice
THE doubts surrounding the action of halothane on the liver remain unresolved. Apparently 23 deaths from liver failure have so far been associated with the drug.1 Though this number is only a minute fraction of the many thousands of patients who by now must have been anaesthetised with the aid of halothane, the suggestion that such deaths can occur at all have made many wonder whether its continued use is justified.
The relatively high frequency of halothane jaundice and fatal liver failure in the United States of America has led to inquiry whether there was something in the way in which this drug was given which might account for its apparently greater toxicity there.2 It has been suggested, for example, that inadequate carbon-dioxide elimination, which is known to increase the hepatotoxicity of halothanewas likelier in a country where assisted respiration under anaesthesia is preferred to controlled respiration.4 It is generally agreed that effective assistance of respiration, short of the production of hypocapnia and apnoea, is exceedingly difficult to achieve; and indeed in unskilled hands this technique is more likely to cause carbon-dioxide accumulation than to ensure elimination of this gas. Another explanation draws on the work of HILL and LOWEwho showed that, when controlled respiration was used, the amount of halothane delivered by a’Fluotec ’ vaporiser was very much greater than that shown on the dial setting. It has been suggested that the inadvertent administration of large concentrations of halothane might explain the cases of liver failure.6 This explanation indeed carries some conviction, because the errors noted by HILL and LowE were greatest with low total gas flows, and these are much commoner in anxsthesia as practised in the United States than they are in the United Kingdom. Such an explanation of course is incompatible with hypotheses relating to inadequate carbon-dioxide elimination and
:assisted respiration. Another CoHEN
et
possible explanation has been put forward. a compound, 2,3-dichloro-
al.found that
1, 1, 1,4,4,4-hexafluorobutene-2,
was
present in
some
1. New York Times, Sept. 12, 1963. 2. Heidenberg, W. J., Torio, I. S., Cebula, J. Lancet, 1963, i, 1185. 3. Morris, L. E. Anesthesiology, 1960, 21, 109. 4. Seigleman, M. Lancet, 1963, i, 1377. 5. Hill, D. W., Lowe, H. J. Anesthesiology, 1962, 23, 291. 6. Adams, H. J. Lancet, Sept. 28, 1963, p. 692. 7. Cohen, E. N., Bellville, J. W., Budzikiewicz, H., Williams, D. H. Science, 1963, 141, 899.
preparations of halothane. In their experiments halothane kept in contact with copper or refluxed in contact with copper filings contained a much larger proportion of this substance. Experimentally the compound was found to produce severe pulmonary congestion and degenerative changes in the liver and kidney, and it was therefore suggested that it might be the causal factor in halothane jaundice. At first this seemed not only to explain the condition but to indicate why it should be so much more in the United States, the land of the copperkettle vaporiser, than anywhere else. Unfortunately, details of the pharmacological studies on this substituted hexafluorobutene are not yet available. It was, however, investigated some ten years ago along with other compounds which seemed as if they might be useful as halogenated anoesthetics.Rats to which this compound was administered all had postanxsthetic analgesia and all died within eighteen hours after exposure to the drug. In addition some animals had convulsions while aneesthetised. This last finding is probably not significant, because trichloroethylene will produce convulsions in small animals. The persistent analgesia, however, is reminiscent of the neurological disturbance produced by dichloracetylene-which is formed when soda lime acts on trichloroethylene.10 In short, so far as can be learned at the moment, there is little parallelism between halothane jaundice as clinically described and the disturbance produced in laboratory animals by this substituted hexafluorobutene compound. Accordingly this explanation of halothane jaundice seems unlikely to be correct. The other branch of medicine in which iatrogenic jaundice is currently attracting attention is psychiatry: in cases under treatment with a monoamine-oxidase inhibitor drug where jaundice or liver failure develops, the liver disorder will almost certainly be ascribed to the drug. SARGANT 11 has protested against this reasoning. He cites figures from the psychiatric department of St. Thomas’s Hospital, where some 3000-4000 patients have been treated with monoamine-oxidase inhibitors in the past few years, and where the incidence of hepatitis seems to have accorded more or less with that of infective hepatitis in the general population. I wonder ", says SARGANT, how many of the cases of jaundice ... are really due to infective hepatitis." To what extent may this apply also to the halothane deaths ? Another significant factor in halothane jaundice is the number of cases which seem to have arisen after gallbladder surgery.1213 It is certainly not common for jaundice to develop in the postoperative period after cholecystectomy in cases where there is no question of retained stone. Finally there is the clinical picture of halothane jaundice.14 In almost every instance the patient has recovered from the anxsthetic and jaundice has appeared after an interval of some days. This is not the pattern of delayed chloroform poisoning. Here jaundice comes on within some forty-eight hours after anaesthesia 15; the upset common
"
"
Chenoweth, M. B. Personal communication to Cohen et al. (footnote 7). Lu, G., Ling, J. S. L., Krantz, J. C. Anesthesiology, 1953, 14, 466. Carden, S. Brit. med. J. 1944, i, 319. Sargant, W. ibid. Sept. 28, 1963, p. 806. Tornetta, F. J., Tamaki, H. J. J. Amer. med. Ass. 1963, 184, 658. Brody, G. L., Sweet, R. B. Anesthesiology, 1963, 24, 291. 14. Lancet, 1963, i, 1195. 15. Gibberd, G. F. Guy’s Hosp. Rep. 1935, 85, 142.
8. 9. 10. 11. 12. 13.
817
At the Rome conference a further report from this centre confirmed that the results of using streptomycin and a high dose of isoniazid twice weekly under supervision are remarkably good, if the bacilli are sensitive to these
THE LANCET
drugs.
Another approach has been adopted by the East African and British Medical Research Councils. Six years ago they began investigating thiacetazone, a drug first used seventeen years ago but almost entirely Thiacetazone in Tuberculosis abandoned after reports of serious toxicity. The early TREATMENT of pulmonary tuberculosis with streptoinvestigations in East Africa were promising,3 and more mycin, isoniazid, and p-aminosalicylic acid (P.A.S.) is extensive studies were begun. Theresults have just usually thought to be almost 100% effective if the been published.4 Three regimens of isoniazid and bacilli are sensitive to these drugs. But some physicians thiacetazone were tried in patients in hospital with have claimed that this, or any other, chemotherapy will advanced and bacilli sensitive to tuberculosis fail in some patients who are too old or too ill, or have isoniazid. pulmonary Isoniazid and thiacetazone were given in the too extensive disease or too low resistance. If this view doses: 300 mg. with 150 mg.; is right, the failures that occur are due to factors following single daily 200 mg. with 150 mg.; and 300 mg. with 100 mg. The outside the physician’s control. But if it is true that results were compared with those from the " standard " failure is not attributable to inadequacy of the drugs regimen of 100 mg. isoniazid and 5 g. sodium P.A.S. themselves, then it must be attributable to inadequacy twice daily. With this standard treatment the proof the physician or the patient. And this may not be portion of patients assessed at the end of a year as having easy for the physician to accept. a favourable bacteriological status was 78%-a figure A report to the International Tuberculosis Conference similar to that obtained in many other trials with this in Rome last month strongly suggests that it must, in combination. The results with a isoniazid-thiacetazone fact, be accepted. Two of the technical committees of regimen, using high doses of both drugs were as good the International Union against Tuberculosis carried (83%). But with only 200 mg. of isoniazid the results out a large cooperative investigation of the causes were less good (62%); and with the lower dose of of failure of chemotherapy. The investigation, which thiacetazone they were even poorer (48%). A similar involved 29 hospital centres in 21 countries and 5 was undertaken in outpatients, who reference laboratories, was coordinated from London investigation received 200 mg. isoniazid and 150 mg. thiacetazone in and Paris. 652 patients were studied. The prescribed two equal doses in the day. Results were less good than treatment consisted of daily streptomycin, isoniazid, with the isoniazid-P.A.s. regimen. The size of the and P.A.S. for six months followed by isoniazid and P.A.S. individual dose of thiacetazone seems to be critical. for another 6 months. Only 372 had the drugs strictly Toxic effects of thiacetazone were not a serious according to the protocol, and not all these were followed problem. With the most effective regimen-a single daily for the whole period. The treatment could be said to dose of 150 mg. with 300 mg. isoniazid-only 7% of the have failed in only 7 (2%)-4 who died and 3 in whom patients had toxic symptoms, compared with 4% of the bacteriological evidence suggested failure before some isoniazid-P.A.S. group. The major toxic effect that had change in treatment was made. Unfortunately, about previously prevented wider use of thiacetazone was liver 15% of the patients were lost to observation; hence damage. One very malnourished patient treated with some other failures may have occurred without being thiacetazone in the East African trial died of acute recorded. Nevertheless, the results were impressive. necrosis of the liver; but no other serious liver damage Of the 290 who continued the treatment for the whole was observed. Moreover, thiacetazone has been used year, none had a persistently positive sputum at the centres in East Africa for several in certain routinely end of it. The only factor shown to have an important years without serious toxicity being reported. Nevereffect on the results was the sensitivity of the pre- theless the previous reports of toxicity cannot be entirely treatment cultures to the drugs used. more experience should be gained in other and ignored; Unfortunately, this highly effective regimen is not countries before recommending that thiacetazone universally applicable. Not all patients can be persuaded replace P.A.S. as a companion drug for isoniazid. The to follow it even for a year; and two years’ chemotherapy Medical Research Council Tuberculosis Research Unit is now widely regarded as the minimum for most types is already carrying out in various parts of the world a of the disease. Moreover, the regimen is expensive and controlled study of its side-effects. calls for efficient organisation and personnel. For most The promising results from supervised intermittent patients in the world it is at present unattainable; for treatment with streptomycin and isoniazid and single money, staff, and organising skill are all insufficient. daily dose treatment with thiacetazone and isoniazid Much research is, therefore, being directed towards are important advances and will no doubt be followed by finding less expensive and less difficult treatment. The further improvements. But we are still a long way from interim results of one such attempt have been reported 2. Hinshaw, H. C., McDermott, W. Amer. Rev. Tuberc. 1950, 61, 145. from the Tuberculosis Chemotherapy Centre in Madras.l 3. East African/British Medical Research Council, Thiacetazone/DiphenylLONDON
1. Tuberculosis
19
OCTOBER
Chemotherapy Centre,
1963
Madras. Lancet, 1963,
i,
1078.
thiourea Investigation. Tubercle, Lond. 1960, 41, 399. African/British Medical Research Council. ibid. 1963, 44, 301.
4. East
818
the ideal treatment for tuberculosis. This would require a combination of drugs that would be 100% effective even if some of the patients had bacilli resistant to one The treatment would have to be or more of them. cheap, easy to give, non-toxic, tolerable, and not too protracted. Such an ideal may not be attainable. While casting around for the ideal, we should not neglect to make the best use of the highly effective drugs that we already have. In many countries it is at present impossible to use these drugs to the fullest advantage: in others, including our own, it can be done. Not to use them efficaciously in such favourable circumstances would be
inexcusably negligent. Halothane
Jaundice
THE doubts surrounding the action of halothane on the liver remain unresolved. Apparently 23 deaths from liver failure have so far been associated with the drug.1 Though this number is only a minute fraction of the many thousands of patients who by now must have been anaesthetised with the aid of halothane, the suggestion that such deaths can occur at all have made many wonder whether its continued use is justified.
The relatively high frequency of halothane jaundice and fatal liver failure in the United States of America has led to inquiry whether there was something in the way in which this drug was given which might account for its apparently greater toxicity there.2 It has been suggested, for example, that inadequate carbon-dioxide elimination, which is known to increase the hepatotoxicity of halothanewas likelier in a country where assisted respiration under anaesthesia is preferred to controlled respiration.4 It is generally agreed that effective assistance of respiration, short of the production of hypocapnia and apnoea, is exceedingly difficult to achieve; and indeed in unskilled hands this technique is more likely to cause carbon-dioxide accumulation than to ensure elimination of this gas. Another explanation draws on the work of HILL and LOWEwho showed that, when controlled respiration was used, the amount of halothane delivered by a’Fluotec ’ vaporiser was very much greater than that shown on the dial setting. It has been suggested that the inadvertent administration of large concentrations of halothane might explain the cases of liver failure.6 This explanation indeed carries some conviction, because the errors noted by HILL and LowE were greatest with low total gas flows, and these are much commoner in anxsthesia as practised in the United States than they are in the United Kingdom. Such an explanation of course is incompatible with hypotheses relating to inadequate carbon-dioxide elimination and
:assisted respiration. Another CoHEN
et
possible explanation has been put forward. a compound, 2,3-dichloro-
al.found that
1, 1, 1,4,4,4-hexafluorobutene-2,
was
present in
some
1. New York Times, Sept. 12, 1963. 2. Heidenberg, W. J., Torio, I. S., Cebula, J. Lancet, 1963, i, 1185. 3. Morris, L. E. Anesthesiology, 1960, 21, 109. 4. Seigleman, M. Lancet, 1963, i, 1377. 5. Hill, D. W., Lowe, H. J. Anesthesiology, 1962, 23, 291. 6. Adams, H. J. Lancet, Sept. 28, 1963, p. 692. 7. Cohen, E. N., Bellville, J. W., Budzikiewicz, H., Williams, D. H. Science, 1963, 141, 899.
preparations of halothane. In their experiments halothane kept in contact with copper or refluxed in contact with copper filings contained a much larger proportion of this substance. Experimentally the compound was found to produce severe pulmonary congestion and degenerative changes in the liver and kidney, and it was therefore suggested that it might be the causal factor in halothane jaundice. At first this seemed not only to explain the condition but to indicate why it should be so much more in the United States, the land of the copperkettle vaporiser, than anywhere else. Unfortunately, details of the pharmacological studies on this substituted hexafluorobutene are not yet available. It was, however, investigated some ten years ago along with other compounds which seemed as if they might be useful as halogenated anoesthetics.Rats to which this compound was administered all had postanxsthetic analgesia and all died within eighteen hours after exposure to the drug. In addition some animals had convulsions while aneesthetised. This last finding is probably not significant, because trichloroethylene will produce convulsions in small animals. The persistent analgesia, however, is reminiscent of the neurological disturbance produced by dichloracetylene-which is formed when soda lime acts on trichloroethylene.10 In short, so far as can be learned at the moment, there is little parallelism between halothane jaundice as clinically described and the disturbance produced in laboratory animals by this substituted hexafluorobutene compound. Accordingly this explanation of halothane jaundice seems unlikely to be correct. The other branch of medicine in which iatrogenic jaundice is currently attracting attention is psychiatry: in cases under treatment with a monoamine-oxidase inhibitor drug where jaundice or liver failure develops, the liver disorder will almost certainly be ascribed to the drug. SARGANT 11 has protested against this reasoning. He cites figures from the psychiatric department of St. Thomas’s Hospital, where some 3000-4000 patients have been treated with monoamine-oxidase inhibitors in the past few years, and where the incidence of hepatitis seems to have accorded more or less with that of infective hepatitis in the general population. I wonder ", says SARGANT, how many of the cases of jaundice ... are really due to infective hepatitis." To what extent may this apply also to the halothane deaths ? Another significant factor in halothane jaundice is the number of cases which seem to have arisen after gallbladder surgery.1213 It is certainly not common for jaundice to develop in the postoperative period after cholecystectomy in cases where there is no question of retained stone. Finally there is the clinical picture of halothane jaundice.14 In almost every instance the patient has recovered from the anxsthetic and jaundice has appeared after an interval of some days. This is not the pattern of delayed chloroform poisoning. Here jaundice comes on within some forty-eight hours after anaesthesia 15; the upset common
"
"
Chenoweth, M. B. Personal communication to Cohen et al. (footnote 7). Lu, G., Ling, J. S. L., Krantz, J. C. Anesthesiology, 1953, 14, 466. Carden, S. Brit. med. J. 1944, i, 319. Sargant, W. ibid. Sept. 28, 1963, p. 806. Tornetta, F. J., Tamaki, H. J. J. Amer. med. Ass. 1963, 184, 658. Brody, G. L., Sweet, R. B. Anesthesiology, 1963, 24, 291. 14. Lancet, 1963, i, 1195. 15. Gibberd, G. F. Guy’s Hosp. Rep. 1935, 85, 142.
8. 9. 10. 11. 12. 13.