358 PARACETAMOL HEPATOXICITY
SIR,-We would like raised
by
to comment on some
your editorial’ and
by
of the issues (Jan. 2, p.
Dr Dixon’s letter
35). of the 1975 figures for the London of the National Poisons Information Service showed that during that twelve months there were 775 inquiries about paracetamol. 50 of the patients were known to have had high blood-paracetamol levels and 10 of these died. None of these 10 received any specific therapy within 10 h of ingestion, and it is possible that prompt treatment with, say cysteamine or methionine, would have further reduced the mortality. We have elicited reports of 24 patients dying after an overdose of paracetamol. 12 patients were admitted to the liver unit at King’s College Hospital. Reports about the remaining 12 were received following questionnaires sent to inquirers of the National Poisons Information Service. All were adults and all had taken a deliberate overdose. In 14 instances the blood levels were not estimated, or were estimated only late in the patient’s illness. All of the 12 admitted to King’s showed clinical and pathological evidence of hepatic necrosis-hypotension, renal failure, and haemorrhage being common terminal events. Of the remaining 12 patients, a further 6 also died of hepatic necrosis. In the remaining 6 in whom hepatic necrosis was not reported to be the cause of death, it may be significant that other drugs were also involved. 4 died following cardiorespiratory arrest, 3 having taken the narcotic analgesic dextropropoxyphene in addition to paracetamol and 1 additionally took diazepam. The fifth, who had taken a multiple overdose, including diazepam, promethazine, and triclofos, died 3 weeks after admission following a hemiparesis. The sixth, reported as dying from bronchopneumonia, had taken an overdose of glutethimide, aspirin, paracetamol, and alcohol and was admitted unconscious to hospital. Clinical evidence of hepatic necrosis was present 48 h after admission, and the s.G.o.T. was 2500 I.U./l. Aspiration and anoxia, which probably occurred in this patient, are preventable by careful management and nursing care and should not occur once the patient has been admitted A
preliminary analysis
centre
to
hospital.
previously shown that overdose with more than one drug is common,’ and the present series confirms this, 11 of the 24 patients having taken a multiple overdose. We would We have
be interested
know how Dr Dixon could be sure that his patients, alleged to have died from paracetamol poisoning alone, had not taken other drugs as well. Our evidence does not support the view that, in the absence of hepatic necrosis, paracetamol itself has toxic actions on other organs. The impression conveyed by your editorial was, in our opinion, more denigratory towards paracetamol, as a therapeutic agent, than the evidence warranted. Admittedly, although gross abuse by the deliberate swallowing of large overdoses of paracetamol can be accompanied by hepatic necrosis and sometimes death, most abusers recover and the mortality for paracetamol in the U.K. remains substantially below that for aspirin. Finally, we should like to re-emphasise that hepatic necrosis has never been seen after even maximum therapeutic doses, even when used for a long period. Used properly, therefore, rather than misused, paracetamol can, we suggest, still be regarded as a safe analgesic. to
Poisons Unit, New Cross Hospital, London SE14 5ER.
ROY GOULDING G. N. VOLANS PETER CROME BRIAN WIDDOP
Liver Unit
King’s College Hospital, London SE1.
ROGER WILLIAMS
SHORT-COURSE CHEMOTHERAPY OF
TUBERCULOSIS
SIR,- The greatest problem in treating pulmonary tubercu. losis is ensuring that patients actually take an effective combination of drugs in their correct dosage for long enough. Inassociation with our colleagues in East Africa and Hong Kong, we have investigated daily and intermittent short-course regimens with the aim of developing effective, well-tolerated, and economical forms of treatment which can be fully supervised on an outpatient basis and which are followed by very low relapse-rates.’1 The importance of supervision and its problems have been well illustrated by Dr Werner and Dr Sareen (Jan. 3, p. 38), However, we cannot support their recommendation of a 6-month course of treatment with streptomycin plus isoniazid plus ethambutol. The combination of streptomycin plus isoniazid plus ethambutol for 6 months has not been assessed in controlled clinical trials and should not be considered for routine use until it has. Streptomycin plus isoniazid daily for 6 months is an inadequate regimenand its performance is not improved by the addition of either of the bacteriostatic drugs thiacetazoneor p-aminosalicylic acid (P.A.S.).3 We would not expect the addition of ethambutol to streptomycin plus isoniazid to result in an adequate regimen because ethambutol, like thiacetazone and P.A.S., is a bacteriostatic drug in the dosages used 4 The evidence from clinical trials suggests that the combination of ethambutol plus isoniazid is no more effective in the prevention of subsequent relapse than streptomycin plus isoniazid, and may be less so.’ The combination of ethambutol plus isoniazid is one of the least effective regimens so far investigated in sterilising lesions of experimental tuberculosis in the mousse 6 Thus, we would not expect ethambutol to add to the sterilising ability of streptomycin plus isoniazid, although it might have some value in preventing the emergence of drug resistance. Our conclusion, from the results of experimental work and controlled clinical trials, is that short-course regimens must include rifampicin or pyrazinamide or both of these drugs.’ M.R.C. Tuberculosis and Chest Diseases Unit,
Brompton Hospital, Fulham Road, London SW3 6HP
WALLACE FOX
M.R.C. Unit for Laboratory Studies of Tuberculosis, Royal Postgraduate Medical School, Du Cane Road, London W12 0HS
D. A. MITCHISON
SiR,—We were pleased to read the account of the controlled trial of intermittent regimens of rifampicin plus isoniazid for pulmonary tuberculosis in Singapore,7 because we also have growing confidence in the acceptability and efficacy of highdose isoniazid plus low-dose rifampicin twice weekly after initial
Widdop, B. Ciba Fndn. Symp. 1974, no. 26, p. 219.
daily treatment.
In 19718 we reported our experience of disturbing side-effects
when
high-dose rifampicin twice weekly was used and we consequently reduced rifampicin in intermittent regimens from 1200 mg to 600 mg twice weekly. From November, 1M until November, 1972, fifty-one unselected patients receiveda fully supervised regimen comprising streptomycin 07! I. isoniazid 300 mg, and rifampicin 600 mg daily for 3 months 1. Fox, W., Mitchison, D. A. Am. Rev. resp. Dis. 1975, 111, 325. 2. East African/British Medical Research Councils Lancet, 1974, ii, 237 3. Medical Research Council Tuberculosis Chemotherapy Trials Committee Tubercle, 1962, 43, 201. 4. Dickinson, J. M., Mitchison, D. A. Bull. Un. int. Tuberc. (in the press 5. Tripathy, S. P. ibid. 1974, 49, 396. 6. Grumbach, F. Ann. Inst. Pasteur Lille. 1966, 110, 69. 7.
1.
D. J. GIRLING J. F. HEFFERNAN
Singapore Tuberculosis Service/British
Medical Research Council Lancet
1975, ii, 1105. 8. Poole, G., Stradling, P., Worlledge, S. Br. med. J. 1971, iii, 343
SIR,-We would like raised
by
to comment on some
your editorial’ and
by
of the issues (Jan. 2, p.
Dr Dixon’s letter
35). of the 1975 figures for the London of the National Poisons Information Service showed that during that twelve months there were 775 inquiries about paracetamol. 50 of the patients were known to have had high blood-paracetamol levels and 10 of these died. None of these 10 received any specific therapy within 10 h of ingestion, and it is possible that prompt treatment with, say cysteamine or methionine, would have further reduced the mortality. We have elicited reports of 24 patients dying after an overdose of paracetamol. 12 patients were admitted to the liver unit at King’s College Hospital. Reports about the remaining 12 were received following questionnaires sent to inquirers of the National Poisons Information Service. All were adults and all had taken a deliberate overdose. In 14 instances the blood levels were not estimated, or were estimated only late in the patient’s illness. All of the 12 admitted to King’s showed clinical and pathological evidence of hepatic necrosis-hypotension, renal failure, and haemorrhage being common terminal events. Of the remaining 12 patients, a further 6 also died of hepatic necrosis. In the remaining 6 in whom hepatic necrosis was not reported to be the cause of death, it may be significant that other drugs were also involved. 4 died following cardiorespiratory arrest, 3 having taken the narcotic analgesic dextropropoxyphene in addition to paracetamol and 1 additionally took diazepam. The fifth, who had taken a multiple overdose, including diazepam, promethazine, and triclofos, died 3 weeks after admission following a hemiparesis. The sixth, reported as dying from bronchopneumonia, had taken an overdose of glutethimide, aspirin, paracetamol, and alcohol and was admitted unconscious to hospital. Clinical evidence of hepatic necrosis was present 48 h after admission, and the s.G.o.T. was 2500 I.U./l. Aspiration and anoxia, which probably occurred in this patient, are preventable by careful management and nursing care and should not occur once the patient has been admitted A
preliminary analysis
centre
to
hospital.
previously shown that overdose with more than one drug is common,’ and the present series confirms this, 11 of the 24 patients having taken a multiple overdose. We would We have
be interested
know how Dr Dixon could be sure that his patients, alleged to have died from paracetamol poisoning alone, had not taken other drugs as well. Our evidence does not support the view that, in the absence of hepatic necrosis, paracetamol itself has toxic actions on other organs. The impression conveyed by your editorial was, in our opinion, more denigratory towards paracetamol, as a therapeutic agent, than the evidence warranted. Admittedly, although gross abuse by the deliberate swallowing of large overdoses of paracetamol can be accompanied by hepatic necrosis and sometimes death, most abusers recover and the mortality for paracetamol in the U.K. remains substantially below that for aspirin. Finally, we should like to re-emphasise that hepatic necrosis has never been seen after even maximum therapeutic doses, even when used for a long period. Used properly, therefore, rather than misused, paracetamol can, we suggest, still be regarded as a safe analgesic. to
Poisons Unit, New Cross Hospital, London SE14 5ER.
ROY GOULDING G. N. VOLANS PETER CROME BRIAN WIDDOP
Liver Unit
King’s College Hospital, London SE1.
ROGER WILLIAMS
SHORT-COURSE CHEMOTHERAPY OF
TUBERCULOSIS
SIR,- The greatest problem in treating pulmonary tubercu. losis is ensuring that patients actually take an effective combination of drugs in their correct dosage for long enough. Inassociation with our colleagues in East Africa and Hong Kong, we have investigated daily and intermittent short-course regimens with the aim of developing effective, well-tolerated, and economical forms of treatment which can be fully supervised on an outpatient basis and which are followed by very low relapse-rates.’1 The importance of supervision and its problems have been well illustrated by Dr Werner and Dr Sareen (Jan. 3, p. 38), However, we cannot support their recommendation of a 6-month course of treatment with streptomycin plus isoniazid plus ethambutol. The combination of streptomycin plus isoniazid plus ethambutol for 6 months has not been assessed in controlled clinical trials and should not be considered for routine use until it has. Streptomycin plus isoniazid daily for 6 months is an inadequate regimenand its performance is not improved by the addition of either of the bacteriostatic drugs thiacetazoneor p-aminosalicylic acid (P.A.S.).3 We would not expect the addition of ethambutol to streptomycin plus isoniazid to result in an adequate regimen because ethambutol, like thiacetazone and P.A.S., is a bacteriostatic drug in the dosages used 4 The evidence from clinical trials suggests that the combination of ethambutol plus isoniazid is no more effective in the prevention of subsequent relapse than streptomycin plus isoniazid, and may be less so.’ The combination of ethambutol plus isoniazid is one of the least effective regimens so far investigated in sterilising lesions of experimental tuberculosis in the mousse 6 Thus, we would not expect ethambutol to add to the sterilising ability of streptomycin plus isoniazid, although it might have some value in preventing the emergence of drug resistance. Our conclusion, from the results of experimental work and controlled clinical trials, is that short-course regimens must include rifampicin or pyrazinamide or both of these drugs.’ M.R.C. Tuberculosis and Chest Diseases Unit,
Brompton Hospital, Fulham Road, London SW3 6HP
WALLACE FOX
M.R.C. Unit for Laboratory Studies of Tuberculosis, Royal Postgraduate Medical School, Du Cane Road, London W12 0HS
D. A. MITCHISON
SiR,—We were pleased to read the account of the controlled trial of intermittent regimens of rifampicin plus isoniazid for pulmonary tuberculosis in Singapore,7 because we also have growing confidence in the acceptability and efficacy of highdose isoniazid plus low-dose rifampicin twice weekly after initial
Widdop, B. Ciba Fndn. Symp. 1974, no. 26, p. 219.
daily treatment.
In 19718 we reported our experience of disturbing side-effects
when
high-dose rifampicin twice weekly was used and we consequently reduced rifampicin in intermittent regimens from 1200 mg to 600 mg twice weekly. From November, 1M until November, 1972, fifty-one unselected patients receiveda fully supervised regimen comprising streptomycin 07! I. isoniazid 300 mg, and rifampicin 600 mg daily for 3 months 1. Fox, W., Mitchison, D. A. Am. Rev. resp. Dis. 1975, 111, 325. 2. East African/British Medical Research Councils Lancet, 1974, ii, 237 3. Medical Research Council Tuberculosis Chemotherapy Trials Committee Tubercle, 1962, 43, 201. 4. Dickinson, J. M., Mitchison, D. A. Bull. Un. int. Tuberc. (in the press 5. Tripathy, S. P. ibid. 1974, 49, 396. 6. Grumbach, F. Ann. Inst. Pasteur Lille. 1966, 110, 69. 7.
1.
D. J. GIRLING J. F. HEFFERNAN
Singapore Tuberculosis Service/British
Medical Research Council Lancet
1975, ii, 1105. 8. Poole, G., Stradling, P., Worlledge, S. Br. med. J. 1971, iii, 343
