- Email: [email protected]
TREATMENT OF PARACETAMOL POISONING
864 in Toronto (Kavanagh) and Honolulu (Scaff) some four dozen are scheduled to reach the 42 km. marathon distance during the next year. Thus we now have three groups of individuals who appear to be immune from fatal coronary heart-disease: the non-smoking marathon finisher, the non-smoking individual with a normal M.T.S.T., and the non-smoking cardiac patient in a supervised rehabilitation course doing his 6 miles (10 km.) each day. The life-style of the marathon runner appears to reduce most risk factors. He does not smoke. His diet is rich in polyunsaturates, vitamins C and E. He avoids the excessive use of alcohol, refined starch, and sucrose. His interest is
The incidence of resistant strains in other parts of the country is at present undocumented but is worth further study. Ampicillin has proved to be an effective non-toxic substitute for chloramphenicol in treatment of hsmophitus meningitis. In some areas it may still be safe to use it as a first-line antibiotic in treatment of H. infiuenzae meningitis, although bacteriologists and clinicians need to be aware of amnicillin resistance as a cause of treatment failure. London Hospital Medical College, London El. Public Health Laboratory, Stafford.
J. D. WILLIAMS. P. CAVANAGH.
improved racing performance, not coronary protection. However, cardiologists will recognise this life-style as beneficial in reducing the incidence of atherosclerosis and can apply the life-style to their patients. We expect to see individuals who have finished a marathon and subsequently die from coronary atherosclerosis, but we expect these cases will come from those: who lose their marathoning capability by assuming a life-style with several risk factors such as smoking and a diet rich in saturated fats. But cases such as that would " not discourage us from answering your question: can I " avoid heart-attack ? Our answer is : Yes, by assuming: a life-style associated with immunity to heart-disease ... the marathon runner." .
,
"
American Medical Joggers Association, Post Office Box 4704, North Hollywood, California 91607, U.S.A.
T. BASSLER
J. SCAFF.
AMPICILLIN-RESISTANT HÆMOPHILUS INFLUENZÆ MENINGITIS
meningitis due to ampicillinHaemophilus infiuenzae reported in your columns (Feb. 23, p. 313; March 16, p. 453) is of some importance. For many years this organism has changed little in antimicrobial sensitivity, but lately instances of resistance to tetracycline have been noted, and the incidence of sulphonamide resistance has been quantised. Meningitis usually occurs with capsulated strains of H. influenza, but we thought the incidence of ampicillin resistance among " wild strains, which includes capsulated and non-capsulated strains, might be of some interest. The strains isolated from a variety of specimens (sputum, sinuses, cerebrospinal fluid) in the midlands of England are shown in the table. Sensitive strains are inhibited by SIR,-The
occurrence
of
resistant
TEACHING BIOCHEMISTRY TO MEDICALS SIR,-Your editorial (Feb. 23, p. 297) touches on a problem faced by biochemists in medical schools everywhere. Our students and our clinical colleagues protest that biochemists teach useless facts and that a more relevant course is needed. Your editorial suggests that clinicians should help to plan the biochemistry course, assist in teaching it, and see it progress in parallel with clinical work. I wish to draw the attention of your readers to a course taught to medicals at McGill University, 1,2 in which a clinical problem is first presented with the help of a clinical colleague, and the biochemistry necessary to understand the case is subsequently taught by the biochemists. This approach arouses the interests of the student physicians and ensures that the biochemistry is relevant. This approach has been further developed in the teaching of biochemistry at the Medical College of Ohio,3 where a team of instructors is attached to each class of medical students throughout the 3-year programme at the college. The biochemists are now beginning to go on clinical rounds with 3rd-year students in their clerkships in medicine to provide complete integration of biochemistry with the rest of the basic science and clinical instruction. Department of Biochemistry, Medical College of Ohio, Ohio 43614, U.S.A.
Toledo,
MURRAY SAFFRAN.
".
less than 0-5 g. ampicillin per ml., resistant strains by There is some geographical more than 2 g. per ml. variation in the prevalence of resistance of H. infiuenzae to In the Stafford/Wolverhampton area the ampicillin. incidence of resistant strains was appreciable, whereas no resistant strains were found in the Coventry/Birmingham area. It is of interest that one of the cases of ampicillinresistant H. influenzz meningitis occurred in Wolver-
hampton. 1.
Williams, J. D., Andrews, J. Br. med. J. 1974, i, 134.
TREATMENT OF PARACETAMOL POISONING SIR,-We were interested to read the exciting new approach reported by Dr Prescott and his colleagues (April 6, p. 588) to the management, using intravenous cysteamine, of paracetamol-induced liver damage, but we do wish to sound a note of caution. In our experience plasma-paracetamol levels obtained shortly after ingestion are not always a good guide to the severity of ensuing liver damage. We have seen 6 patients in King’s College Hospital over the past year with plasma-paracetamol levels similar to those present in the patients treated by Dr Prescott and his colleagues (including 2 with levels of over 400 (lg. per ml. at 12 hours after ingestion) in whom mild or moderate liver damage developed only without evidence of encephalopathy. In contrast,we saw 30 patients with plasma-paracetamol levels of between 150 and 200 ug. per ml. within 12 hours of ingestion, and in 4 of those severe liver damage with encephalopathy developed. Dr Prescott and his associates point out that it may be difficult to extrapolate the plasma level to a value at 4 hours after ingestion, since the time of the overdose is often not accurately known, and we have also found that the disappearance-rate of the drug from the plasma may be 1. 2. 3.
Saffran, M. J. med. Educ. 1971, 46, 1081. Rubinstein, D. ibid. 1972, 47, 198. Saffran, M. Bull. Biochem. Educ. 1973, 1, no. 3.
865
4 hours. We agree that for
oc-tocopherol is a natural antioxidant which could be incorporated into paracetamol pharmaceutical preparations and may offer protection in the overdose situation. At the concentration of cx-tocopherol used here no toxic effects
given
would result.
initially prolonged by continued paracetamol absorption, and this too will influence estimation of the drug level at cysteamine to be effective it should be early as possible after the overdose, but this is when the prediction of the degree of ensuing liver damage is most difficult, and many patients may therefore be subjected unnecessarily to the unpleasant toxic side-effects of the drug. This is surely an ideal situation in which to conduct a prospective controlled trial. This we propose as
do in collaboration with our Poisons Unit and we would happy to send details to any physicians and casualty departments who would be interested in collaborating.
J. KELLEHER Departments of Medicine and Pathology, St. James’s (University) Hospital, Leeds LS9 7TF.
B. E. WALKER M. F. DIXON M. S. LOSOWSKY.
to
be
B. G. GAZZARD I. M. MURRAY-LYON M. DAVIS R. P. H. THOMPSON ROGER WILLIAMS.
Liver Unit,
King’s College Hospital, London SE5 8RX.
Poisons Unit, Guy’s Hospital,
R. GOULDING.
London SE1.
SIR,-Dr Prescott and his colleagues showed protection against paracetamol hepatotoxicity with intravenous cysteamine up to 10 hours after ingestion. Dr McLean (April 20, p. 729) administered methionine simultaneously with paracetamol to phenobarbitone-pretreated rats and greatly reduced the expected mortality. We have examined the protective effect of oc-tocopherol in rats given large doses of paracetamol. Groups of untreated rats were given paracetamol suspension at various dose levels with or without
INTRANASAL ADMINISTRATION OF LUTEINISING-HORMONE RELEASING FACTOR SIR,-Solbach and Wiegelmann reported that intranasal luteinising-hormone releasing factor (L.H.R.F.) was as effective as an intravenous injection of L.H.R.F. in eliciting L.H. release. Their report has since been fully confirmed by other workers. 2-5 However, Mortimer et al.said that the effect of L.H.R.F. administered intranasally is less certain than when given intravenously. We have to comment on this statement since it might tend to limit the future use of intranasally administered L.H.R.F. Firstly, the conclusions of Mortimer et al. are based on results obtained in only two subjects. Secondly, their report states that the intravenous, intramuscular, and subcutaneous routes, in contrast with the intranasal route, are equally effective in eliciting an L.H. release. However, in one case the L.H. response to intranasal L.H.R.F. was as strong as that evoked by subcutaneous injection in two of the three men investigated. In the second of the two men who received intranasal L.H.R.F. the L.H. response was slightly weaker. Thirdly, the method of the intranasal application used by Mortimer et al. seems both time-consuming and inconvenient. A simple and reliable method for intranasal administration of oxytocinand 1-deamino-8D-arginine vasopressin (D.D.A.V.P.)has long been available. This method-i.e., dissolution of the substance in a small volume (0-2 ml.) of fluid and letting the patient blow it into one of the nasal cavities via a short plastic catheterhas been successfully used for intranasal administration of L.H.R.F.3-5 Department of Obstetrics and Gynæcology, Genera] Hospital, University of Lund, S-21401 Malmö, Sweden.
GERHARD GENNSER PERCY LIEDHOLM.
T.R.H. IN DEPRESSION Mean±S.E.M. for
serum A.S.A.T.
and
A.L.A.T.
in groups of without vitamin E
(24 hours)
12 rats given oral doses of paracetamol with (30% by weight of paracetamol).
or
At all dose levels (see accompanying table) there is a striking reduction in the mean enzyme level for the groups given a-tocopherol which is significant except at the very large dose of 4 g. per kg. which could be equated with an intake of 480 tablets (0-5 g.) in a 70 kg. man. The mechanism of the protective action of cysteamine, methionine, or cx-tocopherol is not clear. All may nonspecifically scavenge the toxic metabolite thought to be responsible for the ensuing necrosis in a manner similar to that for glutathione. Both cysteamine and methionine protection could be related to glutathione metabolism, but this does not explain the protection offered by a-tocopherol. It is possible that x-tocopherol may protect at a later stage than either cysteamine or methionine and by a different mechanism by preventing or retarding autoxidation of essential cell-membrane polyunsaturated lipids, though this mechanism may be contentious.
SIR,-Dr Drayson (Feb. 23, p. 312) and Dr Dimitrikoudi and others (March 16, p. 456) have reported negative results in six depressed patients given thyrotrophin-releasing hormone (T.R.H.). We should like to add four more cases. Our patients
were women, aged 35 to 70 years, who had depression of endogenous type. Three had histories of bipolar courses and one a history of a monopolar course. At the time of T.R.H. administration they were under treatment with tricyclic antidepressants (three cases) or lithium (one case). T.R.H. was given as a slow intravenous injection at 8 A.M., while
severe
1. 2.
3.
4. 5. 6. 7. 8.
Solbach, H. G., Wiegelmann, W. Lancet, 1973, i, 1259. London, D. R., Butt, W. R., Lynch, S. S., Marshall, J. C., Owusu, S., Robinson, W. R., Stephenson, J. M. J. clin. Endocr. Metab. 1973, 37, 829. Gennser, G., Liedholm, P., Thorell, J., Mulder, J. Int. Res. Comm. Syst. 1973 (73-10), 8-9-4. Jeppsson, S., Kullander, S., Rannevik, G., Thorell, J. Br. med. J. 1973, iv, 231. Fink, G., Gennser, G., Liedholm, P., Thorell, J., Mulder, J. J. Endocr. (in the press). Mortimer, C. H., Besser, G. M., Hook, J., McNeilly, A. S. Clin. Endocr. 1974, 3, 19. Borglin, N. E. Acta obstet. gynec. scand. 1962, 41, 237. Andersson, K-E., Arner, B. Acta med. scand. 1972, 192, 21.
The incidence of resistant strains in other parts of the country is at present undocumented but is worth further study. Ampicillin has proved to be an effective non-toxic substitute for chloramphenicol in treatment of hsmophitus meningitis. In some areas it may still be safe to use it as a first-line antibiotic in treatment of H. infiuenzae meningitis, although bacteriologists and clinicians need to be aware of amnicillin resistance as a cause of treatment failure. London Hospital Medical College, London El. Public Health Laboratory, Stafford.
J. D. WILLIAMS. P. CAVANAGH.
improved racing performance, not coronary protection. However, cardiologists will recognise this life-style as beneficial in reducing the incidence of atherosclerosis and can apply the life-style to their patients. We expect to see individuals who have finished a marathon and subsequently die from coronary atherosclerosis, but we expect these cases will come from those: who lose their marathoning capability by assuming a life-style with several risk factors such as smoking and a diet rich in saturated fats. But cases such as that would " not discourage us from answering your question: can I " avoid heart-attack ? Our answer is : Yes, by assuming: a life-style associated with immunity to heart-disease ... the marathon runner." .
,
"
American Medical Joggers Association, Post Office Box 4704, North Hollywood, California 91607, U.S.A.
T. BASSLER
J. SCAFF.
AMPICILLIN-RESISTANT HÆMOPHILUS INFLUENZÆ MENINGITIS
meningitis due to ampicillinHaemophilus infiuenzae reported in your columns (Feb. 23, p. 313; March 16, p. 453) is of some importance. For many years this organism has changed little in antimicrobial sensitivity, but lately instances of resistance to tetracycline have been noted, and the incidence of sulphonamide resistance has been quantised. Meningitis usually occurs with capsulated strains of H. influenza, but we thought the incidence of ampicillin resistance among " wild strains, which includes capsulated and non-capsulated strains, might be of some interest. The strains isolated from a variety of specimens (sputum, sinuses, cerebrospinal fluid) in the midlands of England are shown in the table. Sensitive strains are inhibited by SIR,-The
occurrence
of
resistant
TEACHING BIOCHEMISTRY TO MEDICALS SIR,-Your editorial (Feb. 23, p. 297) touches on a problem faced by biochemists in medical schools everywhere. Our students and our clinical colleagues protest that biochemists teach useless facts and that a more relevant course is needed. Your editorial suggests that clinicians should help to plan the biochemistry course, assist in teaching it, and see it progress in parallel with clinical work. I wish to draw the attention of your readers to a course taught to medicals at McGill University, 1,2 in which a clinical problem is first presented with the help of a clinical colleague, and the biochemistry necessary to understand the case is subsequently taught by the biochemists. This approach arouses the interests of the student physicians and ensures that the biochemistry is relevant. This approach has been further developed in the teaching of biochemistry at the Medical College of Ohio,3 where a team of instructors is attached to each class of medical students throughout the 3-year programme at the college. The biochemists are now beginning to go on clinical rounds with 3rd-year students in their clerkships in medicine to provide complete integration of biochemistry with the rest of the basic science and clinical instruction. Department of Biochemistry, Medical College of Ohio, Ohio 43614, U.S.A.
Toledo,
MURRAY SAFFRAN.
".
less than 0-5 g. ampicillin per ml., resistant strains by There is some geographical more than 2 g. per ml. variation in the prevalence of resistance of H. infiuenzae to In the Stafford/Wolverhampton area the ampicillin. incidence of resistant strains was appreciable, whereas no resistant strains were found in the Coventry/Birmingham area. It is of interest that one of the cases of ampicillinresistant H. influenzz meningitis occurred in Wolver-
hampton. 1.
Williams, J. D., Andrews, J. Br. med. J. 1974, i, 134.
TREATMENT OF PARACETAMOL POISONING SIR,-We were interested to read the exciting new approach reported by Dr Prescott and his colleagues (April 6, p. 588) to the management, using intravenous cysteamine, of paracetamol-induced liver damage, but we do wish to sound a note of caution. In our experience plasma-paracetamol levels obtained shortly after ingestion are not always a good guide to the severity of ensuing liver damage. We have seen 6 patients in King’s College Hospital over the past year with plasma-paracetamol levels similar to those present in the patients treated by Dr Prescott and his colleagues (including 2 with levels of over 400 (lg. per ml. at 12 hours after ingestion) in whom mild or moderate liver damage developed only without evidence of encephalopathy. In contrast,we saw 30 patients with plasma-paracetamol levels of between 150 and 200 ug. per ml. within 12 hours of ingestion, and in 4 of those severe liver damage with encephalopathy developed. Dr Prescott and his associates point out that it may be difficult to extrapolate the plasma level to a value at 4 hours after ingestion, since the time of the overdose is often not accurately known, and we have also found that the disappearance-rate of the drug from the plasma may be 1. 2. 3.
Saffran, M. J. med. Educ. 1971, 46, 1081. Rubinstein, D. ibid. 1972, 47, 198. Saffran, M. Bull. Biochem. Educ. 1973, 1, no. 3.
865
4 hours. We agree that for
oc-tocopherol is a natural antioxidant which could be incorporated into paracetamol pharmaceutical preparations and may offer protection in the overdose situation. At the concentration of cx-tocopherol used here no toxic effects
given
would result.
initially prolonged by continued paracetamol absorption, and this too will influence estimation of the drug level at cysteamine to be effective it should be early as possible after the overdose, but this is when the prediction of the degree of ensuing liver damage is most difficult, and many patients may therefore be subjected unnecessarily to the unpleasant toxic side-effects of the drug. This is surely an ideal situation in which to conduct a prospective controlled trial. This we propose as
do in collaboration with our Poisons Unit and we would happy to send details to any physicians and casualty departments who would be interested in collaborating.
J. KELLEHER Departments of Medicine and Pathology, St. James’s (University) Hospital, Leeds LS9 7TF.
B. E. WALKER M. F. DIXON M. S. LOSOWSKY.
to
be
B. G. GAZZARD I. M. MURRAY-LYON M. DAVIS R. P. H. THOMPSON ROGER WILLIAMS.
Liver Unit,
King’s College Hospital, London SE5 8RX.
Poisons Unit, Guy’s Hospital,
R. GOULDING.
London SE1.
SIR,-Dr Prescott and his colleagues showed protection against paracetamol hepatotoxicity with intravenous cysteamine up to 10 hours after ingestion. Dr McLean (April 20, p. 729) administered methionine simultaneously with paracetamol to phenobarbitone-pretreated rats and greatly reduced the expected mortality. We have examined the protective effect of oc-tocopherol in rats given large doses of paracetamol. Groups of untreated rats were given paracetamol suspension at various dose levels with or without
INTRANASAL ADMINISTRATION OF LUTEINISING-HORMONE RELEASING FACTOR SIR,-Solbach and Wiegelmann reported that intranasal luteinising-hormone releasing factor (L.H.R.F.) was as effective as an intravenous injection of L.H.R.F. in eliciting L.H. release. Their report has since been fully confirmed by other workers. 2-5 However, Mortimer et al.said that the effect of L.H.R.F. administered intranasally is less certain than when given intravenously. We have to comment on this statement since it might tend to limit the future use of intranasally administered L.H.R.F. Firstly, the conclusions of Mortimer et al. are based on results obtained in only two subjects. Secondly, their report states that the intravenous, intramuscular, and subcutaneous routes, in contrast with the intranasal route, are equally effective in eliciting an L.H. release. However, in one case the L.H. response to intranasal L.H.R.F. was as strong as that evoked by subcutaneous injection in two of the three men investigated. In the second of the two men who received intranasal L.H.R.F. the L.H. response was slightly weaker. Thirdly, the method of the intranasal application used by Mortimer et al. seems both time-consuming and inconvenient. A simple and reliable method for intranasal administration of oxytocinand 1-deamino-8D-arginine vasopressin (D.D.A.V.P.)has long been available. This method-i.e., dissolution of the substance in a small volume (0-2 ml.) of fluid and letting the patient blow it into one of the nasal cavities via a short plastic catheterhas been successfully used for intranasal administration of L.H.R.F.3-5 Department of Obstetrics and Gynæcology, Genera] Hospital, University of Lund, S-21401 Malmö, Sweden.
GERHARD GENNSER PERCY LIEDHOLM.
T.R.H. IN DEPRESSION Mean±S.E.M. for
serum A.S.A.T.
and
A.L.A.T.
in groups of without vitamin E
(24 hours)
12 rats given oral doses of paracetamol with (30% by weight of paracetamol).
or
At all dose levels (see accompanying table) there is a striking reduction in the mean enzyme level for the groups given a-tocopherol which is significant except at the very large dose of 4 g. per kg. which could be equated with an intake of 480 tablets (0-5 g.) in a 70 kg. man. The mechanism of the protective action of cysteamine, methionine, or cx-tocopherol is not clear. All may nonspecifically scavenge the toxic metabolite thought to be responsible for the ensuing necrosis in a manner similar to that for glutathione. Both cysteamine and methionine protection could be related to glutathione metabolism, but this does not explain the protection offered by a-tocopherol. It is possible that x-tocopherol may protect at a later stage than either cysteamine or methionine and by a different mechanism by preventing or retarding autoxidation of essential cell-membrane polyunsaturated lipids, though this mechanism may be contentious.
SIR,-Dr Drayson (Feb. 23, p. 312) and Dr Dimitrikoudi and others (March 16, p. 456) have reported negative results in six depressed patients given thyrotrophin-releasing hormone (T.R.H.). We should like to add four more cases. Our patients
were women, aged 35 to 70 years, who had depression of endogenous type. Three had histories of bipolar courses and one a history of a monopolar course. At the time of T.R.H. administration they were under treatment with tricyclic antidepressants (three cases) or lithium (one case). T.R.H. was given as a slow intravenous injection at 8 A.M., while
severe
1. 2.
3.
4. 5. 6. 7. 8.
Solbach, H. G., Wiegelmann, W. Lancet, 1973, i, 1259. London, D. R., Butt, W. R., Lynch, S. S., Marshall, J. C., Owusu, S., Robinson, W. R., Stephenson, J. M. J. clin. Endocr. Metab. 1973, 37, 829. Gennser, G., Liedholm, P., Thorell, J., Mulder, J. Int. Res. Comm. Syst. 1973 (73-10), 8-9-4. Jeppsson, S., Kullander, S., Rannevik, G., Thorell, J. Br. med. J. 1973, iv, 231. Fink, G., Gennser, G., Liedholm, P., Thorell, J., Mulder, J. J. Endocr. (in the press). Mortimer, C. H., Besser, G. M., Hook, J., McNeilly, A. S. Clin. Endocr. 1974, 3, 19. Borglin, N. E. Acta obstet. gynec. scand. 1962, 41, 237. Andersson, K-E., Arner, B. Acta med. scand. 1972, 192, 21.