- Email: [email protected]
ANALGESIC POISONING
1210
penicillamine therapy
in rheumatoid arthritis is the
high lupus erythematosus (SLE)-like syndrome in which a membranous nephropathy of the immune complex type is a prominent feature.7 Thus the paradox-on the one hand, immunosuppression, on the other, transformation to a more vigorous immune-mediated disease. Can the same drug be both immunosuppressive and immunopotentiating? One approach to this question, examination of the effects of penicillamine on lymphocyte and macrophage function in vitro, was discussed at a workshop which reviewed the therapeutic role of penicillamine and explored its mode of action.8 incidence of side-effects including
a
and Ziff have shown that lymphocytes preincubated with a mixture of penicillamine and copper salts in serum-free medium, became hyporesponsive to stimulation with both T-cell and B-cell mitogens, although incubation with either penicillamine or copper alone was without effect. 8,9 Lipsky has also shown, by exposing preparations of monocytes, B-cells, or T-cells individually to the penicillamine/copper mixture, that the effect was due to a specific inhibition of helper-T-cell function.1O Since the concentrations of penicillamine and copper in treated patients often exceed the concentrations used in the studies (12-55 Ilg/ml and 2 pg/ml, respectively) it is tempting to conclude that these in-vitro observations reflect one of the mechanisms leading to immunosuppressive effects in vivo. However, a major drawback is the use of serum-free medium in the preincubation step. This may be one reason why Room and Maini" obtained rather different results. They cultured peripheral blood mononuclear cells from normal subjects or patients with rheumatoid arthritis with different concentrations of D-penicillamine for 72 h in medium supplemented with 10% human serum. A suppressive effect of the drug on the mitogenic response to phytohaemagglutinin was consistently observed with both normal and rheumatoid cells at a penicillamine concentration of 100 g/ml, but at the lower concentration of 10 1.4g/ml inhibitory effects were almost confined to the normal cells. When the same studies were done with purified T-cells, lowdose penicillamine did not affect the mitogenic response of normal cells while in the rheumatoids some cultures showed penicillamine-induced enhancement of cell proliferation. These results are reminiscent of those obtained by Binderup and colleagues who, in penicillamine-treated rats with adjuvant arthritis, found enhanced lymphocyte proliferative responses to the mitogen concanavalin A and increasec’ phagocytic activity of peritoneal and splenic
Thus penicillamine, in different circumstances, can either suppress or enhance the proliferation of lymphocytes; and Room and Maini"have pointed to considerable individual variation in the effect of the drug on the response of rheumatoid lymphocytes. In view of the complexity of the feedback network of immunological interactions determining immune reactivity, these results are not surprising, but many more detailed studies of the effects on rheumatoid cells in vitro and in vivo will be needed before we can say anything definite about the relevance of these observations to the therapeutic effects of penicillamine or to the drug-induced SLE-like syndrome.
Lipsky
macrophages.12,133 Harpey JR Lupus like syndromes induced by drugs. Ann Allergy 1974, 33: 256. 8. Modulation of autoimmunity and disease: The penicillamine experience. Edited by R. N. Maini and H. Berry. Eastbourne and New York Praeger. Pp. 310. £12 9 Lipsky PE, Ziff M. The effect of D-penicillamine on mitogen-induced human lymphocyte proliferation. Synergistic inhibition by D-penicillamine and copper salts J Immunol 1978; 120: 1006-13 10. Lipsky PE. The effect of D-pecicillamine on human helper T cell function. In: Maini RN, Berry H, eds. Modulation of autoimmunity and disease. The penicillamine experience. Eastbourne and New York. Praeger, 1981 79-88 11. Room G, Maini RN The in vitro effect of D-penicillamine on mitogen-induced responses of human mononuclear cell subpopulations In. Maini RN, Berry H, eds. Modulation of autoimmunity and disease. The penicillamine experience. Eastbourne and New York: Praeger, 1981 89-96 12. Arrigoni-Martelli E, Binderup L. Enhancement of macrophage phagocytic activity induced by D-penicillamine in vitro and in vivo In: Maimi RN, Berry H, eds Modulation of autoimmunity and disease. The penicillamine experience. Eastbourne and New York. Praeger, 1981: 104-10 13. Binderup L, Braram E, Arrigoni-Martelli E. Immunological effects of D-penicillamine during experimentally induced inflammation in rats Scand J Immunol 1980 12: 239-47 7.
ANALGESIC POISONING ALTHOUGH drug overdose is one of the commonest reasons for admission to hospital, few centres are engaged in research into its epidemiology and management. In the U.K., the National Poisons Information Service has produced papers about particular drugs but in almost all these projects the reporting of cases was entirely voluntary. The first issue ofa new journal, Human Toxicology, is graced by the results ofaa multicentre prospective study of analgesic poisoning, coordinated from the Guy’s Hospital Poisons Unit.2 This paper is of interest not only because it provides a wider view of the problems of analgesic overdosage than can be obtained from a single-centre study but also because it shows that this sort of reporting system is applicable to the monitoring of other aspects of poisoning. The study was undertaken in five hospitals and comprised 878 consecutive cases of analgesic poisoning treated in the accident and emergency departments. Hospital staff completed questionnaires on all patients and the results were processed by computer. The commonest drugs taken were
aspirin (45%), paracetamol (acetaminophen) (29%), and ’Distalgesic’ (17%), which contains both dextropropoxyphene and paracetamol. Almost half the patients took more than one drug, the commonest being alcohol and benzodiazepines. One-third of the analgesics were known to have been extracted from child-resistant containers or unitdose packages and half the drugs were known to have been purchased without prescription over the counter. Soluble preparations, mainly containing aspirin, accounted for only 10% of the cases. Most of the patients presented within four hours of the overdose and in very few cases did new symptoms develop after arrival in hospital. The poisoning was not usually severe. In those taking aspirin the plasma salicylate levels were often within the therapeutic range and fewer than 1 in 10 patients ingesting paracetamol had biochemical evidence of liver damage (clinical features of hepatic necrosis were observed in only 4). Methionine by mouth was the most commonly used antidote and its administration caused no problems. Both coma due to the dextropropoxyphene component of distalgesic and liver damage due to its paracetamol component were uncommon. 1. Volans GN, Mitchell GM, Proudfoot AT, Shanks RG, Woodcock JA. National Poisons Information Services: Report and comment 1980. Br Med J 1981; 282: 1613-15. 2. The National Poisons Information Service Monitoring Group. Analgesic poisoning A multi-centre, prospective study. Hum Toxicol 1981; 1: 7-23. Human Toxicology (editor, Prof. R. Goulding) will be published quarterly by Macmillan Publishers Ltd (subscription dept, Brunel Road, Basingstoke, Hampshire RG21 2XS, U.K.), annual subscription £40, U.K. and Eire: $U.S. 95, U S A. and Canada; £45 elsewhere.
1211
Comparison of relative toxicities lends some support for the view that aspirin is more dangerous than paracetamol when taken in overdose3-7 aspirin deaths compared with 1 paracetamol and 1 distalgesic. 5 of the aspirin deaths occurred shortly after the patient’s arrival in hospital and the patient who died after a paracetamol overdose was admitted too late for antidotal treatment. There was no evidence that the treatment of these patients was inadequate. The treatment of paracetamol poisoning with oral antidotes is effective and far less troublesome than the forced alkaline diuresis which is used to increase salicylate excretion in severe
aspirin poisoning.
The management of acute poisoning is based on the principles of intensive supportive care backed by specific treatment when necessary. However, there remain several unresolved questions which might be answered readily by this type of multicentre approach. Examples are the evaluation of activated charcoal as an adsorbent of drugs taken by mouth, physostigmine in anticholinergic drug poisoning, and haemoperfusion in severe barbiturate poisoning. Given the necessary resources these centres might also provide the framework for a continuing inquiry into the
epidemiology of poisoning.
RELATIVE OR ATTRIBUTABLE RISK? MUCH of medical research is directed towards the aetiology of disease, and in particular the increased risk of a particular disease arising if a given risk factor is present. This risk can be calculated directly in cohort studies, but a statistical solution must be sought in case-control studies.4 This is the calculation of approximate relative risk, odds ratio, or cross ratio.5 However, crude risks are often unsatisfactory because two or more of the variables are associated and they cannot, therefore, be examined independently. This confounding between variables can be adjusted for by means of a linear logit model,6 and when large numbers of data are to be considered, a computer helps greatly. Although (approximate) relative risk and the odds ratio have enjoyed widespread use as measures of association in research, neither takes into account the actual number of cases of disease which might be related to a given risk factor. If the disease in question has several risk factors varying both in their relative risks and in their prevalences, it is not sufficient to compare the epidemiological importance of these factors in terms only of relative risk. A measure of the effect of a risk factor on the causation of disease in the whole population, rather than in an individual, is attributable risk. Although this may be arrived at by several statistical means,7 Levin’s aetiological fraction is thought to be the most useful.’ The interpretation of these two measures of risk is different, and neither is a substitute for the other. The identification of a particular risk factor with a high relative risk often yields important information about the mechanism 3 Editorial. Aspirin or paracetamol? Lancet 1981; ii: 287-89. P. Statistical methods in medical research. Oxford: Blackwell Scientific Publications, 1971: 426. 5 Cornfield J. A method of estimating comparative rates from clinical data. J Natl Cancer Inst 1951, 11: 1269-75. 5 Armitage P. Statistical methods in medical research. Oxford Blackwell Scientific Publications, 1971: 380. Levin ML The occurrence of lung cancer in man. Acta Un Int Contra Cancrum 1953; 19: 531-41.
4 Armitage
of disease. If, however, because of low prevalence in the population, the factor had a low attributable risk, it would be ofless interest to those planning preventive measures. This is illustrated by lung cancers. Exposure to some industrial carcinogens greatly increases the relative risk of tumours arising in certain workers but there are few such workers so the attributable risk is small. Smoking, by contrast, gives a moderately increased relative risk of lung cancer, but is very prevalent in the population as a whole. The attributable risk from smoking is thus very high and carries an important message for preventive strategies. A fruitful area for perinatal epidemiologists has been the computation and analysis of the many risk factors associated
birth of small-for-dates infants. With the in the prospects for the low-birth-weight preterm infant as a result of better postnatal management, the importance of growth retardation as a factor in quality of survival has been highlighted. Several workers have identified factors associated with small-for-dates pregnancies and have calculated the relative risks associated with them. 8-11 By multiplying together significantly associated relative risks, attempts have also been made to predict the delivery of low-birth-weight infants at term.’ Such factors included previous obstetric history, the presence of hypertension with or without proteinuria, smoking, social class, and maternal weight and height. Although there have been pointers to the distribution of these factors in causing small-for-dates infants,9 their relative contributions have only lately been calculated precisely for a population in terms of attributable risk. 11 Ounsted and co-workers in Oxford found, in common with previous workers, that a history of small babies and hypertension with proteinuria were factors conveying a high risk of growth retardation in the next infant. Smoking, poor weight gain, maternal height and weight, and hypertension without proteinuria were all associated with significant but much smaller relative risks. When the same factors were examined to determine attributable risk a different picture was seen. Although a history of small babies had an attributable risk of 56% and remained dominant, factors such as smoking (39%), hypertension without proteinuria (18%), and maternal height and weight (15%, 13%) came to the fore. Ounsted and her colleagues suggest that if smoking, hypertension, and pre-eclampsia could be eliminated the number of small-for-dates infants could be halved. The adverse effects of smoking in pregnancy are again well delineated by this study. with
the
improvement
Although attributable risk seems a useful means of estimating the effect of modifying risk factor exposure, attributable risk should only be equated with the expected change in disease frequency if the factor is indeed a causal agent, rather than merely associated statistically with the disease. Even if a causal link can be established, the attributable risk may still not represent the actual change in incidence which would be seen if the factor were removed, since factors are rarely fully independent. Nevertheless, a
K, Knight J, eds. Size at birth (Ciba Found Symp no. 27). Amsterdam: Elsevier, 1974: 379-82 9. Dawes G. In. Elliott K, Knight J, eds. Size at birth (Ciba Found Symp no. 27). Amsterdam: Elsevier, 1974: 393 10. Fedrick J, Adelstein P Antenatal identification of women at increased risk of being delivered of a low birth weight infant at term Br J Obstet Gynaecol 1978; 85: 8-11 11. Scott A, Moar V, Ounsted M. The relative contributions of different maternal factors in small for gestational age pregnancies. Eur J Obstet Gynaecol Reprod Biol 1981; 12: 157-65. 8. Butler NR. In: Elliott
penicillamine therapy
in rheumatoid arthritis is the
high lupus erythematosus (SLE)-like syndrome in which a membranous nephropathy of the immune complex type is a prominent feature.7 Thus the paradox-on the one hand, immunosuppression, on the other, transformation to a more vigorous immune-mediated disease. Can the same drug be both immunosuppressive and immunopotentiating? One approach to this question, examination of the effects of penicillamine on lymphocyte and macrophage function in vitro, was discussed at a workshop which reviewed the therapeutic role of penicillamine and explored its mode of action.8 incidence of side-effects including
a
and Ziff have shown that lymphocytes preincubated with a mixture of penicillamine and copper salts in serum-free medium, became hyporesponsive to stimulation with both T-cell and B-cell mitogens, although incubation with either penicillamine or copper alone was without effect. 8,9 Lipsky has also shown, by exposing preparations of monocytes, B-cells, or T-cells individually to the penicillamine/copper mixture, that the effect was due to a specific inhibition of helper-T-cell function.1O Since the concentrations of penicillamine and copper in treated patients often exceed the concentrations used in the studies (12-55 Ilg/ml and 2 pg/ml, respectively) it is tempting to conclude that these in-vitro observations reflect one of the mechanisms leading to immunosuppressive effects in vivo. However, a major drawback is the use of serum-free medium in the preincubation step. This may be one reason why Room and Maini" obtained rather different results. They cultured peripheral blood mononuclear cells from normal subjects or patients with rheumatoid arthritis with different concentrations of D-penicillamine for 72 h in medium supplemented with 10% human serum. A suppressive effect of the drug on the mitogenic response to phytohaemagglutinin was consistently observed with both normal and rheumatoid cells at a penicillamine concentration of 100 g/ml, but at the lower concentration of 10 1.4g/ml inhibitory effects were almost confined to the normal cells. When the same studies were done with purified T-cells, lowdose penicillamine did not affect the mitogenic response of normal cells while in the rheumatoids some cultures showed penicillamine-induced enhancement of cell proliferation. These results are reminiscent of those obtained by Binderup and colleagues who, in penicillamine-treated rats with adjuvant arthritis, found enhanced lymphocyte proliferative responses to the mitogen concanavalin A and increasec’ phagocytic activity of peritoneal and splenic
Thus penicillamine, in different circumstances, can either suppress or enhance the proliferation of lymphocytes; and Room and Maini"have pointed to considerable individual variation in the effect of the drug on the response of rheumatoid lymphocytes. In view of the complexity of the feedback network of immunological interactions determining immune reactivity, these results are not surprising, but many more detailed studies of the effects on rheumatoid cells in vitro and in vivo will be needed before we can say anything definite about the relevance of these observations to the therapeutic effects of penicillamine or to the drug-induced SLE-like syndrome.
Lipsky
macrophages.12,133 Harpey JR Lupus like syndromes induced by drugs. Ann Allergy 1974, 33: 256. 8. Modulation of autoimmunity and disease: The penicillamine experience. Edited by R. N. Maini and H. Berry. Eastbourne and New York Praeger. Pp. 310. £12 9 Lipsky PE, Ziff M. The effect of D-penicillamine on mitogen-induced human lymphocyte proliferation. Synergistic inhibition by D-penicillamine and copper salts J Immunol 1978; 120: 1006-13 10. Lipsky PE. The effect of D-pecicillamine on human helper T cell function. In: Maini RN, Berry H, eds. Modulation of autoimmunity and disease. The penicillamine experience. Eastbourne and New York. Praeger, 1981 79-88 11. Room G, Maini RN The in vitro effect of D-penicillamine on mitogen-induced responses of human mononuclear cell subpopulations In. Maini RN, Berry H, eds. Modulation of autoimmunity and disease. The penicillamine experience. Eastbourne and New York: Praeger, 1981 89-96 12. Arrigoni-Martelli E, Binderup L. Enhancement of macrophage phagocytic activity induced by D-penicillamine in vitro and in vivo In: Maimi RN, Berry H, eds Modulation of autoimmunity and disease. The penicillamine experience. Eastbourne and New York. Praeger, 1981: 104-10 13. Binderup L, Braram E, Arrigoni-Martelli E. Immunological effects of D-penicillamine during experimentally induced inflammation in rats Scand J Immunol 1980 12: 239-47 7.
ANALGESIC POISONING ALTHOUGH drug overdose is one of the commonest reasons for admission to hospital, few centres are engaged in research into its epidemiology and management. In the U.K., the National Poisons Information Service has produced papers about particular drugs but in almost all these projects the reporting of cases was entirely voluntary. The first issue ofa new journal, Human Toxicology, is graced by the results ofaa multicentre prospective study of analgesic poisoning, coordinated from the Guy’s Hospital Poisons Unit.2 This paper is of interest not only because it provides a wider view of the problems of analgesic overdosage than can be obtained from a single-centre study but also because it shows that this sort of reporting system is applicable to the monitoring of other aspects of poisoning. The study was undertaken in five hospitals and comprised 878 consecutive cases of analgesic poisoning treated in the accident and emergency departments. Hospital staff completed questionnaires on all patients and the results were processed by computer. The commonest drugs taken were
aspirin (45%), paracetamol (acetaminophen) (29%), and ’Distalgesic’ (17%), which contains both dextropropoxyphene and paracetamol. Almost half the patients took more than one drug, the commonest being alcohol and benzodiazepines. One-third of the analgesics were known to have been extracted from child-resistant containers or unitdose packages and half the drugs were known to have been purchased without prescription over the counter. Soluble preparations, mainly containing aspirin, accounted for only 10% of the cases. Most of the patients presented within four hours of the overdose and in very few cases did new symptoms develop after arrival in hospital. The poisoning was not usually severe. In those taking aspirin the plasma salicylate levels were often within the therapeutic range and fewer than 1 in 10 patients ingesting paracetamol had biochemical evidence of liver damage (clinical features of hepatic necrosis were observed in only 4). Methionine by mouth was the most commonly used antidote and its administration caused no problems. Both coma due to the dextropropoxyphene component of distalgesic and liver damage due to its paracetamol component were uncommon. 1. Volans GN, Mitchell GM, Proudfoot AT, Shanks RG, Woodcock JA. National Poisons Information Services: Report and comment 1980. Br Med J 1981; 282: 1613-15. 2. The National Poisons Information Service Monitoring Group. Analgesic poisoning A multi-centre, prospective study. Hum Toxicol 1981; 1: 7-23. Human Toxicology (editor, Prof. R. Goulding) will be published quarterly by Macmillan Publishers Ltd (subscription dept, Brunel Road, Basingstoke, Hampshire RG21 2XS, U.K.), annual subscription £40, U.K. and Eire: $U.S. 95, U S A. and Canada; £45 elsewhere.
1211
Comparison of relative toxicities lends some support for the view that aspirin is more dangerous than paracetamol when taken in overdose3-7 aspirin deaths compared with 1 paracetamol and 1 distalgesic. 5 of the aspirin deaths occurred shortly after the patient’s arrival in hospital and the patient who died after a paracetamol overdose was admitted too late for antidotal treatment. There was no evidence that the treatment of these patients was inadequate. The treatment of paracetamol poisoning with oral antidotes is effective and far less troublesome than the forced alkaline diuresis which is used to increase salicylate excretion in severe
aspirin poisoning.
The management of acute poisoning is based on the principles of intensive supportive care backed by specific treatment when necessary. However, there remain several unresolved questions which might be answered readily by this type of multicentre approach. Examples are the evaluation of activated charcoal as an adsorbent of drugs taken by mouth, physostigmine in anticholinergic drug poisoning, and haemoperfusion in severe barbiturate poisoning. Given the necessary resources these centres might also provide the framework for a continuing inquiry into the
epidemiology of poisoning.
RELATIVE OR ATTRIBUTABLE RISK? MUCH of medical research is directed towards the aetiology of disease, and in particular the increased risk of a particular disease arising if a given risk factor is present. This risk can be calculated directly in cohort studies, but a statistical solution must be sought in case-control studies.4 This is the calculation of approximate relative risk, odds ratio, or cross ratio.5 However, crude risks are often unsatisfactory because two or more of the variables are associated and they cannot, therefore, be examined independently. This confounding between variables can be adjusted for by means of a linear logit model,6 and when large numbers of data are to be considered, a computer helps greatly. Although (approximate) relative risk and the odds ratio have enjoyed widespread use as measures of association in research, neither takes into account the actual number of cases of disease which might be related to a given risk factor. If the disease in question has several risk factors varying both in their relative risks and in their prevalences, it is not sufficient to compare the epidemiological importance of these factors in terms only of relative risk. A measure of the effect of a risk factor on the causation of disease in the whole population, rather than in an individual, is attributable risk. Although this may be arrived at by several statistical means,7 Levin’s aetiological fraction is thought to be the most useful.’ The interpretation of these two measures of risk is different, and neither is a substitute for the other. The identification of a particular risk factor with a high relative risk often yields important information about the mechanism 3 Editorial. Aspirin or paracetamol? Lancet 1981; ii: 287-89. P. Statistical methods in medical research. Oxford: Blackwell Scientific Publications, 1971: 426. 5 Cornfield J. A method of estimating comparative rates from clinical data. J Natl Cancer Inst 1951, 11: 1269-75. 5 Armitage P. Statistical methods in medical research. Oxford Blackwell Scientific Publications, 1971: 380. Levin ML The occurrence of lung cancer in man. Acta Un Int Contra Cancrum 1953; 19: 531-41.
4 Armitage
of disease. If, however, because of low prevalence in the population, the factor had a low attributable risk, it would be ofless interest to those planning preventive measures. This is illustrated by lung cancers. Exposure to some industrial carcinogens greatly increases the relative risk of tumours arising in certain workers but there are few such workers so the attributable risk is small. Smoking, by contrast, gives a moderately increased relative risk of lung cancer, but is very prevalent in the population as a whole. The attributable risk from smoking is thus very high and carries an important message for preventive strategies. A fruitful area for perinatal epidemiologists has been the computation and analysis of the many risk factors associated
birth of small-for-dates infants. With the in the prospects for the low-birth-weight preterm infant as a result of better postnatal management, the importance of growth retardation as a factor in quality of survival has been highlighted. Several workers have identified factors associated with small-for-dates pregnancies and have calculated the relative risks associated with them. 8-11 By multiplying together significantly associated relative risks, attempts have also been made to predict the delivery of low-birth-weight infants at term.’ Such factors included previous obstetric history, the presence of hypertension with or without proteinuria, smoking, social class, and maternal weight and height. Although there have been pointers to the distribution of these factors in causing small-for-dates infants,9 their relative contributions have only lately been calculated precisely for a population in terms of attributable risk. 11 Ounsted and co-workers in Oxford found, in common with previous workers, that a history of small babies and hypertension with proteinuria were factors conveying a high risk of growth retardation in the next infant. Smoking, poor weight gain, maternal height and weight, and hypertension without proteinuria were all associated with significant but much smaller relative risks. When the same factors were examined to determine attributable risk a different picture was seen. Although a history of small babies had an attributable risk of 56% and remained dominant, factors such as smoking (39%), hypertension without proteinuria (18%), and maternal height and weight (15%, 13%) came to the fore. Ounsted and her colleagues suggest that if smoking, hypertension, and pre-eclampsia could be eliminated the number of small-for-dates infants could be halved. The adverse effects of smoking in pregnancy are again well delineated by this study. with
the
improvement
Although attributable risk seems a useful means of estimating the effect of modifying risk factor exposure, attributable risk should only be equated with the expected change in disease frequency if the factor is indeed a causal agent, rather than merely associated statistically with the disease. Even if a causal link can be established, the attributable risk may still not represent the actual change in incidence which would be seen if the factor were removed, since factors are rarely fully independent. Nevertheless, a
K, Knight J, eds. Size at birth (Ciba Found Symp no. 27). Amsterdam: Elsevier, 1974: 379-82 9. Dawes G. In. Elliott K, Knight J, eds. Size at birth (Ciba Found Symp no. 27). Amsterdam: Elsevier, 1974: 393 10. Fedrick J, Adelstein P Antenatal identification of women at increased risk of being delivered of a low birth weight infant at term Br J Obstet Gynaecol 1978; 85: 8-11 11. Scott A, Moar V, Ounsted M. The relative contributions of different maternal factors in small for gestational age pregnancies. Eur J Obstet Gynaecol Reprod Biol 1981; 12: 157-65. 8. Butler NR. In: Elliott