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DRUG REACTIONS
1227 ness
may be mediated through its release of lipoprotein
lipase. 10 In a study of 14 male surgical patients, Mr. Negus and his colleagues confirmed an earlier observation 10 that intravenous heparin (10 l.u. per kg.) produces a significant fall in the high level of platelet stickiness reached on the second postoperative day. This fall is evident ten minutes after the injection. An hour after the injection, platelet stickiness has returned almost to its pre-heparin level, and it is still at this level after a further hour. As platelet stickiness falls after heparin, so lipoprotein-lipase activity rises, returning to pre-heparin levels by one hour after the injection and remaining at this level after a further hour. These observations, though interesting, could not be used as the basis of a prophylactic regimen covering the period of operations, since to maintain satisfactory levels of platelet stickiness and lipoprotein-lipase activity the dose of 10 l.u. of heparin per kg. would have to be repeated every half hour (thus a 70 kg. patient would need 8400 units of heparin over six hours). But Mr. Negus and his associates repeated their observations on the effect of heparin on platelet stickiness in another 8 male surgical patients, this time using only 1 I.U. per kg., and they found that this muchreduced dose has as great an effect. With this small dose, a clinical trial of heparin given prophylactically before, during, and after operation becomes feasible. Although the main object must be to determine whether heparin at this dosage reduces the incidence of postoperative venous thrombosis, it would also be interesting to find out whether it affects lipoproteinlipase activity as well as platelet stickiness.
DRUG REACTIONS
DESPITE the generally good safety record of modern drugs, there are incontrovertible reasons why prediction of safety can never be entirely secure; and a symposium1 in London last month took another look at drug reactions and all the difficulties that surround them. Animal tests can be expected to demonstrate direct dose-related effects, but the rodents used are usually, and other species are sometimes, pure-bred strains which respond uniformly. Man, by contrast, is a mongrel. No animal species, not even among primates, metabolises drugs by routes and at rates similar " enough to average man " to serve as a consistently reliable indicator. The difficulty is enormously compounded by individual differences in human response as a result of genetic and environmental causes, physiological status, disease, drug interactions, and immunological reactions.2 Hence, there is ultimately no substitute for experience in man. The first tests conducted in man are in considerable depth and, if preliminary results are favourable, the emphasis shifts increasingly from depth to breadth. By the time a new compound is marketed, however, the total experience is unlikely to amount to more than a few hundred patients. More often than not they 1. Held at the Royal College of Physicians of London and organised by the Association of the Medical Advisers in the Pharmaceutical Industry. The proceedings will shortly be published. 2. Drug Responses in Man (edited by G. E. W. Wolstenholme and R. Porter). London, 1967.
have mostly been observed under the rather artificial conditions of controlled trials predominantly in hospitals and, although adverse effects are always recorded, comparative efficacy is the centre of interest. An adverse effect that occurs often enough will be picked up in the course of clinical trials, but the converse of the old adage that " common things most commonly occur " is equally true. For example, it would be necessary to study nearly 4000 patients to have a 95% chance of observing an event which happens once in 1000 cases.3 Obviously far more patients would have to be treated to establish the incidence reasonably accurately, and to indicate whether the reaction is associated with any particular set of circumstances. When other things are reasonably equal, trivial but common side-effects may determine the prescriber’s choice between alternative preparations, but even though a minor incident may presage something worse, public safety is probably best served by concentrating on rare but serious reactions.4 In order to provide the necessary numerator// denominator type of information, a number of intensive drug-monitoring schemes have been set up. Most of these are conducted in a hospital setting,5 but since about 90% of all drugs prescribed in the United Kingdom are taken outside hospital, there are cogent reasons for studying drug usage and its effects in the community.6 For some years past Wade and his colleagues have taken advantage of the favourable conditions in Northern Ireland, where all prescriptions are recorded by computer. Opportunities are good, therefore, for studying the incidence of adverse reactions, immediate and delayed, and interactions between drugs under local practice conditions. But uncritical extrapolation is unwarranted, since, as Wade and his associates are the first to emphasise, there are considerable national and international variations; and that is one reason why the increasing international collaboration on adverse reactions is so desirable. Another is that in the United Kingdom only about 10% of all adverse reactions are reported, and the situation is much the same in Scandinavia and elsewhere. It is true that serious or unexpected reactions are more likely to be notified, but motivation of the reporting doctor is an important unresolved problem, which is closely related to the question of feedbacksuch as is provided in Britain by the valuable Adverse Drug Reaction Bulletin, which is now issued periodically with Drug and Therapeutics Bulletin. Despite the difficulties and limitations, very profitable work on the epidemiology and clinical pharmacology of adverse reactions has been done in the past few years. An outstanding example was the discovery that an extra 3500 deaths among asthmatic sufferers had occurred in the space of about six years, largely because of the injudicious use of bronchodilator aerosols.7.s Unfortunately, the resources devoted to this type of research are quite inadequate to cope with the many problems thrown up by national and local monitoring schemes. 3. Wendel, H. A. Pharmac. Clin. 1969, 2, 58. 4. Doll, W. R. S. Br. med. J. 1969, ii, 69. 5. Wld Hlth Org. tech. Rep. Ser. 1969, no. 425. 6. Wade, O. L. Br. med. Bull. 1970, 26, 240. 7. Inman, W. H. W. Proc. R. Soc. Med. 1970, 63, 1302. 8. Inman, W. H. W., Adelstein, A. M. Lancet, 1969, ii, 279.
may be mediated through its release of lipoprotein
lipase. 10 In a study of 14 male surgical patients, Mr. Negus and his colleagues confirmed an earlier observation 10 that intravenous heparin (10 l.u. per kg.) produces a significant fall in the high level of platelet stickiness reached on the second postoperative day. This fall is evident ten minutes after the injection. An hour after the injection, platelet stickiness has returned almost to its pre-heparin level, and it is still at this level after a further hour. As platelet stickiness falls after heparin, so lipoprotein-lipase activity rises, returning to pre-heparin levels by one hour after the injection and remaining at this level after a further hour. These observations, though interesting, could not be used as the basis of a prophylactic regimen covering the period of operations, since to maintain satisfactory levels of platelet stickiness and lipoprotein-lipase activity the dose of 10 l.u. of heparin per kg. would have to be repeated every half hour (thus a 70 kg. patient would need 8400 units of heparin over six hours). But Mr. Negus and his associates repeated their observations on the effect of heparin on platelet stickiness in another 8 male surgical patients, this time using only 1 I.U. per kg., and they found that this muchreduced dose has as great an effect. With this small dose, a clinical trial of heparin given prophylactically before, during, and after operation becomes feasible. Although the main object must be to determine whether heparin at this dosage reduces the incidence of postoperative venous thrombosis, it would also be interesting to find out whether it affects lipoproteinlipase activity as well as platelet stickiness.
DRUG REACTIONS
DESPITE the generally good safety record of modern drugs, there are incontrovertible reasons why prediction of safety can never be entirely secure; and a symposium1 in London last month took another look at drug reactions and all the difficulties that surround them. Animal tests can be expected to demonstrate direct dose-related effects, but the rodents used are usually, and other species are sometimes, pure-bred strains which respond uniformly. Man, by contrast, is a mongrel. No animal species, not even among primates, metabolises drugs by routes and at rates similar " enough to average man " to serve as a consistently reliable indicator. The difficulty is enormously compounded by individual differences in human response as a result of genetic and environmental causes, physiological status, disease, drug interactions, and immunological reactions.2 Hence, there is ultimately no substitute for experience in man. The first tests conducted in man are in considerable depth and, if preliminary results are favourable, the emphasis shifts increasingly from depth to breadth. By the time a new compound is marketed, however, the total experience is unlikely to amount to more than a few hundred patients. More often than not they 1. Held at the Royal College of Physicians of London and organised by the Association of the Medical Advisers in the Pharmaceutical Industry. The proceedings will shortly be published. 2. Drug Responses in Man (edited by G. E. W. Wolstenholme and R. Porter). London, 1967.
have mostly been observed under the rather artificial conditions of controlled trials predominantly in hospitals and, although adverse effects are always recorded, comparative efficacy is the centre of interest. An adverse effect that occurs often enough will be picked up in the course of clinical trials, but the converse of the old adage that " common things most commonly occur " is equally true. For example, it would be necessary to study nearly 4000 patients to have a 95% chance of observing an event which happens once in 1000 cases.3 Obviously far more patients would have to be treated to establish the incidence reasonably accurately, and to indicate whether the reaction is associated with any particular set of circumstances. When other things are reasonably equal, trivial but common side-effects may determine the prescriber’s choice between alternative preparations, but even though a minor incident may presage something worse, public safety is probably best served by concentrating on rare but serious reactions.4 In order to provide the necessary numerator// denominator type of information, a number of intensive drug-monitoring schemes have been set up. Most of these are conducted in a hospital setting,5 but since about 90% of all drugs prescribed in the United Kingdom are taken outside hospital, there are cogent reasons for studying drug usage and its effects in the community.6 For some years past Wade and his colleagues have taken advantage of the favourable conditions in Northern Ireland, where all prescriptions are recorded by computer. Opportunities are good, therefore, for studying the incidence of adverse reactions, immediate and delayed, and interactions between drugs under local practice conditions. But uncritical extrapolation is unwarranted, since, as Wade and his associates are the first to emphasise, there are considerable national and international variations; and that is one reason why the increasing international collaboration on adverse reactions is so desirable. Another is that in the United Kingdom only about 10% of all adverse reactions are reported, and the situation is much the same in Scandinavia and elsewhere. It is true that serious or unexpected reactions are more likely to be notified, but motivation of the reporting doctor is an important unresolved problem, which is closely related to the question of feedbacksuch as is provided in Britain by the valuable Adverse Drug Reaction Bulletin, which is now issued periodically with Drug and Therapeutics Bulletin. Despite the difficulties and limitations, very profitable work on the epidemiology and clinical pharmacology of adverse reactions has been done in the past few years. An outstanding example was the discovery that an extra 3500 deaths among asthmatic sufferers had occurred in the space of about six years, largely because of the injudicious use of bronchodilator aerosols.7.s Unfortunately, the resources devoted to this type of research are quite inadequate to cope with the many problems thrown up by national and local monitoring schemes. 3. Wendel, H. A. Pharmac. Clin. 1969, 2, 58. 4. Doll, W. R. S. Br. med. J. 1969, ii, 69. 5. Wld Hlth Org. tech. Rep. Ser. 1969, no. 425. 6. Wade, O. L. Br. med. Bull. 1970, 26, 240. 7. Inman, W. H. W. Proc. R. Soc. Med. 1970, 63, 1302. 8. Inman, W. H. W., Adelstein, A. M. Lancet, 1969, ii, 279.