- Email: [email protected]
FENFLURAMINE OVERDOSAGE
1289
urgent consideration and the drug
was
very
quickly
released, as the manufacturer had requested, for clinical trials. We understand that this acceptably pure form of L-dopa is now being made in increasing quantities by Roche Products Ltd. in a new plant in Switzerland. This preparation is at present available in Britain in quantities sufficient only for the M.R.C. trials which are under way in five centres. The committee has been aware for some time, however, that other preparations of L-dopa, mainly in the form of a laboratory reagent, have been available in considerable quantities and have been widely used by a number of doctors. The committee has met the distributors of these preparations and has tried to encourage the submission of the necessary data. Despite the committee’s efforts, however, adequate information has not yet been received and the committee has therefore been unable to satisfy itself as to the quality and safety of these materials. The committee wishes to make it clear that it has no intention of interfering with the right of individual doctors to prescribe for their patients whatever appears to them right and desirable. It emphasises, however, that it has been unable to assess the quality and safety of any preparation of L-dopa, other than. that in use in the M.R.C. trials, and doctors who wish to use these other materials must do so entirely on their own responsibility. Finally, the committee says it is impressed by the evidence of the value of L-dopa in the treatment of some forms of parkinsonism and is doing all in its power to ensure that the supply of L-dopa in a safe and satisfactory form is encouraged as
rapidly as possible.
and
to
arrange the distribution of leaflets. The official
opening of the campaign by the Lord Mayor was followed by a meeting of representatives of the Press, city business houses, and manufacturers of noise measuring and control equipment. A brief questionary was sent to city rate-payers asking how much annoyance was caused by noise, the source of that noise, and what might be done about it. Only about 8% of the questionaries were returned, because, the report suggests, most city rate-payers are unworried by noise or resigned to it. The returned questionaries made 2002 complaints of noise, both within offices and outside, and nearly half of them concerned traffic. A similar finding was reported by the Wilson committee3 and supported by objective measurements of noise in a wider survey of the central London boroughs. The report on the city campaign mentions building sites, street repairs, and aircraft as other important external sources of noice. Within the buildings, telephones and office machinery caused the most complaints. Many of the noises which caused annoyance could be reduced or eliminated if those concerned were of the problem and if the means were given to solve it. Difficulties were experienced in the operation of the Noise Abatement Act; and the report points out that the law on noise concerns not only public-health departments but also other departments of central and local government and the public themselves. The Noise Abatement Society has set out4 the provisions of the existing law in a clear way which will help the authorities make more effective use of their powers of noise control. The importance of planning in eliminating and diminishing environmental noise in London5 is also emphasised in the report. aware
LONDON NOISES
THE noise of a modern city troubles many people: it may cause emotional and psychological problems; it may affect efficiency at work; and there is evidence that town dwellers suffer a greater decline in hearing acuity with age than those who live in quieter surroundings ; and a paper on p. 1275 this weeks records a higher rate of admission to a psychiatric hospital among citizens living in the area of maximum noise near London Airport (Heathrow). Noise is certainly an important hazard to the public health.’ Most local-authority health departments have concentrated on their function of the abatement of noise nuisance-that is, the investigation of complaints of noise and the reduction or removal of the offending noise, either informally or by using powers under the Noise Abatement Act, 1960, and Public Health Act, 1936. A report2 of the Port and City of London health committee describes a campaign to tackle the wider public-health problem of reducing the noise level in the city environment by health education and by the identification and reduction of noise nuisance. The week’s campaign was preceded by a briefing session for personnel officers and public relations officers of city business houses to publicise the event 1.
Rodger, T. F. in The Theory and Practice of Public Health (edited by W. Hobson). London, 1969. 2. The Quiet City Campaign. Report of the Port and City of London Health Committee. London, 1969.
FENFLURAMINE OVERDOSAGE
AMPHETAMINES and related compounds are prescribed on an enormous scale-over 4 million scripts in Britain alone during 1968-because they are believed either to overcome depression or to dull appetite and so help in the treatment of obesity. Scepticism about the validity of these therapeutic indications is widespread.6 Moreover, since amphetamines figure prominently in the addiction scene, total rejection by doctors of this group of drugs is increasingly urged. But, when so many of the so-called civilised population of the world are overweight, and thus likely to live shorter-thannormal lives, efforts are understandably directed to achieving weight-loss by drugs. When restriction of food intake so often fails to slim, the quest is naturally for a simple and harmless philtre that will guarantee the lithe and supple figure without interfering with established habits of good living. The latest contender for this role is fenfluramine. 7 ,8 It is said to behave, not so much as an anorectic, as a novel metabolic influ" ence-a glycolyptic ". Clinical reports tell of the 3. Noise: Final Report of the Committee on the Problem of Noise. H.M. Stationery Office, 1963. 4. Noise Abatement Society: The Law on Noise. London, 1969. 5. Stephenson, R. J. Q. Bull. res. Intell. Unit GLC, 1968, no. 4, p. 3. 6. Report of Working Party on Amphetamine Preparations. British Medical Association 1968. 7. Butterfield, W. J. H., Whichelow, M. J. Lancet, 1968, ii, 109. 8. Pawan, G. L. S. ibid. 1969, i, 498.
1290
efficacy of fenfluramine in the cause of weight-loss.9-12 There is no evidence, from observations in animals or man, that it excites the central nervous system; and its modification of sleep patterns apparently differs from that of earlier drugs used in the treatment of obesity. 13 Thus, the risk of fenfluramine becoming a drug of
dependence
seems
slight.
As with any drug, however, the effects of overdosage can be all too real; and more incidents of fenfluramine poisoning are being reported, especially in children. The fatal dose is not high. To judge from a recent report 14 and others on p. 1306 of this issue, 20-30 tablets can produce alarming reactions; and death can follow a dose that is not much greater. Anything in the way of specific treatment is for the moment unknown. The convulsions associated with overdosage suggest, after all, stimulation of the central nervous system; and animals subjected to tests of acute toxicity displayed tremors, clonic convulsions, and rigidity of the limbs, before succumbing in coma. In rats and dogs fenfluramine may cause a transient fall of blood-pressure, succeeded by a more prolonged pressor response. After overdosage in man tachycardia and ventricular extrasystoles may be observed, culminating in ventricular fibrillation. Dr. Gold and his associates (p. 1306) believe that further pharmacological and toxicological inquiries are urgently required, particularly so far as the action of fenfluramine on the heart is concerned An analytical method has been developed, using gas chromatography, for estimating blood and urine levels of fenfluramine. A knowledge of blood levels can be invaluable in estimating severity, dose taken, and prognosis. Quantitative studies on excretion are also feasible. So far as they go, these inquiries indicate that acid diuresis is not very helpful in promoting elimination of fenfluramine.
FAMILIAL CANCER
FAMILIAL types of cancer have long been intensively studied; and, as closer attention is being paid to cancer in children, more and more syndromes are coming to light. The work of Miller and his co-workers 15-17 on the epidemiology of childhood cancer in the U.S.A. has revealed some unusual associations. Li and Fraumeni 18 have now identified four kindreds in which an association exists between soft-tissue sarcomas in children, and cancers appearing at an early age in one or both parents and in near relatives. In such families multiple primary malignancies appear with high frequency. The soft-tissue sarcomas of the children were often rhabdomyosarcomas (seen in three sib pairs); and three of the mothers had breast carcinomas at an early age (one woman was first affected at 22 and later had carcinoma in the other breast, followed by a 9. Duncan, E. H., Hyde, C. A., Regan, N. A., Sweetman, B. Br. J. clin. Pract. 1965, 127, 45. 10. Traherne, J. B. Practitioner, 1965, 197, 677. 11. Brodbin, P., O’Connor, C. A. ibid. 1967, 198, 707. 12. Gaind, R. Br. J. Psychiat. 1969, 115, 963. 13. Oswald, I., Jones, H. S., Mannerheim, J. E. Br. med. J. 1968, i, 796. 14. Riley, I., Corson, J., Haider, I., Oswald, I. Lancet, Nov. 29, 1969,
p. 1162. 15. Miller, R. W. New Engl. J. Med. 1968, 279, 122. 16. Miller, R. W., Fraumeni, J. F., Manning, M. D. ibid. 1964, 270, 922. 17. Fraumeni, J. F., Miller, R. W. J. Pediat. 1967, 70, 129. 18. Li, F. P., Fraumeni, J. F. Ann intern. Med. 1969, 71, 747.
papillary carcinoma of the thyroid gland at 34). Two of the fathers had malignant disease-acute myelocytic leukxmia and disseminated squamous carcinoma of the skin respectively. Relatives of the parents also had high frequencies of breast cancer and soft-tissue sarcomas. Though there have been previous isolated reports of association between rhabdomyosarcomas 19 and other soft-tissue sarcomas 20 in children whose mothers had breast cancer, no similar series of families has been recorded. Moreover, none of the children had any of the congenital defects described as accompaniments of soft-tissue sarcomas in children. 21 The familial aggregation of these tumours seems inexplicable by chance occurrence, since no instances of a sib and a parent of the proband having a neoplasm were uncovered by surveys of many children with other types of cancer.1s The three sib pairs with rhabdomyosarcoma were found from a survey of 649 children with this type of tumour, so this syndrome seems to be rare. Now that it is recognised, however, other families may come to light, and some clinical implications are obvious. When a rhabdomyosarcoma appears in a child, close inquiry is called for into the family experience of cancer; and if breast cancer arises at an early age in a mother then the possibility exists of rhabdomyosarcoma or other soft-tissue sarcoma in the children. The cause of this association is not yet clear." There was no history of consanguinity, of exposure to radiation or chemotherapy, or other unusual environmental circumstances. Environmental agencies, such as viruses, cannot be ruled out; but, since in each family one of the children died before the other affected one was born, direct transmission from child to child was impossible. Vertical transmission remains a possibility, and further inquiries are in progress. Like much other information, this knowledge has come from study of large numbers of children with cancer. Since the results of treatment remains so bad despite speedy diagnosis, advances in childhood cancer can be made only if there is concentration of patients and efforts.22.23 19. Remzi, D., Kendi, S. Turk. J. Pediat. 1966, 8, 143. 20. Bottomby, R. H., Condit, P. T. Cancer Bull. 1968, 20, 22. 21. Sloane, J. A., Hubbell, M. M. Cancer, N.Y. 1969, 23, 175. 22. Pearson, D., Steward, J. K. Proc. R. Soc. Med. 1969, 62, 685. 23. See Lancet, 1968, ii, 32.
SPECIAL SUBSCRIPTION TO THE LANCET
From Jan. 1, 1970, the annual subscription is be reduced to 25s. for medical students, and to E2 10s. for doctors in the five years from provisional registration in the United Kingdom (or from medical graduation in other countries). The new rates will be automatically extended, on renewal of subscriptions, to those who already receive the journal at a reduced rate. In North America, where The Lancet is published by Little, Brown and Company, 34 Beacon Street, Boston, Mass. 02106, the full subscription is$15, with a special rate for residents and interns of $9 per annum. to
urgent consideration and the drug
was
very
quickly
released, as the manufacturer had requested, for clinical trials. We understand that this acceptably pure form of L-dopa is now being made in increasing quantities by Roche Products Ltd. in a new plant in Switzerland. This preparation is at present available in Britain in quantities sufficient only for the M.R.C. trials which are under way in five centres. The committee has been aware for some time, however, that other preparations of L-dopa, mainly in the form of a laboratory reagent, have been available in considerable quantities and have been widely used by a number of doctors. The committee has met the distributors of these preparations and has tried to encourage the submission of the necessary data. Despite the committee’s efforts, however, adequate information has not yet been received and the committee has therefore been unable to satisfy itself as to the quality and safety of these materials. The committee wishes to make it clear that it has no intention of interfering with the right of individual doctors to prescribe for their patients whatever appears to them right and desirable. It emphasises, however, that it has been unable to assess the quality and safety of any preparation of L-dopa, other than. that in use in the M.R.C. trials, and doctors who wish to use these other materials must do so entirely on their own responsibility. Finally, the committee says it is impressed by the evidence of the value of L-dopa in the treatment of some forms of parkinsonism and is doing all in its power to ensure that the supply of L-dopa in a safe and satisfactory form is encouraged as
rapidly as possible.
and
to
arrange the distribution of leaflets. The official
opening of the campaign by the Lord Mayor was followed by a meeting of representatives of the Press, city business houses, and manufacturers of noise measuring and control equipment. A brief questionary was sent to city rate-payers asking how much annoyance was caused by noise, the source of that noise, and what might be done about it. Only about 8% of the questionaries were returned, because, the report suggests, most city rate-payers are unworried by noise or resigned to it. The returned questionaries made 2002 complaints of noise, both within offices and outside, and nearly half of them concerned traffic. A similar finding was reported by the Wilson committee3 and supported by objective measurements of noise in a wider survey of the central London boroughs. The report on the city campaign mentions building sites, street repairs, and aircraft as other important external sources of noice. Within the buildings, telephones and office machinery caused the most complaints. Many of the noises which caused annoyance could be reduced or eliminated if those concerned were of the problem and if the means were given to solve it. Difficulties were experienced in the operation of the Noise Abatement Act; and the report points out that the law on noise concerns not only public-health departments but also other departments of central and local government and the public themselves. The Noise Abatement Society has set out4 the provisions of the existing law in a clear way which will help the authorities make more effective use of their powers of noise control. The importance of planning in eliminating and diminishing environmental noise in London5 is also emphasised in the report. aware
LONDON NOISES
THE noise of a modern city troubles many people: it may cause emotional and psychological problems; it may affect efficiency at work; and there is evidence that town dwellers suffer a greater decline in hearing acuity with age than those who live in quieter surroundings ; and a paper on p. 1275 this weeks records a higher rate of admission to a psychiatric hospital among citizens living in the area of maximum noise near London Airport (Heathrow). Noise is certainly an important hazard to the public health.’ Most local-authority health departments have concentrated on their function of the abatement of noise nuisance-that is, the investigation of complaints of noise and the reduction or removal of the offending noise, either informally or by using powers under the Noise Abatement Act, 1960, and Public Health Act, 1936. A report2 of the Port and City of London health committee describes a campaign to tackle the wider public-health problem of reducing the noise level in the city environment by health education and by the identification and reduction of noise nuisance. The week’s campaign was preceded by a briefing session for personnel officers and public relations officers of city business houses to publicise the event 1.
Rodger, T. F. in The Theory and Practice of Public Health (edited by W. Hobson). London, 1969. 2. The Quiet City Campaign. Report of the Port and City of London Health Committee. London, 1969.
FENFLURAMINE OVERDOSAGE
AMPHETAMINES and related compounds are prescribed on an enormous scale-over 4 million scripts in Britain alone during 1968-because they are believed either to overcome depression or to dull appetite and so help in the treatment of obesity. Scepticism about the validity of these therapeutic indications is widespread.6 Moreover, since amphetamines figure prominently in the addiction scene, total rejection by doctors of this group of drugs is increasingly urged. But, when so many of the so-called civilised population of the world are overweight, and thus likely to live shorter-thannormal lives, efforts are understandably directed to achieving weight-loss by drugs. When restriction of food intake so often fails to slim, the quest is naturally for a simple and harmless philtre that will guarantee the lithe and supple figure without interfering with established habits of good living. The latest contender for this role is fenfluramine. 7 ,8 It is said to behave, not so much as an anorectic, as a novel metabolic influ" ence-a glycolyptic ". Clinical reports tell of the 3. Noise: Final Report of the Committee on the Problem of Noise. H.M. Stationery Office, 1963. 4. Noise Abatement Society: The Law on Noise. London, 1969. 5. Stephenson, R. J. Q. Bull. res. Intell. Unit GLC, 1968, no. 4, p. 3. 6. Report of Working Party on Amphetamine Preparations. British Medical Association 1968. 7. Butterfield, W. J. H., Whichelow, M. J. Lancet, 1968, ii, 109. 8. Pawan, G. L. S. ibid. 1969, i, 498.
1290
efficacy of fenfluramine in the cause of weight-loss.9-12 There is no evidence, from observations in animals or man, that it excites the central nervous system; and its modification of sleep patterns apparently differs from that of earlier drugs used in the treatment of obesity. 13 Thus, the risk of fenfluramine becoming a drug of
dependence
seems
slight.
As with any drug, however, the effects of overdosage can be all too real; and more incidents of fenfluramine poisoning are being reported, especially in children. The fatal dose is not high. To judge from a recent report 14 and others on p. 1306 of this issue, 20-30 tablets can produce alarming reactions; and death can follow a dose that is not much greater. Anything in the way of specific treatment is for the moment unknown. The convulsions associated with overdosage suggest, after all, stimulation of the central nervous system; and animals subjected to tests of acute toxicity displayed tremors, clonic convulsions, and rigidity of the limbs, before succumbing in coma. In rats and dogs fenfluramine may cause a transient fall of blood-pressure, succeeded by a more prolonged pressor response. After overdosage in man tachycardia and ventricular extrasystoles may be observed, culminating in ventricular fibrillation. Dr. Gold and his associates (p. 1306) believe that further pharmacological and toxicological inquiries are urgently required, particularly so far as the action of fenfluramine on the heart is concerned An analytical method has been developed, using gas chromatography, for estimating blood and urine levels of fenfluramine. A knowledge of blood levels can be invaluable in estimating severity, dose taken, and prognosis. Quantitative studies on excretion are also feasible. So far as they go, these inquiries indicate that acid diuresis is not very helpful in promoting elimination of fenfluramine.
FAMILIAL CANCER
FAMILIAL types of cancer have long been intensively studied; and, as closer attention is being paid to cancer in children, more and more syndromes are coming to light. The work of Miller and his co-workers 15-17 on the epidemiology of childhood cancer in the U.S.A. has revealed some unusual associations. Li and Fraumeni 18 have now identified four kindreds in which an association exists between soft-tissue sarcomas in children, and cancers appearing at an early age in one or both parents and in near relatives. In such families multiple primary malignancies appear with high frequency. The soft-tissue sarcomas of the children were often rhabdomyosarcomas (seen in three sib pairs); and three of the mothers had breast carcinomas at an early age (one woman was first affected at 22 and later had carcinoma in the other breast, followed by a 9. Duncan, E. H., Hyde, C. A., Regan, N. A., Sweetman, B. Br. J. clin. Pract. 1965, 127, 45. 10. Traherne, J. B. Practitioner, 1965, 197, 677. 11. Brodbin, P., O’Connor, C. A. ibid. 1967, 198, 707. 12. Gaind, R. Br. J. Psychiat. 1969, 115, 963. 13. Oswald, I., Jones, H. S., Mannerheim, J. E. Br. med. J. 1968, i, 796. 14. Riley, I., Corson, J., Haider, I., Oswald, I. Lancet, Nov. 29, 1969,
p. 1162. 15. Miller, R. W. New Engl. J. Med. 1968, 279, 122. 16. Miller, R. W., Fraumeni, J. F., Manning, M. D. ibid. 1964, 270, 922. 17. Fraumeni, J. F., Miller, R. W. J. Pediat. 1967, 70, 129. 18. Li, F. P., Fraumeni, J. F. Ann intern. Med. 1969, 71, 747.
papillary carcinoma of the thyroid gland at 34). Two of the fathers had malignant disease-acute myelocytic leukxmia and disseminated squamous carcinoma of the skin respectively. Relatives of the parents also had high frequencies of breast cancer and soft-tissue sarcomas. Though there have been previous isolated reports of association between rhabdomyosarcomas 19 and other soft-tissue sarcomas 20 in children whose mothers had breast cancer, no similar series of families has been recorded. Moreover, none of the children had any of the congenital defects described as accompaniments of soft-tissue sarcomas in children. 21 The familial aggregation of these tumours seems inexplicable by chance occurrence, since no instances of a sib and a parent of the proband having a neoplasm were uncovered by surveys of many children with other types of cancer.1s The three sib pairs with rhabdomyosarcoma were found from a survey of 649 children with this type of tumour, so this syndrome seems to be rare. Now that it is recognised, however, other families may come to light, and some clinical implications are obvious. When a rhabdomyosarcoma appears in a child, close inquiry is called for into the family experience of cancer; and if breast cancer arises at an early age in a mother then the possibility exists of rhabdomyosarcoma or other soft-tissue sarcoma in the children. The cause of this association is not yet clear." There was no history of consanguinity, of exposure to radiation or chemotherapy, or other unusual environmental circumstances. Environmental agencies, such as viruses, cannot be ruled out; but, since in each family one of the children died before the other affected one was born, direct transmission from child to child was impossible. Vertical transmission remains a possibility, and further inquiries are in progress. Like much other information, this knowledge has come from study of large numbers of children with cancer. Since the results of treatment remains so bad despite speedy diagnosis, advances in childhood cancer can be made only if there is concentration of patients and efforts.22.23 19. Remzi, D., Kendi, S. Turk. J. Pediat. 1966, 8, 143. 20. Bottomby, R. H., Condit, P. T. Cancer Bull. 1968, 20, 22. 21. Sloane, J. A., Hubbell, M. M. Cancer, N.Y. 1969, 23, 175. 22. Pearson, D., Steward, J. K. Proc. R. Soc. Med. 1969, 62, 685. 23. See Lancet, 1968, ii, 32.
SPECIAL SUBSCRIPTION TO THE LANCET
From Jan. 1, 1970, the annual subscription is be reduced to 25s. for medical students, and to E2 10s. for doctors in the five years from provisional registration in the United Kingdom (or from medical graduation in other countries). The new rates will be automatically extended, on renewal of subscriptions, to those who already receive the journal at a reduced rate. In North America, where The Lancet is published by Little, Brown and Company, 34 Beacon Street, Boston, Mass. 02106, the full subscription is$15, with a special rate for residents and interns of $9 per annum. to