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RADIATION AND BREAST CANCER
440 normal diet
rarely develop iron-deficiency anaemia. Although experiments have been designed which demonstrate defective iron absorption in the presence of gastritis and impaired gastric secretion, it has yet to be shown conclusively that the magnitude of this defect is sufficient to lead to iron-deficiency anxmia. It seems likely that iron deficiency leads to gastritis, and if one also accepts that gastritis leads to clinical iron deficiency a vicious cycle is established. Once both iron deficiency and chronic gastritis have developed it is exceedingly difficult to determine which is cause and which is effect. Dr. Delamore and Dr. Shearman note that some overlap between their groups may be expected; it seems to us, however, that where there is established iron deficiency and gastritis both mechanisms would operate to some degree in the same patient. This is illustrated by the failure of patients with iron deficiency and chronic gastritis, when analysed retrospectively, to fall into the two distinct groups proposed by Dr. Delamore and Dr. Shearman. Further understanding of the interrelation between gastritis and iron deficiency awaits a prospective investigation in which iron deficiency is induced under controlled conditions and serial studies are made of gastric acid secretion, the histological appearances of the gastric mucosa, and iron absorption. Department of Medicine, Queen’s University, L. S. VALBERG Kingston, Ontario, W. E. C. WILSON. Canada.
OLIGÆMIA IN SURGICAL SHOCK SIR,-Dr. Walters and Dr. McGowanstate that, when oligaemia in surgical shock " is insufficient to account for the hypotension ", infection is likely to be the primary cause. Nevertheless, they treat the oligxmia by transfusion of blood in sufficient quantity to raise a lowered central venous pressure (c.v.P.) to normal. They prefer the normal c.v.P. to the estimated normal blood-volume as the guide to volume therapy, on the ground that the error in estimating the normal bloodvolume is too great relative to the size of the deficit. Moreover, they see little value even in accurate blood-volume data, since the goal is to achieve a normal c.v.p., regardless of how much blood is required. To rely on the level of the c.v.p. as the more correct index of the need to transfuse is to assume that a significant deficit does not exist if the c.v.p. is normal; that the deficit has been sufficiently made up when a lowered pressure has been returned to normal by transfusion; and that a dangerous plethora will not be produced so long as this pressure is in the normal range. Unfortunately, the data of Dr. Walters and Dr. McGowan are not adequate to support such a claim. They report one bloodvolume determination before the transfusion therapy, but blood-volume measurements soon after transfusion were not made. Numerous studies have demonstrated that repeated reliable determinations at short intervals can be obtained with the ’Volemetron ’.23 Work in progress with this instrument shows a good correlation between measured deficits and c.v.P. early in oligaemic shock, as well as in patients with a good circulation. But late in oligaemic shock and in all stages of septic shock the c.v.p. cannot be trusted as a guide to transfusion therapy because the value of the c.v.p. bears no consistent relation to the measured deficit, especially if there is myocardial weakness-which is common enough in middle and advanced age.4-6 A transfusion given rapidly to correct a volume deficit in septic shock frequently raises the c.v.p. to well above normal, long before a measured deficit can be made up. On the other hand, a transfusion given slowly to correct a measured deficit may not raise the c.v.p. to normal or beyond 1. 2. 3.
4. 5. 6.
Walters, G., McGowan, G. K. Lancet, 1965, i, 1236. Williams, J., Fine, J. New Engl. J. Med. 1961, 264, 842; Williams, J., Grable, E., Frank, H. A., Fine, J. Am. Surg. 1962, 156, 648; Grable, E., Israel, J., Williams, J., Fine, J. ibid. 1963, 157, 361. Cartmill, T., Ricks, R., Garrett, H., Williams, J., DeBakey, M. Surgery, Gynec. Obstet. (in the press). Spencer, F. C., Shao-Chi Yu, Rossi, N. P. Am. Surg. 1965, 162, 74. Flanagan, J. P., Steinmetz, G. P., Crawford, E. W., Merandino, K. A. Surgery, St. Louis, 1964, 56, 925. Berger, R. L., Boyd, T. F., Maras, P. S. New Engl. J. Med. 1964, 271, 59.
the normal range, even though a plethora sufficient to cause pulmonary oedema has already been produced. Apart from their value in shock, serial blood-volume determinations have their uses in patients who are not in shock. In acute trauma, accidental or surgical, the c.v.p. can still be in the normal range after a substantial blood-volume loss has been sustained. Monitoring the blood-volume and the c.v.p. provides a much more precise way of treating blood-volume deficits in shock than does monitoring c.v.p. alone. But when the circulation is compensated, the blood-volume measurement is a safer guide for the prevention of shock than the c.v.p. JACOB FINE. Boston, Massachusetts 02215, U.S.A.
ISONIAZID-INDUCED ENCEPHALOPATHY SiR,ŇThe report by Dr. Adams and Dr. Whiter of a patient who developed encephalopathy due to isoniazid, has prompted me to summarise our experience at this centre. This type of drug toxicity has been encountered in 8 patients,2-5 6 of whom also developed peripheral neuropathy. 6 patients had convulsions of the grand-mal type, and the remaining 2 had symptoms of toxic psychosis. Of the 8 patients, 6 (5 with convulsions and 1 with psychosis) 34 were on a single daily dose of isoniazid alone (on average, 14 mg. per kg. body-weight, or 650 mg. for patients weighing 45-4 kg. [100 lb.] ; 1 (with convulsions)was on this dose of isoniazid twice weekly, in combination with streptomycin; and 1 (with psychosis)2 was on a single daily dose of isoniazid alone (400 mg.). The proportion of patients developing encephalopathy on these 3 regimens were 6 of 153 (3-9%), 1 of 78 (1-3%), and 1 of 74 (1°4°%) respectively. No case of encephalopathy was encountered among more than 400 patients treated with lower daily dosages of isoniazid (100 mg. twice a day for patients weighing 45-4 kg. or more) alone or in combination with p-aminosalicylic acid.2 56 There was a suggestion that pyridoxine was effective in prevention and also treatment of encephalopathy even when isoniazid was continued.3-5 Dr. Adams and Dr. White, although stating that pyridoxine is ineffective in the prevention of fits and psychoses due to isoniazid, prescribed this vitamin therapeutically for their patient. The suggestion, made in 1960 (to which Dr. Adams and Dr. White drew attention), that slow inactivators of isoniazid may be more prone to develop neurological complications than rapid inactivators,’’ was in fact demonstrated at this centre in that year.2 In all, 43 cases of neurotoxicity due to isoniazid have been encountered at this centre,2-6 all but 2 of them having developed peripheral neuropathy. Of these 43 patients, 36 (83-7%) were slow inactivators of isoniazid. The proportion of slow inactivators among tuberculous patients in South India was found to be approximately 60%.48 Tuberculosis Chemotherapy Centre, S. DEVADATTA. Madras, 31.
RADIATION AND BREAST CANCER SIR,-I read your annotation (July 31) with a sense of dismay. On hurried reading, this title could suggest that any radiation exposure to breast tissues may invoke future mammary cancers. This alarming implication could throw an unwarranted shadow over a
It is
diagnostic technique: mammography. entirely possible that Dr. Mackenzie’s conjecture, which
vital
cite, is correct. Certain mammary cancers could have resulted from patient-exposure to repeated fluoroscopic examinations during artificial pneumothorax therapy for tuberculosis years previously. I know of two phthisiologists who died of leukaemia, which, I strongly suspect, resulted
you
1. 2. 3. 4. 5. 6. 7. 8.
Adams, P., White, C. Lancet, 1965, i, 680. Devadatta, S., Gangadharam, P. R. J., Andrews, R. H., Fox, W., Ramakrishnan, C. V., Selkon, J. B., Velu, S. Bull. Wld Hlth Org. 1960, 23, 587. Tuberculosis Chemotherapy Centre, ibid. 1963, 28, 455. Tuberculosis Chemotherapy Centre, ibid. 1963, 29, 457. Tuberculosis Chemotherapy Centre, ibid. 1964, 31, 247. Tuberculosis Chemotherapy Centre, ibid. 1959, 21, 51. Evans, D. A. P., Manley, K. A., McKusick, V. A. Br. med. J. 1960, ii, 485. Gangadharam, P. R. J., Bhatia, A. L., Radhakrishna, S., Selkon, J. B. Bull. Wld Hlth Org. 1961, 25, 765.
441 from cumulative radiation due to undisciplined fluoroscopy. Mammography, however, which employs low kilovoltages and adequate filtration, with sharp collimation of the X-ray beam, can hardly be equated with fluoroscopic irradiation (so commonly uncontrolled) by physicians concerned with artificial pneumothorax. In the hands of a skilled radiologist, who exercises all the proper controls, mammography entails insignificant risk. This is true even when repeated X-ray studies are necessary, as in breast screening surveys. Each exposure is of the order of one rad to the skin, limited essentially to the breast, with negligible irradiation of the mediastinum, lungs, or ovaries. I sincerely hope that readers of your annotation will not construe it as an indictment of mammography, which is a thoroughly safe and extremely valuable diagnostic procedure. Division of Radiology, Albert Einstein Medical Center,
Philadelphia, Pennsylvania 19141, U.S.A.
J. GERSHON-COHEN.
ADVERSE REACTIONS TO NALIDIXIC ACID SIR,-Early in 1965 the Committee on Safety of Drugs asked doctors to report any rashes or disturbances of the central nervous system occurring in patients who were taking nalidixic acid (’Negram’). The reports received following this request appear to confirm the first impressions that, although there seems no reasonable doubt that a causal relation exists between the use of the drug and such reactions, these are transient and reversible. It is the view of the committee that the fear of producing these reactions in some patients need not, in the present state of knowledge, deter doctors from prescribing this drug when it is positively indicated. Nevertheless, since some of the effects may be alarming to patients, doctors might care to them of their possible occurrence. When the reactions affect the nervous system, they usually occur within half an hour of taking the drug, and persist for two or three hours. Sometimes, however, they are first or third dose and increase in after the second experienced with doses. Visual disturbances, exciteseverity subsequent ment, depression, confusion, and hallucinations have been reported. Headache, giddiness, drowsiness, syncope, and sensory disturbances have also occurred in a few instances. One patient had a grand mal attack which might have been due to the drug. The exact incidence of reactions is difficult to assess, but between May, 1964, and April, 1965, 52 cases of skin rashes and 126 cases of reactions affecting the nervous system, in patients being treated with. nalidixic acid, were reported to the committee. Between January, 1964, and February, 1965, general practitioners alone issued about 77,000 prescriptions for the drug. The committee would like to thank doctors for their help, and to acknowledge the cooperation of the manufacturers in the inquiry. Committee on Safety of Drugs, D. A. CAHAL Queen Anne’s Mansions, Queen Anne’s Gate, Medical Assessor. London, S.W.1. warn
METHYLDOPA AND AMITRIPTYLINE to a wide variety of drugs 1-4 and foodstuffs5 in patients receiving monoamine-oxidase (M.A.o.) inhibitors are now well known, and the dangers of a too-rapid change from an antidepressant of this group to imipramine or amitriptyline are established. The following case-history suggests that concurrent administration of methyldopa and amitriptyline may not be without risk.
SIR,-Untoward reactions
Investigation of a 50-year-old man with hypertension showed that the left kidney was smaller than the right and was supplied by two renal arteries, the lower of which was stenosed near its 1. 2. 3. 4. 5.
Dally, P. J. Practitioner, 1962, 188, 1235. Gates, J. C. Br. med. J. 1963, ii, 683. Mason, A. Lancet, 1962, i, 1073. Low-Beer, G. A., Tidmarsh, D. Br. med. J. 1963, ii, Blackwell, B. Practitioner, 1963, 191, 414, 849.
683.
origin. He became moderately depressed after treatment with a reserpine derivative; this was therefore discontinued, and his blood-pressure was thereafter controlled at 120/80-150/90 mm. Hg by methyldopa, 250 mg. thrice daily, and a thiazide diuretic. He complained of some mental slowing, but continued work. During the following 2 months he again became depressed, and was treated with amitriptyline, 25 mg. thrice daily, at home. On attendance at the medical clinic, 10 days after commencing amitriptyline, he was agitated, and there was a fine tremor in his hands. He was no longer depressed, but complained of palpitations. On examination, his pulse, usually 80 per minute, had risen to 148 per minute, and his blood-pressure was 170/110. All treatment was stopped forthwith. A week later he stated that he felt a different person "; his pulse and blood-pressure had fallen to 100 per minute and 160/90 respectively. The manufacturers of methyldopa and amitriptyline con"
tacted so far have no record of similar reactions to the one described. Both methyldopa and reserpine may produce excitation if administered with drugs of the M.A.0. -inhibitor group. Amitriptyline can produce some elevation of the pulse-rate from an atropine-like action, but its full mechanism of action remains uncertain. It probably potentiates noradrenaline or one of its precursors. The vanilloyl-mandelic acid/creatinine ratio of a specimen of urine at the time of the reaction in this patient was within the normal range. The case is reported as a potential therapeutic hazard, and in the hope that it may shed some light on modes of drug action. I
am
grateful
to
Dr. Cecil
Symons for permission
to
publish this
case.
New End Hospital, London, N.W.3.
ANTHONY G. WHITE.
LEUKAÆMIA AFTER OXYPHENYLBUTAZONE SiR,—Leukaemia after treatment with oxyphenylbutazone (’Tanderil’) seems not to have been described despite many observations of leucopenia and thrombocytopenia. We have seen two fatal cases of acute leukxmia: one soon after a total dose of 1 g., the other 13 months after about 1-9 g. We have also observed a patient with leucocytosis and one with a severe leukxmoid reaction (white blood-cells, 114,000 per c.mm.). We wish to stress the importance of blood-controls, and of correct indications for the use of this drug. SVEN-GÖSTA SJÖBERG Central Hospital, DANIEL PERERS. Eskilstuna, Sweden. MEDICAL TREATMENT OF OSTEOARTHRITIS SIR, Your leading article2 is a timely reminder that we do not know the aetiology in the majority of cases of osteoarthritis; attempts at prevention and treatment are therefore largely fruitless. Sadly this view is not generally accepted, and patients are sometimes subjected to surgery on rather flimsy evidence. Clinically, the hip-joint is the most important site of osteoarthritis. I am not aware of any reports of controlled comparisons between surgical (or any other) treatment and non-treatment in osteoarthritis of the hip. Yet in other areas of medicine it is an accepted rule that proposed treatment should have been shown to be more effective than non-treatment. Unfortunately, a uniform system of classification and examination of osteoarthritis of the hip does not exist,3 and your suggestion that patients " have been lumped together in one group, no matter what stage the condition had reached " is
largely
correct.
Danielsson4 has reported on the natural history of osteoarthritis of the hip from observations in virtually all cases diagnosed over a five-year period in a quarter-million population. He found that the diagnosis must be based on X-ray evidence of structural or joint-space changes. Patients who had only osteophytes in 1951 were found, on review in 1962, only rarely to have pain, decreased range of motion, or impaired 1. Sjoberg, S.-G., Perers, D. Läkartidn. (in the press). 2. Lancet, 1965, i, 947. 3. Milbank meml Fund q. Bull. 1965. 43, part 3. 4. Danielsson, L. G. Acta orthop. scand. 1964, suppl. 66.
rarely develop iron-deficiency anaemia. Although experiments have been designed which demonstrate defective iron absorption in the presence of gastritis and impaired gastric secretion, it has yet to be shown conclusively that the magnitude of this defect is sufficient to lead to iron-deficiency anxmia. It seems likely that iron deficiency leads to gastritis, and if one also accepts that gastritis leads to clinical iron deficiency a vicious cycle is established. Once both iron deficiency and chronic gastritis have developed it is exceedingly difficult to determine which is cause and which is effect. Dr. Delamore and Dr. Shearman note that some overlap between their groups may be expected; it seems to us, however, that where there is established iron deficiency and gastritis both mechanisms would operate to some degree in the same patient. This is illustrated by the failure of patients with iron deficiency and chronic gastritis, when analysed retrospectively, to fall into the two distinct groups proposed by Dr. Delamore and Dr. Shearman. Further understanding of the interrelation between gastritis and iron deficiency awaits a prospective investigation in which iron deficiency is induced under controlled conditions and serial studies are made of gastric acid secretion, the histological appearances of the gastric mucosa, and iron absorption. Department of Medicine, Queen’s University, L. S. VALBERG Kingston, Ontario, W. E. C. WILSON. Canada.
OLIGÆMIA IN SURGICAL SHOCK SIR,-Dr. Walters and Dr. McGowanstate that, when oligaemia in surgical shock " is insufficient to account for the hypotension ", infection is likely to be the primary cause. Nevertheless, they treat the oligxmia by transfusion of blood in sufficient quantity to raise a lowered central venous pressure (c.v.P.) to normal. They prefer the normal c.v.P. to the estimated normal blood-volume as the guide to volume therapy, on the ground that the error in estimating the normal bloodvolume is too great relative to the size of the deficit. Moreover, they see little value even in accurate blood-volume data, since the goal is to achieve a normal c.v.p., regardless of how much blood is required. To rely on the level of the c.v.p. as the more correct index of the need to transfuse is to assume that a significant deficit does not exist if the c.v.p. is normal; that the deficit has been sufficiently made up when a lowered pressure has been returned to normal by transfusion; and that a dangerous plethora will not be produced so long as this pressure is in the normal range. Unfortunately, the data of Dr. Walters and Dr. McGowan are not adequate to support such a claim. They report one bloodvolume determination before the transfusion therapy, but blood-volume measurements soon after transfusion were not made. Numerous studies have demonstrated that repeated reliable determinations at short intervals can be obtained with the ’Volemetron ’.23 Work in progress with this instrument shows a good correlation between measured deficits and c.v.P. early in oligaemic shock, as well as in patients with a good circulation. But late in oligaemic shock and in all stages of septic shock the c.v.p. cannot be trusted as a guide to transfusion therapy because the value of the c.v.p. bears no consistent relation to the measured deficit, especially if there is myocardial weakness-which is common enough in middle and advanced age.4-6 A transfusion given rapidly to correct a volume deficit in septic shock frequently raises the c.v.p. to well above normal, long before a measured deficit can be made up. On the other hand, a transfusion given slowly to correct a measured deficit may not raise the c.v.p. to normal or beyond 1. 2. 3.
4. 5. 6.
Walters, G., McGowan, G. K. Lancet, 1965, i, 1236. Williams, J., Fine, J. New Engl. J. Med. 1961, 264, 842; Williams, J., Grable, E., Frank, H. A., Fine, J. Am. Surg. 1962, 156, 648; Grable, E., Israel, J., Williams, J., Fine, J. ibid. 1963, 157, 361. Cartmill, T., Ricks, R., Garrett, H., Williams, J., DeBakey, M. Surgery, Gynec. Obstet. (in the press). Spencer, F. C., Shao-Chi Yu, Rossi, N. P. Am. Surg. 1965, 162, 74. Flanagan, J. P., Steinmetz, G. P., Crawford, E. W., Merandino, K. A. Surgery, St. Louis, 1964, 56, 925. Berger, R. L., Boyd, T. F., Maras, P. S. New Engl. J. Med. 1964, 271, 59.
the normal range, even though a plethora sufficient to cause pulmonary oedema has already been produced. Apart from their value in shock, serial blood-volume determinations have their uses in patients who are not in shock. In acute trauma, accidental or surgical, the c.v.p. can still be in the normal range after a substantial blood-volume loss has been sustained. Monitoring the blood-volume and the c.v.p. provides a much more precise way of treating blood-volume deficits in shock than does monitoring c.v.p. alone. But when the circulation is compensated, the blood-volume measurement is a safer guide for the prevention of shock than the c.v.p. JACOB FINE. Boston, Massachusetts 02215, U.S.A.
ISONIAZID-INDUCED ENCEPHALOPATHY SiR,ŇThe report by Dr. Adams and Dr. Whiter of a patient who developed encephalopathy due to isoniazid, has prompted me to summarise our experience at this centre. This type of drug toxicity has been encountered in 8 patients,2-5 6 of whom also developed peripheral neuropathy. 6 patients had convulsions of the grand-mal type, and the remaining 2 had symptoms of toxic psychosis. Of the 8 patients, 6 (5 with convulsions and 1 with psychosis) 34 were on a single daily dose of isoniazid alone (on average, 14 mg. per kg. body-weight, or 650 mg. for patients weighing 45-4 kg. [100 lb.] ; 1 (with convulsions)was on this dose of isoniazid twice weekly, in combination with streptomycin; and 1 (with psychosis)2 was on a single daily dose of isoniazid alone (400 mg.). The proportion of patients developing encephalopathy on these 3 regimens were 6 of 153 (3-9%), 1 of 78 (1-3%), and 1 of 74 (1°4°%) respectively. No case of encephalopathy was encountered among more than 400 patients treated with lower daily dosages of isoniazid (100 mg. twice a day for patients weighing 45-4 kg. or more) alone or in combination with p-aminosalicylic acid.2 56 There was a suggestion that pyridoxine was effective in prevention and also treatment of encephalopathy even when isoniazid was continued.3-5 Dr. Adams and Dr. White, although stating that pyridoxine is ineffective in the prevention of fits and psychoses due to isoniazid, prescribed this vitamin therapeutically for their patient. The suggestion, made in 1960 (to which Dr. Adams and Dr. White drew attention), that slow inactivators of isoniazid may be more prone to develop neurological complications than rapid inactivators,’’ was in fact demonstrated at this centre in that year.2 In all, 43 cases of neurotoxicity due to isoniazid have been encountered at this centre,2-6 all but 2 of them having developed peripheral neuropathy. Of these 43 patients, 36 (83-7%) were slow inactivators of isoniazid. The proportion of slow inactivators among tuberculous patients in South India was found to be approximately 60%.48 Tuberculosis Chemotherapy Centre, S. DEVADATTA. Madras, 31.
RADIATION AND BREAST CANCER SIR,-I read your annotation (July 31) with a sense of dismay. On hurried reading, this title could suggest that any radiation exposure to breast tissues may invoke future mammary cancers. This alarming implication could throw an unwarranted shadow over a
It is
diagnostic technique: mammography. entirely possible that Dr. Mackenzie’s conjecture, which
vital
cite, is correct. Certain mammary cancers could have resulted from patient-exposure to repeated fluoroscopic examinations during artificial pneumothorax therapy for tuberculosis years previously. I know of two phthisiologists who died of leukaemia, which, I strongly suspect, resulted
you
1. 2. 3. 4. 5. 6. 7. 8.
Adams, P., White, C. Lancet, 1965, i, 680. Devadatta, S., Gangadharam, P. R. J., Andrews, R. H., Fox, W., Ramakrishnan, C. V., Selkon, J. B., Velu, S. Bull. Wld Hlth Org. 1960, 23, 587. Tuberculosis Chemotherapy Centre, ibid. 1963, 28, 455. Tuberculosis Chemotherapy Centre, ibid. 1963, 29, 457. Tuberculosis Chemotherapy Centre, ibid. 1964, 31, 247. Tuberculosis Chemotherapy Centre, ibid. 1959, 21, 51. Evans, D. A. P., Manley, K. A., McKusick, V. A. Br. med. J. 1960, ii, 485. Gangadharam, P. R. J., Bhatia, A. L., Radhakrishna, S., Selkon, J. B. Bull. Wld Hlth Org. 1961, 25, 765.
441 from cumulative radiation due to undisciplined fluoroscopy. Mammography, however, which employs low kilovoltages and adequate filtration, with sharp collimation of the X-ray beam, can hardly be equated with fluoroscopic irradiation (so commonly uncontrolled) by physicians concerned with artificial pneumothorax. In the hands of a skilled radiologist, who exercises all the proper controls, mammography entails insignificant risk. This is true even when repeated X-ray studies are necessary, as in breast screening surveys. Each exposure is of the order of one rad to the skin, limited essentially to the breast, with negligible irradiation of the mediastinum, lungs, or ovaries. I sincerely hope that readers of your annotation will not construe it as an indictment of mammography, which is a thoroughly safe and extremely valuable diagnostic procedure. Division of Radiology, Albert Einstein Medical Center,
Philadelphia, Pennsylvania 19141, U.S.A.
J. GERSHON-COHEN.
ADVERSE REACTIONS TO NALIDIXIC ACID SIR,-Early in 1965 the Committee on Safety of Drugs asked doctors to report any rashes or disturbances of the central nervous system occurring in patients who were taking nalidixic acid (’Negram’). The reports received following this request appear to confirm the first impressions that, although there seems no reasonable doubt that a causal relation exists between the use of the drug and such reactions, these are transient and reversible. It is the view of the committee that the fear of producing these reactions in some patients need not, in the present state of knowledge, deter doctors from prescribing this drug when it is positively indicated. Nevertheless, since some of the effects may be alarming to patients, doctors might care to them of their possible occurrence. When the reactions affect the nervous system, they usually occur within half an hour of taking the drug, and persist for two or three hours. Sometimes, however, they are first or third dose and increase in after the second experienced with doses. Visual disturbances, exciteseverity subsequent ment, depression, confusion, and hallucinations have been reported. Headache, giddiness, drowsiness, syncope, and sensory disturbances have also occurred in a few instances. One patient had a grand mal attack which might have been due to the drug. The exact incidence of reactions is difficult to assess, but between May, 1964, and April, 1965, 52 cases of skin rashes and 126 cases of reactions affecting the nervous system, in patients being treated with. nalidixic acid, were reported to the committee. Between January, 1964, and February, 1965, general practitioners alone issued about 77,000 prescriptions for the drug. The committee would like to thank doctors for their help, and to acknowledge the cooperation of the manufacturers in the inquiry. Committee on Safety of Drugs, D. A. CAHAL Queen Anne’s Mansions, Queen Anne’s Gate, Medical Assessor. London, S.W.1. warn
METHYLDOPA AND AMITRIPTYLINE to a wide variety of drugs 1-4 and foodstuffs5 in patients receiving monoamine-oxidase (M.A.o.) inhibitors are now well known, and the dangers of a too-rapid change from an antidepressant of this group to imipramine or amitriptyline are established. The following case-history suggests that concurrent administration of methyldopa and amitriptyline may not be without risk.
SIR,-Untoward reactions
Investigation of a 50-year-old man with hypertension showed that the left kidney was smaller than the right and was supplied by two renal arteries, the lower of which was stenosed near its 1. 2. 3. 4. 5.
Dally, P. J. Practitioner, 1962, 188, 1235. Gates, J. C. Br. med. J. 1963, ii, 683. Mason, A. Lancet, 1962, i, 1073. Low-Beer, G. A., Tidmarsh, D. Br. med. J. 1963, ii, Blackwell, B. Practitioner, 1963, 191, 414, 849.
683.
origin. He became moderately depressed after treatment with a reserpine derivative; this was therefore discontinued, and his blood-pressure was thereafter controlled at 120/80-150/90 mm. Hg by methyldopa, 250 mg. thrice daily, and a thiazide diuretic. He complained of some mental slowing, but continued work. During the following 2 months he again became depressed, and was treated with amitriptyline, 25 mg. thrice daily, at home. On attendance at the medical clinic, 10 days after commencing amitriptyline, he was agitated, and there was a fine tremor in his hands. He was no longer depressed, but complained of palpitations. On examination, his pulse, usually 80 per minute, had risen to 148 per minute, and his blood-pressure was 170/110. All treatment was stopped forthwith. A week later he stated that he felt a different person "; his pulse and blood-pressure had fallen to 100 per minute and 160/90 respectively. The manufacturers of methyldopa and amitriptyline con"
tacted so far have no record of similar reactions to the one described. Both methyldopa and reserpine may produce excitation if administered with drugs of the M.A.0. -inhibitor group. Amitriptyline can produce some elevation of the pulse-rate from an atropine-like action, but its full mechanism of action remains uncertain. It probably potentiates noradrenaline or one of its precursors. The vanilloyl-mandelic acid/creatinine ratio of a specimen of urine at the time of the reaction in this patient was within the normal range. The case is reported as a potential therapeutic hazard, and in the hope that it may shed some light on modes of drug action. I
am
grateful
to
Dr. Cecil
Symons for permission
to
publish this
case.
New End Hospital, London, N.W.3.
ANTHONY G. WHITE.
LEUKAÆMIA AFTER OXYPHENYLBUTAZONE SiR,—Leukaemia after treatment with oxyphenylbutazone (’Tanderil’) seems not to have been described despite many observations of leucopenia and thrombocytopenia. We have seen two fatal cases of acute leukxmia: one soon after a total dose of 1 g., the other 13 months after about 1-9 g. We have also observed a patient with leucocytosis and one with a severe leukxmoid reaction (white blood-cells, 114,000 per c.mm.). We wish to stress the importance of blood-controls, and of correct indications for the use of this drug. SVEN-GÖSTA SJÖBERG Central Hospital, DANIEL PERERS. Eskilstuna, Sweden. MEDICAL TREATMENT OF OSTEOARTHRITIS SIR, Your leading article2 is a timely reminder that we do not know the aetiology in the majority of cases of osteoarthritis; attempts at prevention and treatment are therefore largely fruitless. Sadly this view is not generally accepted, and patients are sometimes subjected to surgery on rather flimsy evidence. Clinically, the hip-joint is the most important site of osteoarthritis. I am not aware of any reports of controlled comparisons between surgical (or any other) treatment and non-treatment in osteoarthritis of the hip. Yet in other areas of medicine it is an accepted rule that proposed treatment should have been shown to be more effective than non-treatment. Unfortunately, a uniform system of classification and examination of osteoarthritis of the hip does not exist,3 and your suggestion that patients " have been lumped together in one group, no matter what stage the condition had reached " is
largely
correct.
Danielsson4 has reported on the natural history of osteoarthritis of the hip from observations in virtually all cases diagnosed over a five-year period in a quarter-million population. He found that the diagnosis must be based on X-ray evidence of structural or joint-space changes. Patients who had only osteophytes in 1951 were found, on review in 1962, only rarely to have pain, decreased range of motion, or impaired 1. Sjoberg, S.-G., Perers, D. Läkartidn. (in the press). 2. Lancet, 1965, i, 947. 3. Milbank meml Fund q. Bull. 1965. 43, part 3. 4. Danielsson, L. G. Acta orthop. scand. 1964, suppl. 66.