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CYCLOPHOSPHAMIDE IN HUMAN MILK
912 We suggest that physicians refrain from adding any medication directly to a blood-transfusion without preliminary study of the effects on the red cell. Many drugs tested, including hydrocortisone, stilboestrol, progesterone, and diphenylhydantoin, have been found to be toxic to the red cell in the same range of concentrations as ethacrynic acid. Department of Respiratory Diseases, City of Hope Medical Center, Duarte, California.
JACK LIEBERMAN WALLACE KANESHIRO.
placebo.
No symptoms were noticed which could be put down to folic-acid treatment. A further volunteer took 30 mg. daily for ten weeks (not double-blind) but noticed no physical or mental change. It seems unnecessary, therefore, to search for possible biochemical explanations for a stimulant effect of folic acid in normal individuals when probably no such effect occurs. The change in mental state (and in fit frequency) which has been observed in epileptic patients can now be very satisfactorily explained by the observation 2,3 that the serum-phenytoin concentration falls during folic-acid treatment.
SELECTIVE CULLING OF HOSPITAL MEDICAL RECORDS Lennox and Mr. White (March 6, SIR,—Professor p. 489) are to be congratulated on their success in tackling that malignant proliferation of paper, for which the name hyperpapyrosis might be coined. This disease is now found in all walks of life-the present Census forms will weigh hundreds of tons. It is especially serious in medicine, however, where so often a paper wall comes between our patients and ourselves-the tracings in one research case are said to have extended to "millions of miles". It is not only the present position that is so serious, but the future prospects for ourselves and our descendants are shown by the findings in this article, that the space now required for one year’s records is equal to that which formerly sufficed for 60 years, and that there is a 10% compound annual escalation of paper. The gordian knot can only be cut by early radical surgery. "Every desk should have a rubber stamp with a large " D to be used liberally on documents to indicate their early destruction. One of the most successful business firms in the country some time ago increased its efficiency by a ruthless pruning of paper, and even experienced civil-servants are beginning to realise the disadvantages of always putting something on paper. Those who have spent weary hours in damp hospital cellars or dusty attics, searching, often in vain, for information among mountains of paper, will agree with me, I am sure, that there is a Law of Paper-" The value of paper is in inverse proportion to its volume ". BRYAN WILLIAMS.
TOXICITY OF FOLIC ACID
SIR,-Dr. Hellstrom (Jan. 9, p. 59), in a double-blind placebo-controlled study, was unable to confirm the findings of Hunter et al.1 that folic acid in a dose of 15 mg. daily produced a variety of physical and mental symptoms in normal volunteers. Dr. Hunter and Dr. Barnes (April 10, p. 755) suggest that this failure to reproduce their findings might have been " in part " due to the lower serum concentrations of folic acid reached in Dr. Hellstrom’s trial. However, the subjects in both trials received the same daily dose of the vitamin, and there is no reason to suppose that the metabolic handling of folic acid differed between the two groups. The difference in the final serum concentrations is likely to have resulted from differences in bioassay technique in the two laboratories. Comparing results of serum-folate estimations between laboratories is unwise unless comparative data on normal values are available. I have lately completed a double-blind placebo-controlled trial of similar design to that of Dr. Hellstrom. 15 mg. of folic acid daily for one month in twelve normal volunteers produced no significant change in physical or mental state when compared with a similar period on a 1.
Hunter, R., Barnes, J., Oakeley, H. F., Matthews, 1970, i, 61.
D. M.
Lancet,
St. Bartholomew’s Hospital, London E.C.1.
ALAN RICHENS.
CYCLOPHOSPHAMIDE IN HUMAN MILK SIR,-We recently had the opportunity to care for a 22-year-old woman with generalised lymphosarcoma, who was 8 months postpartum and lactating. Because of the progressive nature of her disease we felt that the patient required therapy. She was given vincristine 0-9 mg. and
cyclophosphamide 500 mg. intravenously by rapid injection, and kept in hospital so that she would not be able to nurse her baby. Breast milk was collected before injection and at intervals beginning 1 hour after the cyclophosphamide injection. By means of high resolution mass spectrometry unmetabolised cyclophosphamide was qualitatively identified in samples taken at 1 hour, 3 hours, 5 hours, and 6 hours after the cyclophosphamide injection. To our knowledge this is the first demonstration of secretion of cyclophosphamide by the human mammary gland and, because of this finding, we must recommend that lactating women receiving cyclophosphamide not nurse their babies. Details of this analytical technique will be published elsewhere. This work
was
supported by N.I.H. grants GM-1183, GM-
16492, and FR-5378 and N.S.F. grant GB-7866. Division of Oncology, Department of Medicine, and Department of Pharmacology, and Experimental Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
PETER H. WIERNIK J. H. DUNCAN.
TOLBUTAMIDE editorial Sm, Your (Jan. 23, p. 171) asks a question, " How could a sulphonylurea drug damage the cardiovascular system ? " and follows with the statement: " An early report of increased frequency of myocarditis and visceral microgranuloma in 29 necropsies of patients treated with tolbutamide has not been confirmed. It is hard to think of any other mechanism."
The postal strike made it difficult to follow up this controversy, but I have not noticed any comment or query as to why the respectable hypothesis advanced earlier in your own columns by Sir Edward Colt,4 which answers the question, was thus passed over. He suggested that tolbutamide might accelerate cardiovascular damage by stimulating the secretion of insulin and cited the work of Stout. õ.6 With regard to the arguments against following the recommendation of the Food and Drug Administration in the United States to use oral antidiabetic drugs only 2. 3. 4. 5. 6.
Baylis, E. M., Crowley, J. M., Preece, J. M., Sylvester, P. E., Marks, V. ibid. Jan. 9, 1971, p. 62. Olesen, O. V., Jensen, O. N. Acta pharmac. tox. 1970, 28, 265. Colt, E. W. D. Lancet, 1970, ii, 1132. Stout, R. W. Br. med. J. 1970, iii, 685. Stout, R. W. Lancet, 1968, ii, 702.
JACK LIEBERMAN WALLACE KANESHIRO.
placebo.
No symptoms were noticed which could be put down to folic-acid treatment. A further volunteer took 30 mg. daily for ten weeks (not double-blind) but noticed no physical or mental change. It seems unnecessary, therefore, to search for possible biochemical explanations for a stimulant effect of folic acid in normal individuals when probably no such effect occurs. The change in mental state (and in fit frequency) which has been observed in epileptic patients can now be very satisfactorily explained by the observation 2,3 that the serum-phenytoin concentration falls during folic-acid treatment.
SELECTIVE CULLING OF HOSPITAL MEDICAL RECORDS Lennox and Mr. White (March 6, SIR,—Professor p. 489) are to be congratulated on their success in tackling that malignant proliferation of paper, for which the name hyperpapyrosis might be coined. This disease is now found in all walks of life-the present Census forms will weigh hundreds of tons. It is especially serious in medicine, however, where so often a paper wall comes between our patients and ourselves-the tracings in one research case are said to have extended to "millions of miles". It is not only the present position that is so serious, but the future prospects for ourselves and our descendants are shown by the findings in this article, that the space now required for one year’s records is equal to that which formerly sufficed for 60 years, and that there is a 10% compound annual escalation of paper. The gordian knot can only be cut by early radical surgery. "Every desk should have a rubber stamp with a large " D to be used liberally on documents to indicate their early destruction. One of the most successful business firms in the country some time ago increased its efficiency by a ruthless pruning of paper, and even experienced civil-servants are beginning to realise the disadvantages of always putting something on paper. Those who have spent weary hours in damp hospital cellars or dusty attics, searching, often in vain, for information among mountains of paper, will agree with me, I am sure, that there is a Law of Paper-" The value of paper is in inverse proportion to its volume ". BRYAN WILLIAMS.
TOXICITY OF FOLIC ACID
SIR,-Dr. Hellstrom (Jan. 9, p. 59), in a double-blind placebo-controlled study, was unable to confirm the findings of Hunter et al.1 that folic acid in a dose of 15 mg. daily produced a variety of physical and mental symptoms in normal volunteers. Dr. Hunter and Dr. Barnes (April 10, p. 755) suggest that this failure to reproduce their findings might have been " in part " due to the lower serum concentrations of folic acid reached in Dr. Hellstrom’s trial. However, the subjects in both trials received the same daily dose of the vitamin, and there is no reason to suppose that the metabolic handling of folic acid differed between the two groups. The difference in the final serum concentrations is likely to have resulted from differences in bioassay technique in the two laboratories. Comparing results of serum-folate estimations between laboratories is unwise unless comparative data on normal values are available. I have lately completed a double-blind placebo-controlled trial of similar design to that of Dr. Hellstrom. 15 mg. of folic acid daily for one month in twelve normal volunteers produced no significant change in physical or mental state when compared with a similar period on a 1.
Hunter, R., Barnes, J., Oakeley, H. F., Matthews, 1970, i, 61.
D. M.
Lancet,
St. Bartholomew’s Hospital, London E.C.1.
ALAN RICHENS.
CYCLOPHOSPHAMIDE IN HUMAN MILK SIR,-We recently had the opportunity to care for a 22-year-old woman with generalised lymphosarcoma, who was 8 months postpartum and lactating. Because of the progressive nature of her disease we felt that the patient required therapy. She was given vincristine 0-9 mg. and
cyclophosphamide 500 mg. intravenously by rapid injection, and kept in hospital so that she would not be able to nurse her baby. Breast milk was collected before injection and at intervals beginning 1 hour after the cyclophosphamide injection. By means of high resolution mass spectrometry unmetabolised cyclophosphamide was qualitatively identified in samples taken at 1 hour, 3 hours, 5 hours, and 6 hours after the cyclophosphamide injection. To our knowledge this is the first demonstration of secretion of cyclophosphamide by the human mammary gland and, because of this finding, we must recommend that lactating women receiving cyclophosphamide not nurse their babies. Details of this analytical technique will be published elsewhere. This work
was
supported by N.I.H. grants GM-1183, GM-
16492, and FR-5378 and N.S.F. grant GB-7866. Division of Oncology, Department of Medicine, and Department of Pharmacology, and Experimental Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
PETER H. WIERNIK J. H. DUNCAN.
TOLBUTAMIDE editorial Sm, Your (Jan. 23, p. 171) asks a question, " How could a sulphonylurea drug damage the cardiovascular system ? " and follows with the statement: " An early report of increased frequency of myocarditis and visceral microgranuloma in 29 necropsies of patients treated with tolbutamide has not been confirmed. It is hard to think of any other mechanism."
The postal strike made it difficult to follow up this controversy, but I have not noticed any comment or query as to why the respectable hypothesis advanced earlier in your own columns by Sir Edward Colt,4 which answers the question, was thus passed over. He suggested that tolbutamide might accelerate cardiovascular damage by stimulating the secretion of insulin and cited the work of Stout. õ.6 With regard to the arguments against following the recommendation of the Food and Drug Administration in the United States to use oral antidiabetic drugs only 2. 3. 4. 5. 6.
Baylis, E. M., Crowley, J. M., Preece, J. M., Sylvester, P. E., Marks, V. ibid. Jan. 9, 1971, p. 62. Olesen, O. V., Jensen, O. N. Acta pharmac. tox. 1970, 28, 265. Colt, E. W. D. Lancet, 1970, ii, 1132. Stout, R. W. Br. med. J. 1970, iii, 685. Stout, R. W. Lancet, 1968, ii, 702.