- Email: [email protected]
MEDICAL EQUIPMENT AND V.A.T.
1570 doubt that the inclusion of non-communicable infections is a major factor accounting for the strength of this specialty in the U.S. In addition to improving patient care, the infectious-disease divisions should also play a part in the surveillance of nosocomial hospital infection, examine hospital use of antibiotics, and interact closely with the In many hospitals, medical microbiology laboratory. medical microbiology is within the infectious-disease division, or the clinical microbiologist who has tended to stay within pathology, may have an appointment within infectious diseases. An infectious-disease division is especially important in teaching hospitals when students, interns, and residents can obtain experience in all types of infections in addition to the communicable diseases, including bacterial (aerobic and anaerobic), viral, and fungal infections and parasitology. Infectious diseases as a has its specialty undoubtedly greatest strength in the teachand is one of the most important and popular ing hospital services for training students, interns, and residents. Infectious-disease specialists seem to be less well established outside teaching hospitals. Medical internists with a major part of their practice in infectious diseases may have an important role to play in the management of patients, working closely with or supervising the microbiology laboratory and nurse epidemiologist and surveillance of nosocomial hospital infections through hospital infection committees. Harbor General Hospital Campus, 1000 Carson Street,
Torrance, California 90509, U.S.A.
JOHN Z. MONTGOMERIE.
ÆTIOLOGY OF SYSTEMIC LUPUS ERYTHEMATOSUS
SiRj—Your editorial (Nov. 30, p. 1302) on systemic lupus erythematosus (S.L.E.) limited itself to speculation about a viral aaiology. In obscure immunological disorders this suggestion may be as acceptable as any other, but a hypothesis for s.L.E. should take into account the fact that a very similar syndrome can be caused by drugs: hydrallazine, procainamide, and isoniazid are well-known culprits.1 These drugs all happen to be subject to metabolic acetylation in the body, and individuals who are slow acetylators seem to be more susceptible to this particular drug-induced side-effect. 2,3 In addition, Reidenberg and Martin4 demonstrated a preponderance of slow acetylators in a group of 14 patients with " spontaneous " (i.e., not drug-induced) S.L.E. It would appear from these observations that some as yet unidentified environmental chemicals or drugs deserve equal consideration as causative agents. A satisfactory aetiological hypothesis should incorporate the above evidence into a reasonable explanation for the production of anti-D.N.A. antibody. May I suggest that the relative deficiency of acetylation may possibly favour an alternative metabolic pathway, producing chemically reactive metabolites, which then become antigenic as a result of covalent binding to nuclear material, thereby provoking the synthesis of anti-D.N.A. antibody ? This would explain why slow acetylation is one genetic feature of the so-called " lupus diathesis ".1 Such covalent nuclear binding could also be the mechanism of the s.L.E. syndrome described in association with anticonvulsant therapy.1 Epileptics are likely to have enhanced drugmetabolising enzyme activity, and in laboratory animals this phenomenon of enzyme induction has been shown 1. 2.
3. 4.
Alarcon-Segovia, D. Mayo Clin. Proc. 1969, 44, 664. Perry, H. M., Tan, E. M., Carmody, S., Sakamoto, A. J. Lab. clin. Med. 1970, 76, 114. Alarcon-Segovia, D., Fishbein, E., Alcala, H. Arthr. Rheum. 1971, 14, 748. Reidenberg, M. M., Martin, J. H. Drug Metabolism and Disposition, 1974, 2, 71.
potentiate the covalent tissue binding of cytotoxic metabolites of certain drugs and chemicals. By this argument, epileptics who are " induced " would therefore be more susceptible to a chemical which, through formation of a nucleophilic chemically reactive metabolite, causes s.L.E. If future work did happen to implicate a virus more clearly, one would then have to develop different hypotheses: that certain chemicals or their metabolites facilitate viral infection or influence the body’s immune response to it: or that chemicals and virus initiate the disease by independent use of the same aetiological mechanism. However, at the moment a chemical cause of spontaneous s.L.E. seems more likely than a viral one. I believe there is evidence that we would profit from a closer examination of the pathways of drug metabolism and the characteristics of tissue binding of drugs and metabolites in affected individuals and their relatives. to
Department of Therapeutics, Ninewells Hospital and Medical School, Dundee DD2 1UD.
JOHN MCEWEN.
LUPUS ERYTHEMATOSUS, D.N.A. ANTIBODIES, AND SUPPRESSION OF
ERYTHROPOIESIS that SiR,-Dr Gabrielsen (Nov. 9, p. 1116) suggests " in and antinuclear antibodies anti-D.N.A. develop erythropoietically stressed " women extruding erythroid nonfunctional nuclei, and-leaving aside the malaria issueshe feels that the prolongation of median survival in hypertransfused female NZB/NZW mice v. age-matched controls supports her hypothesis. But would it not have been more pertinent to state the behaviour of the anti-D.N.A. antibodies? Prolongation of survival in these animals may be due to a variety of factors somehow connected with the transfusions; and anyway the hypothesis to be tested was and is that the suppression of erythropoiesis curtails, in the genetically prone mammal, whether human or mouse, the synthesis of D.N.A. antibodies because of a reduction of D.N.A. discard. The astiopathogenesis of S.L.E. is already so much confused with non-proven hypotheses that any experiment designed to elucidate an important point, such as the causation of anti-D.N.A. immunity, should stick very strictly to the point it wishes to prove. Division of Hæmatology and Clinical Immunology, Ospedale Generale Regionale, 16132
Genova, Italy.
ALBERTO M. MARMONT.
MEDICAL
EQUIPMENT AND V.A.T. SIR,-If the introduction of value-added tax (V.A.T.) in the Finance Act of 1972 was the most publicised tax reform of the century, then the related Value Added Tax (Donated Medical Equipment) Order 1974 must be the best-kept secret. This order came into force on Aug. 23, 1974, but its existence is not generally known. It exempts from v.A.T. charges, equipment purchased with the funds of registered charities or by voluntary contributions and donated to designated hospital and research institutions for medical research, diagnosis, or treatment. Medical and research workers wishing to take advantage of v.A.T. exemption should enclose the following signed and dated statement with each equipment order: Value-added Tax " Item 3 of group 16 of schedule 4 to the Finance Act 1972. I hereby certify. that the equipment to which this order relates is being purchased with the funds of and/or with voluntary contributions collected from the public and that it will be ...
5.
Mitchell, J. R., Jollow, D. J., Potter, W. Z., Davis, D. C., Gillette, J. R., Brodie, B. B.J. Pharmac. exp. Ther. 1973, 187, 185.
1571 donated to . : . for use solely in medical research, diagnosis, or treatment. Further information can be obtained from local H.M. Customs and Excise offices or by applying to H.M. Stationery Office for Statutory Instruments 1974, no. 1331. "
W. E. Dunn Unit of Cardiology, Department of Biology, University of Keele,
Keele, Staffordshire ST5 5BG.
G. WRIGHT.
ARE RAUWOLFIA ALKALOIDS
CARCINOGENIC ?
SIR You have published epidemiological evidence which incriminates Rauwolfia alkaloids as a cause of breast cancer in women treated with these alkaloids for hypertension. 1-3 In the absence of direct experimental evidence on the carcinogenicity of rauwolfia alkaloids, the epidemiological data elicited some contradictory opinions in your correspondence columns. In a review,4 written without knowledge of the epidemiological data, I pointed out the desirability of testing rauwolfia alkaloids for carcinogenic action, on the basis of chemical considerations and the presence in their structures of a 3,4,5-trimethoxyphenyl moiety. The alkaloids are esters of reserpic acid. Rescinnamine is a 3,4,5-trimethoxycinnamoyl ester, while reserpine is a 3,4,5-trimethoxybenzoyl ester.5 They probably undergo hydrolysis and might yield, in the course of further metabolic changes in the body, activated entities similar to those derived from the
carcinogenic 3,4,5-trimethoxyphenylpropenaldehyde (3,4,5trimethoxycinnamaldehyde), a compound which can induce nasal squamous-cell carcinomas and certain other tumours in rats.6 Rauwolfia alkaloids have not only antihypertensive activity but also tranquillising action and have been used as mood-modifying agents. A trimethoxyphenyl moiety is present in several psychoactive compounds-e.g., elemicin and isoelemicin (constituents of nutmeg), anhalinine, mescaline, and some of the most effective synthetic amphetamines.’ Methoxy groups in appropriate positions increase the carcinogenic potency of several types of car-
cinogenic compounds.8 The 3,4,5-trimethoxyphenyl moiety is present in the antitumour agent podophyllotoxin, a lignan from Podophyllum peltatum, juniperus. virginiana, and from certain other juniperus species.9 Podophyllotoxin can induce striking hyperplastic and possibly also neoplastic lesions. It might be one of the factors which are responsible for the high incidence of mammary and hepatic tumours in mice of the C3H-AvyfB strain, in the laboratories of the National Institutes of Health in Bethesda, U.S.A., where y. virginiana wood-shavings are used as bedding. The tumour incidence in this strain of mice decreased drastically when the animals were brought to Australia, kept on bedding from Douglas fir wood, and given Australian commercial laboratory animals diet.9,10 1. Boston Collaborative Drug Surveillance Program. Lancet, 1974, ii, 669. 2. Armstrong, B., Stevens, N., Doll, R. ibid. p. 672. 3. Heinonen, O. P., Shapiro, S., Tuominen, L., Turunen, M. I. ibid. p. 675. 4. Schoental, R. in Chemical Carcinogens (edited by C. E. Searle). (In 5. 6.
the press.) Goodman, L. S., Gilman, A. The Pharmacological Basis of Therapeutics; p. 179. New York, 1965. Schoental, R., Gibbard, S. Br. J. Cancer, 1972, 26, 504; and unpub-
lished. 7. Kalbhen, D. A. Angew. Chem. Int. Ed. 1971, 10, 370. 8. Schoental, R. Nature, 1957, 183, 719. 9. Schoental, R. Cancer Res. 1974, 34, 2419. 10. Sabine, J. R., Horton, B. J., Wicks, M. B.J. natn. Cancer Inst. 50, 1237.
1973,
Chemical structures.
(a) Rescinnamine. (b) Reserpine.
(c) 3,4,5-trimethoxycinnamaldehyde. R=reserpic acid moiety.
The organs in which tumours develop as a result of exposure to a chemical carcinogen are strongly affected not
only by its structure, dose, and route of its entry, but also by the diet, as well as the hormonal and enzymatic fitness of the individual at the time of exposure. The carcinogenic entity which is formed metabolically from the trimethoxyphenyl compounds can at present be only surmised. Some evidence on its structure might be obtained by testing the various trimethoxyphenyl compounds and their metabolically formed derivatives for carcinogenic activity. Then it might become possible to formulate drugs which are free of carcinogenic potentialities and to warn people of the hazards of using those " natural " psychoactive products which
prove to
be carcinogenic in animals.
Department of Pathology, Royal Veterinary College, Royal College Street, London NW1.
R. SCHOENTAL.
RAUWOLFIA DERIVATIVES AND BREAST CANCER your editorial of Sept. 21 (p. 701) commenting the three articles on this subject in the same issue, you foresaw that critics would concentrate their attacks on the selection of controls. Professor Immich (Sept. 28, p. 774) was the first to open fire. We would rather comment on possible mechanisms whereby reserpine might influence the development of breast cancer. It has been suggested by all three groups that the increased frequency of breast cancer during treatment with reserpine may be related to increased prolactin secretion, since it is known that reserpine increases prolactin secretion in man and in rodents. The growth of
SiR,—In
on
7,12-dimethylbenzanthracene-induced mammary tumours in rats is accelerated by reserpine only if it is administered after the carcinogen. However, there are other mechanisms by which reserpine may influence cancer growth. Reserpine has been shown to have a profound influence on the immune system. Administered to adult rats, reserpine induces atrophy of the thymus, and impairs delayed hypersensitivity reactions and antibody formation. 1,2 The interrelationships between immunity and cancer are well recognised, cellular and humoral immunodeficiency facilitating the development of malignancies.3 These effects of reserpine would tend to promote tumour growth. On the other hand, other effects of reserpine have been 1. 2. 3.
Draškoci, M., Jankovič, B. D. Nature, 1964, 202, 408. Devoino, L. V., Yeliseyeva, L. S. Eur. J. Pharmac. 1971, 14, Gatti, R. A., Good, R. A. Cancer, 1971, 28, 89.
71.
Torrance, California 90509, U.S.A.
JOHN Z. MONTGOMERIE.
ÆTIOLOGY OF SYSTEMIC LUPUS ERYTHEMATOSUS
SiRj—Your editorial (Nov. 30, p. 1302) on systemic lupus erythematosus (S.L.E.) limited itself to speculation about a viral aaiology. In obscure immunological disorders this suggestion may be as acceptable as any other, but a hypothesis for s.L.E. should take into account the fact that a very similar syndrome can be caused by drugs: hydrallazine, procainamide, and isoniazid are well-known culprits.1 These drugs all happen to be subject to metabolic acetylation in the body, and individuals who are slow acetylators seem to be more susceptible to this particular drug-induced side-effect. 2,3 In addition, Reidenberg and Martin4 demonstrated a preponderance of slow acetylators in a group of 14 patients with " spontaneous " (i.e., not drug-induced) S.L.E. It would appear from these observations that some as yet unidentified environmental chemicals or drugs deserve equal consideration as causative agents. A satisfactory aetiological hypothesis should incorporate the above evidence into a reasonable explanation for the production of anti-D.N.A. antibody. May I suggest that the relative deficiency of acetylation may possibly favour an alternative metabolic pathway, producing chemically reactive metabolites, which then become antigenic as a result of covalent binding to nuclear material, thereby provoking the synthesis of anti-D.N.A. antibody ? This would explain why slow acetylation is one genetic feature of the so-called " lupus diathesis ".1 Such covalent nuclear binding could also be the mechanism of the s.L.E. syndrome described in association with anticonvulsant therapy.1 Epileptics are likely to have enhanced drugmetabolising enzyme activity, and in laboratory animals this phenomenon of enzyme induction has been shown 1. 2.
3. 4.
Alarcon-Segovia, D. Mayo Clin. Proc. 1969, 44, 664. Perry, H. M., Tan, E. M., Carmody, S., Sakamoto, A. J. Lab. clin. Med. 1970, 76, 114. Alarcon-Segovia, D., Fishbein, E., Alcala, H. Arthr. Rheum. 1971, 14, 748. Reidenberg, M. M., Martin, J. H. Drug Metabolism and Disposition, 1974, 2, 71.
potentiate the covalent tissue binding of cytotoxic metabolites of certain drugs and chemicals. By this argument, epileptics who are " induced " would therefore be more susceptible to a chemical which, through formation of a nucleophilic chemically reactive metabolite, causes s.L.E. If future work did happen to implicate a virus more clearly, one would then have to develop different hypotheses: that certain chemicals or their metabolites facilitate viral infection or influence the body’s immune response to it: or that chemicals and virus initiate the disease by independent use of the same aetiological mechanism. However, at the moment a chemical cause of spontaneous s.L.E. seems more likely than a viral one. I believe there is evidence that we would profit from a closer examination of the pathways of drug metabolism and the characteristics of tissue binding of drugs and metabolites in affected individuals and their relatives. to
Department of Therapeutics, Ninewells Hospital and Medical School, Dundee DD2 1UD.
JOHN MCEWEN.
LUPUS ERYTHEMATOSUS, D.N.A. ANTIBODIES, AND SUPPRESSION OF
ERYTHROPOIESIS that SiR,-Dr Gabrielsen (Nov. 9, p. 1116) suggests " in and antinuclear antibodies anti-D.N.A. develop erythropoietically stressed " women extruding erythroid nonfunctional nuclei, and-leaving aside the malaria issueshe feels that the prolongation of median survival in hypertransfused female NZB/NZW mice v. age-matched controls supports her hypothesis. But would it not have been more pertinent to state the behaviour of the anti-D.N.A. antibodies? Prolongation of survival in these animals may be due to a variety of factors somehow connected with the transfusions; and anyway the hypothesis to be tested was and is that the suppression of erythropoiesis curtails, in the genetically prone mammal, whether human or mouse, the synthesis of D.N.A. antibodies because of a reduction of D.N.A. discard. The astiopathogenesis of S.L.E. is already so much confused with non-proven hypotheses that any experiment designed to elucidate an important point, such as the causation of anti-D.N.A. immunity, should stick very strictly to the point it wishes to prove. Division of Hæmatology and Clinical Immunology, Ospedale Generale Regionale, 16132
Genova, Italy.
ALBERTO M. MARMONT.
MEDICAL
EQUIPMENT AND V.A.T. SIR,-If the introduction of value-added tax (V.A.T.) in the Finance Act of 1972 was the most publicised tax reform of the century, then the related Value Added Tax (Donated Medical Equipment) Order 1974 must be the best-kept secret. This order came into force on Aug. 23, 1974, but its existence is not generally known. It exempts from v.A.T. charges, equipment purchased with the funds of registered charities or by voluntary contributions and donated to designated hospital and research institutions for medical research, diagnosis, or treatment. Medical and research workers wishing to take advantage of v.A.T. exemption should enclose the following signed and dated statement with each equipment order: Value-added Tax " Item 3 of group 16 of schedule 4 to the Finance Act 1972. I hereby certify. that the equipment to which this order relates is being purchased with the funds of and/or with voluntary contributions collected from the public and that it will be ...
5.
Mitchell, J. R., Jollow, D. J., Potter, W. Z., Davis, D. C., Gillette, J. R., Brodie, B. B.J. Pharmac. exp. Ther. 1973, 187, 185.
1571 donated to . : . for use solely in medical research, diagnosis, or treatment. Further information can be obtained from local H.M. Customs and Excise offices or by applying to H.M. Stationery Office for Statutory Instruments 1974, no. 1331. "
W. E. Dunn Unit of Cardiology, Department of Biology, University of Keele,
Keele, Staffordshire ST5 5BG.
G. WRIGHT.
ARE RAUWOLFIA ALKALOIDS
CARCINOGENIC ?
SIR You have published epidemiological evidence which incriminates Rauwolfia alkaloids as a cause of breast cancer in women treated with these alkaloids for hypertension. 1-3 In the absence of direct experimental evidence on the carcinogenicity of rauwolfia alkaloids, the epidemiological data elicited some contradictory opinions in your correspondence columns. In a review,4 written without knowledge of the epidemiological data, I pointed out the desirability of testing rauwolfia alkaloids for carcinogenic action, on the basis of chemical considerations and the presence in their structures of a 3,4,5-trimethoxyphenyl moiety. The alkaloids are esters of reserpic acid. Rescinnamine is a 3,4,5-trimethoxycinnamoyl ester, while reserpine is a 3,4,5-trimethoxybenzoyl ester.5 They probably undergo hydrolysis and might yield, in the course of further metabolic changes in the body, activated entities similar to those derived from the
carcinogenic 3,4,5-trimethoxyphenylpropenaldehyde (3,4,5trimethoxycinnamaldehyde), a compound which can induce nasal squamous-cell carcinomas and certain other tumours in rats.6 Rauwolfia alkaloids have not only antihypertensive activity but also tranquillising action and have been used as mood-modifying agents. A trimethoxyphenyl moiety is present in several psychoactive compounds-e.g., elemicin and isoelemicin (constituents of nutmeg), anhalinine, mescaline, and some of the most effective synthetic amphetamines.’ Methoxy groups in appropriate positions increase the carcinogenic potency of several types of car-
cinogenic compounds.8 The 3,4,5-trimethoxyphenyl moiety is present in the antitumour agent podophyllotoxin, a lignan from Podophyllum peltatum, juniperus. virginiana, and from certain other juniperus species.9 Podophyllotoxin can induce striking hyperplastic and possibly also neoplastic lesions. It might be one of the factors which are responsible for the high incidence of mammary and hepatic tumours in mice of the C3H-AvyfB strain, in the laboratories of the National Institutes of Health in Bethesda, U.S.A., where y. virginiana wood-shavings are used as bedding. The tumour incidence in this strain of mice decreased drastically when the animals were brought to Australia, kept on bedding from Douglas fir wood, and given Australian commercial laboratory animals diet.9,10 1. Boston Collaborative Drug Surveillance Program. Lancet, 1974, ii, 669. 2. Armstrong, B., Stevens, N., Doll, R. ibid. p. 672. 3. Heinonen, O. P., Shapiro, S., Tuominen, L., Turunen, M. I. ibid. p. 675. 4. Schoental, R. in Chemical Carcinogens (edited by C. E. Searle). (In 5. 6.
the press.) Goodman, L. S., Gilman, A. The Pharmacological Basis of Therapeutics; p. 179. New York, 1965. Schoental, R., Gibbard, S. Br. J. Cancer, 1972, 26, 504; and unpub-
lished. 7. Kalbhen, D. A. Angew. Chem. Int. Ed. 1971, 10, 370. 8. Schoental, R. Nature, 1957, 183, 719. 9. Schoental, R. Cancer Res. 1974, 34, 2419. 10. Sabine, J. R., Horton, B. J., Wicks, M. B.J. natn. Cancer Inst. 50, 1237.
1973,
Chemical structures.
(a) Rescinnamine. (b) Reserpine.
(c) 3,4,5-trimethoxycinnamaldehyde. R=reserpic acid moiety.
The organs in which tumours develop as a result of exposure to a chemical carcinogen are strongly affected not
only by its structure, dose, and route of its entry, but also by the diet, as well as the hormonal and enzymatic fitness of the individual at the time of exposure. The carcinogenic entity which is formed metabolically from the trimethoxyphenyl compounds can at present be only surmised. Some evidence on its structure might be obtained by testing the various trimethoxyphenyl compounds and their metabolically formed derivatives for carcinogenic activity. Then it might become possible to formulate drugs which are free of carcinogenic potentialities and to warn people of the hazards of using those " natural " psychoactive products which
prove to
be carcinogenic in animals.
Department of Pathology, Royal Veterinary College, Royal College Street, London NW1.
R. SCHOENTAL.
RAUWOLFIA DERIVATIVES AND BREAST CANCER your editorial of Sept. 21 (p. 701) commenting the three articles on this subject in the same issue, you foresaw that critics would concentrate their attacks on the selection of controls. Professor Immich (Sept. 28, p. 774) was the first to open fire. We would rather comment on possible mechanisms whereby reserpine might influence the development of breast cancer. It has been suggested by all three groups that the increased frequency of breast cancer during treatment with reserpine may be related to increased prolactin secretion, since it is known that reserpine increases prolactin secretion in man and in rodents. The growth of
SiR,—In
on
7,12-dimethylbenzanthracene-induced mammary tumours in rats is accelerated by reserpine only if it is administered after the carcinogen. However, there are other mechanisms by which reserpine may influence cancer growth. Reserpine has been shown to have a profound influence on the immune system. Administered to adult rats, reserpine induces atrophy of the thymus, and impairs delayed hypersensitivity reactions and antibody formation. 1,2 The interrelationships between immunity and cancer are well recognised, cellular and humoral immunodeficiency facilitating the development of malignancies.3 These effects of reserpine would tend to promote tumour growth. On the other hand, other effects of reserpine have been 1. 2. 3.
Draškoci, M., Jankovič, B. D. Nature, 1964, 202, 408. Devoino, L. V., Yeliseyeva, L. S. Eur. J. Pharmac. 1971, 14, Gatti, R. A., Good, R. A. Cancer, 1971, 28, 89.
71.