926 There have been many studies of enterotoxin production by E. coli strains from travellers’ diarrhoea although it is unfortunate that in most of the studies the serotypes have been incompletely reported and often completely omitted.9-11 Conversely, enterotoxin tests have been rarely used in studies of enteropathogenic E. coli from epidemics of infantile enteritis. We have used the infant mouse test9 for heat-stable enterotoxin (s.T.) and the Chinese hamster ovary-cell test’2 for heat labile enterotoxin (L.T.), in the study of epidemic strains of E. coli from well-documented outbreaks of infantile enteritis in the British Isles. There is little doubt that these strains were the causative organism of these outbreaks and yet we were unable to show enterotoxin production using either of these tests although control strains consistently behaved correctly. In Western Europe infantile enteritis remains the main problem associated with enteropathogenic E. coli, and at the present time clinical laboratories have no alternative to serotyping in their investigations of outbreaks. We recommend that serotyping of E. coli should continue and suggest that there is a need for extensive evaluation of the relationship between serotype, enterotoxin production, and enteropathogenicity. Conclusions resulting from the study of the travellers’ diarrhcea situation should not be extrapolated without qualification to the infantile-enteritis problem. Salmonella and Shigella Reference Laboratory, Central Public Health Laboratory, Colindale Avenue, London NW9 5HT.
B. ROWE R. J. GROSS SYLVIA M. SCOTLAND
CURABILITY OF BREAST CANCER
SIR,—Dr Brinkley and Dr Haybittle (July 19. p.95) point the limitations involved in defining "cure" in terms of general population mortality, since they found a rather high
to
death rate due to breast cancer in the cancer group followed for 25 years. They comment: "the probability of dying from cancer of the breast in this [cancer] group is still greater than that [probability] in the normal population, and one would therefore hesitate to say that they are cured." What Brinkley and Haybittle have shown is not so much a problem with defining "cure" in terms of general-population mortality, but rather a lack of knowledge on our part-in this case, about breast cancer. Without fairly extensive knowledge of causal mechanisms and initiating circumstances, there is little to rely on in applying the term "cure", except perhaps general-population mortality. The paradigm kind of cure is probably surgical removal of an offending organ or destruction of bacteria, where the destruction can be confirmed. In these instances, flare-ups can usually be distinguished from new cases, certainly an important factor in applying the term "cured." But cancer of the breast does not yet sit nicely near these paradigmatic cures. Brinkley and Haybittle’s conclusion that "one would hesitate to say they [the breast-cancer group] are cured" might better be expressed as an inability to say which members of the breast-cancer group are cured-in a sense of "cured" independent from general-population mortality. But it does not follow-nor, I realise, did they mean to imply that it didthat sorne members aren’t indeed cured. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania 17033, U.S.A.
Milton S.
ARTHUR ZUCKER
Ching, Y.-C., Williams, R. G., Harden, L. B. J. infect. Dis. 1972, 125, 407. 10. Evans, D. G., Evans, D. J., Gorbach, S. L. Infect. Immun. 1973, 8., 731. 11. Gorbach, S. L., Kean, B. H., Evans, D. G., Evans, D. J., Bessudo, D. New Engl.J Med. 1975, 292, 933. 12. Guerrant, R. L., Brunton, L. L., Schnaitman, T. C., Rebhurn, L. I., Gilman, A. G Infect Immun. 1974, 10, 320. 9. Dean, E G.,
SERUM-PHENYTOIN LEVELS
SIR,—Dr Richens and Mr Dunlop (Aug. 9, p. 247) propose rational approach to the monitoring of serum total-dilantin concentration based on the application of Michaelis Menten kinetics to the metabolism of dilantin which does not follow first-order kinetics.’-3 The use of their nomogram, which enables one to predict serum total-dilantin concentrations in a patient on various dosages of dilantin, has two major pitfalls for the unwary. Firstly, there is great inter and intra individual variation in both of the factors Vmax and Km (in the authors’ study of the order 100-1000 mg/day and 2.5-25 mg/l respectively). These can vary with age, sex, height, weight;° genetic differences;s duration of dilantin intake;6 competition from the major metabolite of dilantin;7 other drug intake;! and different disease states.s Secondly, while serum-protein-binding may have little effect on the metabolism of dilantin, since its volume of distribution is high,9 it does have a great effect on the serum concentration of free active drug present for a given serum total-dilantin concentration. 10 Protein binding of dilantin is affected by the serum-protein concentration and by the affinity of the protein for dilantin, and there are inter-individual differences for both."Serum-protein concentration can vary in the same individual with posture,12 venous stasis,different disease states, and possibly with age-" and affinity is affected by competition from the major metabolite of dilantin,7 other drugs," disease states,9 15 temperature," and other phy siological constituents (e.g., bilirubin and free fatty acids 16). Patients given a dose of dilantin predicted by the nomogram of Richens and Dunlop, or taking a constant dose of dilantin, could develop widely varying serum total-dilantin concentrations under certain conditions. These problems could be overcome by being aware of the inter and intra individual variation of Km and Vmax, giving small increments of dosage, and monitoring serum total-dilantin concentrations at appropriate intervals. If one could measure serum-free dilantin concentration one could overcome the problem of protein-binding. Although the free concentration can be estimated by ultrafiltration or possibly by a tourniquet test similar to that described for calcium,17 these methods are unfortunately not routinely available. Such measurements would be of great value in those patients in whom the serum-protein concentration or affinity might be significantly abnormal (e.g., in cases of hypoproteinaemia or in patients taking another drug which affects dilantin binding). a
Division of Clinical Chemistry, Institute of Medical and
Veterinary Science, Box 14, Rundle Street Post Office, Adelaide, South Australia.
P. J. PHILLIPS R. W. PAIN B. MCL. DUNCAN
1. 2.
Ashley, J. J., Levy, G. Res. Commun. chem Path. Pharmac. 1972, 4, 297 Gerber, N., Wagner, G. J. ibid. 1972, 3, 455. 3. Bochner, F., Hooper, W. D., Tyrer, J. H., Eadie, M. J. Neurol. Neurosurg Psychiat. 1972, 35, 873. 4. Houghton, G. W., Richens, A., Leighton, M. Br. J clin. Pharmac 1975, 2, 251. 5. Kult, H. Ann. N. Y. Acad. Sci. 1971, 179, 704. 6. Bochner, F., Hooper, W., Tyrer, J., Eadie, M. Proc Aust Ass Neurol 1973, 7.
9, 171. Litteri, J. M., Mellk, H., Louis, S., Kutt, H., Durante, P., Glasko. A New
Engl. J. Med. 1971, 285, 648. Kutt, H. in Antiepileptic Drugs, (edited by D. Woodbury), J K. Penry and R.P. Schmidt); chapt. 12. New York, 1972. 9. Odar Cederlöf, I., Borgå, O. Enr. J. clin. Path. 1974, 7, 31. 10. Hayes, M. J., Langman, M. J. S., Short, A. H. Br. J. clin. Pharmac 1975. 2, 73. 11. Lunde, K. M., Rane, A., Yaffe, S. J., Lund, L., Sjoqvist, F Clin Pharmac Ther. 1970, 11, 849. 12. Statland, B. E., Bokelund, H., Winkel, P. Clin. Chem. 1974, 20, 1513 13. Christiansen, C., Naestoft, J., Hvidberg, E. F., Larsen, N. E, Peterten, B Clinica. chim Acta, 1975, 62, 65. 14. Woodford-Williams, E., Alvarez, A. S., Webster, D., Landless, B., Divon, M P. Gerontologia, 1964, 10, 86. 15 Lund, L., Lunde, P. K., Rane, A., Borgå, O Sjoqvist, F Ann N YAcad Sci. 1971, 179, 723. 16. Fredholm, B. B. Rane, A., Persson, B. Pediat. Res 1975, 9, 26 17. Pain, R. W., Rowland, K. R., Phillips, P. J., Duncan, B McL Br med J (in the press). 8.
B. ROWE R. J. GROSS SYLVIA M. SCOTLAND
CURABILITY OF BREAST CANCER
SIR,—Dr Brinkley and Dr Haybittle (July 19. p.95) point the limitations involved in defining "cure" in terms of general population mortality, since they found a rather high
to
death rate due to breast cancer in the cancer group followed for 25 years. They comment: "the probability of dying from cancer of the breast in this [cancer] group is still greater than that [probability] in the normal population, and one would therefore hesitate to say that they are cured." What Brinkley and Haybittle have shown is not so much a problem with defining "cure" in terms of general-population mortality, but rather a lack of knowledge on our part-in this case, about breast cancer. Without fairly extensive knowledge of causal mechanisms and initiating circumstances, there is little to rely on in applying the term "cure", except perhaps general-population mortality. The paradigm kind of cure is probably surgical removal of an offending organ or destruction of bacteria, where the destruction can be confirmed. In these instances, flare-ups can usually be distinguished from new cases, certainly an important factor in applying the term "cured." But cancer of the breast does not yet sit nicely near these paradigmatic cures. Brinkley and Haybittle’s conclusion that "one would hesitate to say they [the breast-cancer group] are cured" might better be expressed as an inability to say which members of the breast-cancer group are cured-in a sense of "cured" independent from general-population mortality. But it does not follow-nor, I realise, did they mean to imply that it didthat sorne members aren’t indeed cured. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania 17033, U.S.A.
Milton S.
ARTHUR ZUCKER
Ching, Y.-C., Williams, R. G., Harden, L. B. J. infect. Dis. 1972, 125, 407. 10. Evans, D. G., Evans, D. J., Gorbach, S. L. Infect. Immun. 1973, 8., 731. 11. Gorbach, S. L., Kean, B. H., Evans, D. G., Evans, D. J., Bessudo, D. New Engl.J Med. 1975, 292, 933. 12. Guerrant, R. L., Brunton, L. L., Schnaitman, T. C., Rebhurn, L. I., Gilman, A. G Infect Immun. 1974, 10, 320. 9. Dean, E G.,
SERUM-PHENYTOIN LEVELS
SIR,—Dr Richens and Mr Dunlop (Aug. 9, p. 247) propose rational approach to the monitoring of serum total-dilantin concentration based on the application of Michaelis Menten kinetics to the metabolism of dilantin which does not follow first-order kinetics.’-3 The use of their nomogram, which enables one to predict serum total-dilantin concentrations in a patient on various dosages of dilantin, has two major pitfalls for the unwary. Firstly, there is great inter and intra individual variation in both of the factors Vmax and Km (in the authors’ study of the order 100-1000 mg/day and 2.5-25 mg/l respectively). These can vary with age, sex, height, weight;° genetic differences;s duration of dilantin intake;6 competition from the major metabolite of dilantin;7 other drug intake;! and different disease states.s Secondly, while serum-protein-binding may have little effect on the metabolism of dilantin, since its volume of distribution is high,9 it does have a great effect on the serum concentration of free active drug present for a given serum total-dilantin concentration. 10 Protein binding of dilantin is affected by the serum-protein concentration and by the affinity of the protein for dilantin, and there are inter-individual differences for both."Serum-protein concentration can vary in the same individual with posture,12 venous stasis,different disease states, and possibly with age-" and affinity is affected by competition from the major metabolite of dilantin,7 other drugs," disease states,9 15 temperature," and other phy siological constituents (e.g., bilirubin and free fatty acids 16). Patients given a dose of dilantin predicted by the nomogram of Richens and Dunlop, or taking a constant dose of dilantin, could develop widely varying serum total-dilantin concentrations under certain conditions. These problems could be overcome by being aware of the inter and intra individual variation of Km and Vmax, giving small increments of dosage, and monitoring serum total-dilantin concentrations at appropriate intervals. If one could measure serum-free dilantin concentration one could overcome the problem of protein-binding. Although the free concentration can be estimated by ultrafiltration or possibly by a tourniquet test similar to that described for calcium,17 these methods are unfortunately not routinely available. Such measurements would be of great value in those patients in whom the serum-protein concentration or affinity might be significantly abnormal (e.g., in cases of hypoproteinaemia or in patients taking another drug which affects dilantin binding). a
Division of Clinical Chemistry, Institute of Medical and
Veterinary Science, Box 14, Rundle Street Post Office, Adelaide, South Australia.
P. J. PHILLIPS R. W. PAIN B. MCL. DUNCAN
1. 2.
Ashley, J. J., Levy, G. Res. Commun. chem Path. Pharmac. 1972, 4, 297 Gerber, N., Wagner, G. J. ibid. 1972, 3, 455. 3. Bochner, F., Hooper, W. D., Tyrer, J. H., Eadie, M. J. Neurol. Neurosurg Psychiat. 1972, 35, 873. 4. Houghton, G. W., Richens, A., Leighton, M. Br. J clin. Pharmac 1975, 2, 251. 5. Kult, H. Ann. N. Y. Acad. Sci. 1971, 179, 704. 6. Bochner, F., Hooper, W., Tyrer, J., Eadie, M. Proc Aust Ass Neurol 1973, 7.
9, 171. Litteri, J. M., Mellk, H., Louis, S., Kutt, H., Durante, P., Glasko. A New
Engl. J. Med. 1971, 285, 648. Kutt, H. in Antiepileptic Drugs, (edited by D. Woodbury), J K. Penry and R.P. Schmidt); chapt. 12. New York, 1972. 9. Odar Cederlöf, I., Borgå, O. Enr. J. clin. Path. 1974, 7, 31. 10. Hayes, M. J., Langman, M. J. S., Short, A. H. Br. J. clin. Pharmac 1975. 2, 73. 11. Lunde, K. M., Rane, A., Yaffe, S. J., Lund, L., Sjoqvist, F Clin Pharmac Ther. 1970, 11, 849. 12. Statland, B. E., Bokelund, H., Winkel, P. Clin. Chem. 1974, 20, 1513 13. Christiansen, C., Naestoft, J., Hvidberg, E. F., Larsen, N. E, Peterten, B Clinica. chim Acta, 1975, 62, 65. 14. Woodford-Williams, E., Alvarez, A. S., Webster, D., Landless, B., Divon, M P. Gerontologia, 1964, 10, 86. 15 Lund, L., Lunde, P. K., Rane, A., Borgå, O Sjoqvist, F Ann N YAcad Sci. 1971, 179, 723. 16. Fredholm, B. B. Rane, A., Persson, B. Pediat. Res 1975, 9, 26 17. Pain, R. W., Rowland, K. R., Phillips, P. J., Duncan, B McL Br med J (in the press). 8.
