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SERUM-GENTAMICIN
1185
refurbished sanctions other horrors, a secret plan 14, including, among is " intended to which formula for general practice cause the maximum discomfort to the administration with the minimum of inconvenience to the doctor " and which " should demonstrate to patients the cost of medical care in current values of money". The announcement of this plan last week was described by the B.M.J. as " well-timed ". In cricket, they say, timing is everything: if the same goes for public relations, then the perpetrator of this lamentable stroke should be trudging back to the pavilion. These agitations have a familiar feverishness about them, and a new danger; for they come in the worst year ever for the N.H.S. If (and we doubt it) the issue of private beds is " being used as a political smokescreen to hide the Government’s refusal to face the realities of the N.H.S.’s current financial crisis ",3 then the hostilities of the B.M.A. and the H.C.S.A. can scarcely be said to have improved the public’s range of vision. The bewildered community has a right to ask that the air be cleared and that the N.H.S. be given all possible support by Government and profession. The cry may be in vain: if the country is doomed to economic ruin and political upheaval, the N.H.S. is lost. But survival, in any part of the organism, can hardly be encouraged by displays of disruptive militancy from those far more fortunate in money, possessions, and position than mostdisplays which carry the threat of dismemberment for a structure of health care on which the citizens have placed a high value. B.M.A.’s
resurrected
and
SERUM-GENTAMICIN ARGUMENT 15,16 about serum-gentamicin concentrations after intravenous bolus injection 17-19 has centred on the question of whether serum levels during the first 10 minutes after the cessation of injection exceed the toxic level, which some take to be 12-5 µg. per ml. Is this flurry of activity much ado about nothing ? No investigation has yet defined conclusively a peak serum level beyond which the risk of ototoxicity increases. Jackson and Arcieri 20 in an exhaustive retrospective investigation into ototoxicity were wise enough to skirt this issue, and, as Hewitt 21 points out, most investigators tentatively suggest a level of 12-15 µg. per ml. as being " potentially " ototoxic. Furthermore, ototoxicity may arise when serum levels are below 10 µg. per ml. 22 Perhaps the real problem is that relating toxicity to a peak level is an oversimplification. Line et al. 23 14. ibid.
p. 357.
15. Van de Walle, J., Adriaensen, H. Lancet, Aug. 21, 1974, p. 525. 16. Michel, J., Sacks, T., Stressman, J., Licht, A. ibid. 17. Stratford, B. C., Dixson, S., Cobcroft, A. J. ibid. 1974, i, 378. 18. George, R. H., Bint, A. J., Prangnell, D. R. ibid. p. 576. 19. Bailey, R. R., Lynn, K. L. ibid. p. 730. 20. Jackson, G. G., Arcieri, G. J. infect. Dis. 1971, suppl. 124, p. 130. 21. Hewitt, W. L. Acta path. microbiol. scand. B, 1973, 81, suppl. 241, p.
22. 23
151.
Tjernström, Ö., Banck, G., Belfrage, S., Juhlin, I., Nordström, L., Toremalm, N. G. ibid. p. 73. Line, D. H., Poole, G. W., Waterworth, P. M. Tubercle, 1970, 51, 76.
observed during antituberculous therapy that streptomycin ototoxicity was related to the low serum concentrations just before a dose (trough levels) and
peak levels; and now other workers 24,25 report that ototoxicity associated with gentamicin therapy is related to trough levels or to a mathematical function of trough levels and length of administration. Experiments in animals 26 show that diffusion of another aminoglycoside, kanamycin, into and particularly out of the lymph of the inner ear is very slow, as might be expected for a large, lipid-insoluble molecule, suggesting that concentrations there and the ensuing toxicity may be related more to total diffusion pressure from the blood (reflected by part or all of the area under a blood-concentration curve) rather than to a transient peak. The most important known risk factor for ototoxicity associated with gentamicin therapy is impairment of renal function 20,25, 27—a state which leads to large increases in trough levels even when dosage is modified to give suitable peak levels. There may, of course, be other factors contributing to gentamicin ototoxicity in renal failure. There are differences in reported serum levels when gentamicin is given on a body-weight basis. Although this may represent biological variation in the small number of subjects studied, it may just as well be not
to
due to technical errors in assay 18 or to a lack of technical standardisation between centres. Quality-control results for gentamicin assays in the U.K. show that many laboratories have trouble in achieving an accuracy acceptable for clinical assays-let alone the more precise requirements for pharmacological studies. Under the circumstances, future reports should perhaps incorporate some statistical value (such as 95% confidence limits) for the accuracy of the assay method. Furthermore, it would be useful for workers to exchange samples, so as to ensure national and international standardisation. Verification of a new or modified technique by doubling-dilution tube assays 2B is unsuitable because this method cannot give accurate results over the range of therapeutic serum levels.
BEYOND THE EXAMINING FINGER
MANY organisations have made early diagnosis, by clinical and ancillary methods, the spearhead of attempts to control cancer. Therefore it is a serious matter when a shift in the pattern of cancer devalues one of the simplest of clinical diagnostic methods. Yet this is believed to have happened in the U.S.A. with regard to rectal cancer.29 The longstanding dogma is that most rectal cancers can be palpated by an examining finger inserted via the anus-in other words, that most arise or extend to within 6 cm. of the anusand that the rectal is a vital part of a medical examination. Now striking differences have emerged in the 24.
Nordström, L., Banck, G., Belfrage, S., Juhlin, I., Tjernström, Ö., Toremalm, N. G. Acta path. microbiol. scand. B, 1973, 81, suppl. 241, p. 58.
25. Mawer, G. E., Ahmad, R., Dobbs, S. M., McGough, J. G., Lucas, S. B., Tooth, J. A. Br. J. clin. Pharm. 1973, 1, 45. 26. Voldrich, L. Acta otolaryng. 1965, 60, 243.
Banck, G., Belfrage, S., Juhlin, I., Nordström, L., Tjernström, Ö., Toremalm, N. G. Acta path. microbiol. scand. B, 1973, 81, suppl. 241, p. 54. 28. Edmunds, P. N., Heddle, A. C. Lancet, Aug. 31, 1974, p. 526. 29. Berg, J. W., Howell, M. A. Cancer, 1974, 34, suppl., p. 807. 27.
refurbished sanctions other horrors, a secret plan 14, including, among is " intended to which formula for general practice cause the maximum discomfort to the administration with the minimum of inconvenience to the doctor " and which " should demonstrate to patients the cost of medical care in current values of money". The announcement of this plan last week was described by the B.M.J. as " well-timed ". In cricket, they say, timing is everything: if the same goes for public relations, then the perpetrator of this lamentable stroke should be trudging back to the pavilion. These agitations have a familiar feverishness about them, and a new danger; for they come in the worst year ever for the N.H.S. If (and we doubt it) the issue of private beds is " being used as a political smokescreen to hide the Government’s refusal to face the realities of the N.H.S.’s current financial crisis ",3 then the hostilities of the B.M.A. and the H.C.S.A. can scarcely be said to have improved the public’s range of vision. The bewildered community has a right to ask that the air be cleared and that the N.H.S. be given all possible support by Government and profession. The cry may be in vain: if the country is doomed to economic ruin and political upheaval, the N.H.S. is lost. But survival, in any part of the organism, can hardly be encouraged by displays of disruptive militancy from those far more fortunate in money, possessions, and position than mostdisplays which carry the threat of dismemberment for a structure of health care on which the citizens have placed a high value. B.M.A.’s
resurrected
and
SERUM-GENTAMICIN ARGUMENT 15,16 about serum-gentamicin concentrations after intravenous bolus injection 17-19 has centred on the question of whether serum levels during the first 10 minutes after the cessation of injection exceed the toxic level, which some take to be 12-5 µg. per ml. Is this flurry of activity much ado about nothing ? No investigation has yet defined conclusively a peak serum level beyond which the risk of ototoxicity increases. Jackson and Arcieri 20 in an exhaustive retrospective investigation into ototoxicity were wise enough to skirt this issue, and, as Hewitt 21 points out, most investigators tentatively suggest a level of 12-15 µg. per ml. as being " potentially " ototoxic. Furthermore, ototoxicity may arise when serum levels are below 10 µg. per ml. 22 Perhaps the real problem is that relating toxicity to a peak level is an oversimplification. Line et al. 23 14. ibid.
p. 357.
15. Van de Walle, J., Adriaensen, H. Lancet, Aug. 21, 1974, p. 525. 16. Michel, J., Sacks, T., Stressman, J., Licht, A. ibid. 17. Stratford, B. C., Dixson, S., Cobcroft, A. J. ibid. 1974, i, 378. 18. George, R. H., Bint, A. J., Prangnell, D. R. ibid. p. 576. 19. Bailey, R. R., Lynn, K. L. ibid. p. 730. 20. Jackson, G. G., Arcieri, G. J. infect. Dis. 1971, suppl. 124, p. 130. 21. Hewitt, W. L. Acta path. microbiol. scand. B, 1973, 81, suppl. 241, p.
22. 23
151.
Tjernström, Ö., Banck, G., Belfrage, S., Juhlin, I., Nordström, L., Toremalm, N. G. ibid. p. 73. Line, D. H., Poole, G. W., Waterworth, P. M. Tubercle, 1970, 51, 76.
observed during antituberculous therapy that streptomycin ototoxicity was related to the low serum concentrations just before a dose (trough levels) and
peak levels; and now other workers 24,25 report that ototoxicity associated with gentamicin therapy is related to trough levels or to a mathematical function of trough levels and length of administration. Experiments in animals 26 show that diffusion of another aminoglycoside, kanamycin, into and particularly out of the lymph of the inner ear is very slow, as might be expected for a large, lipid-insoluble molecule, suggesting that concentrations there and the ensuing toxicity may be related more to total diffusion pressure from the blood (reflected by part or all of the area under a blood-concentration curve) rather than to a transient peak. The most important known risk factor for ototoxicity associated with gentamicin therapy is impairment of renal function 20,25, 27—a state which leads to large increases in trough levels even when dosage is modified to give suitable peak levels. There may, of course, be other factors contributing to gentamicin ototoxicity in renal failure. There are differences in reported serum levels when gentamicin is given on a body-weight basis. Although this may represent biological variation in the small number of subjects studied, it may just as well be not
to
due to technical errors in assay 18 or to a lack of technical standardisation between centres. Quality-control results for gentamicin assays in the U.K. show that many laboratories have trouble in achieving an accuracy acceptable for clinical assays-let alone the more precise requirements for pharmacological studies. Under the circumstances, future reports should perhaps incorporate some statistical value (such as 95% confidence limits) for the accuracy of the assay method. Furthermore, it would be useful for workers to exchange samples, so as to ensure national and international standardisation. Verification of a new or modified technique by doubling-dilution tube assays 2B is unsuitable because this method cannot give accurate results over the range of therapeutic serum levels.
BEYOND THE EXAMINING FINGER
MANY organisations have made early diagnosis, by clinical and ancillary methods, the spearhead of attempts to control cancer. Therefore it is a serious matter when a shift in the pattern of cancer devalues one of the simplest of clinical diagnostic methods. Yet this is believed to have happened in the U.S.A. with regard to rectal cancer.29 The longstanding dogma is that most rectal cancers can be palpated by an examining finger inserted via the anus-in other words, that most arise or extend to within 6 cm. of the anusand that the rectal is a vital part of a medical examination. Now striking differences have emerged in the 24.
Nordström, L., Banck, G., Belfrage, S., Juhlin, I., Tjernström, Ö., Toremalm, N. G. Acta path. microbiol. scand. B, 1973, 81, suppl. 241, p. 58.
25. Mawer, G. E., Ahmad, R., Dobbs, S. M., McGough, J. G., Lucas, S. B., Tooth, J. A. Br. J. clin. Pharm. 1973, 1, 45. 26. Voldrich, L. Acta otolaryng. 1965, 60, 243.
Banck, G., Belfrage, S., Juhlin, I., Nordström, L., Tjernström, Ö., Toremalm, N. G. Acta path. microbiol. scand. B, 1973, 81, suppl. 241, p. 54. 28. Edmunds, P. N., Heddle, A. C. Lancet, Aug. 31, 1974, p. 526. 29. Berg, J. W., Howell, M. A. Cancer, 1974, 34, suppl., p. 807. 27.