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permit the responses P<0.05; regression 50% P<0.02) conclusion that chemotherapy is improved by taking into


account the circadian

rhythm of tumoral proliferation.

Institute de Pathologie,

Université de Liège, et Clinique Sainte Elisabeth,


4020 Liège, Belgium


SIR,-Your editorial of Aug. 21 (p. 405) was appreciated. Especially cogent, I think, were your remarks on the clinical usefulness of "correctly interpreted" measurements of serumdigoxin. You put the weight of your opinion behind the moderate view-neither complete espousal nor utter rejection of serum-digoxin levels-and left assessment of laboratory value in the hands of the experienced physician, which is where it


Had Lasagna qualified his similar remarks in an editorial which accompanied the provocative paper of Ingelfinger and Goldman,2 the case for clinical evaluation of laboratory values would have emerged much more clearly. I am sure that physicians are impatient with the clinical pharmacologists for creating confusion-particularly when they criticise published papers, tell us how to do it better, but then do not attempt it. I would plead for interpretation of serum-digoxin levels with intervening clinical judgment. If the physician’s judgment differs from the laboratory value, this should (and often does) force him to evaluate the test results more critically and brings them into line with the patient’s problem. This must result in better patient care.3 L’ntike Ingelfinger and Goldman, I believe that digoxin serum levels are of value in diagnosing digitalis intoxication; indeed, they may assist in the evaluation of management of overt toxicity with digoxin-specific antibodies.4

SIR There is now good evidence that phenytoin treatment of epilepsy is assisted by routine monitoring of the plasma drug concentration.1-6 Present methods for estimating plasmaphenytoin measure total drug levels, whereas only the non-protein-bound (free) fraction is considered to be biologically active. Since salivary phenytoin levels correlate closely with plasma-freeand cerebrospinal-fluid levels,. Dr Reynolds and her colleagues (Aug. 21, p. 384) have suggested that phenytoin therapy could be more appropriately monitored by measurement of drug concentrations in mixed saliva. If generally adopted, this method will generate large numbers of samples which cannot be accommodated readily by current gas-chromatographic techniques. In contrast, the radioimmunoassay for salivary phenytoin which we have described elsewhere9 is well suited for this application, as it is simple, specific, and sensitive (detection limit 0.4 nmol/1). Results on up to 100 samples can be obtained in less than 3 h. The small volume of sample required for radioimmunoassay (40 µl saliva for duplicate determination) makes unnecessary the external stimulation with citric acid advocated by Reynolds and her colleagues

Division of Cardiology, University of Arkansas for Medical Sciences/

V.A. Hospital Complex, Little Rock, Arkansas


72206, U.S.A.



SIR,—With reference to the article by Dr Reynolds and her colleagues (Aug. 21, p. 384), we should like to suggest that

Correlation between rate of phenytoin parotid saliva in one subject.

0, first experiment. Linear regression equation, 0444, with correlation coefficient (r)

salivary levels are especially valuable for monitoring antiepileptic-drug levels in outpatients, who can easily collect saliva samples at home. Plasma-levels of phenytoin, phenobarbitone, and primidone can be predicted from salivary concentrations regardless of other medication.5 With antiepileptic drugs which are not protein-bound, such as primidone or ethosuximide, salivary and plasma levels should be identical. In fact, 50 ethosuximide concentrations in saliva and plasma of 30 patients showed excellent agreement,

y = 1.956x —


in order



of correlation




mean±S.D.) of the plasma-concentration being found in the saliva. Owing to a low pKa value of 46, salivary levels of 28), dipropylacetate were only 0.9±0.5% (meanis.D., n even though about 6% of the plasma-concentration is reportedlv unbound,6 Therefore dipropylacetate levels cannot be =

(D.P.H.) secretion and flow-rate of



2 h later. Linear regression equation, y = 1.688x+ 0.024, with r = 0.999. The gradients of the lines represent the mean D.P.H. concentration (nmol/ml) in the parotid fluid during the time of the experiment.

, repeat


(Reproduced by kind Clinical Pharmacology.)


of the

Editor, British Journal of

to obtain adequate volumes of saliva for gas chromatography (0.5—2.0ml). Using this radioimmunoassay and techniques for collection of saliva from individual glands, we have investigated certain aspects of salivary phenytoin secretion which help to validate



of saliva measurements. 10

conveniently monitored in saliva. Buchthal, F., Svensmark, O., Schiller, P. J. Archs Neurol., Chicago, 1960, 2, 624. 2. Kutt, H., Penry, J. K. ibid. 1974, 31, 383. 3. Lund, L. ibid. p. 289. 4. Richens, A., Dunlop, A. Lancet, 1975, ii, 247. 5. Lancet, 1975, ii, 264. 6. Reynolds, E. H., Chadwick, D., Galbraith, A. W. Lancet, 1976, i, 923. 7. Bochner, F., Hooper, W. D., Sutherland, J. M., Eadie, M. J., Tyrer, J. H. Archs Neurol., Chicago, 1974, 31, 57. 8. Lambie, D. G., Paxton, J. W., Nanda, R. N., Johnson, E. H., Ratcliffe, J. G., Melville, I. D., Morrice, G. D. Scott. med. J. 1976, 21, 93. 9. Paxton, J. W., Rowell, F. J., Ratcliffe, J. G., Lambie, D. G., Nanda, R., Melville, I. D., Johnson, R. M. Eur. J. clin. Pharmac. (in the press). 10. Paxton, J. W., Whiting, B., Stephen, K. Br. J. clin. Pharmac. (in the press). 1.

Abtellung für Neurologie, Klinikum Charlottenburg, Freie Universität Berlin, 1000 Berlin 19, West Germany


1 Lasagna, L New Engl. J. Med. 1976, 294, 867. 2 Ingelfinger, J., Goldman, P. ibid. p. 867. 3 Doherty, J. E. in Controversy in Cardiology (edited by


Chung). New

York, 1976. 4 Smith, T. W., Haber, E., Yeatman, L., Butler, V. P., Jr. New Engl. J. Med. 1976, 294, 797 5 Schmidt, D., Kupferberg, H. J. Epilepsia, 1975, 16, 735. 6 Gugler, R Personal communication.