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255 SERUM-PHENYTOIN LEVELS IN NINE SYMPTOMLESS MALES RECEIVING ORAL PHENYTOIN AS TABLETS CAPSULES OR SUSPENSION (S)
(T),
(C),
jjLg/ml,7 and most results were in the therapeutic range for this drug. Mean ± S. D. serum-phenytoin concentrations produced by different brands of phenytoin acid (twenty patients) and phenytoin sodium
(nineteen patients). toin levels than did the sodium salt. Dill et al. have stated that phenytoin acid may be preferable because the drug is present in plasma for longer after its administration than after equivalent doses of the sodium salt. We agree with them and with Richens and Dunlop3 who stated that many epileptics will be fully controlled at lower serum-phenytoin levels than 40 iillIoV1; in our trial a low mean serum-phenytoin of 24’8±8-9 mol/1 dunng a course of difhydan seemed not to provoke seizures. However, one cannot change brands of phenytoin without risking serious toxicity. Four patients on dihydantoin and two on enkefal course had a serum-phenytoin > 100 .mol/1. No correlation between particle size and serum concentration achieved was found.
P. TAMMISTO K. KAUKO M. VIUKARI
Rinnekoti Institute, 02980 Majalampi, Finland
SERUM-PHENYTOIN
SIR,- The assay of serum-phenytoin and its use in the management of epilepsy has received considerable attention lately 6The assay was set up in this laboratory using a gaschromatographic method with the simultaneous determination of phenobarbitone. Early on, samples were paired and assays were duplicated by the West Midlands Regional Toxicology Laboratory, Dudley Road Hospital, Birmingham with a considerable measure of agreement. Subsequently we have done 43 serum-phenytoin assays on twenty-six adult epileptic patients who had received the recommended dose of 5 mg phenytoin (diphenylhydantoin)/kg body-weight for at least 3 months, producing a mean serum-phenytoin of 3.22 .g/ml and range 0-22, and 11 assays in three children with a mean serum-phenytoin of 6.9 11-9/Ml and range 0-18. 28 sera from adults had 3 g/ml or less. The adults were receiving phenytoin tablets B.P. (Boots) and the children were on ’Epanutin’ suspension (phenytoin mixture B.P., Parke Davis). The therapeutic range for serum-phenytoin is undecided but the most generally applicable would seem to be an upper limit of 20 i’glml to possibly as low as 5 jig/ml. Thus in most of our adults therapeutic levels were not attained. During the same period we also did 31 serum-phenobarbitone assays on twentyfive epileptic patients and found a mean of 12.1(range 0-42) 5. Dill, 6.
W. A., Kazenko, A., Wolf, L. M., Glazko, A. J. J. Pharmac. exp. 1956, 118, 270. Richens, A., Dunlop, A. Lancet, 1975, ii, 247.
7 ibid. 1975, ii, 275.
The possible causes of the low serum-phenytoin levels in our adult patients are analytical error, patients not taking the dose prescribed, or differing bioavailability of the drug preparations in use. Analytical error is unlikely because many of our results were duplicated by the regional laboratory. It seems unlikely, too, that so many patients were not taking their tablets; the clinician B.E.M. was convinced that most were taking the tablets, and the phenobarbitone levels corroborate this. This left bioavailability, and to investigate this a small trial was set up on nine symptomless male laboratory staff. Three groups of three volunteers each received epanutin capsules, epanutin suspension, or phenytoin tablets B.P. (150 mg at 9 A.M. and 9 P.M.) for 8 days and then changed to one of the other preparations for a further 4 days. Blood was collected at about 4 P.M. on each day of venesection. No serious side-effects were encountered except that most of the men felt sleepy and the amount of minor bickering increased considerably in a normally happy laboratory. Two subjects dropped out of the trial after 4 days. The suspension was the most efficacious preparation, producing a level of 13 fLWml after 7 days in one man and 11 }jLg/ml in two others when they changed to suspension for the second part of the trial. The capsules produced reasonable phenytoin concentrations after 7 days, but levels built up by the suspension were difficult to maintain. The tablets on the other hand failed to achieve therapeutic levels after 7 days, and the reasonable levels obtained with the capsule fell when tablets were taken instead. It takes 7 or 8 days to achieve therapeutic levels of phenytoin with repeated oral dosage.8 Our small numbers preclude any definite conclusion, but our results, taken in conjunction with our previous findings, suggest a possible bioavailability problem with the phenytoin (diphenylhydantoin) sodium in tablet form. Department of Medicine, Department of Clinical Chemistry, County Hospital,
B. E. MILES E. C. ATTWOOD R. M. SEDDON
Hereford HR1 2ER
WHY DO YOU WRITE?
SiR,—There are plain answers to Dr Healy’s pious question (Jan. 24, p. 204) in George Orwell’s essay, Why I Write.9 Sheer egoism heads the list, trailing stuff like aesthetic enthusiasm (for medical writers, fun), historical impulse, and political purpose (medical intelligence). George Orwell fine writer. Do lofty motives make good papers? 28 Sopwell Lane, St Albans, Herts, AL1 1RR.
was a
very
THOMAS SHERWOOD
Ther. 8. 9.
Eadie, M. J., Tyrer, J. H. Anticonvulsant Drugs; p. 44. London, 1974. Orwell, G. in Decline of the English Murder and Other Essays; p. 180. Har mondsworth, Middlesex, 1965.
(T),
(C),
jjLg/ml,7 and most results were in the therapeutic range for this drug. Mean ± S. D. serum-phenytoin concentrations produced by different brands of phenytoin acid (twenty patients) and phenytoin sodium
(nineteen patients). toin levels than did the sodium salt. Dill et al. have stated that phenytoin acid may be preferable because the drug is present in plasma for longer after its administration than after equivalent doses of the sodium salt. We agree with them and with Richens and Dunlop3 who stated that many epileptics will be fully controlled at lower serum-phenytoin levels than 40 iillIoV1; in our trial a low mean serum-phenytoin of 24’8±8-9 mol/1 dunng a course of difhydan seemed not to provoke seizures. However, one cannot change brands of phenytoin without risking serious toxicity. Four patients on dihydantoin and two on enkefal course had a serum-phenytoin > 100 .mol/1. No correlation between particle size and serum concentration achieved was found.
P. TAMMISTO K. KAUKO M. VIUKARI
Rinnekoti Institute, 02980 Majalampi, Finland
SERUM-PHENYTOIN
SIR,- The assay of serum-phenytoin and its use in the management of epilepsy has received considerable attention lately 6The assay was set up in this laboratory using a gaschromatographic method with the simultaneous determination of phenobarbitone. Early on, samples were paired and assays were duplicated by the West Midlands Regional Toxicology Laboratory, Dudley Road Hospital, Birmingham with a considerable measure of agreement. Subsequently we have done 43 serum-phenytoin assays on twenty-six adult epileptic patients who had received the recommended dose of 5 mg phenytoin (diphenylhydantoin)/kg body-weight for at least 3 months, producing a mean serum-phenytoin of 3.22 .g/ml and range 0-22, and 11 assays in three children with a mean serum-phenytoin of 6.9 11-9/Ml and range 0-18. 28 sera from adults had 3 g/ml or less. The adults were receiving phenytoin tablets B.P. (Boots) and the children were on ’Epanutin’ suspension (phenytoin mixture B.P., Parke Davis). The therapeutic range for serum-phenytoin is undecided but the most generally applicable would seem to be an upper limit of 20 i’glml to possibly as low as 5 jig/ml. Thus in most of our adults therapeutic levels were not attained. During the same period we also did 31 serum-phenobarbitone assays on twentyfive epileptic patients and found a mean of 12.1(range 0-42) 5. Dill, 6.
W. A., Kazenko, A., Wolf, L. M., Glazko, A. J. J. Pharmac. exp. 1956, 118, 270. Richens, A., Dunlop, A. Lancet, 1975, ii, 247.
7 ibid. 1975, ii, 275.
The possible causes of the low serum-phenytoin levels in our adult patients are analytical error, patients not taking the dose prescribed, or differing bioavailability of the drug preparations in use. Analytical error is unlikely because many of our results were duplicated by the regional laboratory. It seems unlikely, too, that so many patients were not taking their tablets; the clinician B.E.M. was convinced that most were taking the tablets, and the phenobarbitone levels corroborate this. This left bioavailability, and to investigate this a small trial was set up on nine symptomless male laboratory staff. Three groups of three volunteers each received epanutin capsules, epanutin suspension, or phenytoin tablets B.P. (150 mg at 9 A.M. and 9 P.M.) for 8 days and then changed to one of the other preparations for a further 4 days. Blood was collected at about 4 P.M. on each day of venesection. No serious side-effects were encountered except that most of the men felt sleepy and the amount of minor bickering increased considerably in a normally happy laboratory. Two subjects dropped out of the trial after 4 days. The suspension was the most efficacious preparation, producing a level of 13 fLWml after 7 days in one man and 11 }jLg/ml in two others when they changed to suspension for the second part of the trial. The capsules produced reasonable phenytoin concentrations after 7 days, but levels built up by the suspension were difficult to maintain. The tablets on the other hand failed to achieve therapeutic levels after 7 days, and the reasonable levels obtained with the capsule fell when tablets were taken instead. It takes 7 or 8 days to achieve therapeutic levels of phenytoin with repeated oral dosage.8 Our small numbers preclude any definite conclusion, but our results, taken in conjunction with our previous findings, suggest a possible bioavailability problem with the phenytoin (diphenylhydantoin) sodium in tablet form. Department of Medicine, Department of Clinical Chemistry, County Hospital,
B. E. MILES E. C. ATTWOOD R. M. SEDDON
Hereford HR1 2ER
WHY DO YOU WRITE?
SiR,—There are plain answers to Dr Healy’s pious question (Jan. 24, p. 204) in George Orwell’s essay, Why I Write.9 Sheer egoism heads the list, trailing stuff like aesthetic enthusiasm (for medical writers, fun), historical impulse, and political purpose (medical intelligence). George Orwell fine writer. Do lofty motives make good papers? 28 Sopwell Lane, St Albans, Herts, AL1 1RR.
was a
very
THOMAS SHERWOOD
Ther. 8. 9.
Eadie, M. J., Tyrer, J. H. Anticonvulsant Drugs; p. 44. London, 1974. Orwell, G. in Decline of the English Murder and Other Essays; p. 180. Har mondsworth, Middlesex, 1965.