1407 stimulate the large-scale production of human interferon for further clinical trials. Universitätsaugenklinik, D-78 Freiburg im Breisgau, West

R. SUNDMACHER

Germany der Universität

Hygiene-Zentrum Abteilung für Virologie,

D. NEUMANN-HAEFELIN

Freiburg im Breisgau Central Public Health Laboratory,

K. CANTELL

Helsinki, Finland

METRONIDAZOLE AND TISSUE ZINC/IRON RATIO IN CANCER THERAPY

SIR,-Since the original suggestion’ that metronidazole may be

a useful adjunct in cancer radiotherapy a lot has been learned about its mechanism of action.2-6 In view of the probable wider use of the drug following the report of the phase-n clinical trial by Urtasun and colleagues’ I would like

make two points.

to

a cautionary note; peripheral neuropathy may occur patients after administration of metronidazole in high doses for extended periods. Patients particularly at risk are likely to be those who are in poor nutritional state possibly due to disease or to the previous administration of radiation or chemotherapeutic drugs such as bleomycin. It appears probable that the tissue zinc/iron ratio of such patients will be low.

First,

in

some

Secondly, I have suggested. that increased iron levels are likely to lead to increased radiation-induced tissue damage. Laboratory studies now show that zinc can compete effectively with iron for essential thiol groups and thereby protect them. Increased damage may also be associated therefore with a decreased level of zinc, so the zinc/iron ratio is the more likely critical variable. Further experiments to substantiate these findings are in progress. Meanwhile it is of interest to point out that the metabolism of metronidazole by anaerobic bacteria, which involves iron-sulphur systems, is considerably inhibited by zinc.9-11 Photosensitisation of the skin, an effect closely related to radiosensitisation, is alleviated by zinc. In. acute intermittent porphyria porphyrins are excreted as zinc complexes and peripheral neuropathy is common. In congenital porphyria, the porphyrins are excreted uncomplexed and the skin is very sensitive to light.12 Bleomycin increases the sensitivity of mouse skin to radiation damage. Decreases in serum-zinc after administration of the drug correlate .well with the onset of skin

lesions.3

°

;.

A knowledge of the tissue zinc and iron levels may thus be useful in determining not only the safe levels of metronidazole or a related drug but also the actual doses of radiation or chemotherapeutic drugs to be given.

Biochemistry Department, Brunel University, Uxbridge, Middlesex UB8 3PH 1. 2. 3.

SIR,-Dr Reynolds and his colleagues (May 1, p. 923) suggest that "many epileptic patients could be satisfactorily treated with one drug instead of the polypharmacy which they usually receive." Their findings are neither surprising nor new. The institution of antiepileptic drug therapy with one medication has been standard at the Johns Hopkins Hospital epilepsy clinic since 1945, and we first published this precept in 1954.1 Unfortunately, the policy of initiating anticonvulsant therapy with two or three drugs persists. This is not a scientific approach and therapy prescribed in this manner presents many problems in patients whose seizures are not, by chance, controlled. Our objections are fourfold: (1) When two or more drugs are initially prescribed and the patient subsequently manifests an untoward reaction such as a cutaneous eruption or drowsiness, it may be difficult to determine which drug was responsible. (2) In patients who continue to experience seizures, the physician has no alternative but to increase the dosages of all the drugs or "to toss a coin" to decide which should be increased. (3) Since the number of effective drugs is-relatively small and because the optimal dosage of each medication varies from patient to patient, the physician may exhaust the anticonvulsant armamentarium before any one drug has been given a satisfactory trial. (4) Polypharmacy invites the possibility of drug interaction: The use of a multiple anticonvulsant drug programme on the grounds of synergism has been challenged by Buchthal and Lennox-Buc6thal:Z "There is a venerable clinical belief that a combination of anticonvulsant drugs is more apt to control seizures than one, and there is even a school which advocates giving a number of drugs in small doses, in the belief that toxic effects will be avoided and that the drugs potentiate each other in an anticonvulsant effect. There is no decisive proof that this is so, documented by the serum concentration." We agree. One of us has recommended that a blood-lêvel be measured in every patient before assuming that an anticonvulsant is ineffective.3 The merit of this advice was also demonstrated by Dr Reynolds and his colleagues: "... without the guidance of serum concentrations sixteen [patients] (54%) might have been treated with a further drug." Many physicians now claim that,measurenients of serum levels are indispensible in the management of epilepsy. However, our 15 years’ experience with phenobarbitone and phenytoin determinations has demonstrated that these measurements need not be routine in every patient. Serum levels have little to offer when. the patient responds satisfactorily to drug therapy and when the physician knows the side-effects of antiepileptic medications. The indications we use for the determination of anticonvulsant drug blood levels are. described else’

ROBIN L. WILLSON

Foster, J. L., Willson, R. L. Br. J. Radiol. 1973, 46, 234. Asquith, J. C., Foster, J. L., Willson, R. L., Ings, R. J. M., McFadzean, J. A. ibid. 1974, 47, 474. Willson, R. L., Cramp, W. A., Ings, R. M. J. Int. J. Radiat. Biol. 1974, 26, 557.

.

where.4

of measuring,drug concentrations has been to the extent that some practitioners now treat the exaggerated blood-level instead of the patient. We have often been asked whether phenytoin should be discontinued in uncontrolled patients with "maximal therapeutic" serum levels of 20 (ig/ml. In patients with phenytoin blood-levels of 20fLglml who are free of signs of toxicity but continue to have seizures, we increase the dosage until they present clinical symptoms of overdosage or a satisfactory response. We have even been asked whether the phenytoin dose should be increased in seizure-free The

Willson, R. L., Searle, A. J. F. Nature, 1975, 255, 498. Foster, J. L., Willson, R. L. in Chemotherapy (Proc. IX int. Congr. Chemother.) (edited by K. Hellmann and T. A. Connors); vol. vii, p. 215. New York, 1976. 6. Foster, J. L., Conroy, P. J., Searle, A. J. F., Willson, R. L. Br. J. Cancer, 1976, 33, 485. 7. Urtasun, R., Band, P., Chapman, J. D., Feldstein, M. L., Mielke, B., Fryer, C. New Engl. J. Med. (in the press). 8. Willson, R. L. Lancet, 1976, i, 304. 9. Willson, R. L. ibid. 1974, i, 810. 10. Eakins, M. N., Conroy, P. T., Searle, A. J., Slater, T. F., Willson, R. L. Biochem. Pharmac. 1976, 25, 1151. 11. Searle, A. J. F., Willson, R. L. Xenobiotica, (in the press). 12. Watson, C. J., Larson, E. A. Physiol. Rev. 1947, 27, 478. 13. Leith, J. T., Lewinsky, B. S., Schilling, W. A. Radiat. Res. 1975, 61, 100. 4. 5.

ONE-DRUG REGIMENS FOR EPILEPSY

importance

Diagnosis and Treatment of Convulsive Disorders in Springfield, Illinois, 1954. 2. Buchthal, F., Lennox-Buchthal, M. A. in Antiepileptic Drugs (edited by D. M. Woodbury, J. K. Penry, and R. P. Schmidt). New York, 1972. 3. Livingston, S. in Current Pediatric Therapy (edited by S. S. Gellis and B. M. Kagan). Philadelphia, 1973. 4. Livingston, S., Berman, W., Pauli, L. L. J. Am. med. Ass. 1975, 232, 60. 5. Borofsky, L. G., Louis, S., Kutt, H., Roginsky, M. J. Pediat. 1972, 81, 995.

1.

Livingston,

Children.

S. The