METHOTREXATE IN PSORIASIS

205 tests were repeated that afternoon, when the second wave was always found to have disappeared; they were tested again thereafter daily for a week or until the test returned to normal. Although a very few of the volunteers might have become " spontaneous non-responders ",’ it will be seen that this test was always abnormal for 2-6 days even after the ingestion of a single, subclinical dose of 0-15 g. of aspirin. The other tests affected by aspirin also remained abnormal for roughly the same time. P.R.P. collected into heparin did not show these clearcut abnormalities so regularly. It was also shown that the addition of a tenth part of normal P.R.P. regularly corrected the abnormal test of P.R.P. prepared from a volunteer a day after aspirin ingestion. Normal platelet-poor plasma did not however have this corrective effect. These findings suggest that aspirin produces a permanent block in some specific metablic pathway, presumably involving the release of intrinsic A.D.P. from the platelet. It may even damage the megakaryocytes, since apparently 2-6 days must elapse before a volunteer has sufficient normal platelets to give a normal response to adrenaline. The only other example of a longstanding effect of small doses of aspirin seems to be that related to the erythema produced by thurfyl nicotinate.8 It may be relevant that in other situations salicylates uncouple oxidative phosphorylation.9 I agree with Dr. Evans and his colleagues that aspirin ingestion can alter some aspects of platelet physiology which are now shown to persist for days. Aspirin ingestion should always be considered when a mild bleeding diathesis or abnormal tests are found. Since this drug produces these clearcut changes it almost certainly has some effect in vivo, and Dr. Weiss and Dr. Aledort are not the first to report a lengthening of the Ivy bleeding-time. It may well also have an effect on thrombosis.

figure, and the

This work was carried out during the tenure of a grant from the Wellcome Trust which is gratefully acknowledged, as is the technical assistance of Mrs. S. Shoobridge and Miss G. Dore. Portsmouth and Isle of Wight Area Pathological Service, Milton Road, Portsmouth, Hants.

J. R. O’BRIEN.

INFECTIVE HEPATITIS SIR,-In your annotation (Jan. 13, p. 79) you refer to my figures drawn from experience of the disease in Leicester. In support of a statement that the " high infectivity of hepatitis is now beyond dispute " you cite the Leicester 10 and Bristol 11 outbreaks in which " nearly 40% of children and 10% of adults in infected households contracted clinical disease." These percentages, however, included the primary cases in each household and are therefore not a true indication of the degree of infectivity of the disease within the household. The relevant figure for this purpose is of course the secondary attack-rate, which in Leicester was 11-8% amongst child family contacts and 1-9%amongst adult family contacts. Mosley et al.12 quoted an overall secondary attack-rate amongst family contacts not protected with y-globulin of 10%. In the Leicester outbreak attack-rates amongst less intimate contacts (e.g., in schools) were, generally speaking, considerably lower than this. These figures of course throw a somewhat different light on the infectivity of the disease from that implied in your annotation, although of course they refer only to clinical illness and do not take into account subclinical cases. St. Albans Divisional Health and Welfare Executive, Hertfordshire County Council, St. Albans, Herts. 7. 8.

C. BURNS.

O’Brien, J. R. ibid. 1964, 202, 1188. Adams, S. S., Cobb, R. Salicylates. An International Symposium; p. 127. London, 1963. 9. Smith, M. J. H., Smith, P. K. The Salicylates; p. 58. London, 1966. 10. Bothwell, P. W., Martin, D., Macara, A. W., Skone, J. F., Wofinden, R. C. Br. med. J. 1963, ii, 1613. 11. Burns, C. ibid. 1967, iii, 773. 12. Mosley, W. H., Speers, J. F., Chin, T. D. Y. Am. J.publ. Hlth, 1963, 53, 1603.

METHOTREXATE IN PSORIASIS SIR,-It is ingenuous of Dr. Greenwald (Jan. 13, p. 97) to suggest that folic-acid deficiency alone is likely to explain the increased susceptibility of some psoriatic patients to the action of methotrexate. It has been suspected for some years that folate deficiency may condition such susceptibility in malnourished subjects.1 Barbiturates and nitrofurantoin given over long periods have also been reported to impair folic-acid absorption and may thus enhance the effect of folic-acid antagonists,2 but other drugs may possibly have the same effect in different ways. Sulphonamides,3 and salicylate,’4 displace methotrexate from plasma-proteins in vitro, leading to an increase in unbound-drug concentration; furthermore, therapeutic blood-levels of salicylate, as might be given for associated psoriatic arthritis, impair the renal clearance of methotrexate.4 The toxicity of methotrexate probably depends as much on the duration as on the height of blood and tissue-fluid levels of unbound drug. Three of the patients who have died following therapy5 had just received 5 mg. daily by mouth for at least 5 days, a dosage level which some would consider dangerously high. It may also be relevant that most of the methotrexate fatalities have occurred in patients who had previously received systemic steroid therapy for their psoriasis.56 It is not impossible that steroids conditioned their abnormal responses to methotrexate. Dr. Greenwald’s suggestion of giving leucovorin before methotrexate in patients suspected of being folate deficient requires comment. Dean and Hinshelwoodhave argued that restoration of- a missing metabolite needed for cell division might induce a phase of mitotic synchrony in which a cell population would divide in step instead of at random. This might temporarily increase the susceptibility of the cell population to methotrexate, which is known to have a direct effect on mitosis as well as on D.N.A. synthesis. A clinical instance in the management of leukxmia, supporting this possibility, has been reported by Dr. Hughes-Davies (Jan. 6, p. 52). Surely the obvious import of suspected increased susceptibility in a’patient deemed to need methotrexate should be to reduce the dose of the latter-not to prescribe another substance whose proposed antidotal use might be based on a auite sourious rationale. The Institute of Dermatology, St. John’s Hospital for Diseases of the London E.9.

Skin;

HARVEY BAKER.

VERVET-MONKEY-DISEASE AGENT IN TISSUE-CULTURE have SIR,-We given details8 of a disease in man associated with handling tissues and blood from vervet monkeys (Cercopithecus aethiops). Since then nine passages have been carried out in guineapigs and four in rhesus and vervet monkeys. Material

9th-passage guineapig spleen and rhesus-monkey liver previously passaged nine times in guineapigs and twice in vervet monkeys has been inoculated into baby-hamster kidney (B.H.K.) cells and the agent has now been maintained in four from

B.H.K.

passages. cells grown

B.H.K.

cytoplasmic,

on

coverslips developed basophilic, intrashapes and sizes

inclusion bodies of various

Scott, E. J., Auerbach, R., Weinstein, G. D. Archs Derm. 1964, 89, 550. 2. Ryan, T. J., Vickers, H. R., Salem, S. N., Callender, S. J., Badenoch, J Br. J. Derm. 1964, 76, 555. 3. Dixon, R. L., Henderson, E. S., Rall, D. P. Fedn Proc. Fedn Am. Socs exp. Biol. 1965, 24, 454. 4. Liegler, D., Henderson, E., Hahn, M. A., Oliverio, V. Proc. Am. Ass. Cancer Res. 1967, 8, 41. 5. Shrank, A. B., Blendis, L. M. Br. med. J. 1965, ii, 156. Haim, S., Alroy, G. Lancet, 1967, i, 1165. 6. Black, R. L., O’Brien, W. M., Van Scott, E. J., Auerbach, R., Zusen, A. Z., Bunim, J. J. J. Am. med. Ass. 1964, 189, 743. Lyell, A. Br. J. Derm. 1967, 79, 367. McKenzie, A. W., Aitken, C. V. E. ibid. p. 122. 7. Dean, A. C. R., Hinshelwood, C. Nature, Lond. 1967, 214, 1081. 8. Smith, C. E. G., Simpson, D. I. H., Bowen, E. T. W., Zlotnik, I. Lancet 1967, ii, 1119. 1. Van