** The following letter from Sir Eric Scowen, on behalf of the Committee on Safety of Medicines, was sent to doctors in the U.K. on Oct. 6.-ED. L "The Committee on Safety of Medicines has considered the two reports on mortality among women using oral contraceptives, published in The Lancet of October 8, 1977. The first described the results of a study by the Royal College of General Practitioners (R.C.G.P.) and the second a study conducted by the Oxford Department of Social and Community Medicine in collaboration with the Family Planning Association. The numbers in the studies are too small to allow precise conclusions to be reached about the over-all risk of using oral contraceptives or any residual risk which may remain from previous use. However, the findings in both studies are in line with the trend noted in earlier investigations that the risk of arterial thrombosis with oral contraceptives increases with age-particularly in the later part of reproductive life-and that this risk is aggravated by cigarette smoking. In one study the figures show an excess mortality from subarachnoid haemorrhage both in users and in ex-users of oral contraceptives. There is no similar finding in the other study. Further studies will therefore be needed before any conclusion can be reached. During the course of these studies major changes have occurred in the composition of oral contraceptive products due to a progressive reduction in their oestrogen content. In addition, some preparations containing the progestogen, megestrol acetate, in use at the start of the investigations have been removed from the market. It is therefore impossible at present to make any reasonable assessment of the findings discussed in the two reports in relation to the oral contraceptives now currently in use. In the view of the Committee of Safety of Medicines the present studies do not indicate the necessity for any change in the warnings and precautions for oral contraceptives, except to emphasise the importance of the increased risk for women in the later age group, especially those who are cigarette smokers.""

expected superiority of a corticosteroid in



group in Cardiff confirms

eczema, and



that, for chronic hand

no active ingredients as effective 0.025% betametha("unguentum Merck") isone valerate over a one-month period. Clearly, the use of topical corticosteroids should be critically assessed by the prescriber who should realise that he is only temporarily damping down inflammation and that simpler (and cheaper) materials may be as effective. Pharmaceutical houses are similarly addicted. It is not their fault: they produce compounds which appear effective and which are prescribed extensively. Because topical corticosteroids have to be used over long periods and because the prescribers are hooked on them, large amounts are sold (sales of plain corticosteroid preparations in 1976-77 amounted to approximately LI0 million). For these reasons the pharmaceutical industry has been slow to realise that these products are far from ideal for the patient, and we are still some way off the production of compounds that have a more fundamental action than the suppression of inflammation. eczema at





was as

of Medicine, Welsh National School of Medicine, Cardiff CF4 4XN



SIR,-In your excellent editorial (Sept. 3, p. 487) you review the various undesirable effects of fluorinated steroids and conclude: "the hope must be that powerful anti-inflammatory agents can be developed which do not have ’fluorinated problems’ ". At the same time I read an equally authoritative article on corticosteroids in skin diseases by Dr D. D. Munro in the August issue of the Prescribers’ Journal. Munro states: "Most potent preparations are halogenated steroids, usually with one or more fluorine atoms, but neither the potency nor any complications are directly related to the fluorination, and equally potent non-halogenated compunds give rise to the same local and systemic side-effects". I am confused about these fundamentally opposite views on structure-activity relationships among the topical steróids. Elmdene Alcoholic Treatment Unit,


SIR,-The "jungle topical steroids" is more hazardous than your editorial (Sept. 3, p. 487) suggests. Although masked infection, skin atrophy, pituitary-adrenal axis suppression, and habituation have all correctly been highlighted, other dangers exist. It is not only patients and their dermatoses who become "hooked" on steroids; doctors are also easily addicted to prescribing them. They see the rapid effects of the corticosteroids on their patient’s abnormal skin and vicariously experience the relief of symptoms. Topical corticosteroids suppress the inflammatory response of skin disease although we are not sure how.’ They do not fundamentally influence the natural history of skin disease. Consequently, relief lasts only as long as the application. The dramatic response of acutely inflamed skin to topical corticosteroids causes prescribers to forget the mild (but safe and useful) anti-inflammatory effects of simple bland creams and other preparations containing materials such as zinc and tar. How such bland preparations work is as mysterious as the mode of action of corticosteroids but some placebo preparations have an antimitotic effect for inflamed epidermis2 and others seem to have a vasoconstrictor action.3 There have been few studies contrasting the action of corticosteroids with simpler remedies. However, one such trial4 failed to show the

Bexley Hospital, Bexley, Kent DA5




Wilson, L. C., Marks, R. in Mechanisms of Topical Corticosteroid Activity (edited by L. Wilson, and R. Marks). Edinburgh, 1976. 2. Tree, S., Marks, R. Br. J. Derm. 1975, 92, 195. 3. Woodford, R., Barry, B. W. ibid. 1973, 98, 53. 4. Medansky, R. S., Handler, R. M. Clin. Med. 1974, 81, 27. 1.

*** It is the fluorinated steroid that has mostly been misused, and it so happens it is only the fluorinated steroid that has a high inherent potency, interfering with the H.P.A. axis. Certainly, non-fluorinated steroids if used wrongly—e.g., with prolonged occlusion-have produced side-effects. For simplicity, all the difficulties were labelled "fluorinated problems", though it is not the fluorine component per se that is to blame.-ED.L. GLYCOSYLATED HÆMOGLOBIN IN DIABETES AND RENAL FAILURE your editorial (July 2, p. 22) you draw attention the increase of the glycosylated haemoglobin HbAlc in diabetes mellitus and the risk of reduced oxygen supply to the tissues. In renal failure, most patients have impaired glucose tolerance and those on chronic dialysis are usually dialysed against fluid with a high glucose content. It seems important therefore to study the level of HbA1c in patients on chronic dialysis in relation to their glucose metabolism. HbA1c was measured by the method of Trivelli et al, with minor modifications.1,2 In 18 normal subjects the HbAlc level



1. Trivelli, L.

A., Ranney, H. M., Lai, H. T. New Engl. J. Med. 1971, 284,

353. 2.


H. M


759 the


drugs during our trial

as a

predictable (or even reasonable)

factor. Department of Pharmacology and Therapeutics, London Hospital Medical College, CHAPUT D. M. C London E1 2AD





SIR,-Dr Roberts and his colleagues (Aug. 13, p. 319) described

Fig. 1-HbAl in normal subjects (A), patients on chronic dialysis (B), newly diagnosed insulin-dependent diabetics (C) and insulin-dependent diabetic outpatients (D). Fig. 2-Correlation between HbAle and blood-glucose after dialysis in patients on chronic dialysis.

3-6±1-6% (mean +S.D.), which accords with Trivelli’s In 6 newly diagnosed insulin-dependent diabetics, a of 7.9% to 14.2% was found, while in an unselected range group of insulin-dependent diabetic outpatients values varied from 4.6% to 11.4%.



In 30

patients on chronic dialysis (twice weekly for 6 to 9 h against fluid containing 5% w/v glucose) HbA1c was clearly increased and varied from 3.5 to 9-9% (6.3±1-5% meanis.D.) (fig. 1). As HbA1c reflects the degree of long-term blood-glucose regulation, we looked for a correlation between HbAl and glucose metabolism. The single point blood-glucose roughly reflects glucose metabolic efficiency after dialysis. There was no correlation between HbAlc levels and blood-glucose (r=0.37) (fig. 2). Taking into account the shortened life span of erythrocytes in chronic renal failure and the low level of HbAlc in young red cells,3 the HbAl levels in patients on chronic dialysis are rather high, especially since their glucose levels are only slightly raised. Factors other than chronic high blood-glucose levels may therefore influence the formation of HbA1c in patients on chronic dialysis. We are now investigating the role of uraemia and the effect of dialysis with a glucose-free dialysate.

of Internal Medicine and Ziekenhuis de Weezenlanden,



Zwolle, Netherlands



SIR,-Your reply to our letter (Oct. 1, p. 718) clarifies your problem admirably. It is indeed true that no-one could have known in advance how nasty practolol might be. But the situation where we lack knowledge must not be allowed to cloud the decision in those cases where we have it. A recent example from our own experience may help. In a trial of the culling of patients’ notes it was clear before the trial began that to cull a note which should not be culled would endanger the patient, but not to cull a note which should have been culled would be a mere nuisance. Asymmetric a boundaries were set for the test. We would contend that, on the basis of reasonable anticipation, one not only can but should set such boundaries for they represent the real risks, and costs, of the exercise to the researcher to the best of his knowledge at that time. This we have done, but do not regard the sudden change in the cost of 3

Fitzgibbons, J. F., Koler,


D., Jones, R. T. J. clin. Invest. 1976, 58, 820.

radioimmunoassay (R.I.A.) for MB creatine kinase (MB-c.K.). They claimed that the R.I.A. was more advantageous than electrophoresis for early detection of acute myocardial infarction (A.M.I.). In support of this claim they presented simultaneous determinations in one patient demonstrating that the R.I.A. detected. a significant increase in MB-c.K. 1 h earlier than did the electrophoretic method. It appears that the R.I.A. is slightly more sensitive than the electrophoretic method, but a

proper evaluation also demands information on the times taken to do these assays and on their specificities. Roberts et al. do not say how long their R.I.A. required, but it may take about 30 h, according to others.’ MB-c.K. is detectable by electrophoresis 6-8 h after onset of symptoms,2,3 and the deter-







mination need only take a few hours.4-6 Furthermore, BB-c.K. reacts in the R.I.A. method, which explains the statement: "Samples could be screened to verify the absence of BB by electrophoresis, with enzymatic detection, or by chromatographic fractionation". To demonstrate the sensitivity and specificity of our electrophoretic method for determination of MB-c.K., we report our results here. From October, 1976, to March, 1977, 466 patients were admitted to the coronary-care unit at Glostrup Hospital with suspected A.M.I. 45 died or were discharged before sufficient data were obtained. 20 had "questionable" A.M.I. This left 401 patients for further investigation. Bloodsamples were drawn on admission and thereafter about 12, 24, 36, 48, and 72 h after admission. MB-c.K., c.K., lactate dehydrogenase (L.D.H.) and aspartate aminotransferase (A.S.A.T.) were measured in duplicate. A.M.I. was diagnosed according to W.H.O. criteria without knowledge of the MB-c.K. results. The predictive values of a positive test and a negative test for the four measured enzyme activities and electrocardiography (E.c.G.) are given in the table. The predictive value of a negative test was very high for all enzymes, in contrast to the E.C.G. The predictive value for a positive test was very high for MB-c.K. and for E.c.G. but not for the three routine enzymes. We agree with Roberts et al. that early detection of A.M.I. is desirable, but we do not agree that electrophoresis is not sensitive enough. Furthermore, we think that if the R.I.A. ana1. Neumeier, D., Hofstetter, R., Glück, B. Clin. chim. Acta, 1977, 79, 107. 2. Roberts, R., Gowda, K. S., Ludbrook, P. A., Sobel, B. E. Am. J. Cardiol.

1975, 36, 433. 3. Roe, C. R., Limbird, L. E., Wagner, G. S. J. Lab. clin. Med. 1972, 80, 577. 4. Wong, P. C. P., Smith, A. F. Clin. chim. Acta, 1975, 65, 99. 5. Morin, L. G. Clin. Chem. 1977, 23, 205. 6. Grande, P., Christiansen, C., Næstoft, J. Unpublished.

Glycosylated haemoglobin in diabetes and renal failure.

758 ** The following letter from Sir Eric Scowen, on behalf of the Committee on Safety of Medicines, was sent to doctors in the U.K. on Oct. 6.-ED. L...
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