WHEAT SENSITIVE—BUT NOT CŒLIAC

43 world. The Hartlepool rate was high compared with other reported surveys but was significantly correlated with low socioeconomic status and prematurity. Over the decade 1960-69 housing conditions in Hartlepool improved considerably and it was concluded that when an attempt was made to unravel the various factors associated with death from s.l.D.S. housing would appear to be of less importance than poverty and low socio-economic status. These conclusions have been further reinforced by the review of the sodium levels in the water supply in Hartlepool as supplied by the Hartlepool Water Company. In the decade 1950-59 the average level of sodium was 92.3 parts per million. During the period 1955-62 there was a transitional period in which the quantity of domestic water supply from Dalton Piercey pumping station progressively increased and the older sources were phased out. From 1963 onwards domestic supplies (blended borehole waters) was supplied mainly from the Dalton Piercey pumping station. The average level of sodium in the decade 1960-69 was 47.9parts per million, a fall of almost 50%. In the decade, therefore, despite significant improvements in housing conditions and a significant fall in the level of water sodium there was not a significant fall in the incidence of S.LD.S. in Hartlepool. Hartlepool Health District, General Hospital, Hartlepool TS24 9AH

H. C. MILLIGAN

HYPERTRANSFUSION DURING REMISSION INDUCTION IN A.L.L.

SIR,-May I support the suggestions of Dr Willie.Since the Skipperzthere have been two bases for antileukxmic cytotoxic therapy-drugs that kill more malignant blasts than normal cells and regimens of similar toxicity to normal and neoplastic cells which exploit the faster regeneration of normal cells.3 Many antileukxmic regimens combine these principles. A careful examination of the kinetics of chemotherapy shows a third possibility, that of a treatment schedule which specifically protects normal cells by holding them in the intermitotic rest phase (Go) while leukaemic cells are permitted to replicate and suffer damage from cycle-stage-specinc agents such as antimetabolites and spindle inhibitors. Baron4 suggested that blocking the Hz receptors of marrow cells might prevent them from proliferating. If this applied to normal, but not neoplastic cells, Hz receptor blockers might be suitable. Cimetidine has now been used extensively, and very rarely causes marrow depression. It may still be worth investigating derivatives of metiamide in the hope of finding an agent which predictably and reversibly reduces marrow activity. work of

Because it is necessary to inhibit normal cells without inhicells toxic agents are unlikely to be useful. Pretreatment of patients with cyclophosphamide5 has been reported to accelerate marrow recovery from melphalan therapy but this effect was not attributed to marrow protection. The most hopeful possibility would be to use a normal feedback mechanism to which the neoplastic cells were insensitive. Many acute leuksmic patients receive granulocyte transfusions at the time of diagnosis. It would be interesting to know if granulocyte transfusions given before (and perhaps during) induction therapy can render the marrow less sensitive to the effects of antileukmmic drugs. Ford and Cullen6 make no mention of marrow recovery in their series of leukaemic patients treated prophylactically with granulocytes. However,

biting neoplastic

1. Willie. G R Lancet, 1978, ii, 1152 2. Skipper, H E. in Perspectives in Leukæmia edited by W. Dameshek and R N Dutcher p 187. New York, 1968 3. Spiers, A. S D in Clinics in Hæmatology, Volume 1. No. 1 edited by S. Roath p 127. London, 19-2 4 Bvron. J W. Lancet, 1976, ii, 1350 5 Hedley. D W., McElwain. T. J. Millar. J. L., Gordon. M. Y. Lancet, 1978, ii, 966. 6. Ford, J M. Cullen, M H. Exp Hœmat. 1977, 5, Supplement 65. 7. Sachs, L. Br J. Hœmat. 1978, 40, 509.

their study was of low-dose granulocyte transfusion (mean 14 - 9 x 109 cells on alternate days), and higher doses might be

required. Until the maturation of neoplastic cells can be manipulated and these cells rendered unable to proliferate7 any possible method of making chemotherapy more tolerable merits examination. Glasgow and West of Scotland Blood Transfusion Service,

Law Hospital, Carluke, Lanarkshire

ML8 5ES

R.

J. CRAWFORD

SIR,-Dr Toogood and colleagues have made

out a

very

granulopoiesis resulting from hypertransfusion in patients recovering from the induction phase of remission chemotherapy in acute leuka:mia. I think their comments on the meaning of this finding in terms of stem-cell competition (or perhaps clonal diversion) are of great interest. However, before we begin to apply hypertransfusion as a form of adjunctive therapy in unselected patients with acute leukaemia, it should be pointed out that there is evidence that while the leucocyte-count (or, more accurately, the blastcount) is high, transfusion even to "normal" levels may in itself be injurious. When the leucocyte-count is over 100 x 109/1 transfusion may be lethal in this disease.2 This can probably be explained on the basis of hyperviscosity and cerebrovascular reasonable

case

for increased

stasis due to the increased blast-count-a factor which is associated with poor prognosis in this disease.34 This tendency to hyperviscosity is partly countered by the low packed-cell volume found in many patients with acute leukaemia. If the haematocrit is corrected then viscosity, especially that measured at a low shear-rate, may well become pathologically raised and death may ensue. For this reason patients with higher blast-counts, especially in the range noted by Harris,2 would probably not benefit from transfusion or hypertransfusion at this stage of their disease. Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO9 4XY

S. ROATH

WHEAT SENSITIVE—BUT NOT CŒLIAC

Sir,-Dr Jones1 has drawn attention to the similar clinical presentation of coeliac disease and wheat-flour intestinal allergy in childhood, the distinction being of prognostic importance. This diagnostic problem is also seen in adults. A 24-year-old woman had had for a month, nausea, vomiting, and abdominal pain beginning 30 min after meals and lasting 2-3 h. She had 8-10 loose stools every day and had lost 7 kg in weight. A diet of milk and biscuits made things much worse. The preliminary diagnosis was coeliac disease, especially since all symptoms disappeared on a diet not containing wheat flour.

She had no family history of atopic disorders and had never had eczema, rhinitis, or asthma. Her eosinophil-count was 800/u.I. Serum-IgE was 300 units/ml (normal below 122). Prick tests were positive for timothy-grass pollen, gluten, and wheat flour. IgE radioallergosorbent tests gave a class-3 reaction for timothy-grass, a class-1 reaction for wheat flour, and a class-2 reaction for gluten. Small-intestinal biopsy showed slight villous oedema. Fat, xylose, and lactose absorption tests were normal. Oral challenge with 5 g wheat flour resulted in nausea, abdominal pain, and diarrhoea, whereas 30 g gluten was tolerated. This patient seems to have an allergy to wheat flour. The

1 Toogood, I R. G. and others, Lancet, 1978, ii, 826. 2. Harris, A. L. Br. med. J 1978, i, 1169. 3. Frei. E., and others, Blood, 1958, 13, 1126. 4. Roath, S , and others, Q.JlMed. 1964, 33, 257.

-

44 MECHANISM OF ACTION OF AMINOGLUTETHIMIDE IN BREAST CANCER

illustrates the value of allergy testing in patients suspected of having coeliac disease or other gastrointestinal disorder.

case

Department of Medicine II, Aarhus County Hospital, DK 800 Aarhus C, Denmark

RONALD DAHL

CIMETIDINE FOR DUODENAL ULCER

SIR,-While there ,

I agree with most of your editorial of Dec. 9 points which require correction. In par-

are one or two

ticular, I would dispute the assertion that cimetidine is the only drug which has been tested satisfactorily in the management of duodenal ulcer. Within the past two years five doubleblind controlled trials on a total of 371 patients have been publishedl-5 all giving the same answer-namely, that carbenoxolone sodium (’Duogastrone’) is as effective in healing duodenal ulcers as cimetidine. Lengthy animal studies before its introduction into clinical use and therapeutic experience for over a decade have produced no evidence of lasting harmful effects. A multicentre trial is now under way to compare directly the therapeutic effects of carbenoxolone and cimetidine, not only during the initial ulcer episode but also when the ulcers have relapsed. Until the results of this and other studies are known it is premature to state that only three courses of action are open in the treatment of ulcer relapses-intermittent cimetidine, continuous cimetidine, or surgery. While chastising the medical profession for introducing very bad habits in their use of cimetidine, your editorial is also guilty of overstatement, thereby reducing the effectiveness of its strictures. We do not know the long-term effects of cimetidine, but unexpected ill-effects have already been described and are cited in your editorial. Until there is conclusive evidence that cimetidine is safe when used in long-term treatment, its usefulness is going to be limited, and even the indications for short-term use must be carefully defined. In the meantime carbenoxolone is available as a proven and equally effective agent for the treatment of this pernicious relapsing condition. ’

Wexham Park Hospital, Slough SL2 4HL

P. I. REED

SiR,—Your editorial does not compare cimetidine with more conventional regimens for the treatment of duodenal ulcer. You also imply that antacids are the only real alternative and state that all other drugs have more side-effects than cimetidine. We have recently been looking for an alternative therapy to cimetidine for patients with duodenal ulcer who do not have intractable dyspepsia. In a single-blind study, 20 consecutive patients with endoscopically proven duodenal ulceration were randomly allocated to either cimetidine 200 mg three times a day and 400 mg at night or ’Caved-S’ (a compound preparation containing deglycyrrhizinised liquorice) two tablets five times a day between meals. Each patient was then re-endoscoped 6 weeks later to check for ulcer healing. 9 out of 10 patients in each treatment group were found to have healed ulcers. There were no sideeffects in either group, and relief of symptoms was similar in both. Further trials comparing cimetidine with other conventional drug therapy for patients with duodenal ulceration are required so that a more rational approach to the use of cimetidine can be determined. A. G. MORGAN Endoscopy Unit, W. A. F. MCADAM Airedale General Hospital, C. PACSOO Steeton, Keighley 1. Davies, W. A., Reed, P. I. Gut, 1977, 18, 78. 2. Archambault, A., and others Can. med. Ass. J. 1977, 117, 1155. 3. Sahel, J., and others Gut, 1977, 18, 717. 4. Nagy, G. S. Gastroenterology, 1978, 74, 7. 5. Young, G. P., and others in Peptic Ulcer Healing; recent studies benoxolone (edited by F. A. Jones, M. J. S. Langman, and R. D. p. 117. Lancaster, 1978.

a

SIR,-Dr Smith and colleagues (Sept. 23, p. 646) reported 37 - 5% objective response rate to treatment with aminogluteth-

imide (A.G.) and cortisone acetate as a method of suppressing adrenal function in women with metastatic breast carcinoma. With an identical dose of A.G. (250 mg four times daily) and replacement glucocorticoid, we have reported an objective tumour regression rate of 38% in 50 patients entering an open study without regard to oestrogen receptor status’ and in 10 of 21 women treated in the A.G. arm of a randomised trial of A.G. vs hypophysectomy.2 In our randomised study of A.G. vs surgical adrenalectomy response rates in 48 patients treated in either way appeared to be similar. We point out, however, that the mechanism 01 action of A.G. in patients with breast carcinoma is not solely its inhibition of cholesterol-to-pregnenolone conversion in the adrenal. The blockade of this early steroid biosynthetic step is only partial and produces less than complete suppression of the A’ class of steroids (progesterone, 17()(-hydroxyprogesterone, androstenedione, testosterone, dihydrotestosterone) but marked inhibition of the f’l5 compounds such as dihydrotestosterone sulphate and 17-hydroxypregnenolone.3 An additional action of A.G., the blockade of cestrogen synthesis outside the adrenal gland, has been described.7 This effect is important because the adrenal gland secretes no oestrogen directly but produces a prehormone, androstenedione, which is converted to oestrone, and then aestradiol in extraglandular tissues.5 Oestradiol in postmenopausal women can also be derived directly from testosterone as well as oestrone. Nearly all of the cestrogen produced in postmenopausal or castrate women can be accounted for by this extra-adrenal metabolic pathway. The enzymes required for the androstenedione-to-oestrone conversion (aromatisation) are present in fat tissue, liver, muscle, and also in some mammary tumours.5-7 A.G. is an extremely potent inhibitor (95-98%) of aromatisation and, thus, of extraglandular oestrogen production in postmenopausal women with breast carcinoma.48Consequently, by blocking both adrenal prehormones and oestrogen synthesis in extraglandular tissues (and perhaps in the mammary tumour itself), A.G. can lower the plasma cestrogens to levels (12-3±1-1pg/ml cestrone and 5-6±0-65 pg/ml oestradiol) nearly identical to those observed in patients treated by surgical adrenalectomy (12-0±1-4 oestrone; 5-8±0-555 ozstradiol). Since a reduction of oestrogen production is likely to be an important mechanism for mediation of the effects of surgical adrenalectomy, the action of A.G. on extraglandular oestradiol production is of considerable importance. While not discussed by Smith et al., their use of cortisone acetate as glucocorticoid replacement is preferable to administration of synthetic glucocorticoids such as dexamethasone. A.G. induces accelerated metabolism and consequently reduced biopotency of dexamethasone.9 Thus, three to four times the usual replacement doses of dexamethasone, and presumably of other long-acting synthetic glucocorticoids, must be given with aminoglutethnnide to accomplish adrenal suppression.’" On the other hand, the metabolism of hydrocortisone (and pre-

1. Wells, S. A., and others Ann. Surg. 1978, 187, 475. Harvey, H. A., Santen, R. J., Osterman, J., Samojlik, E., White, D., Lipton, A. Cancer, (in the press). 3. Samojlik, E., Santen, R. J.J. clin. Endocr. Metab. 1978, 47, 717. 4. Santen, R. J., Santner, S., Davis, B., Veldhuis, J., Samojlik, E., Ruby, E. ibid. (in the press). 5. Siiteri, P. K., Williams, J. E., Takaki, N. K. J. Steroid Biochem. 1976, 7, 897. 6. Jones, D., Cameron, E. H. D., Griffiths, K., Gleare, E. N., Forrest, A. P. M.

2.

Biochem. J. 1970, 116, 919.

on car-

Mann);

7. Adams, J. B., Li, K. Br. J. Cancer, 1975, 31, 429. 8. Samojlik, E., Santen, R. J., Wells, S. A. J. clin. Endocr. Metab. 1977, 45, 480. 9. Santen, R. J., Lipton, A., Kendall, J. J. Am. med. Ass 1974, 230, 1661. 10. Santen, R. J., Wells, S. A., Runic, S., Gupta, C., Kendall, J., Ruby, E. B., Samojlik, E. J. clin. Endocr. Metab. 1977, 45, 469.