INDIGENISED PHARMACEUTICALS AND APLASTIC ANAEMIA

1019 TAMOXIFEN AND ENDOMETRIAL CANCER p 563) for bringing to the wider audience my lecture at the International Symposium on Hormone Therapy in Oncology, in Bologna. Hardell provides some provocative epidemiological data but it should come as no surprise that some patients with breast cancer who are treated with tamoxifen will acquire endometrial carcinoma. Only a minority of metastatic tumours respond to endocrine therapy, and the development of all tumours would not be expected to be controlled by this drug. On the basis of animal experiments! I proposed that tamoxifen was a tumoristatic agent and should be used in extended treatment regimens (5 years or more) for the adjuvant therapy of breast cancer. The early results from clinical trials have demonstrated that long-term adjuvant tamoxifen therapy is both safe and effective.2,3 Adjuvant tamoxifen has now become the therapy of choice for most breast cancer patients with node-negative or node-positive disease. Since long-term treatments of young women will become commonplace, the toxicological and associated effects of tamoxifen have now become a primary concern. There would seem to be little advantage to the use of tamoxifen in node-negative disease if those treated were put at risk of some as yet unknown toxic side-effect. We have shown4 that athymic mice transplanted with a hormonedependent breast tumour and endometrial tumour can respond differently to tamoxifen: the oestrogen-stimulated growth of the breast tumour is controlled but growth of the endometrial tumour is not. This could be clinically relevant in long-term adjuvant therapy with tamoxifen if occult endometrial carcinoma is present. Nevertheless, questions need to be addressed. Is the endometrial tumour developed by Dr P. G. Satyaswaroop4 the only human endometrial tumour to have a growth response to tamoxifen? Does the athymic mouse model reflect the treatment of patients? The answers can only be obtained by further experiments but whatever the results it is, I think, prudent to alert physicians to the possibility that occult endometrial carcinoma may not be controlled during the adjuvant therapy of breast cancer by tamoxifen. There is no suggestion from any laboratory studies that tamoxifen may induce endometrial carcinoma. The clinical relevance of the laboratory findings can be judged from large randomised clinical studies, such as the Scottish trial,3 by careful monitoring over the next few years.

SiR,—I thank Dr Hardell (Sept 3,

attention of

a

Department of Human Oncology, University of Wisconsin Clinical Cancer Center, Madison, Wisconsin 53792, USA

V. CRAIG

JORDAN

1979. 19-26.

Tormey DC, Jordan VC. Long-term tamoxifen adjuvant therapy in node-positive breast cancer: a metabolic and pilot clinical study Breast Cancer Res Treat 1984; 4:

297-302. 3. Scottish Cancer Trials Office.

Department of Haematology, Universitaire Ziekenhuizen, 3000 Leuven, Belgium

R. L. VERWILGHEN

* The library of the Pharmaceutical Society informs us that ’Ambra-Sinto’ does indeed contain chloramphenicol as well as tetracycline.-ED. L. MEFENAMIC ACID OVERDOSE MIMICKING BRAINSTEM STROKE

SiR,—An 81-year-old woman was admitted after being found unconscious. She had been taking mefenamic acid for joint pains and was on no other medication. She was deeply unconscious with minimum response to painful stimuli and pinpoint pupils. A gag reflex was present and there was generalised hyperreflexia and bilateral extensor plantar responses. She was given 1-2 mg naloxone with no effect, and it was initially felt on clinical grounds that she had had a brainstem stroke. However, toxicology screening revealed extremely high serum levels of mefenamic acid (levels on admission, 462 mg/1, and at 2 hours, 261 mg/l; the upper therapeutic concentration is 10 mg/1). Full screening, including salicylates, paracetamol, barbiturates, and tricyclic antidepressants, was otherwise negative. Treatment was supportive; she remained unconscious for about 24 hours and eventually made a full recovery. The patient later admitted taking 100 mefenamic acid 500 mg tablets, and denied taking any other medications or alcohol. Mefenamic acid overdose has been associated with several signs of central nervous system toxicity, especially convulsions,m3 and dyskinesia. The one case of coma that has been reported was of short duration, did not have specific neurological signs, and was associated with much lower serum levels of mefenamic acid (below 25 mg/1).5 We suggest that the prolonged coma and neurological signs in our case were the result of very high serum levels of the drug and that mefenamic acid overdose should be considered in patients presenting with coma and brainstem signs. I thank Dr A. R. W. Forrest (department of chemical pathology) for serum analysis of mefenamic acid and Dr D. R. Triger for permission to report this case.

1. Jordon VC, Dix CJ, Allen KE. The effectiveness of long-term tamoxifen in a laboratory model for adjuvant hormone therapy of breast cancer. In: Jones SE, Salmon SE, eds. Adjuvant therapy of cancer II New York: Grune and Stratton, 2.

patients died from aplastic anaemia a few months after taking this drug. Is ambra-sinto the same as ambrasynth? Does it contain chloramphenicol? If so, its use should be discouraged.

the management of operable breast cancer: the Scottish trial. Lancet 1987; ii: 171-75. 4 Gottardis MM, Robinson SP, Satyaswaroop PG, Jordan VC. Contrasting actions of tamoxifen on endometnal and breast tumor growth in the athymic mouse. Cancer Res 1988, 48: 812-15.

Adjuvant tamoxifen

in

INDIGENISED PHARMACEUTICALS AND APLASTIC ANAEMIA

SIR,-Aplastic anaemia is becoming a rare disease in the developed world but is still prevalent in developing countries. The dangerous use of drugs, solvents, and insecticides is often incriminated, but little is known about the real risk factors, which makes prevention difficult. Dr Haak and Dr Hardon (Sept 10, p 620) report that ’Ambra-Sinto’ is widely used in Brazil and probably also in other South American countries. They record that ambra-sinto is a trade name for tetracycline. Until 1978 ’Ambrasynth’ was available in Belgium. It was a "new and safe antibiotic" and one had to read the small print to learn that the capsule contained not only 100 mg tetracycline but also 150 mg chloramphenicol, which is myelotoxic. The use of chloramphenicol is restricted to specific indications. Many practitioners, however, prescribed ambrasynth without suspicion, and one of our young

Department of Medicine, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JF

M. T. HENDRICKSE

1. Young RJ. Mefenamic acid poisoning and epilepsy. Br Med J 1979; ii: 1438. 2. Robson RH, Balali M, Critchley J, Proudfoot A, Prescott L Mefenamic acid poisoning and epilepsy. Br Med J 1979; ii: 672 3. Balali-Mood M, Critchley JA, Proudfoot AT, Prescott LF. Mefenamic acid overdose.

Lancet 1981; i 1354-56. 4. Medmond AD.

Dyskinesia induced by mefenamic acid? J R Soc Med 1981, 74:

558-59. 5.

Gossinger H, Hruby K, Haubenstock A, Jung M, Zwerina N.

Coma

m

mefenamic

acid poisoning. Lancet 1982; ii.384.

PATIENT’S CHOICE OF ANIMAL OR HUMAN INSULIN and many diabetic patients have had to change from human insulin. I would like to know what benefit I am supposed to have derived from the stoppage of the manufacture of animal insulin and the change to human insulin. It may be advantageous to make human insulin in a laboratory, but many diabetic patients (myself included) are going through a difficult time adapting to human insulin-eg, being taken into custody for being drunk and disorderly, or waking up 3 hours’ journey from home with no recollection of how or why it happened. In addition, two daily injections are required instead of one because the suspension insulins do not have the same long action as the

SIR,-I

animal

to

predecessors. Moreover, I think that patients such as myself, who have kept fit and healthy for thirty years or more on one daily injection of animal insulin, should have been given a choice. I should not have been