DEATH ASSOCIATED WITH TRANYLCYPROMINE AND CHEESE

1076 TABLE

III-URINARY

CESTRONE

ACTIVITY OF

EXCRETION

AND

SERUM-FOLIC-ACID

35 PREGNANT WOMEN

the association between low oestrogen excretion and low serum-folic-acid activity might be not a direct metabolic

interference, but indirect. Further work is necessary elucidate these problems. In

an

oestrone

Summary investigation of 72 patients reduced urinary excretion in pregnancy was found to be sig-

99-9% confidence level with reduced serum-folic-acid activity. When all cases of reduced urinary excretion of oestrone, oestrone plus oestriol, and oestrone plus cestriol and oestradiol 17p were considered, serum-folic-acid activity was found to be significantly reduced at the 960 nificantly associated

activity and those of the normal group (table n). Further analysis showed that it was reduced urinary oestrone excretion which was significantly associated with reduced serum-folic-acid activity at the 99-9% confidence level (table ill). No such association was found for low urinary oestrone-plus-oestriol excretion (x-O’08). The association between low serum-folic-acid activity and low urinary oestrone, cestriol, and oestradiol 17- was of indeterminate significance (X2=2.6; 95% significance X2=3.S). Discussion

Low urinary oestrogen excretion is known to be associated with reduced foetal weight (Coyle and Brown 1963). Women with megaloblastic anxmia of pregnancy, who may have low serum-folic-acid activity, tend to have smaller babies than healthy women. Thus there might be an association between reduced urinary oestrogen excretion and low serum-folic-acid activity. Good nutritional status of the mother has long been recognised as essential to successful pregnancy, and in 1950 Prof. W. C. W. Nixon, at University College Hospital, London, was giving folic acid and other vitamin supplements in early pregnancy to patients with bad obstetric histories. There are good theoretical grounds for this therapy. Hertz (1945) demonstrated that chicks maintained on a folic-acid-deficient diet showed only a fourfold increase in oviduct weight, whereas birds given a stock diet had a fortyfold increase following stilboestrol administration. His observations were confirmed by Kline and Dorfman (1951), who suggested that folic acid was essential to the action of oestrogen in promoting proliferation in the chick oviduct at the level of the endorgan itself. Silver (1954) showed that in folic-aciddeficient rats the response of the uterus and mammary gland to cestrogen stimulation differed from that of the controls. In our studies in the human we have never found evidence of folic-acid deficiency in the umbilicalcord blood or in placental tissue. We therefore assumed that, if the observed deficiency of folic acid were important in pregnancy, it would be in relation to the oestrogenic response of the uterus. Ovarian hormones cannot modify a deficiency of folic acid as they can other substances (such as thiamine, pyridoxine, or protein). Thus, once a defi-

occurred, repair of any resulting damage may ciency not be possible. If folic acid plays any part in the prevention of certain cases of unsuccessful pregnancy, it will probably have to be given before conception in order that the greatest response of the uterus to oestrogen may be obtained when pregnancy does occur. An association between oestrogenic hormones and folic acid seems to be established, but a reasonable biochemical explanation is difficult at the present stage of knowledge. In general, vitamin deficiency could interfere seriously with the production of hormones, for some vitamins are known to have an important role as coenzymes in metabolism. Thus a folic-acid derivative acts as a coenzyme in the transfer of C1 fragments (activated formic acid). Other folic-acid derivatives serve as coenzymes of certain oxidation/reduction systems. On the other hand, has

to

at

the

ú

confidence level. We should like to thank Dr. F. A. Brisbout for carrying out the statistical analysis, and Mr. A. Kelly and Miss M. Bedrick for technical assistance. REFERENCES

Brown, J. B. (1960) Advanc. clin. Chem. 3, 167, 214. Coyle, M. G., Brown, J. B. (1963) J. Obstet. Gynœc. Brit. Cwlth, 70, 225. Davis, R. E., Kelly, A. (1962) Aust. J. exp. Biol. med. Sci. 40, 437. Hertz, R. (1945) Endocrinology, 37, 1. Kline, I. T., Dorfman, R. I. (1951) ibid. 48, 345. Martin, J. D., Davis, R. E., Hähnel, R. (1963) Lancet, ii, 716. Silver, M. (1954) J. Endocrin. 10, 95.

DEATH ASSOCIATED WITH TRANYLCYPROMINE AND CHEESE

J. M. CUTHILL M.B.

Glasg., M.R.C.P. Glasg., D.P.M.

CONSULTANT PSYCHIATRIST TO MORGANNWG

BRIDGEND,

HOSPITAL,

GLAMORGAN

A. B. GRIFFITHS M.R.C.S. REGISTRAR IN

M.D.

PSYCHIATRY,

MORGANNWG HOSPITAL

D. E. B. POWELL Edin., M.R.C.P., M.C.Path.

CONSULTANT PATHOLOGIST TO BRIDGEND GENERAL HOSPITAL AND MORGANNWG HOSPITAL

dangers associated with the use of monoamine(M.O.A.) inhibitor drugs have received considerable publicity in the past 2 years. More recently there has been increasing evidence of many alarming reactions related to the ingestion of cheese, especially in patients taking tranylcypromine. The United States Food and Drug Administration have recently withdrawn this drug, but in Great Britain, the Committee on Safety of Drugs, while warning doctors of the adverse reactions, has not recommended the discontinuation of tranylcypromine or THE oxidase

other M.o.A. inhibitors. Fatal reactions should therefore be reported.

Case-report

Clinical Details A man, aged 40, employed as a clerk, had suffered from an obsessional neurosis for 14 years. In 1960 barbiturate addiction developed, he became morbidly depressed, and he attempted suicide by taking pentobarbitone, after which he received 6 weeks’ inpatient psychiatric treatment. He was seen regularly for the next 21/2 years, and his tension was controlled with chlordiazepoxide (’ Librium ’) capsules 10 mg. twice daily. On Sept. 3, 1963, he complained of depression to his family doctor, who prescribed 50 tranylcypromine (’Pamate’) tablets of 10 mg., one to be taken twice daily. 3 weeks later he reported little improvement and requested further chlordiazepoxide capsules. On Oct. 4 he was admitted to Morgannwg Hospital in a state of acute excitement. The previous evening he had complained of a slight headache, but he had enjoyed a full supper of beef casserole, and cheese and biscuits, with tea. He had had about 4 ounces of cheese-Cheddar, Caerphilly, or Danish blue. When he went to bed at 11.15 P.M., his headst: ached and he felt giddy. He awakened at 2 A.M. with a violent headache, severe dizziness, and nausea. He vomited repeatedly

1077

hour, and then sat upright in a chair because he felt when lying down. By 6 A.M. he felt better, and returned to bed. He joined the family for breakfast at 7.30 A.M., and ate two or three large slices of cheese of unknown type. As he felt very tired, he agreed to go back to bed after his wife went out at 8.30 A.M. At 11.30 A.M., the baker’s roundsman found him distressed and incoherent, with the furniture disarranged. His wife said that at 12.15 P.M. he was confused and pale; he had been bleeding from his nose, and had cut his left thumb on a broken glass. For short periods he was rational, and he complained of throbbing pains in his chest and a feeling of warmth; he was often overcome by violent tremors. His family doctor sent him to hospital, and during the hour’s journey his mental state deteriorated, with aggressive outbursts. On admission to hospital he was confused, disorientated, shouting incoherently, and extremely restless. He became manageable only after 30 ml. of paraldehyde, given intramuscularly. The skin was hot, dry, and flushed; the axillary temperature was 104-5°F, pulse 115 per minute, and bloodpressure 145/80 mm. Hg. The pupils were dilated and fixed, and the corneal reflexes absent. The fundi were hyperasmic, and the optic discs oedematous. Respirations were 25 per minute, and crepitations with harsh rhonchi were heard over both lung bases. At lumbar puncture, the pressure was 80 mm. of water; the cerebrospinal fluid was slightly bloodstained, but there were no significant findings, and culture was sterile. The blood-sugar was 93 mg. per 100 ml., and the blood-urea was 66 mg. per 100 ml. When respiratory embarrassment became pronounced, with increasing cyanosis, he was transferred to Bridgend General Hospital. Peripheral circulatory failure supervened rapidly, and he died at 8.30 P.M.

for

an

worse

Pathological Findings At necropsy, there were several recent bruises on the face and forehead. The conjunctive were severely congested. Both lungs showed much oedema, and fluid poured from the cut surfaces. The brain was swollen, with intense vascular congestion, and there were a few petechiae in the white matter, but no frank haemorrhage. The liver was large, pale, and greasy. The kidneys showed medullary pallor. There was severe coronary atheroma, with old obliteration and recanalisation of the right coronary artery. Microscopic examination of the lungs, brain, kidneys, and liver showed intense vascular engorgement, with microhxmorrhages in the lungs and kidneys. The liver also showed

fatty change. Bacteriological and virological examination of the viscera yielded no pathogens. Blood-culture was sterile. Toxicological analysis of the organs was performed at the forensic science laboratory. No barbiturates were detected. Chlordiazepoxide was found in the following total quantities: liver and kidneys 3-5 mg., lungs and spleen 6-4 mg., intestines 47 mg., and urine 0.5 mg. per 100 ml. Tranylcypromine was found in the intestines 5-3 mg. (0-1 mg. per 100 ml), spleen and lungs 1.3 mg. (0-1 mg. per 100 ml), and liver and kidneys severe

2-6

mz.

(0-1

ms. oer

100 ml.-.

Discussion

A detailed account of the events before admission was not available till after death. The diagnosis of an encephalitis or septicxmia was considered most probable, but necropsy findings did not support either possibility. The finding of chlordiazepoxide in the organs was expected, and the urinary level suggests a high dose (Scott 1964), but the clinical picture was quite unlike that of an overdose. As no tranylcypromine tablets were recovered from his home, it is possible that he was taking both this and chlordiazepoxide during his last 10 days. The clinical picture resembles that reported in patients taking tranylcypromine in medicinal or excessive dosage. This, combined with the excessive ingestion of cheese a few hours previously, and with the pathological and toxicological findings, make the diagnosis of a fatal reaction to

tranylcypromine

most

probable.

The pathological findings differed in several respects from previously reported cases. The worst hazard in patients taking M.O.A. inhibitors is a hypertensive crisis, occasionally associated with intracranial haemorrhage (Zeck 1961, McClure 1962, Mason 1962, Ehtishamuddin 1963). On the other hand, fatal reactions can occur without intracranial haemorrhage (Enoch 1963, Womack 1963a and b). In our case, the severity and extent of pulmonary congestion and haemorrhage was extreme; the brain, although congested, showed no hsemorrhage; and the liver was severely damaged. The reason for this last feature is obscure; although M.O.A. inibitors are recognised hepatotoxic agents, tranylcypromine has hitherto been excluded from this class of drugs because it is a nonhydrazine derivative (Holdsworth et al. 1961). The presence of severe coronary-artery disease, which was unrecognised before death, may also have been an important contributory factor, because the makers state that tranylcypromine is contraindicated in such cases. This case again illustrates the potential danger of M.O.A. inhibitors, and in particular the unfortunate effects of combining a normal item of diet-namely cheese-with tranylcypromine. In our experience, advising patients taking tranylcypromine to avoid cheese and alcohol has dramatically reduced the side-effects which were previously encountered. We have also had to limit the use of this drug to those patients who are capable of full cooperation, and with whom we can keep regular contact. As the majority of depressed patients are not able to cooperate fully, the various warnings may go unheeded, especially if a concomitant course of electroplexy is given. In such circumstances these drugs, which represent a therapeutic advance in many respects, become potentially lethal. We are thus increasingly concerned about the ethical implications of their continued general use. We wish to thank Mr. Owen Rees, M.B.E., H.M. Coroner for East Glamorgan, for permission to publish this case-report and the toxicological reports; and Dr. F. Thomas for permission to use his case-notes.

REFERENCES

Enoch, M. D. (1963) Lancet, ii, 463. Ehtishamuddin, M. (1963) ibid. p. 1015. Holdsworth, C. D., Atkinson, M., Goldie, W. (1961) ibid. ii, 621. Mason, A. (1962) ibid. i, 1073. McClure, J. L. (1962) ibid. p. 1351. Scott, D. L. (1964) Personal communication. Womack, A. M. (1963a) Brit. med. J. ii, 366. (1963b) Lancet, ii, 463. Zeck, P. (1961) Med. J. Aust. i, 607. —

Preliminary

Communications

EFFECT OF X-IRRADIATION OF THE POPLITEAL LYMPH-NODE ON ITS OUTPUT OF LYMPHOCYTES AND IMMUNOLOGICAL RESPONSIVENESS THE work of Gowans et al.l has indicated that lymphocytes in the blood are capable of re-entering the lymphatic system by crossing the endothelium of precapillary venules within lymph-nodes. Having entered the node, some of them, under certain conditions, differentiate into large basophilic cells. It is from these cells that the cells characteristic of an immune response probably arise. In general terms the work of Gowans et aLl suggests that the events of an immune response are initiated by a population of recirculating lymphocytes which are attracted to reticuloendothelial cells that have taken up antigenic material. 1. 2.

Gowans, J. L., McGregor, D. D., Cowen, D. M., Ford, C. E. Nature, Lond. 1962, 196, 651. Hall, J. G., Morris, B. Quart. J. exp. Physiol. 1963, 48, 235.