.275 'I~RANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE. Vol. 45. No. 2. O c t o b e r , 1951.
ACUTE MEPACRINE POISONING. BY
GERALD C. DOCKERAY, M.D., M.se., F.a.e.p.t., D.P.H., Medical Research Laboratory, NairobL
The numerous drugs which are used in the treatment and causal prevention of malaria today bear a chemical relationship to one another. Considering the frequency with which they are used, they give rise to relatively few toxic symptoms, and deaths which can be attributed directly to them even when used in excessive dosage, are rare. Two deaths and a third case in which recovery took place, will be described below. Mepacrine has many synonyms. The original German trade name was atebrin (1932), and the correct official names in Britain and America are mepacrine and quinacrine. Its salts are the dihydrochloride used for oral treatment, and the dimethyl sulphonate used for intramuscular injection, the former having a solubility in coldwater of 1 in 30, and the latter 1 in 3. The toxic effects are important as they may involve claims for pension or compensation. They have been reviewed fully by FINDLEY (1947). Serious toxicity is rare. In suppressive doses mepacrine may cause anorexia, nausea and vague gastro-intestinal symptOms; yellow staining of the skin; slate-blue pigmentation of the nails, hard palate, gums, tip of nose, ear lobes, tongue or prepuce; eczematoid or lichenoid dermatitis; mental depression, lassitude and insomnia. It should be given after food. In therapeutic doses it may cause gastro-intestinal symptoms such as anorexia, vomiting or diarrhoea ; toxic psychoses ; tachycardia ; aplastic anaemia ; and is said to have precipitated blackwater fever, although the widespread use of mepacrine reduced the incidence of the latter in Greece, and eradicated it in West Africa. I*
276
ACUTE MEPACRINE POISONING
Single doses of gramme 1"0 to 1.5 have often been given without a bad effect whilst larger doses have sometimes been taken in error or with suicidal intent. BURNHAM (1946) records a case of complete recovery where a man took gramme 6-0 in an attempt at suicide. There were no residual signs of liver damage. MARKSONand DAWSON (1945) report the case of a patient who, after taking gramme 0.7 weekly for 16 months as a suppressive, swallowed 250 tablets (gramme 25) with suicidal intention. Ten minutes later he began to vomit and to have diarrhoea; he then became weak and drowsy. When found 3 hours later he was collapsed and stuporose with a cold clammy skin and barely perceptible pulse. The plasma mepacrine was 906/~gm. per 1. Next day it was 183 /zgm. and on the 3rd day 90 /~gm. At no time did any appear in the C.S.F. In 24 hours the patient recovered having been given adrenaline, 2 pints of 30 per cent. glucose saline and 5 mg. of riboflavin intravenously. GOVlNDASWAM¥ (1936) described a man aged 32 who developed delirium tremens. He=was a total abstainer. He shouted that he saw snakes and fantastic animals crawling on the floor and he reacted so Violently to these hallucinations that it was necessary to restrain him. He was deeply jaundiced. His mental symptoms cleared up in 3 days, and the yellow colour of the skin in 7 days. During the 8 days previous to admission to hospital he had had two atebrin pills daily and three injections of atebrin musonate. BISPHAM (1941) found among 49,681 persons treated with either prophylactic or therapeutic doses, only 38 cases in which there were severe symptoms such as vomiting, diarrhoea, epigastric or precordial pain. In about 2 per cent, of cases such symptoms necessitated the withdrawal of suppressive treatment. BRUCE-CHWATT and BRUCE-CHWATT (1950) report that 11 cases of acute toxic reactions to the intramuscular injection of mepacrine were reported in infants or small children given normal therapeutic doses between gramme 0.05 and 0.15. They say that the symptoms commenced 10 to 20 minutes after the injection, and consisted of an epileptiform seizure with facial twitching, clonic convulsions, cyanosis, loss of control over the constrictors and occasional vomiting. Recovery within 1 to 2 hours is the rule but one fatal case was observed. MAEGRAITH (1948) recommends for children not more than 150 rag. of mepacrine i n the day up to the age of 2 years ; and 300 rag. at 10 years. The circumstances which the fatalities now described arose are as follows : Three African infants, aged about 7 to 12 months old, had been in hospital f o r about 2 weeks suffering from non-tuberculous pulmonary infections. They had become •convalescent with normal temperatures when all three had a sharp rise of temperature to 105 °, 104 ° and 102 ° F. This was suspected to be due to malaria. Slides were taken and the doctor in charge prescribed one " a m p o u l e , of a proprietary preparation o f mepacrine, believing that an ampoule contained 100 mg. In actual fact three varieties of ampoule were
GERALD
C. D O C K E R A Y
277
available of 100 mg., 300 mg., and 360 mg., respectively. A few of the 100-rag. and 360-mg. strength were stored in a box with 300-mg. ampoules. T h e lid of this box was clearly labelled by the maker as containing ampoules of a strength of 300 rag., and nearly all the ampoules were of this strength. T h e 100-rag. and the 300-rag. ampoules were s o m e w h a t similar in appearance, but the 360-rag. ampoule by a different maker was of a different shape and type of labelling. T h e 300-mg. ampoules were labelled b y a s t a m p e d marking g r a m m e 0.3, but the dye of the " 3 " was indecipherable on most of the ampoules. T h r e e of these were given to a hospital assistant, who administered t h e m intramuscularly to the three infants. W h e n he had injected the second infant he f o u n d that the first had c o m m e n c e d to v o m i t and had become pale. T h e first two died in ½ hour, and the third recovered after nearly dying. It was given oxygen and coramine. H e did not notice any twitchings or epileptiform convulsions. T h e p o s t m o r t e m examinations were p e r f o r m e d 3 hours after death, the details being as follows : P . M . No. 5696. Male African aged 8 months. Rather wasted. Lower lobe of the left lung showed pneumonic consolidation. The right side of the heart was dilated. The liver was normal in appearance. The spleen was slightly enlarged. There was a single horse-shoe kidney present. The brain appeared normal. The urine was normal in colour. The blood taken before death was negative for malaria parasites. P . M . No. 5697. Male African aged about 7 months. Normal in development. The right lung was adherent to the chest wall and among these adhesions was about 1 c.c. of pus. There was no evidence of tuberculosis. The right side of the heart was congested. The brain was normal in appearance. The spleen was slightly enlarged. The suprarenals and kidneys were normal in appearance. There was no urine in the bladder:. The mesenteric glands were enlarged but not tuberculous. The gastro-intestinal tract and liver were normal in appearance as were the other organs. A blood film made before death was reported negative for malaria parasites. Sections of the right lung and a mesenteric gland were taken for microscopic examination. Some broncho-pneumonic consolidation was found in the former and no specific pathological Change in the latter. The cause of death was given as heart failure due to an intramuscular injection of 300 rag. of mepacrine in both cases ; the first child having been suffering from lobar pneumonia and malnutrition, and the second having been suffering from bronchopneumonia and a small empyema. T h e dose was considered excessive for infants of this age. T h e i r clinical state was poor although t h e y were improving until they got the bout of pyrexia. I n coming to the conclusion that mepacrine was the cause of death, consideration was taken of the fact that three children of about the same age were injected with the same dose and two died within ½ hour, whilst the third appeared very ill but recovered. This third child was aged 1 year and had been in hospital for 10 days suffering f r o m gastro-enteritis, kwashiokor and enlarged hilar glands. T h e conclusions which can be drawn f r o m these cases is that intramusculai" mepacrine in an overdosage of 300 rag. m a y be rapidly fatal to sick African children aged 7 m o n t h s to a year old. BRUCE-CHWATT and BRUCE-CHWATT~s report (1950) has been m e n t i o n e d already.
278
ACUTE MEPACRINE POISONING
Mepacrine should therefore be prescribed especially cautiously for children. The practice of prescribing drugs by the " ampoule " or by the " tablet " is open to obvious objections. In the present cases it caused a dose of 300 rag. of mepacrine to be administered instead of the intended dose of 100 mg. A practitioner may not be aware that there may be ampoules of different strength of the same drug, or when a single firm is the only firm supplying a drug for a considerable period he may become familiar with their product and if the hospital supply is changed to some other maker at a later date he may not realize that there has been perhaps a change in the strength. A mistake is particularly likely to arise if a doctor should advise some less experienced doctor to give a patient " an ampoule " of some particular drug. Errors are also liable to occur when very large numbers of patients are being treated by a single doctor who, through shortage of time, may be led into abbreviating his writing of prescriptions and the mistake may be such as not to be apparent to a dispensing chemist. Although this paper deals with two fatal cases of mepacrine poisoning and mentions other toxic manifestations which may be caused by the drug, it should not be thought to detract in any way from the fact that mepacrine is a very safe drug which has been given to many thousands of people with no ill effects. REFERENCES. BISPHAM, W.N. (1941). Amer. ft. trop. Med., 21, 455 ; Trop. Dis. Bull., 89, 178. BRUCE-CHWATT,L. J. & BRUcE-CHWATT,J. M. (1950). Brit. reed. ft., 2, 7. BURNHAM,R. C. (1946). Nay. reed. Bull. Wash., 46, 434 ; Trop. Dis. Bull., 43, 525. FINDLAY, G. M. (1947). Trop. Dis. Bull., 44, 763. GOVINDASWAMY,M.V. (1936). Lancet, 1, 56. MA~aRAITH,B. (1948). Pathological processes in Malaria and Blackwater Fever. Oxford : Blackwell, 22. M~mKSON, J. L. & DAWSON,J. (1945). Ann. trop. Med. Parasit., 39, 117 ; Trop. Dis. Bull, 48, 12.
Printed in Great Britain by H, R, GRU~B, L~rl)., Croydon