275 says: "the results of a recent trial in Glasgow. led to some discussion about the optimum dose of L-tryptophan. This difficulty had arisen because the drug induces the activity of the main degradative enzyme of tryptophan in the liver, tryptophan pyrrolase. Doses of tryptophan over 4 g per day might be self defeating insofar as they result in a more rapid degradation of the amino-acid in the liver". Try as I might, I am unable to see anything in this statement which suggests that tryptophan in doses over 4 g a day seems to provoke depression. What the B.M.J. seems to be saying is that the antidepressive action of L-tryptophan is not enhanced by increasingthe dose beyond the 4 g per day. This statement, which can be justified on theoretical grounds has not, however, been borne out in clinical practice in which a dosage of 6 g of L-tryptophan daily has been shown to be as effective an antidepressant as recommended doses of imipramine and amitriptyline; 1-3 in no case has depression been "provoked".

BM-1. which ...

E. Merck Ltd., Four Marks,

Alton, Hampshire GU34 5HG

ALAN

J. COOPER

*t*We apologise for the misleading reference. In speculating about a possible adverse effect of high doses we had in mind four investigations comparing tryptophan with electroconvulsive therapy. Two of them employed less than 4 g L-tryptophan(or less than 8 g D,L-tryptophan5) daily, and the drug proved at leastaseffective as E.c.T. In the other two the dose of L-tryptophan was over 4 g daily, and the results were inferior to those of E.C.T.;6" a quarter of Carroll’s tryptophan group6 were more depressed at the end of the trial than at the beginning. The editorial suggested a biochemical mechanism whereby a big dose of tryptophan might worsen depression.-ED. L.

ACUTE PERCUTANEOUS PARAQUAT POISONING SIR,-A 44-year-old man using paraquat as a weedkiller did not follow the manufacturer’s instructions and added only eight litres of water to two litres of paraquat. He then used an old sprayer which leaked fluid freely down his neck, back, and legs. After four hours of spraying he complained of a burning feeling on his neck and scrotum. On hospital admission six days later the patient had a cough and respiratory difficulties. X-ray showed no abnormalities but the next day, when his breathing had become worse and he was cyanosed, X-ray showed small speckles with a tendency to coalesce in both lungs. He had a compensated metabolic acidosis and partial respiratory insufficiency with hyposaturation which after an alveocapillary block progressed to a decompensated metabolic and respiratory acidosis and total respiratory insufficiency which required artificial ventilation. Oedema of the lungs appeared and the patient was given corticosteroids, cardiotonics, diuretics, antibiotics, and bicarbonate. The patient’s blood-urea-nitrogen and serum-creatinine raised and protein and red and white blood-cells were found in his urine. He died of renal and respiratory insufficiency three days after admission. At necropsy, there was dry bloody necrosis of the skin at several sites on the neck and scrotum. In the lungs there was oedema and necrotising alveolitis. The kidneys were in a state of shock and showed parenchymal dystrophy. There was steatosis in the liver. This case shows that paraquat can be absorbed by healthy were

1. Jensen, K. and others. Lancet, 1975, ii, 920. 2. Rao, B., Broadhurst, A. D. Br. med. J. 1976, i, 460. 3. Herrington, R. N. and others. Psychol. med. 1976, 6, 673. 4. Coppen, A., Shaw, D. M., Herzberg, B., Maggs, R. Lancet, 1967, ii, 1179. 5. MacSweeney, D. A. ibid. 1975, ii, 510. 6. Carroll, B. J., Mowbray, R. M., Davies, B. ibid. 1970, i, 967. 7. Herrington, J. N., Bruce, A., Johnstone, E. C., Lader, M. H. ibid. 1974, ii,

731.

skin with fatal consequences especially if it is according to the manufacturer’s instructions. Trenčin Hospital, Osvienčimská 1960-II-12, Czechoslovakia

not

diluted

FRANTISEK JAROŠ

ADVERSE REACTIONS TO DRUGS

SIR,-Your editorial referring

to my letter (Jan. 21 issue) concerned with the case for post-marketing surveillance for adverse reactions and with encouraging clinicians to report possible adverse responses to drugs. I support both these concepts, and was disappointed at the indirect inference that I wished to modify your practice and suppress communication about adverse effects. I wrote my letter because I have been concerned about the reactions from individual clinicians to reports in The Lancet of isolated incidents suggesting adverse effects. Clinicians tend to consider the appearance of a letter or other report in The Lancet as firm evidence of an established side-effect of a drug. The real situation is that these reports are usually preliminary, and further inquiry often totally alters the interpretation. I did not intend to suggest that information should be suppressed : on the contrary I would like to encourage disclosure of possible side-effects by exposure in The Lancet and their reporting to the Department of Health and the manufacturing pharmaceutical company’s medical director. However, I would prefer them to be presented in a way which does not unnecessarily alarm or confuse the reader. was

Research Institute, Smith Kline & French Laboratories Ltd, Welwyn Garden City, Hertfordshire

W. L. BURLAND

SiR,-Surely the point at issue on small numbers of individual reports is that they are of suspected adverse reactions? 11 Castle Hill Avenue, Berkhamsted, Herts. HP4 1HJ

S. RUTTLE

ACUTE CHOLANGITIS AFTER ALLOPURINOL TREATMENT

SIR,-A 48-year-old Yugoslavian mason presented with a dragging pain in his groin and hip. His E.S.R. was raised and his erythrocyte count low. Renal insufficiency due to chronic nephritis was diagnosed on biochemical, X-ray, and sonographic findings. His serum-uric-acid was raised. 300 mg allopurinol daily was given and, 3 weeks after admission, amoxycillin was added (250 mg, 3 times daily). 10 days later, the patient had maculous exanthema of the trunk and the adjacent extremities typical of skin sensitivity to ampicillin, with facial oedema and fever. Amoxycillin, but not allopurinol, was stopped and no other antibiotic was given for 10 days. The fever subsided during the following week and blood and urine cultures were sterile. Fever then reappeared, the exanthema began to scale, and eczema appeared on palms and soles and ulcers in the oral mucosa. 12 days after amoxycillin was stopped there was a 10% eosinophilia which, during the next 10 days, increased to 45% and subsequently decreased. At its onset, the serum-bilirubin was normal (1.1 mg/dl) but after 4 days the concentration was 3-35 mg/dl total (direct, 2.97). During the next few days the patient had an acute abdomen. This improved without surgery which was contraindicated because of renal insufficiency (which required dialysis) and sepsis. Laparoscopy was done. Bilirubin was 7.69 mg/dl (direct 6.4). Serum-glutamic-oxaloacetic-transaminase (S.G.O.T.) was 62 units/1 and serum-glutamic-pyruvic transaminase (S.G.P.T.) was 134 units/I, compared wÎ.þ. 27 and 11 units/I, respectively, on admission. Biopsy specimens of the liver showed disseminated parenchymal damage with signs of severe eosinophilic

276

cholangitis and pericholangitis with cholostasis. Allopurinol was stopped. Lymph-nodes were generally swollen and in an extracted node there was histological evidence of allergichyperallergic reactions and B-lymphocyte stimulation-i.e., increased plasma cells and eosinophils. 3 weeks later, the alkaline phosphatase was still high (1317 units/1). S.G.O.T. and S.G.P.T. had decreased to 31 and 47 units/1 respectively, and the bilirubin had fallen to 3-72 mg/dl. The patient’s general condition, however, had deteriorated and after increasing respiratory distress he died. At necropsy, Balkan nephropathy was found and pneumonia was judged to be the cause of death. Colisepsis diagnosed 3 weeks before was not confirmed. Pathological changes in the liver appeared to be regressing and cholangitis and pericholangitis had decreased. Amoxycillin, ampicillin and allopurinol2 are known to cause skin rashes. Ampicillin and allopurinol together induce these rashes more frequently than ampicillin alone.3 Generalised lymphadenopathy and eosinophilia,I,4 and liver damage presenting as granulomatous hepatitis have been found after allopurinol treatment’ but have not been reported 10 follow amoxycillin or ampicillin treatment. We thus think that the combination of amoxycillin and allopurinol caused the skin rash at 10 days. Allopurinol probably caused the severe cholangitis and pericholangitis with jaundice which developed parallel to severe eosinophilia and generalised lymphadenopathy. Indomethacin, the only other drug given to this patient, does not induce eosinophilia. Bleeding due to the lack of clotting factors was also observed which may be connected with the allergic liver-damage. This case suggests that allopurinol may cause severe cholangitis with jaundice and amoxycillin, like ampicillin, may interact with allopurinol with results not restricted to skin reactions. Severe side-effects after allopurinol alone are especially frequent in renal insufficiency2,6 and treatment with allopurinol plus amoxycillin or ampicillin thus needs careful evaluation in these cases. Institute of Pathology, "Ludwig Aschoff-Haus", University of Freiburg Medical School,

Freiburg, Germany

H. C. KORTING R. LESCH

RESPIRATORY DISEASE ASSOCIATED WITH PRACTOLOL THERAPY

SIR,-The report by Marshall et al.’ of 6 patients with respiratory disease who had had practolol-induced sclerosing peritonitis brings to mind the case that we reported in 1975.8 This patient had been on practolol for 3 years. He died of sarcoid heart-disease9 in May, 1976, about 2 years after practolol

was

stopped. 6 months after practolol was withdrawn he became dyspnoeic and was found to have bilateral pleural effusions. These increased greatly in size and were bloodstained and associated with great pleural thickening. Pleural biopsy showed fibrotic thickening with a few non-specific, chronic inflammatory cells. At no time, either during life or at necropsy, was there evidence of pulmonary involvement or significant peritoneal involvement. At necropsy in the right chest there was diffuse, smooth, fibrous thickening of the visceral and the parietal pleurae, and there was a 350 ml clear pleural effusion. The left pleura was obliterated by adhesions and showed fibrous thickening of both visceral and parietal pleura’. The pericardial cavity was obliterated by light, fibrous adhesions. In the peri1. Vollhaber, H. H. Chemotherapy, 1973, 18, Suppl., 34. 2. Glyn, J. H., Crofts, P. A. Br. med. J. 1966, ii, 1531. 3. Slone, D., Shapiro, S. in Drug Interactions (edited by P. L. Morselli p. 375. New York, 1974. 4. Mills, R. M. J. Am. med. Ass. 1971, 216, 799. 5. Simmons, F. et al., Gastroenterology, 1972, 62, 101. 6. Kantor. G. L. J. Am. med. Ass. 1970, 212, 478. 7. Marshall, A. J. and others. Lancet, 1977, ii, 1254. 8. Fleming, H. A., Hickling, P. ibid. 1975, ii, 1202. 9. Fleming, H. A. Br. Heart J. 1974, 36, 54.

toneum

there

were

only fibrous adhesions obliterating the right

anterior, subdiaphragmatic recess.

good evidence that while the peritoneum is most involved in practolol-induced sclerosing serositis any or all of the serous cavities may be affected. I have seen a number of cases with pleural thickening but none with parenchymal lung disease. It is sad to remember that no drug has quite replaced practolol in the treatment of certain difficult tachycardias. I have patients who would probably not have survived but for its benefits and others who find the alternatives so unsatisfactory that they plead to be given practolol again, despite being aware of the possible consequences. It is indeed unfortunate that this otherwise valuable drug is associated with such disastrous effects in some patients. There is

commonly

I thank Dr P. G. I. Stovin for the reports. Addenbrooke’s Hospital, Hills Road, Cambridge CB2

pleural biopsy and

2QQ

HUGH A. FLEMING

CO-TRIMOXAZOLE FATALITY

SIR,-A 48-year-old woman was prescribed co-trimoxazole (’Septrin’; trimethoprim and sulphamethoxazole) for a sore throat. After 24 h a generalised maculopapular rash developed and she was admitted to the Manchester Skin Hospital. Subsequently she had colicky abdominal pain, distension, and vomiting, and she was transferred to the surgical unit at Salford Royal Hospital. As a child she had had rheumatic fever, subsequently developing early heart-failure, treated with digoxin and ’Navidrex-K’ (cyclopenthiazide with potassium chloride). On examination she was dehydrated and pyrexial (38-5°C). There was generalised guarding of the abdomen with rebound tenderness in the right iliac fossa. Investigations showed anaemia (Hb 10.7g/dl), leucocytosis (21.3 x 109/1) and poikilocytosis. Platelet-count normal (284 x 109/1) but the prothrombin-time was high (29 s). Biochemically there was a hypokalxmic, hyponatraemic acidosis (sodium 124, potassium 2.6, chloride 86mmol/1, and urea 5 1 mmol/1). Arterial blood analysis showed pH 7.4, PC02 27.2 mm Hg, P02 89.8 mm Hg, bicarbonate 19 mmol/l. Radiological examination revealed distended loops of small bowel with numerous fluid levels, suggestive of subacute intestinal obstruction. Laparotomy revealed patchy, hsemorrhagic lesions throughout the length of the small bowel and ascending colon. The disease was too extensive for resection and steroids and dextran (’Lomodex 70’) were started immediately. 8 h postoperatively there was a fatal cardiorespiratory arrest. Necropsy revealed diffuse gastric and small-intestinal haemorrhagic ulceration with diffuse mucosal bullae characteristic of the Stevens-Johnson syndrome. Secondarily, there was mitral stenosis with cardiac failure but no evidence of thromboembolic disease. Minor skin rashes are common after antibacterial agents especially sulphonamides. Itching and rashes are commoner with co-trimoxazole than with sulphonamides alone.’ Since 1968 only one fatality associated with septrin has been reported to the manufacturers (Wellcome). The Stevens-Johnson syndrome is a severe manifestation of erythema multiforme, affecting the mucous membranes of mouth, nose and conjunctivae. "Martindale" records 3 deaths in one series of 77 cases with the Stevens-Johnson syndrome (40 due to sulphon-

amides).2 Erythema

et

al.);

necropsy

multiforme produces a spectrum of clinical mania few cutaneous lesions to a multisystem disorder that may prove fatal.3 If recognised early, the condition

festations, from

1. Burton, J. P. New Engl. J. Med. 1962, 266, 951. 2. Martindale: Extra Pharmacopœia. London, 1977. 3. Carroll, D. M. and others. J. Am. med. Ass. 1966, 195,

691.