737 RESCUE FROM METHOTREXATE TOXICITY
SIR,-Dr Cotton’s recommendation (Aug. 26, p. 484) that neurotransmitter precursors should accompany methotrexate therapy is supported by reduced phenylalanine clearance after co-trimoxazole1 which, in common with methotrexate, produces rises in biopterin derivatives when used therapeutically.2 There is evidence that folinic acid may not be the folate of choice in rescue therapy, as further rises in biopterin derivatives appear in the serum when folinic acid is administered 24 h after metho.trexate, whereas 5-methyltetrahydrofolic acid produces no such respons’e,2 is a proven rescue agent in the mouse,3 and’is commercially available as a pure compound. The importance of long-term side-effects of methotrexate on the central nervous system4 with and without C.N.S. irradiations increases with the life-expectancy of treated patients. Hæmatology Department, General Hospital, Birmingham B4 6NH
R. J. LEEMING
Chemistry Department, University of Aston in Birmingham
J. A. BLAIR
CONJUNCTIVITIS DUE TO KETOPROFEN SIR,-Ketoprofen (’Orudis’) is a non-steroidal anti-inflamatory agent whose efficacy is said to equal that of indomethacin.6So far serious reactions have not been reported, the common side-eflcts6 being gastrointestinal (nausea, vomiting, epigastric discomfort, abdominal pain, heartburn, indigestion, and constipation) and central-nervous-system disturbances (headache and giddiness). Conjunctivitis has not been reported though one patient complained of sore eyes.7 Ketoprofen also has an anti-oedema activity similar to that of indomethacin.In a trial of ketoprofen in nephrotic syndrome one patient had conjunctivitis and had to be withdrawn from the trial. This 45-year-old Nigerian woman presented with generalised oedema of 1 year’s duration. She had no history of drug allergy. Investigations gave the following results: Hb 10.5g/dl, erythrocyte-sedimentation rate 89 mm/h (Westergren), bloodurea 47 mg/dl, serum-creatinine 1.7 mg/dl. She had massive proteinuria (17.5 g in 24 h). Total serum-protein 5.0 g/dl (albumin 1-7); serum-cholesterol 457 mg/dl; liver-function tests normal. L.E. cells absent. Renal biopsy showed renal amyloidosis. She was put on diuretics and a low-salt, high-protein diet. Later she was accepted into the ketoprofen trial and put on ketoprofen 25 mg three times a day. 48 h after starting this drug the patient had painful swollen eyes with redness. She stopped the drug and the pain seemed to improve; when ketoprofen was introduced at a lower dose (25 mg/day) the pain and redness got worse. The patient then stopped taking the drug altogether, and her eyes started to improve. 2 weeks later she still had some redness of the eyes, particularly on the right. She was treated with hydrocortisone eye-drops and the eyes
quickly improved. anti-inflammatory drug should by itself produce an inflammatory reaction. One possibility is that this is an idiosyncratic reaction in a patient who already has abnormal immune responses (she has amyloidosis). In any event conIt is curious that
an
1. Andrews, T. M.,
Purkiss, P., Chalmers, R. A., Watts, R. W. F., Clin. chim. Acta, 1976, 66, 17 2. Leeming, R. J., Blair, J. A , Melikian, V., O’Gorman, D. J., J. clin. Path., 1976, 29, 444 Searle, C. E., Blair, J. A. Br.J. Cancer, 1970, 24, 603. 4 Meadows, A. T., Evans, A. E. Cancer, 1976, 37, 1079. 5 Eiser, C Archs Dis. Childh. 1978, 53, 391. 6. Gyory, A. N., Bloch, M., Burry, H. C., Grahame, R. Br. med. J. 1972, iv, 3.
398. 7. Zutshi, D W., Stern, D., Bloch, M., Mason, R. M. Rheumat. Rehabil. 1974,
13, 10.
8. Jolou, L., Guyonnet, J. C., Ducrot, R., Garret, C., Bardone, nan, G., Pasquet, J.J. Pharmac., Paris, 1971, 2, 259.
M.
C., Maig-
junctivitis should
now
be
regarded
as a
possible side-effect
of
ketoprofen. Department of Medicine, University of Nigeria Teaching Hospital, Enugu, Nigeria
E. M. UMEZ-ERONINI
LEVAMISOLE-INDUCED NEPHROPATHY
SIR,-Parkinson et al.’ described a patient who had thrombocytopenia, leucopenia, and evidence of circulating immune2 complexes during treatment with levamisole. Secher et al. found a patient in whom granular deposits of immunoglobulin and complement in the dermal-epidermal junction developed during treatment with levamisole and disappeared after it was stopped; the’patient had evidence of type I hypersensitivity to levamisole. We have seen a patient who had deposits in the dermal-epidermal junction and in the glomeruli and nephropathy during treatment with levamisole, but who did not seem to be hypersensitive to levamisole. The patient was a 48-year-old man with highly active, seropositive and erosive rheumatoid arthritis. He took levamisole 150 mg daily. Before treatment his urine was normal but after 10 months of treatment, during which the arthritis improved, he had up to 1-8 g protein in 24 h urine specimens. A kidney biopsy specimen showed by light microscopy slight increase in mesangial width without evidence of cellular proliferation. Immunofluorescence microscopy revealed granular mesangial deposits of IgG, IgM, IgA, and C3. After levamisole was stopped proteinuria disappeared within 6 weeks. During the levamisole treatment the patient had several episodes of a severely itching rash. A punch biopsy specimen of the skin before treatment showed no deposits of immunoglobulin or complement but biopsy specimens 4 and 8 months after the start of levamisole treatment and 2 months after the drug was stopped revealed granular deposits of IgM and C3 in the dermal-epidermal junction. A prick test with levamisole (100 mg/ml) elicited no weal and flare reaction and the patient’s leucocytes did not release histamine when exposed to levamisole. Evidence of
drug-induced immune-complex disease has appeared during treatment with gold salts,3-5 penicillamine,6-9 and levamisole,l2 but although immune-complex nephropathy seems to be a fairly frequent complication of treatment with gold salts3 4 and penicillamine9 we have been able to find only one report of nephropathy after treatment with levamisole. 10 Medical
Department, Rigshospital, Copenhagen,
Denmark
Department of Medicine, Hvidovre Hospital Department of Dermatology, Rigshospital Clinical
Chemistry Department, Municipal Hospital 1.
TROELS MØRK HANSEN JØRGEN PETERSEN POUL HALBERG HENRIK PERMIN
SUSANNE ULLMAN CLAUS BRUN SVEND LARSEN
Parkinson, D. R., Cano, P. O., Jerry, L. M., Capek, A., Shibata, H. R., Mansell, P. W., Lewis, M. G., Marquis, G. Lancet, 1977, i, 1129. 2. Secher, L., Permin, H., Stahl Skov, P., Ullman, S., Halberg, P. ibid. 1977, ii, 932. 3. Skrifvars, B. V., Törnröth, T. S., Tallqvist, G. N. Ann. rheum. Dis. 1977, 36, 549. 4. Törnröth, T., Skrifvars, B. Am. J. Path. 1975, 79, 219. 5. Iveson, J. M., Scott, D. G., Perera, W. D. H., Cunliffe, W. J., Wright, V. Ann. rheum. Dis. 1977, 36, 520. 6. Jaffe, I. A. Postgrad. med. J. 1968, 44, suppl. Oct. 15. 7. Lachmann, P. J. ibid. 1968, 44, suppl. Oct. 23. 8. McCormick, J. N., Wood, P., Bell, D. Penicillamine in Rheumatic Diseases. Symposium, Norway, March 7-10, 1976, p. 268. 9. Bacon, P. A., Tribe, C. R., Mackenzie, J. C., Verrier Jones, J. Lancet, 1975, ii, 75. 10 Levamisole in Rheumatoid Arthritis. Panel Discussion, Royal Society of Medicine, London, June 10, 1977.
SIR,-Dr Cotton’s recommendation (Aug. 26, p. 484) that neurotransmitter precursors should accompany methotrexate therapy is supported by reduced phenylalanine clearance after co-trimoxazole1 which, in common with methotrexate, produces rises in biopterin derivatives when used therapeutically.2 There is evidence that folinic acid may not be the folate of choice in rescue therapy, as further rises in biopterin derivatives appear in the serum when folinic acid is administered 24 h after metho.trexate, whereas 5-methyltetrahydrofolic acid produces no such respons’e,2 is a proven rescue agent in the mouse,3 and’is commercially available as a pure compound. The importance of long-term side-effects of methotrexate on the central nervous system4 with and without C.N.S. irradiations increases with the life-expectancy of treated patients. Hæmatology Department, General Hospital, Birmingham B4 6NH
R. J. LEEMING
Chemistry Department, University of Aston in Birmingham
J. A. BLAIR
CONJUNCTIVITIS DUE TO KETOPROFEN SIR,-Ketoprofen (’Orudis’) is a non-steroidal anti-inflamatory agent whose efficacy is said to equal that of indomethacin.6So far serious reactions have not been reported, the common side-eflcts6 being gastrointestinal (nausea, vomiting, epigastric discomfort, abdominal pain, heartburn, indigestion, and constipation) and central-nervous-system disturbances (headache and giddiness). Conjunctivitis has not been reported though one patient complained of sore eyes.7 Ketoprofen also has an anti-oedema activity similar to that of indomethacin.In a trial of ketoprofen in nephrotic syndrome one patient had conjunctivitis and had to be withdrawn from the trial. This 45-year-old Nigerian woman presented with generalised oedema of 1 year’s duration. She had no history of drug allergy. Investigations gave the following results: Hb 10.5g/dl, erythrocyte-sedimentation rate 89 mm/h (Westergren), bloodurea 47 mg/dl, serum-creatinine 1.7 mg/dl. She had massive proteinuria (17.5 g in 24 h). Total serum-protein 5.0 g/dl (albumin 1-7); serum-cholesterol 457 mg/dl; liver-function tests normal. L.E. cells absent. Renal biopsy showed renal amyloidosis. She was put on diuretics and a low-salt, high-protein diet. Later she was accepted into the ketoprofen trial and put on ketoprofen 25 mg three times a day. 48 h after starting this drug the patient had painful swollen eyes with redness. She stopped the drug and the pain seemed to improve; when ketoprofen was introduced at a lower dose (25 mg/day) the pain and redness got worse. The patient then stopped taking the drug altogether, and her eyes started to improve. 2 weeks later she still had some redness of the eyes, particularly on the right. She was treated with hydrocortisone eye-drops and the eyes
quickly improved. anti-inflammatory drug should by itself produce an inflammatory reaction. One possibility is that this is an idiosyncratic reaction in a patient who already has abnormal immune responses (she has amyloidosis). In any event conIt is curious that
an
1. Andrews, T. M.,
Purkiss, P., Chalmers, R. A., Watts, R. W. F., Clin. chim. Acta, 1976, 66, 17 2. Leeming, R. J., Blair, J. A , Melikian, V., O’Gorman, D. J., J. clin. Path., 1976, 29, 444 Searle, C. E., Blair, J. A. Br.J. Cancer, 1970, 24, 603. 4 Meadows, A. T., Evans, A. E. Cancer, 1976, 37, 1079. 5 Eiser, C Archs Dis. Childh. 1978, 53, 391. 6. Gyory, A. N., Bloch, M., Burry, H. C., Grahame, R. Br. med. J. 1972, iv, 3.
398. 7. Zutshi, D W., Stern, D., Bloch, M., Mason, R. M. Rheumat. Rehabil. 1974,
13, 10.
8. Jolou, L., Guyonnet, J. C., Ducrot, R., Garret, C., Bardone, nan, G., Pasquet, J.J. Pharmac., Paris, 1971, 2, 259.
M.
C., Maig-
junctivitis should
now
be
regarded
as a
possible side-effect
of
ketoprofen. Department of Medicine, University of Nigeria Teaching Hospital, Enugu, Nigeria
E. M. UMEZ-ERONINI
LEVAMISOLE-INDUCED NEPHROPATHY
SIR,-Parkinson et al.’ described a patient who had thrombocytopenia, leucopenia, and evidence of circulating immune2 complexes during treatment with levamisole. Secher et al. found a patient in whom granular deposits of immunoglobulin and complement in the dermal-epidermal junction developed during treatment with levamisole and disappeared after it was stopped; the’patient had evidence of type I hypersensitivity to levamisole. We have seen a patient who had deposits in the dermal-epidermal junction and in the glomeruli and nephropathy during treatment with levamisole, but who did not seem to be hypersensitive to levamisole. The patient was a 48-year-old man with highly active, seropositive and erosive rheumatoid arthritis. He took levamisole 150 mg daily. Before treatment his urine was normal but after 10 months of treatment, during which the arthritis improved, he had up to 1-8 g protein in 24 h urine specimens. A kidney biopsy specimen showed by light microscopy slight increase in mesangial width without evidence of cellular proliferation. Immunofluorescence microscopy revealed granular mesangial deposits of IgG, IgM, IgA, and C3. After levamisole was stopped proteinuria disappeared within 6 weeks. During the levamisole treatment the patient had several episodes of a severely itching rash. A punch biopsy specimen of the skin before treatment showed no deposits of immunoglobulin or complement but biopsy specimens 4 and 8 months after the start of levamisole treatment and 2 months after the drug was stopped revealed granular deposits of IgM and C3 in the dermal-epidermal junction. A prick test with levamisole (100 mg/ml) elicited no weal and flare reaction and the patient’s leucocytes did not release histamine when exposed to levamisole. Evidence of
drug-induced immune-complex disease has appeared during treatment with gold salts,3-5 penicillamine,6-9 and levamisole,l2 but although immune-complex nephropathy seems to be a fairly frequent complication of treatment with gold salts3 4 and penicillamine9 we have been able to find only one report of nephropathy after treatment with levamisole. 10 Medical
Department, Rigshospital, Copenhagen,
Denmark
Department of Medicine, Hvidovre Hospital Department of Dermatology, Rigshospital Clinical
Chemistry Department, Municipal Hospital 1.
TROELS MØRK HANSEN JØRGEN PETERSEN POUL HALBERG HENRIK PERMIN
SUSANNE ULLMAN CLAUS BRUN SVEND LARSEN
Parkinson, D. R., Cano, P. O., Jerry, L. M., Capek, A., Shibata, H. R., Mansell, P. W., Lewis, M. G., Marquis, G. Lancet, 1977, i, 1129. 2. Secher, L., Permin, H., Stahl Skov, P., Ullman, S., Halberg, P. ibid. 1977, ii, 932. 3. Skrifvars, B. V., Törnröth, T. S., Tallqvist, G. N. Ann. rheum. Dis. 1977, 36, 549. 4. Törnröth, T., Skrifvars, B. Am. J. Path. 1975, 79, 219. 5. Iveson, J. M., Scott, D. G., Perera, W. D. H., Cunliffe, W. J., Wright, V. Ann. rheum. Dis. 1977, 36, 520. 6. Jaffe, I. A. Postgrad. med. J. 1968, 44, suppl. Oct. 15. 7. Lachmann, P. J. ibid. 1968, 44, suppl. Oct. 23. 8. McCormick, J. N., Wood, P., Bell, D. Penicillamine in Rheumatic Diseases. Symposium, Norway, March 7-10, 1976, p. 268. 9. Bacon, P. A., Tribe, C. R., Mackenzie, J. C., Verrier Jones, J. Lancet, 1975, ii, 75. 10 Levamisole in Rheumatoid Arthritis. Panel Discussion, Royal Society of Medicine, London, June 10, 1977.
