546 combat their profound toxicity, and 1 each because of gross melocna, rectal abscess, severe psychosis, and severe vomiting which prevented oral therapy. However, we feel that the patients in the study represented the range of severity seen in this illness. (2.) The analysis of the results refers to patients who were culture positive; only a third of these were positive by stool culture alone before therapy. Those few patients who were diagnosed clinically and who had a four-fold or greater rise in antibody titre were not included in the analysis. Their inclusion would not, however, have altered the conclusions. (3.) We are sorry if we gave the impression that the two patients whose intestine perforated during treatment were not failures. Only their removal from the strict therapeutic regimen dictated by the study protocol precluded their inclusion in the analysis of febrile outcome. Both recovered with medical and surgical therapy. (4.) The persistent fever in the co-trimoxazole group is of interest to us also. Six patients in this group had continuing fever and symptoms which were believed on clinical grounds to be a continuation of their underlying illness. While drug fever cannot be ruled out, this incidence would be surprisingly high. We agree that fever is not the ideal yardstick by which to measure response in typhoid fever, but our long experience with this disease in over 1000 trial participants and in the field has substantiated the validity of defervescence as a measure of response to therapy which is superior to subjective observations. Culture negativity as an indicator of efficacy in the face of continuing fever and other symptoms could be misleading. As in all infectious diseases, eradication of the infecting agent is a desirable goal, but one should not confuse bacteriological cure with clinical cure. Division of Infectious
Diseases,
University of Maryland School of Medicine, Baltimore, Maryland 21201, U.S.A.
MERRILL J. SNYDER WILLIAM E. WOODWARD
WITHDRAWAL OF CLONIDINE
SIR,-In hypertensive patients treated with clonidine sudden cessation of therapy may produce a syndrome of anxiety, tremor, and palpitations, sometimes associated with rebound hypertension.’-3 I would like to report two patients with this syndrome and to suggest that the use of clonidine in developing countries is potentially hazardous.
rose again and the dose was increased to 0-3 mg twice daily. Therapy with clonidine was inadvertently interrupted after 2 days and her blood-pressure rose to 250/190 mm Hg. She complained of palpitations and tremor. The highest bloodpressure recorded either before or during treatment had been 230/140 mm Hg. The diastolic blood-pressure remained between 120 and 190 mm Hg over the next 3 days, until clonidine therapy was re-started. Her blood-pressure then fell to 150/100 mm Hg with relief of her symptoms, and gradual
but later
reduction in the dose of clonidine was achieved without further hypertensive overshoot. There are two factors to remember when considering the risks of the use of clonidine in Tanzania. Firstly, drugs are generally regarded as treatment for symptoms, so that it is often difficult to persuade symptom-free patients to take regular treatment. In a study of outpatient treatment in 142 patients with essential hypertension in Tanzania, only 49% were still attending after 12 months; no information is available on the proportion of those who were taking their therapy as prescribed.° The second factor is the irregular supply of drugs, Drugs are often out of stock at health centres or hospitals. As a result, even a patient who is compliant with therapy will be at risk from developing the withdrawal syndrome. The manufacturers have done little to publicise the risk of sudden withdrawal of clonidine. The booklet distributed by Boehringer-Ingelheim in Tanzania does not mention this risk, and gives only two side-effects, contrasting with the advertisements in American journals where 50 adverse reactions and special precautions (including the need for gradual reduction of dosage) are given. This precaution is mentioned in M.l.M.S. but not in African M.I.M.S. There is, moreover, no indication of the dangers of sudden cessation of clonidine therapy even on the package insert distributed in Tanzania, contrasting with the British equivalent. The manufacturers have also distributed free samples of the drug before it is available through the Government stores. This would seem likely to encourage intermittent therapy. I suggest that clonidine is an inappropriate drug for developing countries. The manufacturers should include warnings of the risk of the withdrawal syndrome in all their promotional literature and package inserts. Faculty of Medicine, University of Dar es Salaam, P. O. Box 20693, Dar es Salaam,
JOHN S. YUDKIN
Tanzania
Case 1 A 54-year-old man with an 8-year history of essential hypertension was treated with clonidine 0.15 mg three times per day, propranolol 20 mg twice daily, and bendrofluazide 5 mg daily. After 3 weeks, increasing giddiness and weakness caused him to stop his drugs. Over the next 12 h he experienced severe headaches and giddiness, nausea, palpitation, anxiety, and tremor. His blood-pressure rose to 240/140 mm Hg, a level which had only once been recorded previously. The symptoms were controlled by re-starting therapy with clonidine, and they did not recur during gradual withdrawal of the drug.
Case 2 A 37-year-old woman had proteinuria, oedema, and a bloodpressure of 160/90 mm Hg in the 26th week of pregnancy.
After unsuccessful
treatment with oral methyldopa and intrahydrallazine, she delivered a live infant weighing 1740 g at 34 weeks. Her blood-pressure remained high and on the 5th day post partum she was treated with clonidine z 15 mg three times per day. Her blood-pressure fell to 130/90 mm Hg venous
M. E., Briant, R. H., George, C. F., Pharmac. 1972, 4, 222. 2. Hunyor, S. N., Hansson, L., Harrison, T. S., 1.
Conolly,
Dollery,
C. T. Eur.
J.
APLASTIC ANÆMIA AFTER PROLONGED TREATMENT WITH CHLORPHENIRAMINE
SIR,-Deringer and Maniatis’s letter’ on chlorpheniramineinduced bone-marrow suppression prompts us to present an additional case. In contrast to their patient, who had been on a short course of therapy, ours had aplastic anaemia after prolonged administration of the drug. A 51-year-old man was admitted to hospital on Jan. 20, 1977, for investigation of pancytopenia. From 1966 up to early December, 1976, he had taken one tablet of ’Polaramine’(containing 6 mg chlorpheniramine) per day for 3 or 4 days a week on average, but sometimes with a short break of 10-20 days. He took the drug for allergic rhinitis. Other antihistamines had been taken before chlorpheniramine, but they could not have caused the aplastic anaemia because the typical symptoms of aplastic anaemia developed after prolonged administration of polaramine alone. He had no other medication. Investigations on Sept. 2, 1976, when he was healthy, were almost normal except for a tendency to mild leukopenia: Hb 16.0 gldl, white blood-cells (W.B.c.) 3800/1, and normal values for hepa-
clin.
4. Makene, Africa
Hoobler, S. W. Br. med. J.
Bailey,
R. R. N. Z.
med. J. 1975, 81, 268.
Use and Abuse of Drugs and Chemicals in Tropical F. Bagshawe, G. Mama, and E. N. Mngola); p 585
Nairobi, 1974.
1973, i, 209. 3
J. in The (edited by A.
W.
1.
Deringer, P. M., Maniatis,
A. Lancet,
1976, i, 432.
Diseases,
University of Maryland School of Medicine, Baltimore, Maryland 21201, U.S.A.
MERRILL J. SNYDER WILLIAM E. WOODWARD
WITHDRAWAL OF CLONIDINE
SIR,-In hypertensive patients treated with clonidine sudden cessation of therapy may produce a syndrome of anxiety, tremor, and palpitations, sometimes associated with rebound hypertension.’-3 I would like to report two patients with this syndrome and to suggest that the use of clonidine in developing countries is potentially hazardous.
rose again and the dose was increased to 0-3 mg twice daily. Therapy with clonidine was inadvertently interrupted after 2 days and her blood-pressure rose to 250/190 mm Hg. She complained of palpitations and tremor. The highest bloodpressure recorded either before or during treatment had been 230/140 mm Hg. The diastolic blood-pressure remained between 120 and 190 mm Hg over the next 3 days, until clonidine therapy was re-started. Her blood-pressure then fell to 150/100 mm Hg with relief of her symptoms, and gradual
but later
reduction in the dose of clonidine was achieved without further hypertensive overshoot. There are two factors to remember when considering the risks of the use of clonidine in Tanzania. Firstly, drugs are generally regarded as treatment for symptoms, so that it is often difficult to persuade symptom-free patients to take regular treatment. In a study of outpatient treatment in 142 patients with essential hypertension in Tanzania, only 49% were still attending after 12 months; no information is available on the proportion of those who were taking their therapy as prescribed.° The second factor is the irregular supply of drugs, Drugs are often out of stock at health centres or hospitals. As a result, even a patient who is compliant with therapy will be at risk from developing the withdrawal syndrome. The manufacturers have done little to publicise the risk of sudden withdrawal of clonidine. The booklet distributed by Boehringer-Ingelheim in Tanzania does not mention this risk, and gives only two side-effects, contrasting with the advertisements in American journals where 50 adverse reactions and special precautions (including the need for gradual reduction of dosage) are given. This precaution is mentioned in M.l.M.S. but not in African M.I.M.S. There is, moreover, no indication of the dangers of sudden cessation of clonidine therapy even on the package insert distributed in Tanzania, contrasting with the British equivalent. The manufacturers have also distributed free samples of the drug before it is available through the Government stores. This would seem likely to encourage intermittent therapy. I suggest that clonidine is an inappropriate drug for developing countries. The manufacturers should include warnings of the risk of the withdrawal syndrome in all their promotional literature and package inserts. Faculty of Medicine, University of Dar es Salaam, P. O. Box 20693, Dar es Salaam,
JOHN S. YUDKIN
Tanzania
Case 1 A 54-year-old man with an 8-year history of essential hypertension was treated with clonidine 0.15 mg three times per day, propranolol 20 mg twice daily, and bendrofluazide 5 mg daily. After 3 weeks, increasing giddiness and weakness caused him to stop his drugs. Over the next 12 h he experienced severe headaches and giddiness, nausea, palpitation, anxiety, and tremor. His blood-pressure rose to 240/140 mm Hg, a level which had only once been recorded previously. The symptoms were controlled by re-starting therapy with clonidine, and they did not recur during gradual withdrawal of the drug.
Case 2 A 37-year-old woman had proteinuria, oedema, and a bloodpressure of 160/90 mm Hg in the 26th week of pregnancy.
After unsuccessful
treatment with oral methyldopa and intrahydrallazine, she delivered a live infant weighing 1740 g at 34 weeks. Her blood-pressure remained high and on the 5th day post partum she was treated with clonidine z 15 mg three times per day. Her blood-pressure fell to 130/90 mm Hg venous
M. E., Briant, R. H., George, C. F., Pharmac. 1972, 4, 222. 2. Hunyor, S. N., Hansson, L., Harrison, T. S., 1.
Conolly,
Dollery,
C. T. Eur.
J.
APLASTIC ANÆMIA AFTER PROLONGED TREATMENT WITH CHLORPHENIRAMINE
SIR,-Deringer and Maniatis’s letter’ on chlorpheniramineinduced bone-marrow suppression prompts us to present an additional case. In contrast to their patient, who had been on a short course of therapy, ours had aplastic anaemia after prolonged administration of the drug. A 51-year-old man was admitted to hospital on Jan. 20, 1977, for investigation of pancytopenia. From 1966 up to early December, 1976, he had taken one tablet of ’Polaramine’(containing 6 mg chlorpheniramine) per day for 3 or 4 days a week on average, but sometimes with a short break of 10-20 days. He took the drug for allergic rhinitis. Other antihistamines had been taken before chlorpheniramine, but they could not have caused the aplastic anaemia because the typical symptoms of aplastic anaemia developed after prolonged administration of polaramine alone. He had no other medication. Investigations on Sept. 2, 1976, when he was healthy, were almost normal except for a tendency to mild leukopenia: Hb 16.0 gldl, white blood-cells (W.B.c.) 3800/1, and normal values for hepa-
clin.
4. Makene, Africa
Hoobler, S. W. Br. med. J.
Bailey,
R. R. N. Z.
med. J. 1975, 81, 268.
Use and Abuse of Drugs and Chemicals in Tropical F. Bagshawe, G. Mama, and E. N. Mngola); p 585
Nairobi, 1974.
1973, i, 209. 3
J. in The (edited by A.
W.
1.
Deringer, P. M., Maniatis,
A. Lancet,
1976, i, 432.
