1297 severe forms of hypertension, who received oral antihypertensive drugs. Although we did not encounter cardiac complications with the infusion procedure we agree with your Glasgow correspondents that it would be preferable to prevent the increase in car-
tients with less treatment with
diac output that results from the administration of diazoxide. We are now studying the effects of administration of propranolol 1 h after diazoxide. We now have experience in eleven patients in whom the increase in heart-rate was completely abolished by intravenous propranolol (0-2mg/kg bodyweight) with only a slight effect on blood-pressure. The mean heartrate before diazoxide was 87±14 beats/min; it rose to 106±11 after the infusion but fell to 84±10 after propranolol. The res-
pective blood-pressures
were
204/131 (±23/11), 83/104
(±28/14), and 169/105 (±31/18) mmHg. Our experience so far makes us confident that diazoxide administered by slow infusion is an effective and safe procedure to treat acute hypertensive crises. ’
Nephrology Department, Sint Radboudziekenhuis, 6500 HB Nijmegen, Netherlands
TH. THIEN F. T. M. HUYSMANS R. A. P. KOENE
SERUM-SICKNESS-LIKE SYNDROME WITH MEMBRANOUS GLOMERULOPATHY IN PATIENT ON CAPTOPRIL
SiR,—The converting-enzyme inhibitor captopril is an effective antihypertensive agent. Side-effects listed in Dr Atkinson and Dr Robertson’s review (Oct. 20, p. 838) include dose-dependent rash and fever, angioneurotic oedema, spontaneously reversible loss of taste and nephrotic syndrome, due to membranous glomerulopathy (MGP) which we had reported in one case (Aug. 11, p. 306). Lately, we have seen an allergic reaction resembling serum sickness in a patient tak-
ing captopril. A 52-year-old man presented with accelerated renovascular hypertension. Captopril was started in July, 1979; normotension was reached on a dosage of 150 mg three times a day after addition of a diuretic. Rash and arthralgia developed 4 weeks later and
disappeared completely within a week when the captopril dosage was reduced to 50 mg three times a day. This dosage was increased to 50 mg four times a day in September because high blood-pressure recurred. 3 days later the patient had a generalised rash with epidermolysis, fever, arthralgia, and lymphadenopathy. Laboratory findings included leukocytosis (21 300/:d) with marked eosinophilia in the peripheral blood smear (40-50%), microscopic hsematuria, and slight proteinuria (0.8 g in 24 h). Antinuclear antibodies with a homogenous pattern, previously negative, became positive at a titre of 1:1000. Anti-native-DNA was absent. Complement levels (CC3 and C4) were normal. Chest X-ray demonstrated reticulonodular changes. A renal biopsy showed no abnormalities on light microscopy. On immunofluorescence granular deposition of IgG, IgA, IgM, and C3 was found in the glomerular basement membrane (GBM). Electron-dense deposits were demonstrated along the subepithelial side of the GBM on electron-
microscopy (figure).
Captopril was withdrawn with complete reversal of all clinical and biochemical abnormalities within 2 weeks. A lymphocyte transformation test 6 weeks later, with captopril as an antigen, was positive in the patient whereas there was no stimulation in controls (stimulation index 7-2 with captopril 10
,glml). The clinical picture in this patient resembled serum sicka condition known to be the result of deposition of immune complexes.’ The renal-biopsy findings are compatible with early stage MGP. Captopril or one of its metabolites may ness,
Electron-dense
Pathogenesis
of
serum
subepithelial
side
of
GBM
have acted as a hapten, resulting in antibody formation. The increase in the dosage of the drug may have elicited an allergic systemic reaction, associated with deposition of immune complexes in the GBM. STEVEN J. HOORNTJE JAN J. WEENING Departments of Medicine CEES G. M. KALLENBERG and Pathology, ERIK J. L. PRINS State University Hospital, AB J. M. DONKER 9713 EZ Groningen, Netherlands
APHTHOUS ULCERS OF MOUTH FROM CAPTOPRIL
SiR,—Iwish to record a side-effect of captopril which was observed during a clinical trial of captopril versus propranolol in the treatment of mild and moderate hypertension.I An Indian woman aged 36 had hypertension (W.H.O. criteria 1) and diabetes mellitus. Her blood pressure was 140/105 mm Hg when she was on placebo. The fundi showed vascular changes of hypertension and the other systems were normal. Investigations on Aug. 22, 1978, were: haemoglobin 15 3 g/dl ; leucocyte count 8x 109/1; serum protein 75 gll (albumin 45); blood urea 2-33 and serum cholesterol 5-1, uric acid 0-25, glucose 10-8, calcium 2.4, phosphorus 1-2, chloride 103, and COZ 26, all in mmol/1; serum bilirubin 5-11 .mol/1. Her blood pressure was controlled on propranolol 360 mg daily and she had been on chlorpropamide 500 mg daily for the previous 3 years for her diabetes mellitus. On April 10, 1979, the daily dosage of propranolol was reduced to 120 mg and captopril 100 mg three times a day was added in accordance with the drug trial protocol. Severe aphthous ulcers of the mouth developed on June 8. These ulcers were treated by her general practitioner with 0 1% triamcinolone acetonide in base gelatin, pectin, and sodium carboxymethylcellulose (’Kenalog’ in ’Orabase’; Squibb) applied locally. However, the ulcers persisted. She could not take solid foods until captopril was stopped on June 26. Investigations on June 8 were: haemoglobin 14.7g/dl; leucocyte count 6.7 7 109/1 (neutrophils 79%, lymphocytes 17%, monocytes 3%, eosinophils 0%, basophils 1%); antinuclear factor, LE cells, and anti-DNA antibodies negative; blood sugar 9 -7 mmol/1. Between June 26 and Aug. 28 her blood pressure was controlled on pindolol 10 mg daily and she was symptom-free. On Aug. 28 she was rechallenged with captopril 300 mg daily and within 2 days the aphthous ulcers recurred; they resolved when captopril was stopped. 1. Seedat YK.
1. Dixon FJ, Vazquez JJ, Weigle WO, Cochrane CG. sickness. Arch Pathol 1958; 65: 18-28.
deposits along
(x26 000).
treatment
press).
Comparison of captopril (SQ
225) with propranolol in the hypertension. S Afr Med J (in
14
of mild and moderate essential
1298
Nephrotic syndrome2
and rash and/or fever and loss of
taste3.4 have been reported after captopril therapy, but aphthous ulcers in the mouth have not been previously described. The persistence of the ulcers until captopril was withdrawn, their recurrence on rechallenge with captopril, and the absence of any other obvious cause make it likely that captopril caused the aphthous ulcers in the mouth in this patient. Department of Medicine, University of Natal, Congella, 4013 Natal, South Africa
the whole spectrum of compliance bias may be related to the level of suspiciousness. If other investigators can confirm our findings, suspiciousness will need to be considered in the design of clinical trials on antihypertensive drugs. M. W. O’HALLORAN
Queen
R. ZACEST C. G. BARROW L. L. WILSON
Hospital,
Woodville, 5011 Adelaide, South Australia
Y. K. SEEDAT
ANAPHYLACTOID REACTION TO N-ACETYLCYSTEINE
SUSPICIOUSNESS TRAIT: A FACTOR IN ANTIHYPERTENSIVE DRUG TRIALS?
SiR,—The problem of dropouts from clinical trials is poorly understood, but Caldwell et a1.5 have suggested that personality factors may be significant in patients who discontinue antihypertensive treatment. We have used the questionnaire of Cattell et a1.6 to determine if personality factors show a bias in patients who stop taking their antihypertensive drugs. 70 consecutive hypertensive patients who presented to the outpatient clinic and who were deemed suitable for medical treatment participated in this survey. They all completed form C of the personality questionnaire before being put on antihypertensive drugs. Over a treatment period of twelve months, 13 dropped out for a variety of reasons. Scores for all sixteen factors in the dropouts and in those who continued treatment were compared by the Mann-Whitney U test, allowance being made for the multiplicity of comparisons. A two-tailed probablity table was used to obtain the p value. Only scores for factor L (the measure of the trustfulnesssuspiciousness trait) were different, being higher (p
tients with less treatment with
diac output that results from the administration of diazoxide. We are now studying the effects of administration of propranolol 1 h after diazoxide. We now have experience in eleven patients in whom the increase in heart-rate was completely abolished by intravenous propranolol (0-2mg/kg bodyweight) with only a slight effect on blood-pressure. The mean heartrate before diazoxide was 87±14 beats/min; it rose to 106±11 after the infusion but fell to 84±10 after propranolol. The res-
pective blood-pressures
were
204/131 (±23/11), 83/104
(±28/14), and 169/105 (±31/18) mmHg. Our experience so far makes us confident that diazoxide administered by slow infusion is an effective and safe procedure to treat acute hypertensive crises. ’
Nephrology Department, Sint Radboudziekenhuis, 6500 HB Nijmegen, Netherlands
TH. THIEN F. T. M. HUYSMANS R. A. P. KOENE
SERUM-SICKNESS-LIKE SYNDROME WITH MEMBRANOUS GLOMERULOPATHY IN PATIENT ON CAPTOPRIL
SiR,—The converting-enzyme inhibitor captopril is an effective antihypertensive agent. Side-effects listed in Dr Atkinson and Dr Robertson’s review (Oct. 20, p. 838) include dose-dependent rash and fever, angioneurotic oedema, spontaneously reversible loss of taste and nephrotic syndrome, due to membranous glomerulopathy (MGP) which we had reported in one case (Aug. 11, p. 306). Lately, we have seen an allergic reaction resembling serum sickness in a patient tak-
ing captopril. A 52-year-old man presented with accelerated renovascular hypertension. Captopril was started in July, 1979; normotension was reached on a dosage of 150 mg three times a day after addition of a diuretic. Rash and arthralgia developed 4 weeks later and
disappeared completely within a week when the captopril dosage was reduced to 50 mg three times a day. This dosage was increased to 50 mg four times a day in September because high blood-pressure recurred. 3 days later the patient had a generalised rash with epidermolysis, fever, arthralgia, and lymphadenopathy. Laboratory findings included leukocytosis (21 300/:d) with marked eosinophilia in the peripheral blood smear (40-50%), microscopic hsematuria, and slight proteinuria (0.8 g in 24 h). Antinuclear antibodies with a homogenous pattern, previously negative, became positive at a titre of 1:1000. Anti-native-DNA was absent. Complement levels (CC3 and C4) were normal. Chest X-ray demonstrated reticulonodular changes. A renal biopsy showed no abnormalities on light microscopy. On immunofluorescence granular deposition of IgG, IgA, IgM, and C3 was found in the glomerular basement membrane (GBM). Electron-dense deposits were demonstrated along the subepithelial side of the GBM on electron-
microscopy (figure).
Captopril was withdrawn with complete reversal of all clinical and biochemical abnormalities within 2 weeks. A lymphocyte transformation test 6 weeks later, with captopril as an antigen, was positive in the patient whereas there was no stimulation in controls (stimulation index 7-2 with captopril 10
,glml). The clinical picture in this patient resembled serum sicka condition known to be the result of deposition of immune complexes.’ The renal-biopsy findings are compatible with early stage MGP. Captopril or one of its metabolites may ness,
Electron-dense
Pathogenesis
of
serum
subepithelial
side
of
GBM
have acted as a hapten, resulting in antibody formation. The increase in the dosage of the drug may have elicited an allergic systemic reaction, associated with deposition of immune complexes in the GBM. STEVEN J. HOORNTJE JAN J. WEENING Departments of Medicine CEES G. M. KALLENBERG and Pathology, ERIK J. L. PRINS State University Hospital, AB J. M. DONKER 9713 EZ Groningen, Netherlands
APHTHOUS ULCERS OF MOUTH FROM CAPTOPRIL
SiR,—Iwish to record a side-effect of captopril which was observed during a clinical trial of captopril versus propranolol in the treatment of mild and moderate hypertension.I An Indian woman aged 36 had hypertension (W.H.O. criteria 1) and diabetes mellitus. Her blood pressure was 140/105 mm Hg when she was on placebo. The fundi showed vascular changes of hypertension and the other systems were normal. Investigations on Aug. 22, 1978, were: haemoglobin 15 3 g/dl ; leucocyte count 8x 109/1; serum protein 75 gll (albumin 45); blood urea 2-33 and serum cholesterol 5-1, uric acid 0-25, glucose 10-8, calcium 2.4, phosphorus 1-2, chloride 103, and COZ 26, all in mmol/1; serum bilirubin 5-11 .mol/1. Her blood pressure was controlled on propranolol 360 mg daily and she had been on chlorpropamide 500 mg daily for the previous 3 years for her diabetes mellitus. On April 10, 1979, the daily dosage of propranolol was reduced to 120 mg and captopril 100 mg three times a day was added in accordance with the drug trial protocol. Severe aphthous ulcers of the mouth developed on June 8. These ulcers were treated by her general practitioner with 0 1% triamcinolone acetonide in base gelatin, pectin, and sodium carboxymethylcellulose (’Kenalog’ in ’Orabase’; Squibb) applied locally. However, the ulcers persisted. She could not take solid foods until captopril was stopped on June 26. Investigations on June 8 were: haemoglobin 14.7g/dl; leucocyte count 6.7 7 109/1 (neutrophils 79%, lymphocytes 17%, monocytes 3%, eosinophils 0%, basophils 1%); antinuclear factor, LE cells, and anti-DNA antibodies negative; blood sugar 9 -7 mmol/1. Between June 26 and Aug. 28 her blood pressure was controlled on pindolol 10 mg daily and she was symptom-free. On Aug. 28 she was rechallenged with captopril 300 mg daily and within 2 days the aphthous ulcers recurred; they resolved when captopril was stopped. 1. Seedat YK.
1. Dixon FJ, Vazquez JJ, Weigle WO, Cochrane CG. sickness. Arch Pathol 1958; 65: 18-28.
deposits along
(x26 000).
treatment
press).
Comparison of captopril (SQ
225) with propranolol in the hypertension. S Afr Med J (in
14
of mild and moderate essential
1298
Nephrotic syndrome2
and rash and/or fever and loss of
taste3.4 have been reported after captopril therapy, but aphthous ulcers in the mouth have not been previously described. The persistence of the ulcers until captopril was withdrawn, their recurrence on rechallenge with captopril, and the absence of any other obvious cause make it likely that captopril caused the aphthous ulcers in the mouth in this patient. Department of Medicine, University of Natal, Congella, 4013 Natal, South Africa
the whole spectrum of compliance bias may be related to the level of suspiciousness. If other investigators can confirm our findings, suspiciousness will need to be considered in the design of clinical trials on antihypertensive drugs. M. W. O’HALLORAN
Queen
R. ZACEST C. G. BARROW L. L. WILSON
Hospital,
Woodville, 5011 Adelaide, South Australia
Y. K. SEEDAT
ANAPHYLACTOID REACTION TO N-ACETYLCYSTEINE
SUSPICIOUSNESS TRAIT: A FACTOR IN ANTIHYPERTENSIVE DRUG TRIALS?
SiR,—The problem of dropouts from clinical trials is poorly understood, but Caldwell et a1.5 have suggested that personality factors may be significant in patients who discontinue antihypertensive treatment. We have used the questionnaire of Cattell et a1.6 to determine if personality factors show a bias in patients who stop taking their antihypertensive drugs. 70 consecutive hypertensive patients who presented to the outpatient clinic and who were deemed suitable for medical treatment participated in this survey. They all completed form C of the personality questionnaire before being put on antihypertensive drugs. Over a treatment period of twelve months, 13 dropped out for a variety of reasons. Scores for all sixteen factors in the dropouts and in those who continued treatment were compared by the Mann-Whitney U test, allowance being made for the multiplicity of comparisons. A two-tailed probablity table was used to obtain the p value. Only scores for factor L (the measure of the trustfulnesssuspiciousness trait) were different, being higher (p
