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INDUCTION OF VIBRIO CHOLERAE SPECIFIC BILIARY ANTIBODIES AFTER ORAL IMMUNISATION WITH A CHOLERA CELL-WALL FRACTION
1276 MALFORMATION OF FETUS CONCEIVED 4 MONTHS AFTER TERMINATION OF MATERNAL ETRETINATE TREATMENT
SiR,-Since etretinate (’Tigason’) is teratogenic contraception is women of childbearing potential not only during treatment but also for 24 months after discontinuation (after long-
required for term
administration the
drug’s
elimination half-life is 120
days or
morel,2). Some cases of skeletal and craniofacial disorders in fetuses from women receiving etretinate have been reported, though other
have had normal children.2So far, no malformations have been reported in children whose mothers had become pregnant within 2 years of cessation of etretinate therapy. 1,3 We have observed skeletal deformations in a fetus conceived 4 months after the last dose of etretinate. A 22-year-old woman with Darier’s disease (dyskeratosis follicularis) since the age of 17 had been treated intermittently with etretinate; the last 5-month treatment with 30 mg daily ended 4 months before conception. In her 8th week of pregnancy, the patient sought genetic counselling and a medically indicated termination was decided on. She consented to chorion biopsy and to amniotic fluid investigation. A normal female karyotype was diagnosed from chromosome analysis. Serum concentrations of etretinate and its major metabolite, the carboxylic acid derivative Ro 10-1670, were 7 ng/ml and 8 ng/ml, respectively (therapeutic levels 100-500 ng/mI4,5). The pregnancy was terminated in the 10th week. The fetus (2 -2 cm long) had one lower limb much shorter than the other (5 mm left, 10 mm right). The distal left leg was rudimentary; only one toe was present, the tibia and fibula were missing, and the femur was hypoplastic. No further abnormalities were detected. Craniofacial malformations could not be assessed because the head was badly deformed by the termination. The one sidedness of skeletal deformation and its nature are consistent with an exogenous cause, probably etretinate taken by the mother before women
conception. This case emphasises the need for strict contraception to continue for 2 years after etretinate therapy. This unusual recommendation by the manufacturer is well justified. We thank Hoffmann-La Roche,
Grenzach-Wyhlen
for
measuring
serum
drug concentrations. W. GROTE D. HARMS Departments of Human Genetics, Paediatric Pathology, Dermatology, and Pharmacology, University of Kiel, 2300 Kiel, West Germany 1. 2. 3.
4. 5.
U. JÄNIG H. KIETZMANN U. RAVENS I. SCHWARZE
Bounameaux Y, Fisch T. Teratogene Wirkung von Etretinat beim Menschen. Deutsche Med Wochenschr 1984; 109: 1476-80. Cordero AA, Allevato MA, Donatti L. Ro-10-9359 and pregnancy. In: Retinoids: Advances in basic research and therapy. Berlin: Springer, 1981: 501. Rüther TH, Kietzmann H. Schwangerschaft nach Therapie mit Etretinat (Tigason). Akt Dermatol 1984, 10: 62-63. Paravicini U. Pharmacokinetics and metabolism of oral aromatic retinoids. In: Retinoids: Advances in basic research and therapy. Berlin: Springer, 1981: 13-20. Ward A, Brogden RN, Heel RC, Speight TM, Avery GS. Etretinate. A review of its pharmacological properties and therapeutic efficacy in psoriasis and other skin disorders. Drug 1983; 26: 9-43.
Happle R, Traupe H,
LIMB REDUCTION DEFORMITIES IN CHILD EXPOSED TO ISOTRETINOIN IN UTERO ON GESTATION DAYS 26-40 ONLY
SlR,-I recently saw a child with reduction deformities of the limbs, the mother having taken isotretinoin (’Accutane’) in, pregnancy. She was 26 days’ pregnant when treatment began. A urinary pregnancy test using anti-hCG serum confirmed the
mg/day for the next 14 days until the 40th day of gestation (the half-life of the drug is about 20 h). pregnancy. She took 40
The male child had reduction deformities of all four limbs. The carpals, metacarpals, and the phalanges of the thumbs of both hands were unaffected. The fingers of the left hand were represented by rudimentary proximal phalanges. There were no fingers on the right hand. The femur and upper third of the tibia and fibula were present in the right leg, the tibia and fibula were tapered at the ends.
The left
leg was normal apart from absence of the second and third
phalanges of the second toe. Limb development in man occurs from the 25th to the 42nd days of gestation beginning at stages 12 (upper limb buds) and 13 (lower limb buds). The apical ectodermal ridge (AER) is found during a period of about 10 days and is recognisable until at last digital rays have appeared (stage 17 in the upper limb, stage 18 in the lower limb).Since the limbs were developing at the time of maternal drug ingestion isotretinoin probably caused the malformations. All limbs were affected, to varying degrees, so the mechanism may have been drug damage to the AER. Both thumbs were normal; in the thalidomide syndrome the thumbs were almost always affected. In most cases of malformations reported after ingestion of retinoic acid derivatives the woman has conceived while already on treatment. In this case treatment began on the 26th day of pregnancy, which may explain the normal head, ears, and, possibly, heart in this child. The time frame of exposure to a teratogen will determine the pattern of malformation produced. Foundation 41, Sydney, New South Wales 2010, Australia 1.
W. G. MCBRIDE
R The development and classification of anomalies of the limbs in the human. In: Marius M, ed Prevention of physical and mental congenital defects: Part C. New York: Alan R. Liss, 1985: 85-90.
O’Rahilly
SODIUM VALPROATE AND ENURESIS p 980) is incorrect to that an association between sodium valproate and enuresis has not been previously described. Several studies of valproate in children 1-5 have recorded enuresis as a side-effect, the frequency being 1-7%. The two most likely explanations are that the enuresis is secondary to a central effect on the thirst centre, resulting in polydipsia, or is a consequence of the increased depth of sleep commonly associated with valproate.l Increased thirst has been demonstrated in several studies with valproate.3,5,6
SiR,-Dr Panayiotopoulos (April 27,
state
Department of Pharmacology and Therapeutics, New Medical Building, Ashton Street, PO Box 147, Liverpool L69 3BX
I. A. CHOONARA
1. Heathfield K, Dunlop D, Karanjia P, Retsas S. The long-term results oftreatingthtrtysix patients with intractable epilepsy with sodium valproate (Epilim). In: Legg NJ, ed. Clinical and pharmacological aspects of sodium valproate (Epilim) in the treatment of epilepsy. Kent: MCS Consultants, 1976: 165-70. 2. Egger J, Brett EM. Effects of sodium valproate in 100 children with special reference to weight. Br MedJ 1981,283: 577-81. 3. Herranz JL, Arteaga R, Armijo JA. Side effects of sodium valproate in monotherapy controlled by plasma levels: a study in 88 pediatric patients, EpzlepslQ ] 982; 23: 203-14. 4 Muddiman MJ, Rolles CJ. Epilepsy in general paediatric practice. Br Chn Pract 1983 (suppl 27): 99-104. 5. Herranz JL, Armijo JA, Arteaga R. Effectiveness and toxicity of phenobarbital, pnmidone, and sodium valproate in the prevention of febrile convulsions, controlled by plasma levels. EpzlepSla 1984; 25: 89-95. 6. Dinesen H, Gram L, Andersen T, Dam M. Weight gain during treatment with valproate. Acta Neurol Scand 1984; 69: 65-69.
INDUCTION OF VIBRIO CHOLERAE SPECIFIC BILIARY ANTIBODIES AFTER ORAL IMMUNISATION WITH A CHOLERA CELL-WALL FRACTION
SIR,-In cholera the profuse secretion by the enterocytes is stimulated by the toxin, or rather the "tonin", liberated by the bacteria during lysis. The first step in this process is colonisation of the gastrointestinal tract following bacterium-enterocyte interaction. The classical killed whole-cell vaccine protects 7007o of the immunised population for 5 to 6 months. Several other live attenuated and toxoid vaccines are being tested.1,2 One new oral cholera vaccine produced at Institut Pasteur and now at the end stage of clinical trial consists of CH1+2,3 a purified specific polysaccharide-containing traction derived from the Vibrio clzolaai cell-wall. It does not contain any toxin; the aim is protection from bacterial colonisation by local immunization.Direct proof that 11 results in the presence of specific antibodies m the gastrointestinal tract is still lacking.
1277 TITRES OF V CHOLERAE SPECIFIC ANTIBODIES IN BILE AND SERUM
ND =not determined because of insufficient quantity.
We examined bile from children with extrahepatic bile duct obstruction who were vaccinated preoperatively with their parents’ consent. Two doses of the vaccine were given orally a week apart and bile was collected during surgery, 1-12 days after the second dose. The bile was assayed in parallel with the sera for vibriocidal activity and vaccine-specific antibodies. The latter were detected by a class-specific ELISA using an acid-extracted glycoside from the CH1+22 fraction for the coating and phosphatase-labelled anti-IgG, anti-IgA, and anti-IgM antibodies (Behring, Marburg, FRG; Orion, Finland). Sensitivity and specificity of these assays were confirmed by testing sera from hyperimmune and control subjects. Substantial vibriocidal activity was found in the bile 6 days after the course of immunisation and as early as day 1 (ie, 16 days after the first dose) in the serum, which suggests a dissociation between stimulation of systemic and that of local immunity (see table). The vibriocidal assay detects IgM and IgG antibodies that lyse the cholera vibrio in the presence of complement. Antibodies directed against the glycoside were also detected in bile available from 2 children, 10 and 12 days after vaccination. This activity was restricted to the IgA class (see table). These preliminary findings show that anticholera antibodies of at least two different specificities can be recovered in the bile-IgG or IgM antibodies, which cause lysis of the organisms, and the IgA antibodies, which are directed against the polysaccharide, a constituent of the colonisation factors. The presence of antibodies in the serum indicates that this oral vaccine also stimulates systemic immunity. The production of local intestinal immunity to V cholerae may have been the reason for the efficacy of the vaccine in 4 recent epidemics in Zaire recurring months after immunisation.4
Centre Hospitalier Universitaire Bicetre, Institut Pasteur, Paris
H. CHAMPSAUR S. ISCAKI
O. BERNARD A. DODIN
1 Kuwahara
S, Pierce NF, eds. Advances in research on cholera and related diarrheas. Boston: Marinus Nijhoff, 1983 2. Levine MM, Kaper JB, Black RE, Clements ML. New knowledge on pathogenesis of bacterial enteric infections as applied to vaccine development. Microbiol Rev 1983; 47: 510-50 3 Dodin A, Wiart J. A new vaccinating antigenic fraction obtained from V Cholerae. Ann Microbiol 1975; 126A: 39-56. 4 Dodin A, Masengo B, Loucq C Shaba-Zaire Choleric Epidemy, 1983: field-trial data on the activity of Institut Pasteur anticholeric oral vaccine CR Acad Sc Paris 1984; 299: 205-07.
CAPTOPRIL ONCE DAILY AS MONOTHERAPY IN
PATIENTS WITH HYPERURICAEMIA AND ESSENTIAL HYPERTENSION
SiR,-A multicentre comparative study in patients with essential hypertension showed that captopril 25 mg three times a day partly counteracted the hyperuricaemic response to hydrochlorothiazide 15 mg three times a day when these drugs were administered together.’ Another study showed that prolonged therapy with enalapril alone (10-40 mg once daily) significantly reduced plasma levels in patients with essential hypertension.2 In a placebocontrolled investigationsa single dose of enalapril 40 mg increased the renal clearance of uric acid, corrected for glomerular filtration rate, in fourteen hypertensive patients whereas there was no change urate
in three. A further placebo-controlled study showed that a single dose of captopril 100 mg significantly increased the mean urinary output of uric acid in healthy volunteers, a single dose of hydrochlorothiazide 25 mg had an opposite effect, and 24 h urinary excretion of uric acid did not change when both drugs were given together.3 Captopril 100 mg once daily in patients with moderate to severe essential hypertension significantly reduced blood pressure (BP) measured 22-23 -5h after dosing.44 We have studied twenty patients with hyperuricaemia and essential hypertension. After 4 weeks without active medication patients were treated openly, for ethical reasons, with captopril 100 mg daily for 4 weeks. The ten patients studied in Montevideo (all whites, five male) maintained a low-sodium (60-100 mmol daily), . low-purine diet throughout the run-in and the captopril-treatment periods, whereas the ten male patients in Durban (nine white, one black) persisted with their usual high-sodium (200-300 mmol) and medium-purine diet. Serum uric acid and supine BP were measured at the end of the run-in period and after 4 weeks of active treatment. Post-captopril assessments took place 20-22 h (uric acid) and 22-23-55 h (BP) after the last intake of medication. The serum urate fell from 0 -5 3±0 -07 (mean±SD) to 0 - 46±0 -07 in Durban and from 0-46±0-05 to 0-35±0-07 mmol/1 (p
captopril-induced uricosuria, depends on angiotensin-I convertingenzyme inhibition to any extent remains to be elucidated. The development of leg pain during treatment with captopril has been observed in patients with varicosities on three other occasions by one of us (T. N. A. B.). The mechanism is not known. Department of Experimental and Clinical Pharmacology, University of Natal, Congella 4013, Durban, South Africa Department of Cardiovascular Investigation, Procardias, Montevideo, Uruguay Funcdación
Department of Experimental and Clinical Pharmacology, University of Natal
W. P. LEARY
A. J. REYES T. N. ACOSTA-BARRIOS
B.
MAHARAJ
1 Weinberger MH Blood pressure and metabolic responses to hydrochlorothiazide, captopril, and the combination in black and white mild-to-moderate hypertensive patients J Cardiovasc Pharmacol 1985; 7 (suppl 1): S52-S55 2 Malini PL, Strocchi E, Ambrosioni E, Magnani B. Long-term antihypertensive, metabolic and cellular effects of enalapril J Hypertens 1984, 2 (suppl 2): 101-05 3 Leary WP, Reyes AJ, van der Byl K, Acosta-Barrios TN. Effects of captopril,
hydrochlorothiazide and their combination on timed urinary excretion of water and solutes J Cardiovasc Pharmacol 1985, 7 (suppl 1) S56-S62 4 Reyes AJ, Leary WP, Acosta-Barrios TN Once-daily administration of captopril and hypotensive effect J Cardiovasc Pharmacol 1985, 7 (suppl 1) S16-S19. 5. Chan PS, Rosenberg MA, Cervoni P Acute antihypertensive synergism of angiotensin-converting enzyme inhibitors and diuretics Fed Proc 1984; 43: 1346-50 6 Jackson B, Cubela R, Johnston CI. Effect of dietary sodium on angiotensin-converting enzyme (ACE) inhibition and the acute hypotensive effect of enalapril (MK-421)in essential hypertenion J Hypertens 1984; 2: 371-77
HERBICIDES AND COLON CANCER
SIR,-In response to Newell and colleagues’ report of an association between herbicides and intestinal cancer in New Zealand sheep we examined the farming histories of 57 pathologically confirmed colon cancer cases from a recent interview study. The patients were sampled from all colon cancer cases diagnosed in Kansas during
SiR,-Since etretinate (’Tigason’) is teratogenic contraception is women of childbearing potential not only during treatment but also for 24 months after discontinuation (after long-
required for term
administration the
drug’s
elimination half-life is 120
days or
morel,2). Some cases of skeletal and craniofacial disorders in fetuses from women receiving etretinate have been reported, though other
have had normal children.2So far, no malformations have been reported in children whose mothers had become pregnant within 2 years of cessation of etretinate therapy. 1,3 We have observed skeletal deformations in a fetus conceived 4 months after the last dose of etretinate. A 22-year-old woman with Darier’s disease (dyskeratosis follicularis) since the age of 17 had been treated intermittently with etretinate; the last 5-month treatment with 30 mg daily ended 4 months before conception. In her 8th week of pregnancy, the patient sought genetic counselling and a medically indicated termination was decided on. She consented to chorion biopsy and to amniotic fluid investigation. A normal female karyotype was diagnosed from chromosome analysis. Serum concentrations of etretinate and its major metabolite, the carboxylic acid derivative Ro 10-1670, were 7 ng/ml and 8 ng/ml, respectively (therapeutic levels 100-500 ng/mI4,5). The pregnancy was terminated in the 10th week. The fetus (2 -2 cm long) had one lower limb much shorter than the other (5 mm left, 10 mm right). The distal left leg was rudimentary; only one toe was present, the tibia and fibula were missing, and the femur was hypoplastic. No further abnormalities were detected. Craniofacial malformations could not be assessed because the head was badly deformed by the termination. The one sidedness of skeletal deformation and its nature are consistent with an exogenous cause, probably etretinate taken by the mother before women
conception. This case emphasises the need for strict contraception to continue for 2 years after etretinate therapy. This unusual recommendation by the manufacturer is well justified. We thank Hoffmann-La Roche,
Grenzach-Wyhlen
for
measuring
serum
drug concentrations. W. GROTE D. HARMS Departments of Human Genetics, Paediatric Pathology, Dermatology, and Pharmacology, University of Kiel, 2300 Kiel, West Germany 1. 2. 3.
4. 5.
U. JÄNIG H. KIETZMANN U. RAVENS I. SCHWARZE
Bounameaux Y, Fisch T. Teratogene Wirkung von Etretinat beim Menschen. Deutsche Med Wochenschr 1984; 109: 1476-80. Cordero AA, Allevato MA, Donatti L. Ro-10-9359 and pregnancy. In: Retinoids: Advances in basic research and therapy. Berlin: Springer, 1981: 501. Rüther TH, Kietzmann H. Schwangerschaft nach Therapie mit Etretinat (Tigason). Akt Dermatol 1984, 10: 62-63. Paravicini U. Pharmacokinetics and metabolism of oral aromatic retinoids. In: Retinoids: Advances in basic research and therapy. Berlin: Springer, 1981: 13-20. Ward A, Brogden RN, Heel RC, Speight TM, Avery GS. Etretinate. A review of its pharmacological properties and therapeutic efficacy in psoriasis and other skin disorders. Drug 1983; 26: 9-43.
Happle R, Traupe H,
LIMB REDUCTION DEFORMITIES IN CHILD EXPOSED TO ISOTRETINOIN IN UTERO ON GESTATION DAYS 26-40 ONLY
SlR,-I recently saw a child with reduction deformities of the limbs, the mother having taken isotretinoin (’Accutane’) in, pregnancy. She was 26 days’ pregnant when treatment began. A urinary pregnancy test using anti-hCG serum confirmed the
mg/day for the next 14 days until the 40th day of gestation (the half-life of the drug is about 20 h). pregnancy. She took 40
The male child had reduction deformities of all four limbs. The carpals, metacarpals, and the phalanges of the thumbs of both hands were unaffected. The fingers of the left hand were represented by rudimentary proximal phalanges. There were no fingers on the right hand. The femur and upper third of the tibia and fibula were present in the right leg, the tibia and fibula were tapered at the ends.
The left
leg was normal apart from absence of the second and third
phalanges of the second toe. Limb development in man occurs from the 25th to the 42nd days of gestation beginning at stages 12 (upper limb buds) and 13 (lower limb buds). The apical ectodermal ridge (AER) is found during a period of about 10 days and is recognisable until at last digital rays have appeared (stage 17 in the upper limb, stage 18 in the lower limb).Since the limbs were developing at the time of maternal drug ingestion isotretinoin probably caused the malformations. All limbs were affected, to varying degrees, so the mechanism may have been drug damage to the AER. Both thumbs were normal; in the thalidomide syndrome the thumbs were almost always affected. In most cases of malformations reported after ingestion of retinoic acid derivatives the woman has conceived while already on treatment. In this case treatment began on the 26th day of pregnancy, which may explain the normal head, ears, and, possibly, heart in this child. The time frame of exposure to a teratogen will determine the pattern of malformation produced. Foundation 41, Sydney, New South Wales 2010, Australia 1.
W. G. MCBRIDE
R The development and classification of anomalies of the limbs in the human. In: Marius M, ed Prevention of physical and mental congenital defects: Part C. New York: Alan R. Liss, 1985: 85-90.
O’Rahilly
SODIUM VALPROATE AND ENURESIS p 980) is incorrect to that an association between sodium valproate and enuresis has not been previously described. Several studies of valproate in children 1-5 have recorded enuresis as a side-effect, the frequency being 1-7%. The two most likely explanations are that the enuresis is secondary to a central effect on the thirst centre, resulting in polydipsia, or is a consequence of the increased depth of sleep commonly associated with valproate.l Increased thirst has been demonstrated in several studies with valproate.3,5,6
SiR,-Dr Panayiotopoulos (April 27,
state
Department of Pharmacology and Therapeutics, New Medical Building, Ashton Street, PO Box 147, Liverpool L69 3BX
I. A. CHOONARA
1. Heathfield K, Dunlop D, Karanjia P, Retsas S. The long-term results oftreatingthtrtysix patients with intractable epilepsy with sodium valproate (Epilim). In: Legg NJ, ed. Clinical and pharmacological aspects of sodium valproate (Epilim) in the treatment of epilepsy. Kent: MCS Consultants, 1976: 165-70. 2. Egger J, Brett EM. Effects of sodium valproate in 100 children with special reference to weight. Br MedJ 1981,283: 577-81. 3. Herranz JL, Arteaga R, Armijo JA. Side effects of sodium valproate in monotherapy controlled by plasma levels: a study in 88 pediatric patients, EpzlepslQ ] 982; 23: 203-14. 4 Muddiman MJ, Rolles CJ. Epilepsy in general paediatric practice. Br Chn Pract 1983 (suppl 27): 99-104. 5. Herranz JL, Armijo JA, Arteaga R. Effectiveness and toxicity of phenobarbital, pnmidone, and sodium valproate in the prevention of febrile convulsions, controlled by plasma levels. EpzlepSla 1984; 25: 89-95. 6. Dinesen H, Gram L, Andersen T, Dam M. Weight gain during treatment with valproate. Acta Neurol Scand 1984; 69: 65-69.
INDUCTION OF VIBRIO CHOLERAE SPECIFIC BILIARY ANTIBODIES AFTER ORAL IMMUNISATION WITH A CHOLERA CELL-WALL FRACTION
SIR,-In cholera the profuse secretion by the enterocytes is stimulated by the toxin, or rather the "tonin", liberated by the bacteria during lysis. The first step in this process is colonisation of the gastrointestinal tract following bacterium-enterocyte interaction. The classical killed whole-cell vaccine protects 7007o of the immunised population for 5 to 6 months. Several other live attenuated and toxoid vaccines are being tested.1,2 One new oral cholera vaccine produced at Institut Pasteur and now at the end stage of clinical trial consists of CH1+2,3 a purified specific polysaccharide-containing traction derived from the Vibrio clzolaai cell-wall. It does not contain any toxin; the aim is protection from bacterial colonisation by local immunization.Direct proof that 11 results in the presence of specific antibodies m the gastrointestinal tract is still lacking.
1277 TITRES OF V CHOLERAE SPECIFIC ANTIBODIES IN BILE AND SERUM
ND =not determined because of insufficient quantity.
We examined bile from children with extrahepatic bile duct obstruction who were vaccinated preoperatively with their parents’ consent. Two doses of the vaccine were given orally a week apart and bile was collected during surgery, 1-12 days after the second dose. The bile was assayed in parallel with the sera for vibriocidal activity and vaccine-specific antibodies. The latter were detected by a class-specific ELISA using an acid-extracted glycoside from the CH1+22 fraction for the coating and phosphatase-labelled anti-IgG, anti-IgA, and anti-IgM antibodies (Behring, Marburg, FRG; Orion, Finland). Sensitivity and specificity of these assays were confirmed by testing sera from hyperimmune and control subjects. Substantial vibriocidal activity was found in the bile 6 days after the course of immunisation and as early as day 1 (ie, 16 days after the first dose) in the serum, which suggests a dissociation between stimulation of systemic and that of local immunity (see table). The vibriocidal assay detects IgM and IgG antibodies that lyse the cholera vibrio in the presence of complement. Antibodies directed against the glycoside were also detected in bile available from 2 children, 10 and 12 days after vaccination. This activity was restricted to the IgA class (see table). These preliminary findings show that anticholera antibodies of at least two different specificities can be recovered in the bile-IgG or IgM antibodies, which cause lysis of the organisms, and the IgA antibodies, which are directed against the polysaccharide, a constituent of the colonisation factors. The presence of antibodies in the serum indicates that this oral vaccine also stimulates systemic immunity. The production of local intestinal immunity to V cholerae may have been the reason for the efficacy of the vaccine in 4 recent epidemics in Zaire recurring months after immunisation.4
Centre Hospitalier Universitaire Bicetre, Institut Pasteur, Paris
H. CHAMPSAUR S. ISCAKI
O. BERNARD A. DODIN
1 Kuwahara
S, Pierce NF, eds. Advances in research on cholera and related diarrheas. Boston: Marinus Nijhoff, 1983 2. Levine MM, Kaper JB, Black RE, Clements ML. New knowledge on pathogenesis of bacterial enteric infections as applied to vaccine development. Microbiol Rev 1983; 47: 510-50 3 Dodin A, Wiart J. A new vaccinating antigenic fraction obtained from V Cholerae. Ann Microbiol 1975; 126A: 39-56. 4 Dodin A, Masengo B, Loucq C Shaba-Zaire Choleric Epidemy, 1983: field-trial data on the activity of Institut Pasteur anticholeric oral vaccine CR Acad Sc Paris 1984; 299: 205-07.
CAPTOPRIL ONCE DAILY AS MONOTHERAPY IN
PATIENTS WITH HYPERURICAEMIA AND ESSENTIAL HYPERTENSION
SiR,-A multicentre comparative study in patients with essential hypertension showed that captopril 25 mg three times a day partly counteracted the hyperuricaemic response to hydrochlorothiazide 15 mg three times a day when these drugs were administered together.’ Another study showed that prolonged therapy with enalapril alone (10-40 mg once daily) significantly reduced plasma levels in patients with essential hypertension.2 In a placebocontrolled investigationsa single dose of enalapril 40 mg increased the renal clearance of uric acid, corrected for glomerular filtration rate, in fourteen hypertensive patients whereas there was no change urate
in three. A further placebo-controlled study showed that a single dose of captopril 100 mg significantly increased the mean urinary output of uric acid in healthy volunteers, a single dose of hydrochlorothiazide 25 mg had an opposite effect, and 24 h urinary excretion of uric acid did not change when both drugs were given together.3 Captopril 100 mg once daily in patients with moderate to severe essential hypertension significantly reduced blood pressure (BP) measured 22-23 -5h after dosing.44 We have studied twenty patients with hyperuricaemia and essential hypertension. After 4 weeks without active medication patients were treated openly, for ethical reasons, with captopril 100 mg daily for 4 weeks. The ten patients studied in Montevideo (all whites, five male) maintained a low-sodium (60-100 mmol daily), . low-purine diet throughout the run-in and the captopril-treatment periods, whereas the ten male patients in Durban (nine white, one black) persisted with their usual high-sodium (200-300 mmol) and medium-purine diet. Serum uric acid and supine BP were measured at the end of the run-in period and after 4 weeks of active treatment. Post-captopril assessments took place 20-22 h (uric acid) and 22-23-55 h (BP) after the last intake of medication. The serum urate fell from 0 -5 3±0 -07 (mean±SD) to 0 - 46±0 -07 in Durban and from 0-46±0-05 to 0-35±0-07 mmol/1 (p
captopril-induced uricosuria, depends on angiotensin-I convertingenzyme inhibition to any extent remains to be elucidated. The development of leg pain during treatment with captopril has been observed in patients with varicosities on three other occasions by one of us (T. N. A. B.). The mechanism is not known. Department of Experimental and Clinical Pharmacology, University of Natal, Congella 4013, Durban, South Africa Department of Cardiovascular Investigation, Procardias, Montevideo, Uruguay Funcdación
Department of Experimental and Clinical Pharmacology, University of Natal
W. P. LEARY
A. J. REYES T. N. ACOSTA-BARRIOS
B.
MAHARAJ
1 Weinberger MH Blood pressure and metabolic responses to hydrochlorothiazide, captopril, and the combination in black and white mild-to-moderate hypertensive patients J Cardiovasc Pharmacol 1985; 7 (suppl 1): S52-S55 2 Malini PL, Strocchi E, Ambrosioni E, Magnani B. Long-term antihypertensive, metabolic and cellular effects of enalapril J Hypertens 1984, 2 (suppl 2): 101-05 3 Leary WP, Reyes AJ, van der Byl K, Acosta-Barrios TN. Effects of captopril,
hydrochlorothiazide and their combination on timed urinary excretion of water and solutes J Cardiovasc Pharmacol 1985, 7 (suppl 1) S56-S62 4 Reyes AJ, Leary WP, Acosta-Barrios TN Once-daily administration of captopril and hypotensive effect J Cardiovasc Pharmacol 1985, 7 (suppl 1) S16-S19. 5. Chan PS, Rosenberg MA, Cervoni P Acute antihypertensive synergism of angiotensin-converting enzyme inhibitors and diuretics Fed Proc 1984; 43: 1346-50 6 Jackson B, Cubela R, Johnston CI. Effect of dietary sodium on angiotensin-converting enzyme (ACE) inhibition and the acute hypotensive effect of enalapril (MK-421)in essential hypertenion J Hypertens 1984; 2: 371-77
HERBICIDES AND COLON CANCER
SIR,-In response to Newell and colleagues’ report of an association between herbicides and intestinal cancer in New Zealand sheep we examined the farming histories of 57 pathologically confirmed colon cancer cases from a recent interview study. The patients were sampled from all colon cancer cases diagnosed in Kansas during