HERBICIDES AND COLON CANCER

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

1278 COLON CANCER RISK BY YEARS AND GROUPS OF HERBICIDES

A low-dose oral mebendazole (donated by Janssen Pharmaceutica) 100 mg daily for 45 days) was chosen. Microfilaraemia before treatment varied from 300 to 47 400/ml blood for L loa and from 200 to 1400/ml for Mperstans. L loa parasitaemia fell to zero in two patients and was reduced 20 and 360 fold in the other two, whereas Mperstans microfilariae were eliminated in the two positive cases. Hepatic and renal function, haematological indices, and clinical examination remained normal and no patient reported any side-effects over the 45 day period. The reduction in parasite burden was always gradual, in contrast with the abrupt drop observed under DEC therapy, and this may explain the absence of side-effects with mebendazole. Whether this gradual decrease can be attributed to an essentially embryostatic or microfilaricidal effect or simply to a milder toxicity for microfilariae is unknown. The formation of "medusa-head" or "sunflower" patterns,6,9 in which microfiluriae are trapped in fibrin mats, increased considerably in patients under therapy and paralleled the drop in microfilaraemia. Other mebendazole regimens are under study but it is already clear that this drug deserves attention as a safer alternative to DEC in the chemotherapy of loiasis.

regimen (3 x

1976-82. The controls (n=948) were selected from the general population by random digit dialling, from the Health Care Financing Administration file (Medicare) and the State mortality

files.

Employment on a farm was associated with a non-significant increase in colon cancer risk (odds ratio [OR] =1’ 6; 95% confidence interval [CI] =0 - 8, 3’ 5). 11 cases and 192 controls used herbicides, yielding an OR of 1.5 5 (9507o CI 0 -6,4 -0), which was similar to the risk in farmers who did not report herbicide use (OR=1-6; 95% CI = 0 - 8, 3 - 6). Colon cancer risk did not increase with years of herbicide use (table). Risk was slightly higher for farmers exposed to phenoxy herbicides than to other chemical groups. 6 cases reported use of 2,4-D (OR = 2 - 0; 95% CI 0 -6, 6 -3). 2 of the 6 also reported 2,4,5-T exposure (OR =3-1, 9507o CI= 0-4, 18-6). The risk among study subjects who mixed the herbicides themselves (OR =1-4) was similar to the risk among those who had someone else prepare the chemicals (OR=15). However, subjects who usually applied the herbicides themselves had a slightly higher risk (OR =1-8; 95% CI 0 -6, 5 - 2) than subjects who reported that someone else applied the herbicides (OR -1 -2; 95% CI 0 -2, 4 -8). These data do not support an association between colon cancer and herbicide exposure. Although farmers had a higher risk than non-farmers, the similarity in risk between those using and not using herbicides and the lack of a risk gradient with years of herbicide use argue against an association. These findings, although based on very small numbers, are consistent with Hardell’s report from Sweden.2 =

=

International Medical Research BP 769, Franceville, Gabon

General

University of Kansas Medical Center

FREDERICK F. HOLMES CATHY BOYSEN

Division of Biology, Kansas State University

ROBERT J. ROBEL

Cancer Data

Service,

Phenoxy and picolinic acid herbicides and smallintestinal adenocarcinoma in sheep. Lancet 1984; ii: 1301 2. Hardell L. The relation of soft tissue sarcoma, malignant lymphoma and colon cancer to phenoxy acids, chlorophenols, and other agents. Scand J Work Environment Health 1981; 7: 119-30. 1. Newell KW, Ross AD, Renner RM.

MEBENDAZOLE TREATMENT OF LOIASIS

SIR,-Considerable effort is being put into the development of drugs for filarial infections, especially onchocerciasis and lymphatic filariasis with their heavy morbidity. Although of less pathological importance, Loa loa and Mansonella perstans filariases are widespread in west and central Africa. In some regions of Gabon, over 90% of the population have serological evidence of new

infection with one or both species.’ Diethylcarbamazine citrate can eliminate L loa, but not in most cases, M perstans; however, Mazzotti-type reactions are often serious and can even be

(DEC)

fatal. 2,3

Mebendazole has been

proposed

filariasis,4 onchocerciasis,’

and

for treating human

lymphatic

dipetanelomiasis.6,7 We tested this

drug against the above two parasites in four patients and compared the results with those in twenty-five other patients treated with DEC.

F. FLOCARD

B, Ivanoff B, Frost E, Garin Y, Bourderiou C. Age of appearance of IgG, and IgE antibodies specific for Loa loa in Gabonese children. Microbiol Immunol 1984, 28: 787-92. Van Bogaert L, Dubois A, Janssens P, Radermecker J, Tverdy G, Wansom M. Encephalitis in Loa loa filariasis J Neurol Neurosurg Psychiatry 1955; 18: 103-19. Cauchie C, Rutsaert J, Thys O, Bonnyns M, Perier O. Encéphalite a Loa loa traitée par l’association de courtisone et de carbamazine. Revve Belge Pathol Méd Exp 1965, 31: 232-44. Mak JW, Chan WC. Treatment of Brugia malayi infection with mebendazole and levamisole. SE Asian J Trop Med Public Health 1983; 14: 510-14. Rivas-Alcalá AR, Green BM, Taylor HR, et al Chemotherapy of onchocerciasis a controlled comparison of mebendazole, levamisole and diethylcarbamazine Lancet 1981, ii 485-90. Wahlgren M, Frolov I Treatment of Dipetaneloma perstans infections with mebendazole Trans Roy Soc Trop Med Hyg 1983; 77: 422-23 Maertens K, Wery M Effect of mebendazole and levamisole on Onchocerca volvulus and Dipetaneloma perstans. Trans Roy Soc Trop Med Hyg 1975, 69: 359-60. Yoeh M. Observations on agglutination and thigmotaxis of microfilariae in bancroftian filariasis. Trans Roy Soc Trop Med Hyg 1956; 51: 132-36 McQuay RM, Schmutzer DE Observation on the agglutination phenomenon of microfilariae of Loa loa in citrated blood Am J Trop Med Hyg 1966; 15: 730-34.

IgM,

2 3

4. 5.

=

SHELIA K. HOAR AARON BLAIR

M. VAN HOEGAERDEN

1. Goussard

=

Occupational Studies Section, Environmental Epidemiology Branch, National Cancer Institute, Bethesda, Maryland 20205, USA

Hospital of Franceville

Centre,

6 7. 8. 9.

"COT-SIDES SYNDROME" MEDICOLEGAL ENTITY

SIR,-Instances of brain-damaged patients falling out of bed and

rapidly deteriorating and dying seem to be on the increase-or perhaps the significance of such incidents and the opportunities they afford would-be litigants have become better known. These cases are being collected and analysed, but I thought it might be helpful to mention a few cases to illustrate the medical and legal then

aspects. In one case, the patient had multiple fracture of the limbs and a fissure fracture of the skull vault and base, as a result ofa road-traffic accident. 4 days after the accident, when progressing well, the patient climbed out of bed, which had its cot-sides up, and was found on the floor. There was then rapid deterioration until death 3 days later. Necropsy revealed bruising overlying the skull fracture and beneath this there was cortical contusion. There was also contrecoup contusion on the opposite side of the brain. This was the injury received in the original accident, one week before death. There was no pathological evidence of any additional head injury. Besides the contusion there was evidence of acute, generalised brain oedema. This was considered to be odd in view of the earlier progress and must have happened shortly before death. There was no evidence of fat embolism from the multiple fractures. In a second case, the patient suddenly collapsed and convulsed. A head injury was sustained and there was a transient period of unconsciousness. Investigations suggested intracranial haemorrhage. The patient became restless, confused, and difficult to control, and 3 days after the collapse, was found on the floor, having climbed out over the cot-sides of the bed. There was then a skull fracture, and coma persisted until death the next day. Investigations