1093 an

organism as we have described, which would be unlikely

to

infection in fit young men, may give rise to serious and life-threatening infection in such patients; to ignore such an event puts patients at risk of unnecessary suffering at least. What we need is a closer liaison between clinicians, the patient, and ourselves to interpret our results sensibly and to instigate cause

appropriate therapy or preventive medicine sooner. Chase Farm

Hospital,

Enfield,

R. V. MUMMERY

Middlesex EN2 8JL.

BUMETANIDE

Medical Unit,

SIR,-Your editorial (Nov. 1, p. 860) gives a useful summary of this new and potent diuretic. Occasions when it proves effective after frusemide fails are more frequent than you suggest. In a three-month period in two hospitals, 23 patients were met in whom frusemide in a dose of 80-160 mg by mouth failed to give a satisfactory response1 12 had cor pulmonale, 8 left ventricular failure due to hypertension, coronary, or aortic disease, 2 congestive failure associated with rheumatic valvular disease, and 1 carcinoma with superior vena cava obstruction. These patients were given bumetanide 2-6 mg daily by mouth (4 mg daily in 13), increased in 1 patient to 12 mg daily. 14 patients had a weight loss of over 4 kg and 8 of 2-4 kg. Later some patients deteriorated as would be expected with such advanced disease. Some of these patients might have responded to much higher doses of frusemide especially if given by the intramuscular or intravenous routes. On general grounds, it seems better to give a very much smaller dose of bumetanide in preference, as additionally it saved giving systemic injections. In hospital contracts bumetanide is also much cheaper than frusemide, I am informed. Thus bumetanide should be considered a "first-treatment" diuretic. East Herts Hospital, Hertford SG13 7HU.

A. PINES

MANAGEMENT OF MILD HYPERTENSION

SIR,-You drew attention (Oct. 11, p. 695) to the large-scale national trials which are being carried out to determine the best management for mild hypertension. The Medical Research Council is conducting a pilot trial to assess the feasibility of a full-scale trial in Britain. The pilot phase has been in progress for 2years and has already shown the scientific and ethical feasibility of proceeding to the main trial; at present it includes 22 centres (general practices, industrial clinics, and screening organisations) which together have entered 1100 patients, all aged 35-64, with sustained diastolic (v) pressures within the 90-109 mm Hg range. The 22 clinics have been selected in terms of known interest and enthusiasm. It is estimated that the full trial would need about 18 000 patients, each to be followed for 5 years. This would probably require the recruitment of about 200 collaborating clinics and the pilot trial should, we believe, include a demonstration that this is possible. All area medical officers and secretaries of local medical committees and family-practitioner committees have recently been asked to recommend suitable centres. We hope that this may provide a list of over 200 clinics from which, at this stage, 10 or 15 would be selected by a random method. Recruitment of new centres by this means would show the feasibility of full

expansion. If any of your readers feel that their own practiceswhether G.P. or industrial-could contribute to this trial we would be glad to hear from them. In general practices it has been found that much of the additional workload imposed by 1

can be carried by a suitably trained part-time nurse provided she has ready access to medical advice. The M.R.C. has usually provided funds for such an appointment during the first year when the screening load is considerable. Once screening and the entry of eligible patients to the trial is completed, the follow-up load for a large group practice can be covered by perhaps one doctor session and two nurse sessions a week. Further details and a copy of the trial protocol can be obtained from: The Secretary, M.R.C. Treatment Trial for Mild Hypertension, M.R.C./D.H.S.S. Epidemiology and Medical Care Unit, Northwick Park Hospital, Watford Road, Harrow HA1 3UJ.

the trial

Pines, A., Sreedharan, K. S., Nandi, A. R., Marsh, B. T. Br. J. clin Pract 1974, 28, 311.

W. S. PEART

St. Mary’s Hospital, London W2 1NY.

Chairman,

Epidemiology and Medical Care Unit, Northwick Park Hospital, Watford Road, Harrow HA1

3UJ.

W. E. MIALL, Secretary, M.R.C. Working Party on Mild to Moderate Hypertension

INTRAVENOUS LABETALOL IN SEVERE HYPERTENSION

SIR,-Nearly all the antihypertensive drugs for use intravenously in hypertensive emergencies have major disadvantages. Moreover none can readily be continued as definitive oral therapy. A new drug which combines alpha and beta adrenergic-receptor blocking properties-labetalol (AH 5158, Allen & Hanbury)-has recently become available for the treatment of hypertension.’ We have found that, in many of the patients requiring immediate blood-pressure reduction, its intravenous administration induces a prompt and sustained fall in blood-pressure with few side-effects. Sixteen recumbent hypertensive patients, three of whom were in the malignant phase with bilateral retinal hoemorrhages, exudates, and papilloedema, were given labetalol, 100-125 mg (1.5-2.0 mg/kg) intravenously. In the first twelve, this was injected slowly over 10 minutes; in the subsequent four as a bolus within 1 minute. Few side-effects were observed, but in three patients in whom blood-pressure fell very rapidly there was transient nausea, pallor, sweating, and, despite recumbency, a feeling of faintness without loss of consciousness. FINDINGS IN

16

PATIENTS WHO RECEIVED AN INTRAVENOUS

INJECTION

OF

LABETALOL

In those patients with high initial plasma-angiotensin-ir concentrations there was an associated tachycardia; both angiotensin-n levels and pulse-rate fell to normal or near-normal values concomitantly with the reduction of arterial pressure. By contrast, those patients with normal pulse-rate and initially normal concentrations of plasma-angiotensin-n showed no change in either after the drug was given. We shall present more detailed data on these aspects later. As expected, there was a postural fall of blood-pressure in all instances after the acute injection of labetalol, and sometimes this was sufficiently great to cause fainting on standing. We therefore keep all pa1. Prichard, B. N. C., Thompson, F. O., Boakes, A. molec. Med. 1975, 48, suppl. 2, 97s.

J., Joekes, A. M. Clin. Sci.

1094

repair (see table). Since the amount of bound caralso rose, the high N.A.-A.A.F. repair values must have resulted from increased repair stimulation due to more damaged D.N.A. sites and not from more active repair-synthe-

tients recumbent for 30 minutes after the intravenous administration of labetalol and measure standing blood-pressure under supervision before allowing them to become fully ambulant. The effect of a single injection lasted up to 24 hours in some

induced

patients.

sising enzymes. The potential for increased accumulation of genetic damage in high-blood-pressure individuals was supported by our cytogenetic study, which showed an increased level of chromosome aberrations correlated with high blood-pressure after carcinogen treatment. Together, these results have convinced us that there is an increased genetic risk, probably expressed through an increased mutational frequency, associated with the lymphocytes from hypertensive individuals. Therefore, we can answer "yes" to the question posed by Dyer and his colleagues: "Are there bio-

In this initial small trial, intravenous labetalol has been satisfactory for the rapid reduction of blood-pressure in severely hypertensive patients. We are also continuing treatment with the oral preparation, and, since we have not so far encountered serious side-effects, it seems worthy of more extensive trials. E. AGABITI ROSEI P. M. TRUST M.R.C. Blood Pressure Western Infirmary, Glasgow G11 6NT.

J. J. BROWN

Unit,

A. F. LEVER J. I. S. ROBERTSON

cinogen

chemical variables which are related to both cancer and elevated blood-pressure?". Detailed descriptions of our results are now being prepared for publication. Unit for

Community Care Sciences, Dalby, Sweden, and Department of Medicine, Lund University Hospital.

HYPERTENSION RELATED TO D.N.A. REPAIR SYNTHESIS AND CARCINOGEN UPTAKE

StR,—The genetic aspects of hypertension have, so far, focused mainly on whether hereditary mechanisms are involved in the acquisition of high blood-pressure. We have studied D.N.A. repair synthesis in patients with hypertension (blood-pressure above the 95th percentile and below the 30th percentile), and we have found that subjects with raised bloodpressure are more likely to have D.N.A. damage than subjects with normal or low blood-pressure. Furthermore, the extent of the induced D.N.A. damage in patients with known hypertension could not be distinguished from that in subjects with only slightly elevated blood-pressure. Our results are particularly interesting in the light of a report by Dyer et al.’ pointing out that hypertensive people are at an increased risk of developing cancer.

We have used the carcinogen, N-acetoxy 2-acetylaminofluorene (N.A.-A.A.F.), to induce D.N.A. repair synthesis in lymCOMPARISON OF BLOOD-PRESSURE TO CARCINOGEN INTERACTION IN

Biochemistry 1, University of Lund, Chemical Center.

RONALD W. PERO CARL BRYNGELSSON

Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.

FELIX MITELMAN

ECTOPIC GESTATION AND HYDATIDIFORM MOLE IN CLOMIPHENE-INDUCED PREGNANCIES

SIR,-Dr Berman (Nov. 1, p. 878) pointed to the undesirable consequences of clomiphene-citrate-induced pregnancies, and to the importance of reporting them, because of the widespread use of this drug. We should like to draw attention to the fact that ectopic pregnancy and hydatidiform mole may be other possible, although rare, complications of clomiphene treatment.

During

LYMPHOCYTFSS

AKE NORDÉN BENGT SCHERSTÉN THOMAS THULIN

the past year

we

have

seen

21

cases

of tubal ges-

tation, of which 3 were in clomiphene-induced pregnancies. All 3 patients suffered from sterility (primary or secondary) and,

clomiphene therapy (50-100 mg daily for five to seven all days), investigations indicated that no tubal factor was present ; and in all these cases the diagnosis of anovulatory cycles was confirmed by dilatation and curettage, laparoscopy, and hormonal assessment. During the same period we also saw 2 cases of hydatidiform mole in the group of clomiphene-induced

before

*Incorporation of (3H)dT due to background replicative synthesis in

was

the

same

both groups.

92 individuals with diastolic blood-pressures from 65 to 120 mm Hg. After 1 h exposure to 10 N.A.-A.A.F., the lymphocytes were cultured for 17 h in fresh medium containing 10 mM hydroxyurea to suppress replicative synthesis and 3H-thymidine (10 uCi/ml, 20 Ci/mmol), which was a measure of the degree of repair-synthesis stimulation. Both the incorporated radioactivity and the amount of D.N.A. were measured, so that the method could be reproduced within an experiment to +9.0%. The amount of D.N.A.-bound carcinogen remaining after induction of repair synthesis by 3H-7,12-dimethylbenz(a)anthracene (D.M.B.A.) was used to measure potential differences in carcinogen uptake. Cytogenetic confirmation of D.N.A. damage was also carried out, following phytohaemagglutinin stimulation of cell-division and collection of lymphocytes in metaphase with a colchicine block. The normal number of chromosome aberrations without N.A.-A.A.F. treatment was subtracted from the number of aberrations induced by 1 jAf N.A.-A.A.F. after 17 h repair synthesis. As the diastolic blood-pressure increased, so did N.A.-A.A.F.-

ranging

cet,

reporting the outcome of clomiphene-induced do not refer to these complications, but study of pregnancies the literature revealed some reports confirming our findings. Karow and Payne’ reported an incidence of tubal gestation in clomiphene-treated women of 1/70. Macgregor et a1.2 reported an incidence of 1/90; and in a study by Merrell National Laboratories in the United States (personal communication) the incidence was 28 in 2369 pregnancies (1/84). The overall incidence is therefore approximately 1.25% of the induced pregnancies, much higher than the 0’3-0’7% incidence of ectopic pregnancy in the general population.3 The reported incidence of hydatidiform mole in clomipheneinduced pregnancies in the United States (where control of the drug and registration of its side-effects are of paramount importance) is much higher than that accepted for the untreated general population, ands varies between 1.350 pregnancies to an incidence of 1 - 592/ The incidence of spontaneous abortion in women with cloMost papers

phocytes from

1. Dyer, A. R.,

pregnancies.

Stamler, J., Berkson,

1975, i, 1051.

D.

M., Lindberg, H A , Stevens, E., Lan-

1. Karow, W. G., Payne, S. H. Fertil Steril. 1968, 19, 351. 2. Macgregor, A. H., Johnson, J. E., Bunde, C. A. ibid. p. 616. 3. Lehfeldt, H., Tietze, C, Gorstein, F. Am. J. Obstet. Gynec 1970, 4. Erving, H. W., Bower, J. E. Int. Surg. 1967, 47, 493. 5. Shneiderman, C. I., Waxman, B. Obstet Gynec 1972, 39, 787

108, 1005