31 than an hour of my time, in a series of about 8 or 10 ten-minute sessions. Set against the many hours which may be required by other psychotherapeutic approaches, this represents an important saving to a strained Health


Service. Stanley Royd Hospital, Wakefield, Yorkshire WF1 4DQ.



SIR,—The report of Professor Sackett and his colleagues (May 31, p. 1205) describes preliminary experience of a randomised study of different approaches to antihypertensive therapy. The results might appear to suggest that attempts to facilitate access or enhance patient education have little impact on outcome. However, these conclusions should be viewed with an awareness of several important aspects of the research design. Hypertensive steelworkers were randomised into study groups only if they had not lately received hypotensive therapy. In fact, only 4-6% of the whole population participated in the study. These 230 employees probably represent about one-third of the entire hypertensive population1 and may well include a disproportionate share of employees who assiduously resist medical care. This self-selection may, in turn, explain the remarkably unsatisfactory outcome, in that less than 25% were both compliant and at therapeutic goal. Categorising outcome as the sum of compliance and blood-pressure reduction is somewhat confusing. Although adherence to a therapeutic regimen (which cannot be assessed by change in serum potassium or uric-acid levels 2,3) should correlate with blood-pressure decline, the only significant issue is whether the pressure fell, and by how much. Furthermore, while a diastolic pressure of less than 90 mm. Hg may be a desirable goal, there is good evidence that, failing this, a 10% reduction offers very substantial benefit.4 In certain situations this might be the appropriate therapeutic goal.5 Compliance is indeed the name of the game in hypotensive therapy. However, compliance, and therefore outcome, are not likely to be changed by piecemeal modification of the setting in which care is delivered. Successful hypertension control programmes all share a comprehensive approach to the long-term care of asymptomatic adults. 6-8 Convenience and enhanced education are only components of these systems. They are effective not as isolated additions to the existing system of care, but rather as integral parts of a total care system. As long as the system remains the same with one physician individually treating one patient, the outcome, as Professor Sackett and his colleagues have so elegantly demonstrated, is almost certain to be dismal.9,10 This second phase of the steelworkers’ study promises to be more illuminating. The authors now propose to evaluate changes in the whole system of care tailored to meet the actual needs of patients, 1. National Health Survey, U.S. Department of Health, Education and Welfare, National Center for Health Statistics, series 11, no. 13, 1966. 2. Wilkinson, P. R., Hesp, R., Issler, H., Raftery, E. B. Lancet, 3. 4. 5. 6. 7. 8. 9. 10.

April 5, 1975, p. 759. Bengtsson, C., Johnson, G., Sannerstedt, R., Werko, L. Br. med. J. 1975, i, 197. Taguchi, J., Freis, E. D. New Engl. J. Med. 1974, 291, 329. Freis, E. D. J. Am. med. Ass. 1975, 232, 1017. Finnerty, F. A., Shaw, L. W., Himmelsbach, C. K. Circulation, 1973, 47, 76. Wilber, J. A., Barrow, J. G. Am. J. Med. 1972, 52, 653. Alderman, M. H., Schoenbaum, E. E. New Engl. J. Med. 1975, 293 (in the press). Schoenberger, J. A., Stamler, J., Shekelle, R., Shekelle, S. J. Am. med. Ass. 1972, 222, 559. Langfeld, S. B. Ann. intern. Med. 1973, 78, 19.

and not merely modify the traditional system in accordance with conventional preconceptions. Department of Public Health, New York Hospital/Cornell Medical Center, New York, N.Y. 10021, U.S.A.



SIR,-Your editorial (May 3, p. 1019) states that " subclinical tropical enteropathy is ubiquitous ". This assertion is too sweeping. In the Caribbean area, evidence of subclinical enteropathy has been found only in persons who live or have resided in those countries (Puerto Rico, Cuba, Haiti, and San Domingo) where tropical sprue now exists. 1-4 In contrast there is no published evidence of either sprue or subclinical enteropathy which could have been contracted in Jamaica or in other parts of the Englishspeaking Caribbean. Intestinal biopsy studies from 20 Jamaicans without gastrointestinal disease showed normal villous patterns.5 As far as I am aware subclinical enteropathy has been recorded neither in visitors to the Englishspeaking Caribbean nor in immigrants from this area who now reside in the U.S.A. and in the U.K. The conditions, whose diagnosis depends on laboratory tests, may not have been vigorously searched for in people from those Caribbean regions where sprue is not found, but uncritical acceptance that subclinical enteropathy is ubiquitous in the tropics may be misleading. A careful study of the geographical distribution of subclinical enteropathy may reveal likely causative factors and may also resolve the uncertainty as. to whether this condition and sprue are part of the same disease spectrum. Medical Research Council

Epidemiology Unit, University of the West Indies, Kingston, Jamaica.


PHAGOCYTOSIS IN CHRONIC GRANULOMATOUS DISEASE SIR,-Dr de Gast and co-workers (May 31, p. 1247) correctly point out the importance of the bactericidal capacity of normal leucocytes in estimating the phagocytic capacity of leucocytes from patients with chronic granulomatous disease (C.G.D.). My conclusions (May 3, p. 991) were not drawn from the morphological studies alone, as they suggest, but also from experiments using phenylbutazone which were similar to those that they were prompted to undertake. Specifically, when a bactericidal abnormality was induced in normal leucocytes by phenylbutazone, the number of intracellular bacteria increased 5-10-fold over control leucocytes, while in the same experiment the number of intracellular bacteria in c.G.D. leucocytes was as much as 300-fold. Thus, the increased number of intracellular bacteria in normal leucocytes incubated with phenylbutazone might be explained by the effect of the drug on bacterial killing. It is clear, therefore, from observations reported in my article and from the experiments of de Gast et al., that the number of intracellular bacteria in normal leucocytes depends on the cells’ ability to kill bacteria. However, since the number of intracellular bacteria in c.G.D. leucocytes was far greater than the number of intracellular bacteria in the phenylbutazone-treated normal leucocytes examined in parallel, 1. 2.

3. 4. 5.

F. A., Samloff, I. M., Smarth, G., Schenk, E. A. Am. J. clin. Nutr. 1968, 21, 1042. Klipstein, F. A., Beauchamp, I., Corcino, J. J., Maldonado, M., Tomasini, J. T., Schenk, E. A. Gastroenterology, 1972, 63, 758. Klipstein, F. A., Rubio, C., Montas, S., Tomasini, J. T., Castillo, R. G. Am. J. clin. Nutr. 1973, 26, 87. Klipstein, F. A., Falaiye, J. M. Medicine, 1969, 48, 475. Da Costa, L. R. Am. J. dig. Dis. 1972, 17, 105.


32 it did not appear that the bactericidal abnormality alone would account for my observations. I am pleased that de Gast and co-workers have been able to confirm my observations on the effect of phenylbutazone, and feel that their conclusions concerning the soundness of my interpretations would be best substantiated by performing the

appropriate experiments





I indi-

cated. Department of Immunology, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.



SIR,—We should like to report our encouraging experiof indoramin in preliminary studies in the prevention of migraine. Migraine is thought to begin with a vasoconstrictive phase followed by a vasodilatation of the cranial aneries.1 The nerve-supply of the cranial arteries is thought to be sympathetic in origin and both x andadrenoreceptors have been identified in the cat.2 Human pial arteries have been shown to have both x andreceptors3 and ence

in-vitro experiments have shown strong circular contractions in response to adrenergic drugs. Indoramin, 3-(2-[4 benzamido piperid-1-yl] ethyl) indole, has been shown in animal experiments to have competitive x-blocking properties 4 , 5 and this activity has been confirmed in human tissue.6 Preliminary clinical studies indicated that indoramin had a beneficial effect in patients with essential hypertension,7 and during a further evaluation of its antihypertensive action (when 15 patients with mild essential hypertension were treated with indoramin in doses varying from 80 mg. to 300 mg. daily) 2 of these patients remarked voluntarily that the drug had relieved their migraine.’e On the basis of these theoretical and practical observations it was decided to investigate the efficacy of indoramin An initial pilot study of 30 as a migraine prophylactic. patients receiving oral indoramin in a non-blind openended trial was undertaken to provide further evidence of clinical response, and to gain information on dosage and side-effects. Selected for the trial were male and female outpatients attending the Princess Margaret Migraine Clinic, aged between 18 and 65 years, who were:

(i) diagnosed as suffering from migraine, either classical or according to the criteria laid down by the World


Federation of

Neurology Research Group


Migraine and.


(ii) competent to follow instructions; (iii) suffered from at least 2 and not more than 8 attacks of migraine each month. The informed consent of each patient was obtained. Patients with any coexistent medical or psychiatric complaint, pregnant women, and patients taking any other form of regular prophylactic treatment were


diary record card for one month before this month they took no prophylactic treatment and recorded the frequency of their migraine attacks, The patients


kept During


Graham, J. R., Wolff, H. G. Archs Neurol. Psychiat. 1938, 39, 737. Nielson, K. C., Owman, C. Res. clin. Stud. Headache, 1972, 3, 198. 3. Falck, B., Nielson, K. C., Owman, C. Scand. J. clin. Lab. Invest. 1968, suppl., 102, 96. 4. Collis, M. G., Alps, B. J. J. Pharm. Pharmac. 1973, 25, 621. 5. Alps, B. J., Hill, M., Johnson, E. S., Wilson, A. B. Br. J. Pharmacol. 1972, 44, 52. 6. Variava, D. H., Turner, P. J. Pharm. Pharmac. 1973, 23, 629. 7. Royds, R. B. Br. J. Pharmacol. 1972, 44, 379. 8. White, C. de B., Royds, R. B., Turner, P. Postgrad med. J. 1974, 50, 729. 9. World Federation of Neurology Research Group on Migraine and Headache, in Background to Migraine; p. 181. London, 1969. 1. 2.

the duration in days of each attack, and the severity, graded subjectively by the patient using a simple descriptive three-point rating scale.10 From this data a migraine index was obtained for each patient by multiplying the graded severity of the attack by the number of days of incapacity. Patients were permitted to take their usual symptom-relieving medication, which varied from ergotamine preparations and antiemetics to simple

analgesics. Treatment with indoramin was started at 5 mg. twice daily for the first week and increased to 10 mg. twice daily thereafter. 18 patients continued on this dose of indoramin for three months, and in 8 patients the dose of indoramin was increased to 30 mg. daily. The patients were assessed at monthly intervals.

Patients Of the 30 patients, 24 were women, 21 of whom had common migraine and 3 classical migraine. 6 patients were men, 4 of whom had common migraine and 2 classical migraine. The average age of the patients was 359 years (range 20-56 years). The duration of illness ranged from 3 to 37 years.

Withdrawals One 51-year-old woman withdrew from the trial after one month, claiming that she was unable to tolerate indoramin in a dose of 5 mg. twice daily because it provoked dizziness and hot flushes. In view of the small amount of the drug taken and the coincidence of menstrual irregularity, it was felt that these were menopausal symptoms rather than side-effects of indoramin. 3 patients withdrew from the trial after two months, disheartened because of the lack of response.

Results The patients were assessed as one group, since only 8 were given indoramin at the higher dose level of 30 mg. daily. All the pretreatment mean scores (frequency, duration, and migraine index) were higher than the mean scores obtained during treatment. The difference between pretreatment and second-month mean scores was significant at the 5%level. The one patient who was excluded was not thought to bias the results, because the reason for her exclusion was not connected with treatment. In the 26 patients who completed three months’ treatment there was again a significant difference (p < 005) in the mean scores for frequency, duration of attack, and migraine index, compared with the pretreatment month. It is recognised that the exclusion of the 3 patients who abandoned the trial after two months because they felt the treatment was not effective will give a favourable bias this analysis. The response to indoramin within the group was variable. Using the stringent criterion of a fall in the migraine index of 50%or more before the patient was classified as improved, 4400of the patients showed an improvement after two months, and 42%after three months. The three-month figures included 6 patients (23%) who were migraine-free. Although the remainder of the patients did not show this to

substantial improvement






Side-effects Indoramin


well tolerated and it

was not

felt that any

patient withdrew from the trial because of side-effects. 2 patients complained of an increase in tension headaches and 1 patient of faintness during the first week of treatment, which resolved spontaneously. 2 patients complained of slight drowsiness and 2 of dizziness on rising after the dose




30 mg.

daily. These symptoms


only mildly troublesome. We feel these results give grounds for cautious optimism that indoramin may have a role in the prophylaxis of migraine. It seems that a certain subgroup of migraine sufferers will respond well to the drug. Further scrutiny of our initial data suggests that there is a trend for patients who do not use ergotamine as symptomatic medication to respond better to indoramin, as do those patients in whom the illness is of a shorter duration. Further studies are being conducted in a double-blind crossover style using 10

Keele, K. D. Lancet, 1948, ii, 6.

Letter: Phagocytosis in chronic granulomatous disease.

31 than an hour of my time, in a series of about 8 or 10 ten-minute sessions. Set against the many hours which may be required by other psychotherapeu...
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