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

with

C.G.D.

leucocytes

as

I indi-

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

W. D. BIGGAR.

INDORAMIN IN PREVENTION OF MIGRAINE

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

common,

Federation of

Neurology Research Group

on

Migraine and.

Headache’;

(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

excluded.

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

treatment.

kept During

a

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

no

patient

was

noticeably

worse.

Side-effects Indoramin

was

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

was

increased

to

30 mg.

daily. These symptoms

were

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.

33 indoramin randomised with -placebo to afford better statistical information as to its efficacy, and more precise attempts are being made to determine the characteristics of the population who respond. We wish to thank Monica Leighton, Department of Computing for Medical Science, St. Bartholomew’s Hospital, for help with the statistical analysis. Princess 22

Margaret Migraine Clinic, Charterhouse Square, London EC1.

John Wyeth and Brother Limited.

GILLIAN WAINSCOTT G. N. VOLANS MARCIA WILKINSON.

G. A. FAUX.

LINOLEIC ACID AS AN IMMUNOSUPPRESSIVE AGENT SIR,-Following previous observations 1-3 that certain fatty acids inhibit a number of lymphocyte functions,

including phytohaemagglutinin (P.H.A.)-stimulated transformation, we have been studying the effect of long-chain fatty acids on the stimulation by P.H.A. of uridine uptake by human peripheral lymphocytes. In order to avoid solubility problems and any non-specific toxic effects of the free fatty acids, we used them bound to bovine serumalbumin (fraction v) in a fatty acid/albumin molar ratio of 2/1. The lymphocytes were obtained by the method of B6yum/ and incubated 24 hours in Eagle’s minimum essential medium (0-5 x 106 lymphocytes per tube) with or without the additions stated in the accompanying figure.

unsaturated fatty acid is maintained the inhibition is

greatly reduced and in some cases almost eliminated, despite the fact that the absolute amount of acid added is in these cases twice or three times as great as is the case when single acids are used. This suggests that the inhibition results from a specific biochemical action rather than from a physicochemical effect. The effectiveness of palmitate in overcoming the inhibition by linoleate, oleate, or arachidonate is especially interesting, because palmitate is a major acid of the bloodlipid fractions. In the in-vitro work carried out so far by various workers, the acids have been used in the unesterified form and the implication would be that the non-esterified fatty acids in the blood (which contain about 30% palmitate) would be involved in any in-vivo inhibiting effect. In vivo, however, the esterified acids of the plasmalipoproteins may also play a role. No in-vitro work has so far examined this possibility. If our results were extrapolated to the in-vivo situation they would imply that a rather large increase in the ratio of linoleate and oleate to palmitate would need to be brought about for any change in the degree of lymphocyte response to P.H.A. to be expected. However, we would rather take these results as recommending caution in making any in-vivo prediction from in-vitro observations, because it is apparent that the mechanism of inhibition is more complex than the work of previous authors may have implied. (It has been shown that subcutaneous injection of linoleic acid delays the rejection of skin graftsan in-vivo effect which may, or may not, be related to the in-vitro observations discussed above.) Further work is needed to clarify the detailed nature of these effects, which are of considerable biochemical interest and which may possibly yet lead to a new approach to immunosuppression. C. WEYMAN BELIN J. Courtauld Institute of Biochemistry, D. SMITH A. Middlesex Hospital Medical School, R. H. S. THOMPSON. London W1P 5PR.

IMMUNOLOGICAL CONTROL OF FERTILITY

Inhibition of uridine uptake by fatty acids. of fatty acid added are indicated as follows (60 µg. of each acid): P=palmitate, S=stearate, O=oleate, L=Iinoleate, A=arachidonate. Multiple additions are indicated as in the following example: LP=60 µg. linoleate+60 µg. palmitate. The fatty-acid/albumin ratio was kept constant throughout. The results are the mean values of three recent

The

amounts

experiments. Uridine-2-14C was then added, the incubation continued for a further 18 hours, the cells collected on filter-paper discs, and counted in a liquid scintillation counter.5 We confirmed that long-chain fatty acids inhibit the effect of P.H.A., manifested as increased uridine uptake. As can be seen from the figure, however, our results do not indicate that increasing degree of unsaturation is the main factor determining the degree of inhibition. Moreover, we find that if mixtures of fatty acids are used, a pattern emerges suggesting that if a balance of saturated to Mertin, J., Hughes, D., Stewart-Wynne, E. Lancet, 1974, i, 1005. Offner, H., Clausen, J. ibid. 1974, ii, 1204. Paty, D. W., Cousin, H. K., McDonald, L. E. ibid. 1975, i, 1107. Böyum, A. Scand. J. clin. Lab. Invest. 1968, 21, suppl., p. 97. 5. Peters, J. H., Hausen, P. Eur. J. Biochem. 1971, 19, 502.

1. 2. 3. 4.

SIR,—The task force on immunological methods for the regulation of fertility referred to in your editorial of May’3 (p. 1018) is one of several W.H.O.-supported researchand-development efforts on new methods of fertility control. This task force has directed its attention to purified reproductive specific antigens which could be used for active immunisation in the female. It has been decided that, for the moment, research should continue using only those antigens not normally present in the female and which do not cross-react

with other tissues, organs,

or

hormones.

Synthetic peptides derived from the -subunit of human chorionic gonadotrophin have been used in an attempt to avoid the cross-reaction with luteinising hormone (L.H.). This was thought to be desirable because the potential damage to the pituitary that might be caused by antibodies cross-reacting with L.H., or even by the presence of circulating immune complexes, is at the moment unknown. For this reason W.H.O. is not supporting any work concerned with inhibition of L.H.-releasing hormone or the -subunit of follicle-stimulating hormone. Our fears about the potential dangers involved in such approaches may prove to be groundless, but until evidence from animal experiments is available W.H.O. will restrict itself to the approach mentioned above. The seventh Karolinska Symposium on Research Methods in Reproductive Endocrinology, entitled Immunological Approaches to Fertility Control, was organised with W.H.O.’S collaboration and supported jointly by W.H.O.

W.H.O.’s collaboration andsupported jointly by W.H.O. 6.

Mertin, J. Transplantation (in

the

press).

Letter: Indoramin in prevention of migraine.

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 abl...
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