347

Atherosclerosis, 27 (1977) 347-351 0 Elsevier/North-Holland Scientific Publishers, Ltd.

CONTROLLED TRIAL OF THE EFFECT OF CYCLOALLIIN ON THE FIBRINOLYTIC ACTIVITY OF VENOUS BLOOD

R.K. AGARWAL,

H.A. DEWAR, D.J. NEWELL and B. DAS

Department of Cardiology, Royal Victoria Infirmary, and Department The University, Newcastle upon Tyne, NE1 4LP (Great Britain)

of Medical Statistics,

(Received 21 December, 1976) (Revised, received 3 February, 1977) (Accepted 3 February, 1977)

Summary Cycloalliin is a natural constituent of onion, sulphur-containing but odourless. It was synthesised for this randomised double-blind study; its effect on fibribolytic activity and platelet aggregability was tested in venous blood from 18 male volunteers. It increased the former to a highly significant degree but had no effect on the latter. It was well tolerated and harmless in the single oral dosage used. Key words:

Cycloalliin

- Fibrinolytic

activity

- Onion -Platelet

aggregation

Introduction Previous work on onion has established its power to enhance natural fibrinolysis [ 1,2]. The active principle appears to reside in the essential oil, which is rich in sulphur-containing compounds [ 3,4]. Unfortunately these last are also responsible for the acrid taste and strong odour of onion and these seriously limit its clinical use. Cycloalliin, however, though a sulphur containing amino acid (Fig. 1) and a normal constituent of onion, is free from these features and has been previously shown to have some fibrinolytic potential [ 41. For the experiment to be described the substance was synthesised, not extracted, and its effect assessed on fibrinolytic activity and platelet aggregating activity.

348

0 t

H2

c’s’

CH2

I CH3-HC,/CH-COOH

I

H Fig. 1. Cycloallii

(3-methyl-1.4~thiazam-5

carboxylic acid-l-oxide).

Design of Trial, Subjects and Methods A total of 18 men, aged 19-77 years, volunteered to take part in the trial. Ten were healthy medical students and eight were patients with angina pectoris or old myocardial infarction, but on no drug therapy in the past two weeks. The study was confined to males only, so as to avoid the complications that might arise from the effects of the menstrual cycle upon fibrinolytic activity. The study took the form of a double-blind cross-over randomised trial. Each of the 18 volunteers attended twice, with an interval of not less than 48 h and not more than a week between attendances. On each occasion, the subject arrived fasting and without smoking. He rested for half an hour, whereafter blood was collected without the use of a tourniquet at 9 a.m. The subject was then given a bottle containing a single capsule, and marked “Subject n, first attendance” or “Subject n second attendance” (n = 1. . .18). At 10.30 a.m., after 1: hour rest, blood was again collected from the same arm in a similar manner for the same purpose. Cycloalliin was synthesised by the method of Virtanen and Matikkala [5]. It was given in a dose of 0.25 g per subject; this amount was found most effective in a small pilot trial. Identical looking capsules of Lactose acted as placebo. The bottles were prepared in the hospital dispensary according to a restricted randomisation list. This ensured that each person received one capsule of cycloalliin and one of placebo, in random order, restricted in such a way that, after each successive group of four subjects had been admitted to the trial, two had received these capsules in the order of cycloalliin - placebo and two in the order placebo - cycloalliin. The chief pharmacist supervised the preparation and dispensing of the capsules and kept the code of identification secret. Fibrinolytic activity (FA) was measured by the euglobulin lysis time (ELT) method of Von Kaulla [6], as modified by Menon and Dewar [ 71, the result being expressed as units of activity by multiplying the reciprocal of lysis time in minutes by 10,000. The difference between the 10.30 and initial 9 a.m. reading is called the “effect” of cycloalliin or placebo for the purpose of this paper. The difference between two effects tells us how much the cycloalliin improves FA, after allowing for the placebo effect (which relates to the biological response to the setting of the study and the passage of 1: hours). Platelet aggregability was measured in the initial and 1; hour specimen, in

349 TABLE 1 FIBRINOLYTIC

ACTIVITY

IN 18 SUBJECTS TREATED

WITH CYCLOALLIIN Placebo

CycloaIIiin

Mean ELT (units) Mean difference Standard error of difference (within subjects) P

AND PLACEBO

Before treatment

After treatment

Before treatment

After treatment

34.7

61.3

36.8

39.2

+26.6 3.010 0.4). It must be noted, however, that 60 g of extracted onions yield only 0.012 g of cycloalliin, and their comparable effect is doubtless due to the many other sulphurcontaining and malodorous substances - such as dimethylthiophene and propyl ally1 disulphide - contained therein [4]. The importance of the present work lies in the identification of one constituent, which is without flavour and yet has - in large but tolerable dosage - the property of enhancing natural fibrinolysis. Its usefulness and safety in the long term, its mode of action and its other properties all remain to be examined. In so far, however, as cycloalliin has been shown in these experiments to have no power to decrease the aggregability of platelets, it clearly falls short of being the ideal anti-thrombotic drug as defined by Von Kaulla [ 91. Acknowledgements Our thanks are due to Mr. R. Elder and staff of the Department of Pharmacy for carefully managing the drug allocations, to I.C.I. (Pharmaceuticals) Ltd., for the supply of cycloalliin, to Dr. P. Jones and staff of the Department of Haematology for the studies of platelet aggregation and the blood counts, to Dr. P. Smith and staff of the Department of Biochemistry for the liver function tests, to Mrs. D. Weightman for carrying out the statistical analysis of the results, and especially to the medical students and patients who so kindly volunteered to be the subjects of the trial. References 1 Gupta, N.N.. Methrotra, R.M.L. and Sircar. A.R., Effect of onion on serum cholesterol. blood coagulation factors and fibrinolytic activity in alimentary lipaemia, Indian J. Med. Res., 54 (1966) 46. 2 Menon, IS., Kendal. R.Y.. Dewar, H.A. 2nd Newell, D.J., Effect of onions on blood fibrinolytic activity. Brit. Med. J., 3 (1968) 351.

351 3 Bordia,

A., Bansal,

on alimentary

H.C.,

Arora.

hyperllpemia,

S.K. and Singh, S.V..

Atherosclerosis, M.E., Dewar, H.A.

Effect

21 (1975) 15. and Virden. R..

of the essential

oils of garlic and onion

Partial identification of the fibrinolytic 4 Augusti, K.T., Benaim. activators in onion, Atherosclerosis. 21 (1975) 409. 5 Virtanen, A.I. and Matikkala. E.J.. The structure and synthesis of cycloalllin isolated from Allium cepa, Acta Chem. Stand., 13 (1959) 623. 6 Von Kaulla, K.N., Chemistry of Thrombolysis - Human Fibrinolytic Enzymes, Thomas, Springfield, Ill., 1963. P. 79. 7 Menon. I.S. and Dewar, H.A., Increased fibrinolytic activity in venous blood of hemiplegic limbs, Brit. Med. J., 2 (1967) 613. 8 Born, G.V.R.. Aggregation of blood platelets by A.D.P. and its reversal, Nature (Land.). (1962) 927. 9 Von Kaulla, K.N., Synthetic Fibrinolytic Thrombolytic Agents, Thomas, Springfield. Ill., 1972, p. 427.

Controlled trial of the effect of cycloalliin on the fibrinolytic activity of venous blood.

347 Atherosclerosis, 27 (1977) 347-351 0 Elsevier/North-Holland Scientific Publishers, Ltd. CONTROLLED TRIAL OF THE EFFECT OF CYCLOALLIIN ON THE FIB...
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