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EFFECTS OF CLOFIBRATE ON FIBRINOLYSIS, PLATELET STICKINESS, PLASMA-FIBRINOGEN, AND SERUM-CHOLESTEROL
1007
fibrinolytic activity and reduces plasma-fibrinogen, its effects on platelet stickiness and serum-cholesterol are the of those
Clofibrate is an effective and reduces plasma-fibrinogen; cholesterol-lowering drug on effect its platelet stickiness, however, is not sustained and far from influencing fibrinolysis favourably it has antifibrinolytic properties (Chakrabarti and Fearnley 1968). Phenformin plus ethyloestrenol, on the other hand, exerts a favourable influence on fibrinolysis, platelet stickiness, and plasma-fibrinogen, and also lowers serumcholesterol, though here it may be less potent than clofibrate. It is important that these effects are sustained and undiminished with continued treatment. This combination of drugs, therefore, would seem to be suitable for trial in survivors of vascular occlusions. reverse
desired.
This work was supported by grants from the Nuffield Foundation, Organon Laboratories Ltd., and Bayer Products Ltd. We thank Dr. R. F. Jarrett for referring some of the patients, and Dr. A. Nicol, and Miss Esther Gronow for the cholesterol determinations. Requests for reprints should be addressed to G. R. F. REFERENCES
Chakrabarti, R., Fearnley, G. R. (1967) Lancet, ii, 1012. (1968) ibid. ii, 1007. Fearnley, G. R. (1964) J. clin. Path. 17, 307. Balmforth, G. V., Fearnley, E. (1957) Clin. Sci. 16, 645. Chakrabarti, R., Hocking, E. D. (1967) Lancet, ii, 1008. Sackett, G. E. (1925) J. biol. Chem. 64, 203. Schwartz, M., Mirsky, S., Schaefer, L. (1965) Lancet, i, 959. Sharp, A. A. (1965) ibid. ii, 1296. —
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EFFECTS OF CLOFIBRATE ON FIBRINOLYSIS, PLATELET
STICKINESS, PLASMA-FIBRINOGEN, AND SERUM-CHOLESTEROL R. CHAKRABARTI M.B. Calcutta SENIOR RESEARCH REGISTRAR
G. R. FEARNLEY Lond., F.R.C.P.
M.D.
PHYSICIAN
With the technical assistance J. F. EVANS GLOUCESTERSHIRE ROYAL
HOSPITAL,
of
(i.e., raised plasma-fibrinogen and platelet stickiness, and fibrinolytic activity). Such additional actions by a cholesterol-lowering drug, if sustained, would greatly augment its potential value as a treatment for patients
low
with occlusive vascular disease. Patients and Methods Ten patients, seven men and three women, with occlusive vascular disease entered the trial. Two patients (both male) died during the first month and results are given for the remaining eight patients, one of whom died before the trial was completed. Each patient was given clofibrate 1 g. twice daily for 7 months. The dilute blood-clot lysis-time (B.L.T.), platelet stickiness to glass, plasma-fibrinogen, and serum-cholesterol were measured at 10-11 A.M. once before treatment was started, monthly during treatment, and for 2 months after clofibrate was discontinued. B.L.T. was measured in duplicate by the method of Fearnley, Chakrabarti, and Hocking (1967) with reading of the end-point modified as described by Fearnley (1964). Lysis-time and fibrinolytic activity are inversely related. Platelet stickiness was measured by Sharp’s (1965) glass-bead method, modified slightly by Chakrabarti and Fearnley (1967). Plasma-fibrinogen was estimated gravimetrically (Fearnley and Chakrabarti 1966). Serum-cholesterol was estimated by the method of Sackett (1925). Results
The table
gives the levels of serum-cholesterol, plasmafibrinogen, platelet stickiness, and B.L.T. of the eight patients during the trial. As shown in the figure, mean serum-cholesterol and plasma-fibrinogen levels decreased during treatment and reverted to their control levels after clofibrate was discontinued. Mean platelet stickiness was most reduced at months 2 and 3, after which it rose to 40-50% during months 5-7, returning to the control level when treatment was stopped. The mean B.L.T. rose sharply at month 2 and remained elevated until clofibrate was discontinued when it returned to its control level. Serum-cholesterol
All but one (no. 8) of the patients showed a reduction of serum-cholesterol while receiving clofibrate. The mean reduction (see figure) was about 30%.
Plasma-fibrinogen GLOUCESTER
Plasma-fibrinogen levels
were
reduced
throughout
The effects of clofibrate (’Atromid-S’), 2·0 g. daily, on fibrinolytic activity, platelet stickiness, plasma-fibrinogen, and serum-cholesterol were assessed in eight patients with occlusive vascular disease who were treated for 7 months, and, except for one patient who died, observed for 2 months thereafter. Mean serum-cholesterol was reduced by about 30% and mean plasma-fibrinogen by about 20%. Platelet stickiness was appreciably reduced at first, but after 4-6 months’ treatment much of the effect of clofibrate in this respect was lost, the levels returning to the abnormal range. In five of six patients whose fibrinolytic activity was within normal limits before treatment, the dilute blood-clot lysis-times were prolonged whilst clofibrate was given; in two patients prolongation was temporary, but in three it persisted. Hence clofibrate has antifibrinolytic properties, which should be taken into account if the drug is given to patients with coronary-artery disease before the results of controlled trials of its use in this condition become known.
Sum ary
lipids, clofibrate been claimed to exert a favourable the so-called " thrombogenic abnormalities "
BESIDES reducing (’Atromid-S ’) has
influence
on
Introduction cholesterol and other
Mean serum-cholesterol, platelet stickiness, plasma-fibrinogen, and dilute blood-clot lysis-time of patients 1-8.
1008 EFFECT
OF
CLOFIBRATE
ON :
(a)
SERUM-CHOLESTEROL STICKINESS
I.H.D. = Ischaemic heart-disease.
(rilg. 1 OO ml.), (b) PLASMA-FIBRINOGEN (mg.(100 ml.), (c) (%), AND (d) B.L.T. (hr.)
M.l.=Myocardial infarction.
with clofibrate in three patients (2,4, and 7), and little affected in one (no. 3), reduced towards the end of treatment in three (5, 6 and 8), and temporarily reduced at months 4 and 5 in patient 1.The variability of response among the patients accounts for the gradual fall of the mean plasma-fibrinogen level shown in the figure. Thus clofibrate appreciably reduced the fibrinogen levels of only three of the eight patients, but it should be noted that these were three of the five patients whose control levels were raised above 300 mg. per 100 ml., the upper limit of normal, and that in the remainder plasmafibrinogen was within normal limits before treatment was started. In this connection, Cotton and Wade (1963) observed that clofibrate plus androsterone (’ Atromid ’) reduced plasma-fibrinogen in thirteen of fourteen patients, most of whom had raised levels of this protein, though the effect seemed to tail off after 4 months’ treatment. The long-term effect of clofibrate on plasma-fibrinogen needs further study, but it seems somewhat less effective in this respect than phenformin or metformin combined with
treatment
ethyloestrenol (Fearnley, Chakrabarti,
and
Hocking 1967).
Platelet Stickiness
Except in patient 3 who showed no change, platelet stickiness was appreciably reduced in the remaining patients for varying periods between months 2 and 6, after which most of the effect of the drug in this respect was lost, the percentage platelet stickiness returning to the abnormal range of 40-50%by the 6th or 7th month of treatment (see table). This is reflected by the change of mean platelet stickiness (see figure), from the control level of 54%, to
I.L.D. = IschaE:mic limb disease.
PLATELET
*=Died.
months 2 and 3, after which the level rose to reach month 7-i.e., about 6% lower than it was before clofibrate was given. Clofibrate plus androsterone (atromid) was found by Carson et al. (1963) to reduce platelet stickiness to glass in eighteen of nineteen males with ischaemic heart-disease who were given this drug for 1 month. Symons et al. (1964) gave atromid and atromid-S each for a period of 2 months to six patients with ischxmic heart-disease and found that both drugs reduced platelet stickiness to glass. Carson et al. (1966) studied thirty-five men with ischsemic heart-disease who received atromid and atromid-S for periods of 2 months at a time, and concluded that whilst both drugs reduced platelet stickiness, atromid was more effective than atromid-S in this respect. In none of these series was either agent given for more than 2 months. Our results confirm that clofibrate reduces platelet stickiness to glass, but indicate that most of this effect is lost after a few months’ treatment and that any effect remaining after 6 months is of little consequence. This finding underlines the necessity of long-term investigations of the effects of drugs intended for long-term treatment.
32% 47%
at
at
Fibrinolysis The
B.L.T.S of two patients (1 and 2) were at or near the limit of measurement (24 hours) before clofibrate upper was started, and they remained essentially unaltered throughout the trial. The B.L.T.S of the remaining patients were within the normal range (i.e., 7 hours before treatment) and all but one (in no. 4) were appreciably prolonged whilst clofibrate was given. In two patients
1009
(3 and 8) the B.L.T. was prolonged throughout treatment and in patient 3, who survived, it was reduced after clofibrate was discontinued. In patient 5, despite fluctuations, the B.L.T. was prolonged, compared with its control level, and with the levels after the drug was discontinued, more often than not during treatment with clofibrate. In patients 6 and 7 the B.L.T. was elevated for 3 and 6 months, respectively, and returned to near the control levels before clofibrate was stopped. Thus, of the six patients whose B.L.T.s were within the normal range before treatment was started, five had prolonged B.L.T.s while on clofibrate; in three this effect seemed to be sustained and in two it was temporary. These changes are reflected in the figure by the rise of the mean B.L.T. whilst clofibrate was given and its fall when the drug was stopped. Using a different method, the euglobulin lysis-time, Sweet et al. (1965) found clofibrate to have no effect on fibrinolytic activity in fifteen patients, but treatment was given for only 1-2 months. In contrast to our findings with clofibrate alone, clofibrate plus androsterone gave a temporary reduction of the B.L.T. in arteriopathic patients (Fearnley 1963, Hocking, Chakrabarti, Evans, and Fearnley 1967). That atromid and atromid-S should have opposite effects on fibrinolytic activity, as judged by the B.L.T., can probably be ascribed to the presence and absence of androsterone respectively. Anabolic steroids alone (e.g., ethyloestrenol) taken by mouth temporarily reduce the B.L.T. (Fearnley and Chakrabarti 1964) and the temporary reduction of the B.L.T. by atromid can be attributed to the dose of androsterone the patients were receiving-i.e., 33 mg. daily. Since androsterone is approximately three times as potent on a weight-for-weight basis as ethyloestrenol (Taylor 1968) and since ethylcestrenol 8 mg. daily gives a pronounced, if temporary, reduction of the B.L.T., it is probable that the presence of androsterone in atromid masked the antifibrinolytic properties of clofibrate. Hence removal of androsterone from this preparation has revealed clofibrate as an anti-
1968). Whether the favourable effects of clofibrate on serum-cholesterol and plasma-fibrinogen outweigh its antifibrinolytic properties and temporary influence on platelet stickiness will doubtless be decided by the results of controlled trials now in progress. Meanwhile, if clofibrate is given to patients with coronary-artery disease its apparently adverse influence on fibrinolytic activity should be noted. This work was supported by a grant from the Nuffield Foundation. We thank Dr. R. F. Jarrett for referring some of the patients, Dr. A. Nicol and Miss Esther Gronow for the cholesterol determinations, and Dr. C. C. Downie of Imperial Chemical Industries for supplies of clofibrate. Requests for reprints should be addressed to G. R. F. REFERENCES
Carson, P., McDonald, L., Pickard, S., Pilkington, T., Davies, B., Love, F. (1963) J. Atheroscler. Res. 3, 619. — — — — — — (1966) Br. Heart J. 28, 400. Chakrabarti, R., Fearnley, G. R. (1967) Lancet, ii, 1012. Hocking, E. D., Delitheos, A., Clarke, G. M. (1966) ibid. i, 573. Hocking, E. D., Fearnley, G. R., Mann, R. D., Attwell, T. N., Jackson, D. (1968) ibid. i, 987. Cotton, R. C., Wade, E. C. (1963) J. Atheroscler. Res. 3, 648. Fearnley, G. R. (1963) Lancet, ii, 148. (1964) J. clin. Path. 17, 307. — (1965) Fibrinolysis; p. 174. London. Balmforth, G. V., Fearnley, E. (1957) Clin. Sci. 16, 645. Chakrabarti, R. (1964) J. clin. Path. 17, 328. (1966) Lancet, ii, 757. (1968) ibid. ii, 1004. Hocking, E. D. (1967) ibid. ii, 1008. Hocking, E. D., Chakrabarti, R., Evans, J., Fearnley, G. R. (1967) J. Atheroscler. Res. 7, 121. Sackett, G. E. (1925) J. biol. Chem. 64, 203. Sharp, A. A. (1965) Lancet, ii, 1296. Sweet, B., Rifkind, B. M., McNicol, G. P. (1965) J. Atheroscler. Res. 5, 347. Symons, C., deToszeghi, A., Cook, I. J. Y. (1964) Lancet, ii, 233. Taylor, A. F. (1968) Personal communication. —
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DELAYED HYPERSENSITIVITY TO ENCEPHALITOGENIC PROTEIN IN DISSEMINATED ENCEPHALOMYELITIS
P. O. BEHAN
fibrinolytic drug.
N. GESCHWIND
Discussion
M.B. Leeds
M.D. Harvard
Our results confirm that clofibrate substantially reduces serum-cholesterol. Of the three " thrombogenic abnormalities studied, only plasma-fibrinogen was favourably influenced by clofibrate to any extent. Although clofibrate reduced platelet stickiness the long-term results were unimpressive, most of its influence being lost after 4-6 months’ treatment when the levels were once more abnormal. The effect of clofibrate on platelet stickiness is, therefore, inferior to that of phenformin plus ethyloestrenol which, besides increasing fibrinolytic activity and reducing plasma-fibrinogen and serum-cholesterol (Fearnley, Chakrabarti, and Hocking 1967), gives a pronounced reduction of platelet stickiness which is sustained (Chakrabarti and Fearnley 1967, Fearnley and Chakrabarti
INSTRUCTOR
PROFESSOR AND CHAIRMAN
J. B. LAMARCHE
"
1968). An unexpected finding of this investigation was that clofibrate, far from being a fibrinolytic drug, has antifibrinolytic properties. Although the function of natural fibrinolysis as a defence against vascular occlusions (Fearnley 1965) is conjectural, recent evidence points to a greater incidence of low fibrinolytic activity among survivors of heart attacks than among age-matched controls; and a diminishing difference with age in this respect hints at the possibility that defective fibrinolysis may be an adverse influence on the life-expectancy of patients with coronary-artery disease (Chakrabarti, Fearnley et al. 1966, Chakrabarti, Hocking, Fearnley et al.
M.D. Laval ASSISTANT PROFESSOR OF NEUROLOGY AND PATHOLOGY
DEPARTMENT OF BOSTON UNIVERSITY MEDICAL
NEUROLOGY, SCHOOL, BOSTON, MASS.
R. P. LISAK
M. W. KIES Washington
M.D. Columbia
Ph.D. George
RESEARCH ASSOCIATE
SECTION CHIEF
LABORATORY OF CLINICAL
NATIONAL INSTITUTE OF MENTAL
SCIENCE, HEALTH, BETHESDA, MARYLAND
lymphocytes from primary demyelinating
patients with diseases showed significant transformation when stimulated by a pure encephalitogenic myelin basic protein. In addition lymphoblasts undergoing mitosis were found in their peripheral blood. Radioimmunoassay did not reveal any antibody to the encephalitogenic protein. Both the patients had atopic histories, and one had a brother with disseminated sclerosis. Summary
The
two
Introduction
EXPERIMENTAL allergic encephalomyelitis (E.A.E.) is an experimental autoimmune disease of the central nervous system widely studied as a possible model of human demyelinative diseases (Kabat et al. 1947). The experi-
fibrinolytic activity and reduces plasma-fibrinogen, its effects on platelet stickiness and serum-cholesterol are the of those
Clofibrate is an effective and reduces plasma-fibrinogen; cholesterol-lowering drug on effect its platelet stickiness, however, is not sustained and far from influencing fibrinolysis favourably it has antifibrinolytic properties (Chakrabarti and Fearnley 1968). Phenformin plus ethyloestrenol, on the other hand, exerts a favourable influence on fibrinolysis, platelet stickiness, and plasma-fibrinogen, and also lowers serumcholesterol, though here it may be less potent than clofibrate. It is important that these effects are sustained and undiminished with continued treatment. This combination of drugs, therefore, would seem to be suitable for trial in survivors of vascular occlusions. reverse
desired.
This work was supported by grants from the Nuffield Foundation, Organon Laboratories Ltd., and Bayer Products Ltd. We thank Dr. R. F. Jarrett for referring some of the patients, and Dr. A. Nicol, and Miss Esther Gronow for the cholesterol determinations. Requests for reprints should be addressed to G. R. F. REFERENCES
Chakrabarti, R., Fearnley, G. R. (1967) Lancet, ii, 1012. (1968) ibid. ii, 1007. Fearnley, G. R. (1964) J. clin. Path. 17, 307. Balmforth, G. V., Fearnley, E. (1957) Clin. Sci. 16, 645. Chakrabarti, R., Hocking, E. D. (1967) Lancet, ii, 1008. Sackett, G. E. (1925) J. biol. Chem. 64, 203. Schwartz, M., Mirsky, S., Schaefer, L. (1965) Lancet, i, 959. Sharp, A. A. (1965) ibid. ii, 1296. —
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EFFECTS OF CLOFIBRATE ON FIBRINOLYSIS, PLATELET
STICKINESS, PLASMA-FIBRINOGEN, AND SERUM-CHOLESTEROL R. CHAKRABARTI M.B. Calcutta SENIOR RESEARCH REGISTRAR
G. R. FEARNLEY Lond., F.R.C.P.
M.D.
PHYSICIAN
With the technical assistance J. F. EVANS GLOUCESTERSHIRE ROYAL
HOSPITAL,
of
(i.e., raised plasma-fibrinogen and platelet stickiness, and fibrinolytic activity). Such additional actions by a cholesterol-lowering drug, if sustained, would greatly augment its potential value as a treatment for patients
low
with occlusive vascular disease. Patients and Methods Ten patients, seven men and three women, with occlusive vascular disease entered the trial. Two patients (both male) died during the first month and results are given for the remaining eight patients, one of whom died before the trial was completed. Each patient was given clofibrate 1 g. twice daily for 7 months. The dilute blood-clot lysis-time (B.L.T.), platelet stickiness to glass, plasma-fibrinogen, and serum-cholesterol were measured at 10-11 A.M. once before treatment was started, monthly during treatment, and for 2 months after clofibrate was discontinued. B.L.T. was measured in duplicate by the method of Fearnley, Chakrabarti, and Hocking (1967) with reading of the end-point modified as described by Fearnley (1964). Lysis-time and fibrinolytic activity are inversely related. Platelet stickiness was measured by Sharp’s (1965) glass-bead method, modified slightly by Chakrabarti and Fearnley (1967). Plasma-fibrinogen was estimated gravimetrically (Fearnley and Chakrabarti 1966). Serum-cholesterol was estimated by the method of Sackett (1925). Results
The table
gives the levels of serum-cholesterol, plasmafibrinogen, platelet stickiness, and B.L.T. of the eight patients during the trial. As shown in the figure, mean serum-cholesterol and plasma-fibrinogen levels decreased during treatment and reverted to their control levels after clofibrate was discontinued. Mean platelet stickiness was most reduced at months 2 and 3, after which it rose to 40-50% during months 5-7, returning to the control level when treatment was stopped. The mean B.L.T. rose sharply at month 2 and remained elevated until clofibrate was discontinued when it returned to its control level. Serum-cholesterol
All but one (no. 8) of the patients showed a reduction of serum-cholesterol while receiving clofibrate. The mean reduction (see figure) was about 30%.
Plasma-fibrinogen GLOUCESTER
Plasma-fibrinogen levels
were
reduced
throughout
The effects of clofibrate (’Atromid-S’), 2·0 g. daily, on fibrinolytic activity, platelet stickiness, plasma-fibrinogen, and serum-cholesterol were assessed in eight patients with occlusive vascular disease who were treated for 7 months, and, except for one patient who died, observed for 2 months thereafter. Mean serum-cholesterol was reduced by about 30% and mean plasma-fibrinogen by about 20%. Platelet stickiness was appreciably reduced at first, but after 4-6 months’ treatment much of the effect of clofibrate in this respect was lost, the levels returning to the abnormal range. In five of six patients whose fibrinolytic activity was within normal limits before treatment, the dilute blood-clot lysis-times were prolonged whilst clofibrate was given; in two patients prolongation was temporary, but in three it persisted. Hence clofibrate has antifibrinolytic properties, which should be taken into account if the drug is given to patients with coronary-artery disease before the results of controlled trials of its use in this condition become known.
Sum ary
lipids, clofibrate been claimed to exert a favourable the so-called " thrombogenic abnormalities "
BESIDES reducing (’Atromid-S ’) has
influence
on
Introduction cholesterol and other
Mean serum-cholesterol, platelet stickiness, plasma-fibrinogen, and dilute blood-clot lysis-time of patients 1-8.
1008 EFFECT
OF
CLOFIBRATE
ON :
(a)
SERUM-CHOLESTEROL STICKINESS
I.H.D. = Ischaemic heart-disease.
(rilg. 1 OO ml.), (b) PLASMA-FIBRINOGEN (mg.(100 ml.), (c) (%), AND (d) B.L.T. (hr.)
M.l.=Myocardial infarction.
with clofibrate in three patients (2,4, and 7), and little affected in one (no. 3), reduced towards the end of treatment in three (5, 6 and 8), and temporarily reduced at months 4 and 5 in patient 1.The variability of response among the patients accounts for the gradual fall of the mean plasma-fibrinogen level shown in the figure. Thus clofibrate appreciably reduced the fibrinogen levels of only three of the eight patients, but it should be noted that these were three of the five patients whose control levels were raised above 300 mg. per 100 ml., the upper limit of normal, and that in the remainder plasmafibrinogen was within normal limits before treatment was started. In this connection, Cotton and Wade (1963) observed that clofibrate plus androsterone (’ Atromid ’) reduced plasma-fibrinogen in thirteen of fourteen patients, most of whom had raised levels of this protein, though the effect seemed to tail off after 4 months’ treatment. The long-term effect of clofibrate on plasma-fibrinogen needs further study, but it seems somewhat less effective in this respect than phenformin or metformin combined with
treatment
ethyloestrenol (Fearnley, Chakrabarti,
and
Hocking 1967).
Platelet Stickiness
Except in patient 3 who showed no change, platelet stickiness was appreciably reduced in the remaining patients for varying periods between months 2 and 6, after which most of the effect of the drug in this respect was lost, the percentage platelet stickiness returning to the abnormal range of 40-50%by the 6th or 7th month of treatment (see table). This is reflected by the change of mean platelet stickiness (see figure), from the control level of 54%, to
I.L.D. = IschaE:mic limb disease.
PLATELET
*=Died.
months 2 and 3, after which the level rose to reach month 7-i.e., about 6% lower than it was before clofibrate was given. Clofibrate plus androsterone (atromid) was found by Carson et al. (1963) to reduce platelet stickiness to glass in eighteen of nineteen males with ischaemic heart-disease who were given this drug for 1 month. Symons et al. (1964) gave atromid and atromid-S each for a period of 2 months to six patients with ischxmic heart-disease and found that both drugs reduced platelet stickiness to glass. Carson et al. (1966) studied thirty-five men with ischsemic heart-disease who received atromid and atromid-S for periods of 2 months at a time, and concluded that whilst both drugs reduced platelet stickiness, atromid was more effective than atromid-S in this respect. In none of these series was either agent given for more than 2 months. Our results confirm that clofibrate reduces platelet stickiness to glass, but indicate that most of this effect is lost after a few months’ treatment and that any effect remaining after 6 months is of little consequence. This finding underlines the necessity of long-term investigations of the effects of drugs intended for long-term treatment.
32% 47%
at
at
Fibrinolysis The
B.L.T.S of two patients (1 and 2) were at or near the limit of measurement (24 hours) before clofibrate upper was started, and they remained essentially unaltered throughout the trial. The B.L.T.S of the remaining patients were within the normal range (i.e., 7 hours before treatment) and all but one (in no. 4) were appreciably prolonged whilst clofibrate was given. In two patients
1009
(3 and 8) the B.L.T. was prolonged throughout treatment and in patient 3, who survived, it was reduced after clofibrate was discontinued. In patient 5, despite fluctuations, the B.L.T. was prolonged, compared with its control level, and with the levels after the drug was discontinued, more often than not during treatment with clofibrate. In patients 6 and 7 the B.L.T. was elevated for 3 and 6 months, respectively, and returned to near the control levels before clofibrate was stopped. Thus, of the six patients whose B.L.T.s were within the normal range before treatment was started, five had prolonged B.L.T.s while on clofibrate; in three this effect seemed to be sustained and in two it was temporary. These changes are reflected in the figure by the rise of the mean B.L.T. whilst clofibrate was given and its fall when the drug was stopped. Using a different method, the euglobulin lysis-time, Sweet et al. (1965) found clofibrate to have no effect on fibrinolytic activity in fifteen patients, but treatment was given for only 1-2 months. In contrast to our findings with clofibrate alone, clofibrate plus androsterone gave a temporary reduction of the B.L.T. in arteriopathic patients (Fearnley 1963, Hocking, Chakrabarti, Evans, and Fearnley 1967). That atromid and atromid-S should have opposite effects on fibrinolytic activity, as judged by the B.L.T., can probably be ascribed to the presence and absence of androsterone respectively. Anabolic steroids alone (e.g., ethyloestrenol) taken by mouth temporarily reduce the B.L.T. (Fearnley and Chakrabarti 1964) and the temporary reduction of the B.L.T. by atromid can be attributed to the dose of androsterone the patients were receiving-i.e., 33 mg. daily. Since androsterone is approximately three times as potent on a weight-for-weight basis as ethyloestrenol (Taylor 1968) and since ethylcestrenol 8 mg. daily gives a pronounced, if temporary, reduction of the B.L.T., it is probable that the presence of androsterone in atromid masked the antifibrinolytic properties of clofibrate. Hence removal of androsterone from this preparation has revealed clofibrate as an anti-
1968). Whether the favourable effects of clofibrate on serum-cholesterol and plasma-fibrinogen outweigh its antifibrinolytic properties and temporary influence on platelet stickiness will doubtless be decided by the results of controlled trials now in progress. Meanwhile, if clofibrate is given to patients with coronary-artery disease its apparently adverse influence on fibrinolytic activity should be noted. This work was supported by a grant from the Nuffield Foundation. We thank Dr. R. F. Jarrett for referring some of the patients, Dr. A. Nicol and Miss Esther Gronow for the cholesterol determinations, and Dr. C. C. Downie of Imperial Chemical Industries for supplies of clofibrate. Requests for reprints should be addressed to G. R. F. REFERENCES
Carson, P., McDonald, L., Pickard, S., Pilkington, T., Davies, B., Love, F. (1963) J. Atheroscler. Res. 3, 619. — — — — — — (1966) Br. Heart J. 28, 400. Chakrabarti, R., Fearnley, G. R. (1967) Lancet, ii, 1012. Hocking, E. D., Delitheos, A., Clarke, G. M. (1966) ibid. i, 573. Hocking, E. D., Fearnley, G. R., Mann, R. D., Attwell, T. N., Jackson, D. (1968) ibid. i, 987. Cotton, R. C., Wade, E. C. (1963) J. Atheroscler. Res. 3, 648. Fearnley, G. R. (1963) Lancet, ii, 148. (1964) J. clin. Path. 17, 307. — (1965) Fibrinolysis; p. 174. London. Balmforth, G. V., Fearnley, E. (1957) Clin. Sci. 16, 645. Chakrabarti, R. (1964) J. clin. Path. 17, 328. (1966) Lancet, ii, 757. (1968) ibid. ii, 1004. Hocking, E. D. (1967) ibid. ii, 1008. Hocking, E. D., Chakrabarti, R., Evans, J., Fearnley, G. R. (1967) J. Atheroscler. Res. 7, 121. Sackett, G. E. (1925) J. biol. Chem. 64, 203. Sharp, A. A. (1965) Lancet, ii, 1296. Sweet, B., Rifkind, B. M., McNicol, G. P. (1965) J. Atheroscler. Res. 5, 347. Symons, C., deToszeghi, A., Cook, I. J. Y. (1964) Lancet, ii, 233. Taylor, A. F. (1968) Personal communication. —
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DELAYED HYPERSENSITIVITY TO ENCEPHALITOGENIC PROTEIN IN DISSEMINATED ENCEPHALOMYELITIS
P. O. BEHAN
fibrinolytic drug.
N. GESCHWIND
Discussion
M.B. Leeds
M.D. Harvard
Our results confirm that clofibrate substantially reduces serum-cholesterol. Of the three " thrombogenic abnormalities studied, only plasma-fibrinogen was favourably influenced by clofibrate to any extent. Although clofibrate reduced platelet stickiness the long-term results were unimpressive, most of its influence being lost after 4-6 months’ treatment when the levels were once more abnormal. The effect of clofibrate on platelet stickiness is, therefore, inferior to that of phenformin plus ethyloestrenol which, besides increasing fibrinolytic activity and reducing plasma-fibrinogen and serum-cholesterol (Fearnley, Chakrabarti, and Hocking 1967), gives a pronounced reduction of platelet stickiness which is sustained (Chakrabarti and Fearnley 1967, Fearnley and Chakrabarti
INSTRUCTOR
PROFESSOR AND CHAIRMAN
J. B. LAMARCHE
"
1968). An unexpected finding of this investigation was that clofibrate, far from being a fibrinolytic drug, has antifibrinolytic properties. Although the function of natural fibrinolysis as a defence against vascular occlusions (Fearnley 1965) is conjectural, recent evidence points to a greater incidence of low fibrinolytic activity among survivors of heart attacks than among age-matched controls; and a diminishing difference with age in this respect hints at the possibility that defective fibrinolysis may be an adverse influence on the life-expectancy of patients with coronary-artery disease (Chakrabarti, Fearnley et al. 1966, Chakrabarti, Hocking, Fearnley et al.
M.D. Laval ASSISTANT PROFESSOR OF NEUROLOGY AND PATHOLOGY
DEPARTMENT OF BOSTON UNIVERSITY MEDICAL
NEUROLOGY, SCHOOL, BOSTON, MASS.
R. P. LISAK
M. W. KIES Washington
M.D. Columbia
Ph.D. George
RESEARCH ASSOCIATE
SECTION CHIEF
LABORATORY OF CLINICAL
NATIONAL INSTITUTE OF MENTAL
SCIENCE, HEALTH, BETHESDA, MARYLAND
lymphocytes from primary demyelinating
patients with diseases showed significant transformation when stimulated by a pure encephalitogenic myelin basic protein. In addition lymphoblasts undergoing mitosis were found in their peripheral blood. Radioimmunoassay did not reveal any antibody to the encephalitogenic protein. Both the patients had atopic histories, and one had a brother with disseminated sclerosis. Summary
The
two
Introduction
EXPERIMENTAL allergic encephalomyelitis (E.A.E.) is an experimental autoimmune disease of the central nervous system widely studied as a possible model of human demyelinative diseases (Kabat et al. 1947). The experi-