Effect of Ciba 13,437-Su on serum cholesterol and triglycerides, plasma fibrinogen, fibrinolysis and platelet adhesiveness in patients with ischemic heart disease

Atherosclerosis Elsevier Publishing

Company,

Amsterdam

- Printed in The Netherlands

EFFECT OF CIBA 13,437-Su ON SERUM CHOLESTEROL AND TRIGLYCERIDES, PLASMA FIBRINOGEN, FIBRINOLYSIS AND PLATELET ADHESIVENESS IN PATIENTS WITH ISCHEMIC

HEART

DISEASE

P. M. MANNUCCI,

F. PARETI,

2nd Institute of Medical Pathology, (Received

C. A. MAGGI

AND M. DIAGUARDI

University of Milan, Milan (Italy)

May 1 lth, 1970)

SUMMARY

The effects of the phenolic ether Ciba 13,437-Su (300 mg daily) on serum cholesterol, triglycerides, plasma fibrinogen, fibrinolysis and platelet adhesiveness were assessed in 10 patients with ischemic heart disease treated for 6 months and observed thereafter for 2 months with a placebo. The administration of the drug was free of appreciable side-effects and no evidence of toxicity was seen, Serum transaminases did not show any significant change. Mean serum cholesterol was reduced by about 20 y0 and serum triglycerides by about 50% after the 1st month of treatment. The decrease was sustained and the levels returned to the high initial values when the placebo was started. A progressive fall of plasma fibrinogen was also observed, attaining the lowest values after 5 months of treatment and reverting to the initial values when the active drug was withdrawn. Fibrinolysis was not favourably influenced by the drug, as seen by the prolongation of the euglobulin lysis time and the increase of plasma plasminogen. Platelet adhesiveness was not significantly changed. Hence Ciba 13,437-Su is an effective and well-tolerated agent with a sustained hypolipidemic action. However, a decrease of fibrinolytic activity during the treatment was observed.

Key words: HyPoliPidemic Thrombogenic

agents - Ischemic

heart disease - Tetraline

derivative

-

parameters

INTRODUCTION

It has been recently

shown in preliminary

clinical

trialsr-a,

Atherosclerosis,

that the 1971, 13: 14

2

P. M. MANNUCCI, F. PARETI, C. A. MAGGI, M. DIAGUARDI

administration

of

the

phenolic

thy+phenoxyjpropionic

acid

ether

(Ciba

man. The drug was very well tolerated of 4-10

2-methyl-o-2[$-(1,2,3,4-tetrahydro-l-naph-

13,437-Su)

mg/kg in all types of hyperlipidemias et a1.4, although

FREDRICKSON

exerts

a hypolipidemic

and it was found to be effective

the patients

classified

according

with type

effect

in

at daily doses

to the system

II hypercholesterolemia

of re-

sponded to a lesser degree. In the present study the influence of the long-term the serum lipid parameters heart disease treated we have examined “thrombogenic

for 6 months

fibrinolytic

A favorable

interest

action

of a lipid-lowering

with ischemic

thereafter.

Moreover,

of the drug on the so called

(fibrinogen and plasminogen

activity).

the therapeutic

of the drug on

patients

and followed for 2 months

the effect of the oral administration

parameters”

spontaneous enhance

administration

was studied on 10 hyperlipidemic

levels, platelet adhesiveness, on these tests

would greatly

drug in patients

with ischemic

heart disease. PATIENTS AND METHODS Ten patients,

3 women and 7 men, agreed to take part in the trial. Four had in

the past one or more episodes

of myocardial

effort and signs of myocardial

ischemia

The patients

infarction,

in the resting

were not taking oral anticoagulants

6 presented

or exercise

in 8 patients

The patients

and were at borderline

occasion

at the end of which time placebo tablets

were given for 2 months.

Six patients

at the end of the 3rd month

instructions

serum triglycerides

levels in the remaining

2.

received the drug in a dosage of 300 mg daily in three divided oral

doses before meals for 6 months, appearance

of

or other drugs which are known

to effect serum lipid levels. All had high levels of serum cholesterol; were increased

with angina

ECG.

were given

defaulted

but thereafter

to the patients

regarding

of identical

from examination

attended

regularly.

food intake

during

on one

No special the whole

period of the trial. Baseline plasminogen, aminases

values of serum cholesterol, platelet

(SGPT

adhesiveness

and SGOT)

different determinations patients tests

and alkaline

phosphatase,

carried out at fortnight

interval

plasma fibrinogen

monthly,

phosphatase

and for 2 months

was repeated

Other parameters

were obtained

hemoglobin

bilirubin;

serum protein

from two

in the morning at 11 a.m. on was started,

these

the drug was discontinued.

only at the end of the 4th and the 6th month.

were additionally

including

after

and

lysis time, serum trans-

who had been fasting for at least 12 h. After the treatment

were repeated

Alkaline

serum triglycerides,

to glass and euglobulin

levels, leucocyte

observed before and throughout and platelet

counts;

treatment,

serum urea, glucose and

electrophoresis.

Blood pressure

and body weight were also

was estimated

by the method

of ZLATKIS et a1.2; serum

recorded. Serum triglycerides

cholesterol according

to EGGSTEIN AND KREUTZ~; euglobulinlysistime was meas-

ured by the method of VON Atherosclerosis,

1971, 13: l-8

KAULLA

AND SCHULTZ~, as described by CHAKRABARTI

1

13,437-SU

ON

THE

MAIN

VARIABLES

INVESTIGATED

2

3

1

No.

64

67

43

Age

MI

MI

MI

M

M

IHD

IHD

Diagnosis

M

F

M

Ser

500 115 340 38

315 174 430 104 70 19

: :

: c d ;

227 327

FJ

345 175

:

350 59

30 86

F

F

350 326 440 108

: c d

520 98

290 55

F

:

400 90

315 403

:

a b

levels

Control

295 188 490 127 500 66

280 133 470 154 780 54

210 77 380 95 145 29

325 176 430 132 375 68 295 162 430 137 300 49 230 61 470 119 160 22

285 139 440 160 580 51 270 106 490 118 500 48 240 74 490 108 300 41

-

-

-

-

-

235 104 460 120 105 33

230 119 470 127 75 49

-

270 86 430 100 110 52

230 142 430 137 105 33

305 162 330 170 560 68 225 90 340 114 145 22

305 99 430 120 550 25 235 76 350 134 100 44

245 136 310 94 520 22

260 106 300 115 525 71

5

220 128 350 94 370 54

1

225 100 4soa 91 490 50

4

mg daily),

265 119 390 90 340 66

(300

3

13,437~Su

2

Levels on Ciba month:

200 94 360 136 80 38

295 146 410 119 370 34

285 169 480 125 610 28

210 130 430 106 70 30

230 130 320 94 450 66

6

Normal values: (a) serum cholesterol (150-250 mg/lOO ml); (b) serum triglycerides (74-174 mg/lOO ml); (c) plasma fibrinogen (d) plasma plasminogen (SO-120% of average normal plasma); (e) euglobulin lysis time (55-300 min); (f) platelet adhesiveness SGOT (< 20 mU./ml); alkaline phosphatase (< 25 mU./ml). IHD = ischaemic heart disease. M.I. = myocardial infarction.

EFFECT OF CIBA

TABLE

325 262 460 135 210 57 345 167 530 102 170 39

335 125 390 113 140 40

195 6608 130 310 76

w

%I m

g

u

:

! i;

;; G

90 25 345

g

2 F;

2

Y rln d

G “A

::

R ;;1

&

355 167 540 138 460 33

365 206 520 140 280 22

M

z

262 480 102

305 204 380 118 340 66

305 248 410 104

ml); and

360

8

7

Levels on placebo, month:

(200-400 mg/lOO (24-58 %); SGPT

F

48

S.D.)

IHD

F

51

Mean values (f

IHD

M

32

IHD

MI

M

50

IHD

F

40

270 217 270 101 250 45 325 157 300 108 110 70 280 242 380 101 84 31 332 k?’

; c d : ; c d ; ; c d : a b

(&lOS) 101 I&?

d e

c

210 42

:

317 295

E 460 104

115 40

i

ii

630 87

500 203

:

a b

320 120 440 119 130 45 225 202 400 170 390 50 245 130 290 130 490 59 225 89 280 134 240 57 240 86 5008 143 270 48

350 126 500 115 170 56 225 180 410 122 230 52 240 133 280 108 465 46 230 77 330 112 205 64 275 123 430 137 205 -

280 52 310 130 340 47 280 141 460 145 100 61

-

-

-

-

245 121 390 115 650 60

245 121 320 134 356 71

215 134 290 119 530 52

320 97 490 122 210 55

350 121 520 134 130 60

280 129 380 174 250 65

220 76 280 122 145 36

220 133 310 122 655 53

205 119 330 127 390 72

345 110 500 106 200 57

235 108 410 132 70 56

(113)

($89)

#4’

‘1:;

19)

332 (+531 215 f&W

315 273 450 142 100 50

290 150 300 120 110 50

275 200 330 113 460 30

205 151 320 115 690 49 250 60 330 132 150 50

210 50

290 291 450

460 220 700 114 80 43

190 149 390 127 580 56

375 114 400 108 160 32

(115)

325 162 460 120 85 35

345 181 390 114 120 48

275 180 340 118 320 39

310 226 470 118 190 34

470 218 660 so 70 54

EFFECTS

OF 13,437~%I

IN PATIENTS

WITH

ISCHEMIC

HEART

ClBA

DISEASE

13,437~Su

5

101 ng t.i.d.

I

460

420

380 i

I

1 I

130

120 -

110loo370,

I

Prmtr. valrs Fig.

I

l“month2

I

I

I

1

I

I

1

4

5

E

Pll

PL2

1.

Atherosclerosis,

1971,

13: 1-8

6

P. M. MANNUCCI,F. PARETI, C. A. MAGGI, M. DIAGUARDI

et al.8 with automatic

recording

Recorder,

Carmanan

Instr.

hesiveness

to glass was that of SALZMAN9; fibrinogen

with the method described chemical

and reading of the end point (Euglobulin

Ltd.,

Glasgow,

Scotland);

the method

evaluation

to a two way layout.

by an immuno-

on cellulose acetatell.

by the standard

Trans-

Biochemia

Kits.

has been carried out by the analysis of variance according

Means have been compared

The data have been analysed complete

were determined

ad-

gravimetrically

by HARDISTY AND INGRAMIO; plasminogen

aminases and alkaline phosphatase Statistical

for platelet

was estimated

assay based on single radial immunodiffusion

Clot Lysis

with a routine

according

computing

to the Tukey’s

program

method.

for the analysis

of

layouts.

RESULTS The drug was well tolerated constipation

in the first 2 months

by all patients: of treatment,

evidence of toxicity

was apparent

tion of hemoglobin

levels, leucocyte

serum glucose; bilirubin alkaline phosphatase gives

the

levels

throughout

only 2 patients

which subsequently the treatment

and platelet

counts;

and protein electrophoresis.

did not show any significant

of cholesterol,

triglycerides,

plasminogen

and the euglobulin

examination

and the accompanying

complained

of mild

disappeared.

No

from the regular observablood urea nitrogen

In particular, variation

fibrinogen,

SGOT,

(Table

and and

1). The table also

platelet

lysis time in the 10 patients

SGPT

adhesivenesss,

during the period of

figure shows the mean values,

throughout

the

trial (Fig. I). Serum cholesterol The mean serum cholesterol and thereafter

remained

had decreased

practically

(F = 27.35 with 9 and 63 D.o.F.,

were the pretreatment When

The variation

is highly

values attained

was apparent,

significant

showed some reduction

(No. 3, 4 and 10) had a relatively

some scatter

the drug was discontinued,

values within

by 22% after 1 month of treatment

P < 0.001). All the patients

but this varied in degree: 3 patients Over the period of observation

unchanged.

poor response.

but only in Case No. 10

on two occasions. serum cholesterol

rose again to the initial

1 month.

Serum triglycerides A pronounced triglyceride 22.19;

fall, on a percentage

as well as on absolute basis, was found in the

levels during the first 4 weeks with an average

P < 0.001). This was more marked

values and was maintained values reverted

throughout

in the patients

decrease

of 50%

(F =

with the higher baseline

the period of administration

of the drug. The

to the high initial levels after withdrawal.

Plasma jibrinogen The mean value of plasma fibrinogen, Atherosclerosis,

1971, 13: l-8

which was above the normal range before

EFFECTS

OF

treatment,

13,437&I showed

IN PATIENTS

a significant

WITH

ISCHEMIC

reduction

during

HEART

7

DISEASE

the trial

(F = 4.67; P < 0.01).

Only the patients who had increased or borderline levels at the beginning of treatment (6 out of 10) displayed a consistent reduction. The fall of fibrinogen seemed to be rather slow and the maximum effect was not apparent until 5 months had elapsed. Normal fibrinogen levels were not apparently affected by the drug. Plasminogen

level

A significant

and sustained

average increase

of plasminogen

was evident

after

the 1st month and persisted throughout the whole period of treatment (F = 4.43; P < 0.01). Although the mean value showed some decrease when the drug was withdrawn, after the 1st month on placebo it was still significantly higher than the initial level. None of the subjects had high levels at the beginning of the treatment. In 9 cases plasminogen rose beyond the upper normal limit on several occasions during the 6 months normality

of treatment. While in the majority of cases it returned within the range of after the discontinuation of the active drug, in 3 patients (Case No. 3,4 and

10) it was persistently

high during

the placebo

period.

Euglobulin lysis time

The euglobulin lysis time (ELT) of 2 patients (No. 3 and 4) was prolonged before the beginning of the trial; in the remaining 8 it was within the normal range. In all but 1 patient (No. 2) the ELT was appreciably prolonged during the period of treatment: usually

the variation evident

fluctuation

until

was significant

after the 1st month

(F = 3.17; P < 0.01). The prolongation was and persisted thereafter with some

of treatment

the drug was discontinued.

Platelet adhesiveness to glass

One (No. 9) out of 10 patients had high platelet adhesiveness before starting the treatment, another patient (No. 3) had borderline levels. Non significant change was seen in the whole group of subjects (F < 1). The individual values showed some fluctuations, whose clinical significance is uncertain at the moment and might be related

to the methodological

variation.

DISCUSSION

Ciba 13,437~Su, 100 mg t.i.d. was found to be effective in reducing the raised levels of cholesterol and triglycerides in patients with ischemic heart disease over a period of 6 months and the effect was more marked on triglycerides than on cholesterol. The drug was well tolerated and no complaint of appreciable side effects was mentioned by the patients. Although some fluctuations of the serum lipid levels were observed over the period of observation, the effect was sustained and persisted over the 6-month period of observation, the mean values being, at any time, lower than the initial levels, without any evidence of “escape” phenomenon. The mean values rose very rapidly after .4 therosclerosis,

1971,

13: 1-8

P. M. MANNUCCI,F. PARETI, C. A. MAGGI, M. DIAGUARDI

8

withdrawal of the drug, but no rebound effect was noted. These findings confirm those of BEST AND DUNCANI. Of the four thrombogenic parameters, only fibrinogen level was favorably influenced by Ciba 13,437-Su. No significant variation was seen in platelet adhesiveness, whereas euglobulin lysis time was prolonged and plasminogen levels were increased throughout

the period

those obtained

of administration

of the drug. These findings

by CHAKRABARTI et al.12 with clofibrate.

fibrinolytic activity might be regarded ischemic heart disease, where defective adverse influence on survivalIs.

The decrease

are similar

to

of spontaneous

as an unfavorable effect in patients with fibrinolysis has been suggested to have an

Therefore, the advantages of Ciba 13,437-Su over clofibrate seem to be represented by the lower effective dosage, and the absence of variations of serum transaminase. ACKNOWLEDGMENTS We would like to thank

Drs. P. E. Lucchelli

the statistical analysis, Gvendalina assistance. Ciba, Milan, supplied the drug.

Pannelli

and A. Colombi for their advice and and

Bianca

Bottasso

for technical

REFERENCES BEST, M. M. AND C. H. DUNCAN, Preliminary evaluation of the hypolipidemic effects in man of a new phenolic ether (Ciba 13,437-Su), J. Atheroscler. Res., 1969, 10: 103. 2 HARTMANN, G. AND G. FORSTER, Clinical evaluation of a new hypolipidemic drug, Ciba 13,437Su, J. Atheroscler. Res., 1969, 10: 235. 3 WEISS, P., C. A. DUJOVNE, S. MARGOLIS, L. LASAGNA AND J. R. BIANCHINE, Effects of Su13,437 on serum lipids in hyperlipoproteinemic patients, Clin. Pharmacol. Therap., 1970, 11: 90. 4 FREDRICKSON, D. S.. R. J. LEVY AND R. S. LEES, Fat transport in lipoproteins. An integrated approach to mechanisms and disorders, Nezo Engl. J. Med., 1967, 276: 34. 5 ZLATKIS, A., B. ZAK AND A. J. BOYLE, New method for direct determination of serum cholesterol, J. Lab. Clin. Med., 1953, 41: 486. I3 EGGSTEIN, M. AND F. N. KREUTZ, Eine neue Bestimmungsmethode der Neutralfette im Blutserum und Gewebe, Klin. Wochschr., 1966, 44: 262. 7 VON KAULLA, K. N. AND R. L. SCHULTZ, Methods for the evaluation of human fibrinolysis. Studies with two combined techniques, Am. J. Clin. Pathol.. 1958, 29: 104. s CHAKRABARTI, R., M. BIELAWIEC, J. F. EVANS AND G. R. FEARNLEY, Methodological study and a recommended technique for determining the euglobulin lysis time, J. Clin. Pathol., 1968, 21: 698. 9 SALZMAN, E. M., Measurement of platelet adhesiveness. A simple in vitro technique demonstrating an abnormality in Von Willehand’s disease, J. Lab. Cl&. Med., 1963, 62: 724. 10 HARDISTY, R. M. AND G. I. C. INGRAM, Bleeding Disorders: Investigation and Management, Blackwell, Oxford, 1965, p. 293. 11 MANNUCCI, P. M., R. STABILINI, R. BRAGOTTI, B. MARASINI AND A. AGOSTONI, Enzymatic and immunochemical determination of plasminogen/plasmin in different physiological and pathological states, 1971, In press. 12 C
Atherosclerosis,

1971, 13: l-8