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Effects of probucol on homozygous cases of familial hypercholesterolemia
Atherosclerosis, 48 (1983) 157- 166 Elsevier Scientific Publishers Ireland,
157 Ltd.
ATH 3364
Effects of Probucol on Homozygous Cases of Familial Hypercholesterolemia Akira
Yamamoto
Rikuro
Hayashi
‘, Yuji Matsuzawa Hirobe ‘, Kazuhiko
2, Bun-ichiro 2 and Toshiro
Kishino Kikkawa
3, 3
’National Cardiovascular Center Research Institute, ’ The Second Department of Internal Medicine, Osaka University Hospital, and ‘Sumitomo Hospital, Osaka (Japan)
(Revised,
(Received 23 November, 1982) received 6 January and 8 March, (Accepted 10 March, 1983)
1983)
Summary A marked reduction of serum cholesterol was obtained by treatment with probucol in heterozygous as well as in homozygous cases of familial hypercholesterolemia. A strict dietary regimen (low-fat, low-calories) intensified the hypocholesterolemic effect of the drug. The drug was also useful in diminishing the rebound of serum cholesterol after plasma exchange. Probucol reduced serum triglycerides in heterozygous cases of familial hypercholesterolemia, but there was a slight increase in triglycerides in homozygous cases. Treatment with probucol resulted in the regression of cutaneous and tendon xanthomas. Although it caused a decrease in HDL, it seems to be very effective in the treatment of familial hypercholesterolemia. Key words:
Compactin - Familial hypercholesterolemia - Hyperlipidemia - Plasma cholesterol - Plasma lipids - Plasma lipoproteins - Probucol
Introduction Familial metabolism
hypercholesterolemia (FH) is a hereditary disorder caused by a defect in the low density lipoprotein
Address for correspondence: National Cardiovascular Center
0021-9150/83/$03.00
of plasma lipoprotein (LDL) receptor [1,2].
Akira Yamamoto, M.D., Department of Etiology Research Institute, 5-125, Fujishiro-dai, Suita-shi,
0 1983 Elsevier Scientific
Publishers
Ireland,
Ltd.
and Pathophysiology, Osaka-fu, 565 Japan.
To protect the patients against the critical complications of atherosclerosis and coronary heart disease, it is essential to reduce the serum cholesterol to an optimal level. Cholestyramine resin, clofibrate and nicotinic acid have been used as hypocholesterolemic agents. Although the combination of these drugs is fairly effective with heterozygous cases of FH [3,4], and partially effective with homozygous cases [5], a consistently effective therapy for the latter has yet to be established. Probucol, a sulfur-containing compound, 4,4’-(isopropylidenedithio)bis(2,6-di-tbutylphenol), is a potentially effective drug which can reduce the serum cholesterol level by lo-25% [6-91. Although there is usually a simultaneous decrease in high density lipoprotein (HDL)-cholesterol of the same percentage magnitude as LDLcholesterol, the results of certain studies indicate that the incidence of clinical events in patients with or without coronary heart disease and hypercholesterolemia was reduced by long-term administration of probucol [ 10,111. In this report, we present data showing the change in serum lipids and in xanthomas in 16 patients with heterozygous FH and 9 patients with homozygous FH treated either with probucol alone, with probucol plus strict dietary regimen, or with plasma exchange therapy combined with the administration of probucol or compactin (ML-236B). We compared the cholesterol-lowering effect of probucol and compactin in some of the patients. Subjects of the Study Eight male and 8 female patients with the heterozygous form of FH, aged beween 13 and 64 years, and 4 male and 5 female patients with the homozygous form of FH, were the subjects of the present study (Table 1). The average serum cholesterol in heterozygotes was 372 _+ 59 mg/dl and the daily dose of probucol was 750- 1000 mg. Among the homozygotes, 3 males and 2 females with an initial cholesterol level of 479-754 mg/dl were treated with single drug therapy (probucol7501500 mg/day)
TABLE
1
SUBJECTS
OF THE STUDY
Familial hypercholesterolemia Heterozygote 8 males and 8 females, age: 45.8 f 13.1 years (13 - 64) initial cholesterol level: 372 f 59 mg/dl (292 - 524) dose of probucol: 750 - 1000 mg/day Homozygote (a) treated with probucol and diet 3 males and 2 females, age: 29.8 f 6.3 years (21 - 38) initial cholesterol level: 668 f 112 mg/dl (479 - 754) dose of probucol: 750 - 1500 mg/day (b) combined with intravenous alimentation 9-year-old male, dose of probucol: 500 mg/day (c) combined with plasma exchange 6-, 43- and 45-year-old females, dose of probucol: 500 mg/day
(child); 1000 mg/day
(adults)
159
under regular diet or under strict restriction of fat and calories. As for the other 4 homozygous cases: a 9-year-old boy was first treated with intravenous alimentation (IVA) and treatment with probucol was started just after the withdrawal of IVA therapy. Three females (6, 43 and 45 years old) were repeatedly treated wtih plasma exchange at intervals of 2-3 weeks. Compactin (240 mg/day), cholestyramine (4 g before each meal) or probucol (500 mg/day for a child and 1000 mg/day for adults) was given for a period of several months. Methods Serum cholesterol and triglycerides were determined by enzymatic assay. HDLcholesterol was determined by measuring the cholesterol in the supernatant after precipitation of LDL and VLDL by the addition of heparin and Ca” to serum samples according to the method of Burstein et al. [ 121 with modification for routine assay procedure [ 131. Achilles tendon thickness was measured on X-ray film or on Xeroradiogram (Xerox Co.) at the level of the tibiocalcaneal joint. Results (I) Effects of probucol on serum lipid levels in patients with heterozygous FH Administration of probucol resulted in a 15% reduction of serum cholesterol after a month of treatment. After that, the cholesterol level continued to fall slowly and the maximum effect (22% reduction) was obtained after 4-6 months of treatment (Fig. 1). Both HDL- and (LDL + VLDL)-cholesterol decreased almost at the same rate,
2
60 %
4
6
a
10
12 months
1
Fig. 1. Effects of probucol on serum cholesterol level in heterozygous cases of familial hypercholesterolemia.
160
except in a few cases where the reduction rate of HDL-cholesterol exceeded that of (LDL + VLDL)-cholesterol. There was a slight decrease in triglycerides: from the level of 138 + 49 mg/dl at the start to 110 + 30 mg/dl after 3-5 months of treatment. (2) Effects of probucol with or without combined dietary regimen on serum lipid levels in homozygous cases of FH In 5 adult patients, the administration of probucol at 1.0 g per day resulted in an 8-26% reduction of serum cholesterol (Table 2). The effect of the drug was much more prominent in two patients who were under a strict dietary regimen (low-fat, low-calorie diet, Fig. 2a, b) than in other patients on regular diets. However, by increasing the dosage of probucol (1.5 g/day), a marked reduction in cholesterol (- 29%) - equal to that obtained under combined dietary and drug therapy - was obtained in a patient on regular diet (Table 2, Patient ST.). In one of the patients, an extremely high dosage of compactin (150 mg/day) with or without cholestyramine caused a significant decrease in serum cholesterol, while the administration of probucol alone at the regular dosage resulted in a comparable or rather more marked effect (Fig. 2a). Probucol was also effective in another patient, for whom compactin was not effective even at very high dosage (Fig. 2b). HDL-cholesterol either did not change or increased slightly with compactin or cholestyramine. Treatment with probucol caused a marked decrease in HDLcholesterol which exceeded the decrease in LDL-cholesterol when expressed as a percentage of the original level. An increase in HDL-cholesterol was observed only
TABLE
2
EFFECTS FAMILIAL
OF PROBUCOL ON SERUM HYPERCHOLESTEROLEMIA
Subjects
Diet
Dose
CHOLESTEROL
IN
HOMOZYGOUS
CASES
Serum cholesterol DWing treatment
Before (mg/dL)
Difference
(mg/dL) M.Y. 38 years, female
low calorie
l.Og
502 f 48(5) a
393 *21
(5)
- 22%
K.N. 28 years, male
low calorie
l.Og l.Ogb
637 f 1l(2) 582k 12(2)
470*31(10) 445k 7 (2)
-26% - 24%
S.T. 2 1 years, female
regular regular
l.Og 1.5 g
744 f 45(4)
623k 8 (5) 526+ 38 (5)
- 16% -29%
K.T. 33 years, male
regular
1.0 g
682 f 57(4)
600*48
- 12%
S.H. 29 years, male
regular
l.Og
478f
438+ 16 (2)
a Number of determinations in parentheses. b Combined therapy with compactin (ML-236B)
150 mg/day.
6(2)
(3)
-8%
OF
161
M.Y. + 38yearold
(FH homoay@e)
I
A
Olobrtyramiru24&y
mJE64
I .2WKcal 3 lsso
K.N.
4
5
6
7
8
9
lo
II
I2
1 1901
2
$ 28yemr old (FH homoq#e)
3
4
6
5
7
B
A-C bypass 696 7ml.
ML-2366 Gqmctin)
15Omg/by PmbuWI
(l&/day)
600.
412 m@ldl
Fig. 2. Effects of diet and drug treatment hypercholesterolemia.
on serum cholesterol
in two adult homozygous
cases of familial
in one patient with a higher pretreatment level of triglycerides. In contrast to heterozygous FH, there was a slight increase in triglycerides in homozygous cases after treatment with probucol. Intravenous alimentation (WA) at relatively low calorie levels (30-40 kcal per kg body weight) caused a marked reduction in serum cholesterol [ 141. A 9-year-old boy (K.M., Fig. 3) weighing 30 kg, was given probucol at 500 mg/day just after the withdrawal of IVA. Although the cholesterol level went up again, it was maintained at 24% below the original level. However, when the drug was stopped once for about
162
K.M., 9-year-old male
100 I
c......;........,..;........,,.:~...,_
&,
9
12
3
&,
9
12
3
month (year)
&I,
9
12
3 09%
Fig. 3. Effects of intravenous alimentation and drug treatment (compactin cholesterol in a 9-year-old boy with homozygous familial hypercholesterolemia.
a month, the serum cholesterol failed to reduce the cholesterol
level increased, and re-institution level to that previously obtained
and probucol)
on serum
of drug treatment (Fig. 3).
(3) Comparison of the effect of compactin and probucol in patients with the homozygous form of FH who were under treatment with plasma exchange. In a 6-year-old girl, a 1 liter plasma exchange was repeated every 1 or 2 weeks. Albumin-electrolyte solution was used as a supplement. Compactin (240 mg/day) for two days followed by a non-treatment day or probucol (500 mg/day) was combined with plasma exchange for the purpose of preventing the rebound in serum cholesterol. Rebound was calculated by subtracting the value of serum cholesterol just after the plasma exchange from the value obtained after 1 or 2 weeks; that is, just before the next exchange (Table 3). Compactin suppressed the rebound of cholesterol by 21-249~ and probucol by 11%. Cholestyramine and probucol were administered to another patient (a 43-year-old female). The rebound of cholesterol in the 3 weeks after plasma exchange was 354 mg/dl (increment from 260 mg/dl to 614 mg/dl) when cholestyramine alone was administered. When probucol was combined with cholestyramine, the rebound diminished to 302 mg/dl; i.e. a 15% decrease in the rebound compared with cholestyramine alone. The third patient treated with plasma exchange could not tolerate probucol due to bowel discomfort. (4) Regression of cutaneous and tendon xanthomas by use of probucol Achilles tendon thickness was measured before and after 12- 16 months of probucol treatment. There was a significant decrease in thickness in heterozygotes and even in homozygotes (Figs. 4 and 5). Cutaneous xanthomas shrank significantly
163
TABLE
3
EFFECTS OF PROBUCOL AND COMPACTIN ON THE REBOUND OF SERUM CHOLESTEROL AFTER PLASMA EXCHANGE IN A HOMOZYGOUS CASE OF FAMILIAL HYPERCHOLESTEROLEMIA (Y.S., 6-YEAR-OLD GIRL) Interval between PE
Drug
1 week
Compactin 240 mg/day
2 weeks
2 weeks
Compactin 240 mg/day
No. of PE
(2/3)
(2/3)
Probucol 500 mg/day
Serum cholesterol Immediately after PE
concentration Prior to the next Pe
+
6
179f33
320+21
-
5
153+ 16
338+ 18
+ -
10 4
138*28 131+12
375 +43 418f28
+
10
128*22
379 * 39
(mg/dl) Rebound
R mm
20
10
6 Before
16.3k4.2
After
After 14.6k3.5
16.5k4.1
Fig. 4. Regression of tendon familial hypercholesterolemia
xanthomas following
13.6k3.6
as expressed by a change in Achilles tendon treatment with probucol.
thickness
in two adult homozygous patients who were treated with combined probucol therapy as well as in all the patients who were under treatment exchange.
in cases of
dietary and with plasma
Discussion It has been shown that probucol is one of the most effective anti-cholesterolemic agents in patients with primary hypercholesterolemia [6-91. Regression of xanthomas after long-term treatment with probucol has also been reported [ 1%~.Recently Baker
uopua put snoaumn~ 30 uoyssa&~ ampo.rd 01 oslt? mq ‘~omsa~oq~ r.un.xasampal 01 Quo IOU a1qe s! lomqo.rd yl uopmmsqo qau[l pau.~.~guo~ .slInsaJ luasad mg ‘H+J30 u1.103sno%~zowoq ayl yl!~ a~yl~a33aasp.? s! 1ozmqo1d laql pwodal [9[] ‘p2 la
165
xanthomas in FH homozygotes. It was also shown that the hypocholesterolemic effect of the drug is significantly increased when the patient follows a low-fat and low-calorie diet. The hypocholesterolemic effect of probucol is rather slow in its onset compared with the effect of cholestyramine or compactin. This is probably due to the relatively poor rate of absorption of the drug, as well as to a time lag in attaining equilibrium between plasma proteins and the body compartment where the drug is stored. This last could explain the difference in effectiveness of the drug in the 9-year-old boy who was given probucol immediately after IVA treatment and later at the steady state where he consumed the regular diet. Combined drug therapy with unabsorbable ion-exchange resin and either compactin [ 17,181 or probucol [ 191 is now thought to be the most valuable and reasonable treatment for the heterozygous form of FH. However, an extremely large dosage of compactin is necessary for the treatment of the homozygous form because the drug induces hydroxymethylglutaryl CoA reductase in this peculiar disease state where LDL receptors are completely lacking [20]. Plasmapheresis or plasma exchange is now more widely used for FH homozygotes [21,22]. Our present work and the work reported by Stein et al. [22] suggested that probucol is useful in preventing cholesterol rebound after plasma exchange, even if the effect is less than that of compactin at a very high dosage. The increase in triglycerides in homozygous cases of FH is in sharp contrast to the decrease observed in heterozygotes. It was reported that probucol lowers the activity of lipoprotein lipase [23,24] and also that the remnants are retained during treatment with probucol [25]. The delayed clearance of remnant lipoproteins caused by a deficiency in LDL receptor (B/E receptor) probably aggravated the situation in our homozygous cases. It is noteworthy that tendon xanthomas regressed after treatment with probucol. Cutaneous xanthomas are reabsorbed relatively easily; tendon xanthomas are generally more resistant. Whether or not this observation reflects on the vascular deposition of cholesterol can only be conjecture. However, in all patients under treatment with plasma exchange and probucol, there was a decrease in angina1 attacks and an improvement in the treadmill or MacMaster tests. References 1 Brown, MS. and Goldstein, J.L., Familial hypercholesterolemia - Genetic, biochemical and pathophysiologic considerations, Adv. Intern. Med., 20 (1975) 273-296. 2 Goldstein, J.L. and Brown, MS., The LDL receptor locus and the genetics of familial hypercholesterolemia, Ann. Rev. Genet., 13 (1979) 259-289. 3 Kane, J.P., Malloy, M.J., Tun, P. et al., Normalization of low-density lipoprotein levels in heterozygous familial hypercholesterolemia with a combined drug regimen, N. Engl. J. Med., 304 (1981) 25 I-258. 4 Ora, L., Olsson, A.G., Rossner, S. and Carlson, L.A., Cholestyramine, clofibrate and nicotinic acid as single or combined treatment of type IIa and IIb hyperlipoproteinemia, Postgrad. Med. J., 51 (1975) 76-81. 5 Moutafis, C.D., Myant, N.B., Mancini. M. and Oriente, P., Cholestyramine and nicotinic acid in the
166
6 7 8 9 10 11
12 13
14 15
16 17
18
19 20 21 22 23 24
25
treatment of familial hyperbetalipoproteinemia in the homozygous form, Atherosclerosis, 14 (1971) 247-258. Heel, R.C., Brogden, R.N., Speicht, T.M. and Avery, G.S., Probucol - A review of its pharmacological properties and therapeutic use in patients with hypercholesterolemia, Drug, 15 (1978) 409-428. LeLorier, J., DuBreuil-Quidoz, S., Lussier-Cacan, S., Huang, Y.S. and Davignon, J., Diet and probucol in lowering cholesterol concentrations, Arch. Intern. Med., 137 (1977) 1427- 1434. Riesen, W.F., Keller, M. and Mordasini, R., Probucol in hypercholesterolemia - A double blind study, Atherosclerosis, 36 (1980) 201-207. Enjalbert, M., Lussier-Cacan, S., DuBreuil-Quindoz, S., LeLorier, J. and Davignon, J., Usefulness of probucol in treating primary hypercholesterolemia, Can. Med. Ass. J., 123 (1980) 754-757. Miettinen, T.A., Huttunen, J.K., Strandberg, T., Naukkarinen, V., Mattila, S. and Kumlin, T., Lowered HDL cholesterol and incidence of ischemic heart disease, Lancet, ii (198 1) 478. Tedeschi, R.E., Taylor, H.L. and Martz, B.L., Clinical experience of the safety and cholesterol-lowering action of probucol. In: G. Noseda, B. Lewis and R. Paoletti (Eds.), Diet and Drugs in Atherosclerosis, Raven Press, New York, NY, 1980, p. 199-207. Burstein, M. and Scholnick, H.R., Lipoprotein-polyanion-metal interaction, Adv. Lipid Res., I1 (1973) 68-108. Kajikawa, T., Ishiki, R., Nakao, Y. et al., Determination of high-density lipoprotein cholesterol by heparin-Ca++ precipitation and enzymatic measurement, J. Jpn. Atheroscler. Sot., 9 (1981) 393-398 (Abstract in English). Yamamoto, A., Endo, A., Kitano, Y. et al., Two Japanese kindreds of familial hypercholesterolemia including homozygous cases, Jpn. J. Med., 17 (1978) 230-239. Harris, Jr., R.S., Gilmore, III, H.R., Bricker, L.A., Kiem, I.M. and Rubin, E., Long-term oral administration of probucol (DH-581) in the management of hypercholesterolemia, J. Amer. Geriat. Sot., 22 (1974) 167-175. Baker, S.G., Joffe, B.I., Mendelsohn, D. and Seftel, H.C., Treatment of homozygous familial hypercholesterolemia with probucol, S. Afr. Med. J., 62 (1982) 7-I 1, Kovanen, P.T., Bilheimer, D.W., Goldstein, J.L., Jaramillo, J.J. and Brown, M.S., A regulatory role for hepatic low density lipoprotein receptors in vivo in the dog, Proc. Nat. Acad. Sci. (USA), 78 (1981) 1194-1198. Yamamoto, A., Yamamura, T., Yokoyama, S., Sudo, H. and Matsuzawa, Y., Effect of combined drug regimen, cholestyramine and compactin, on heterozygous familial hypercholesterolemia, Int. J. Clin. Pharmacol. Ther. Toxicol., In press. Pasquali, R., Biso, P., Papenti, M. and Miichonda, N., Combined effects of probucol and cholestyramine in familial type II hyperlipoproteinemia, Lancet, i (1981) 1368. Yamamoto, A., Sudo, H. and Endo, A., Therapeutic effects of ML-236B in primary hypercholesterolemia, Atherosclerosis, 35 (1980) 259-266. Thompson, G.R., Plasma exchange for hypercholesterolemia - A therapeutic mode and investigative tool (Review), Plasma Ther., 1 (1980) 5- 15. Stein, E.A., Glueck, C.J., Wesselman, A. et al., Repetitive intermittent flow plasma exchange in patients with severe hypercholesterolemia, Atherosclerosis, 38 (1981) 149- 164. Miettinen, T.A., Mode of action of a new hypocholesterolemic drug (DH-581) in familial hypercholesterolemia, Atherosclerosis, 15 (1972) 163- 176. Strandberg, T., Kuusi, T., Tilvis, R. and Miettinen, T.A., Effect of probucol on cholesterol synthesis, plasma lipoproteins and the activities of lipoprotein and hepatic lipase in the rat, Atherosclerosis, 40 (1981) 193-201. Oppel, J.J. and Bahler, R., Ultracentrifugal study of metabolic effects of probucol - Plasma lipoproteins in patients with proven coronary artery disease, Artery, 10 (1982) 108- 130.
157 Ltd.
ATH 3364
Effects of Probucol on Homozygous Cases of Familial Hypercholesterolemia Akira
Yamamoto
Rikuro
Hayashi
‘, Yuji Matsuzawa Hirobe ‘, Kazuhiko
2, Bun-ichiro 2 and Toshiro
Kishino Kikkawa
3, 3
’National Cardiovascular Center Research Institute, ’ The Second Department of Internal Medicine, Osaka University Hospital, and ‘Sumitomo Hospital, Osaka (Japan)
(Revised,
(Received 23 November, 1982) received 6 January and 8 March, (Accepted 10 March, 1983)
1983)
Summary A marked reduction of serum cholesterol was obtained by treatment with probucol in heterozygous as well as in homozygous cases of familial hypercholesterolemia. A strict dietary regimen (low-fat, low-calories) intensified the hypocholesterolemic effect of the drug. The drug was also useful in diminishing the rebound of serum cholesterol after plasma exchange. Probucol reduced serum triglycerides in heterozygous cases of familial hypercholesterolemia, but there was a slight increase in triglycerides in homozygous cases. Treatment with probucol resulted in the regression of cutaneous and tendon xanthomas. Although it caused a decrease in HDL, it seems to be very effective in the treatment of familial hypercholesterolemia. Key words:
Compactin - Familial hypercholesterolemia - Hyperlipidemia - Plasma cholesterol - Plasma lipids - Plasma lipoproteins - Probucol
Introduction Familial metabolism
hypercholesterolemia (FH) is a hereditary disorder caused by a defect in the low density lipoprotein
Address for correspondence: National Cardiovascular Center
0021-9150/83/$03.00
of plasma lipoprotein (LDL) receptor [1,2].
Akira Yamamoto, M.D., Department of Etiology Research Institute, 5-125, Fujishiro-dai, Suita-shi,
0 1983 Elsevier Scientific
Publishers
Ireland,
Ltd.
and Pathophysiology, Osaka-fu, 565 Japan.
To protect the patients against the critical complications of atherosclerosis and coronary heart disease, it is essential to reduce the serum cholesterol to an optimal level. Cholestyramine resin, clofibrate and nicotinic acid have been used as hypocholesterolemic agents. Although the combination of these drugs is fairly effective with heterozygous cases of FH [3,4], and partially effective with homozygous cases [5], a consistently effective therapy for the latter has yet to be established. Probucol, a sulfur-containing compound, 4,4’-(isopropylidenedithio)bis(2,6-di-tbutylphenol), is a potentially effective drug which can reduce the serum cholesterol level by lo-25% [6-91. Although there is usually a simultaneous decrease in high density lipoprotein (HDL)-cholesterol of the same percentage magnitude as LDLcholesterol, the results of certain studies indicate that the incidence of clinical events in patients with or without coronary heart disease and hypercholesterolemia was reduced by long-term administration of probucol [ 10,111. In this report, we present data showing the change in serum lipids and in xanthomas in 16 patients with heterozygous FH and 9 patients with homozygous FH treated either with probucol alone, with probucol plus strict dietary regimen, or with plasma exchange therapy combined with the administration of probucol or compactin (ML-236B). We compared the cholesterol-lowering effect of probucol and compactin in some of the patients. Subjects of the Study Eight male and 8 female patients with the heterozygous form of FH, aged beween 13 and 64 years, and 4 male and 5 female patients with the homozygous form of FH, were the subjects of the present study (Table 1). The average serum cholesterol in heterozygotes was 372 _+ 59 mg/dl and the daily dose of probucol was 750- 1000 mg. Among the homozygotes, 3 males and 2 females with an initial cholesterol level of 479-754 mg/dl were treated with single drug therapy (probucol7501500 mg/day)
TABLE
1
SUBJECTS
OF THE STUDY
Familial hypercholesterolemia Heterozygote 8 males and 8 females, age: 45.8 f 13.1 years (13 - 64) initial cholesterol level: 372 f 59 mg/dl (292 - 524) dose of probucol: 750 - 1000 mg/day Homozygote (a) treated with probucol and diet 3 males and 2 females, age: 29.8 f 6.3 years (21 - 38) initial cholesterol level: 668 f 112 mg/dl (479 - 754) dose of probucol: 750 - 1500 mg/day (b) combined with intravenous alimentation 9-year-old male, dose of probucol: 500 mg/day (c) combined with plasma exchange 6-, 43- and 45-year-old females, dose of probucol: 500 mg/day
(child); 1000 mg/day
(adults)
159
under regular diet or under strict restriction of fat and calories. As for the other 4 homozygous cases: a 9-year-old boy was first treated with intravenous alimentation (IVA) and treatment with probucol was started just after the withdrawal of IVA therapy. Three females (6, 43 and 45 years old) were repeatedly treated wtih plasma exchange at intervals of 2-3 weeks. Compactin (240 mg/day), cholestyramine (4 g before each meal) or probucol (500 mg/day for a child and 1000 mg/day for adults) was given for a period of several months. Methods Serum cholesterol and triglycerides were determined by enzymatic assay. HDLcholesterol was determined by measuring the cholesterol in the supernatant after precipitation of LDL and VLDL by the addition of heparin and Ca” to serum samples according to the method of Burstein et al. [ 121 with modification for routine assay procedure [ 131. Achilles tendon thickness was measured on X-ray film or on Xeroradiogram (Xerox Co.) at the level of the tibiocalcaneal joint. Results (I) Effects of probucol on serum lipid levels in patients with heterozygous FH Administration of probucol resulted in a 15% reduction of serum cholesterol after a month of treatment. After that, the cholesterol level continued to fall slowly and the maximum effect (22% reduction) was obtained after 4-6 months of treatment (Fig. 1). Both HDL- and (LDL + VLDL)-cholesterol decreased almost at the same rate,
2
60 %
4
6
a
10
12 months
1
Fig. 1. Effects of probucol on serum cholesterol level in heterozygous cases of familial hypercholesterolemia.
160
except in a few cases where the reduction rate of HDL-cholesterol exceeded that of (LDL + VLDL)-cholesterol. There was a slight decrease in triglycerides: from the level of 138 + 49 mg/dl at the start to 110 + 30 mg/dl after 3-5 months of treatment. (2) Effects of probucol with or without combined dietary regimen on serum lipid levels in homozygous cases of FH In 5 adult patients, the administration of probucol at 1.0 g per day resulted in an 8-26% reduction of serum cholesterol (Table 2). The effect of the drug was much more prominent in two patients who were under a strict dietary regimen (low-fat, low-calorie diet, Fig. 2a, b) than in other patients on regular diets. However, by increasing the dosage of probucol (1.5 g/day), a marked reduction in cholesterol (- 29%) - equal to that obtained under combined dietary and drug therapy - was obtained in a patient on regular diet (Table 2, Patient ST.). In one of the patients, an extremely high dosage of compactin (150 mg/day) with or without cholestyramine caused a significant decrease in serum cholesterol, while the administration of probucol alone at the regular dosage resulted in a comparable or rather more marked effect (Fig. 2a). Probucol was also effective in another patient, for whom compactin was not effective even at very high dosage (Fig. 2b). HDL-cholesterol either did not change or increased slightly with compactin or cholestyramine. Treatment with probucol caused a marked decrease in HDLcholesterol which exceeded the decrease in LDL-cholesterol when expressed as a percentage of the original level. An increase in HDL-cholesterol was observed only
TABLE
2
EFFECTS FAMILIAL
OF PROBUCOL ON SERUM HYPERCHOLESTEROLEMIA
Subjects
Diet
Dose
CHOLESTEROL
IN
HOMOZYGOUS
CASES
Serum cholesterol DWing treatment
Before (mg/dL)
Difference
(mg/dL) M.Y. 38 years, female
low calorie
l.Og
502 f 48(5) a
393 *21
(5)
- 22%
K.N. 28 years, male
low calorie
l.Og l.Ogb
637 f 1l(2) 582k 12(2)
470*31(10) 445k 7 (2)
-26% - 24%
S.T. 2 1 years, female
regular regular
l.Og 1.5 g
744 f 45(4)
623k 8 (5) 526+ 38 (5)
- 16% -29%
K.T. 33 years, male
regular
1.0 g
682 f 57(4)
600*48
- 12%
S.H. 29 years, male
regular
l.Og
478f
438+ 16 (2)
a Number of determinations in parentheses. b Combined therapy with compactin (ML-236B)
150 mg/day.
6(2)
(3)
-8%
OF
161
M.Y. + 38yearold
(FH homoay@e)
I
A
Olobrtyramiru24&y
mJE64
I .2WKcal 3 lsso
K.N.
4
5
6
7
8
9
lo
II
I2
1 1901
2
$ 28yemr old (FH homoq#e)
3
4
6
5
7
B
A-C bypass 696 7ml.
ML-2366 Gqmctin)
15Omg/by PmbuWI
(l&/day)
600.
412 m@ldl
Fig. 2. Effects of diet and drug treatment hypercholesterolemia.
on serum cholesterol
in two adult homozygous
cases of familial
in one patient with a higher pretreatment level of triglycerides. In contrast to heterozygous FH, there was a slight increase in triglycerides in homozygous cases after treatment with probucol. Intravenous alimentation (WA) at relatively low calorie levels (30-40 kcal per kg body weight) caused a marked reduction in serum cholesterol [ 141. A 9-year-old boy (K.M., Fig. 3) weighing 30 kg, was given probucol at 500 mg/day just after the withdrawal of IVA. Although the cholesterol level went up again, it was maintained at 24% below the original level. However, when the drug was stopped once for about
162
K.M., 9-year-old male
100 I
c......;........,..;........,,.:~...,_
&,
9
12
3
&,
9
12
3
month (year)
&I,
9
12
3 09%
Fig. 3. Effects of intravenous alimentation and drug treatment (compactin cholesterol in a 9-year-old boy with homozygous familial hypercholesterolemia.
a month, the serum cholesterol failed to reduce the cholesterol
level increased, and re-institution level to that previously obtained
and probucol)
on serum
of drug treatment (Fig. 3).
(3) Comparison of the effect of compactin and probucol in patients with the homozygous form of FH who were under treatment with plasma exchange. In a 6-year-old girl, a 1 liter plasma exchange was repeated every 1 or 2 weeks. Albumin-electrolyte solution was used as a supplement. Compactin (240 mg/day) for two days followed by a non-treatment day or probucol (500 mg/day) was combined with plasma exchange for the purpose of preventing the rebound in serum cholesterol. Rebound was calculated by subtracting the value of serum cholesterol just after the plasma exchange from the value obtained after 1 or 2 weeks; that is, just before the next exchange (Table 3). Compactin suppressed the rebound of cholesterol by 21-249~ and probucol by 11%. Cholestyramine and probucol were administered to another patient (a 43-year-old female). The rebound of cholesterol in the 3 weeks after plasma exchange was 354 mg/dl (increment from 260 mg/dl to 614 mg/dl) when cholestyramine alone was administered. When probucol was combined with cholestyramine, the rebound diminished to 302 mg/dl; i.e. a 15% decrease in the rebound compared with cholestyramine alone. The third patient treated with plasma exchange could not tolerate probucol due to bowel discomfort. (4) Regression of cutaneous and tendon xanthomas by use of probucol Achilles tendon thickness was measured before and after 12- 16 months of probucol treatment. There was a significant decrease in thickness in heterozygotes and even in homozygotes (Figs. 4 and 5). Cutaneous xanthomas shrank significantly
163
TABLE
3
EFFECTS OF PROBUCOL AND COMPACTIN ON THE REBOUND OF SERUM CHOLESTEROL AFTER PLASMA EXCHANGE IN A HOMOZYGOUS CASE OF FAMILIAL HYPERCHOLESTEROLEMIA (Y.S., 6-YEAR-OLD GIRL) Interval between PE
Drug
1 week
Compactin 240 mg/day
2 weeks
2 weeks
Compactin 240 mg/day
No. of PE
(2/3)
(2/3)
Probucol 500 mg/day
Serum cholesterol Immediately after PE
concentration Prior to the next Pe
+
6
179f33
320+21
-
5
153+ 16
338+ 18
+ -
10 4
138*28 131+12
375 +43 418f28
+
10
128*22
379 * 39
(mg/dl) Rebound
R mm
20
10
6 Before
16.3k4.2
After
After 14.6k3.5
16.5k4.1
Fig. 4. Regression of tendon familial hypercholesterolemia
xanthomas following
13.6k3.6
as expressed by a change in Achilles tendon treatment with probucol.
thickness
in two adult homozygous patients who were treated with combined probucol therapy as well as in all the patients who were under treatment exchange.
in cases of
dietary and with plasma
Discussion It has been shown that probucol is one of the most effective anti-cholesterolemic agents in patients with primary hypercholesterolemia [6-91. Regression of xanthomas after long-term treatment with probucol has also been reported [ 1%~.Recently Baker
uopua put snoaumn~ 30 uoyssa&~ ampo.rd 01 oslt? mq ‘~omsa~oq~ r.un.xasampal 01 Quo IOU a1qe s! lomqo.rd yl uopmmsqo qau[l pau.~.~guo~ .slInsaJ luasad mg ‘H+J30 u1.103sno%~zowoq ayl yl!~ a~yl~a33aasp.? s! 1ozmqo1d laql pwodal [9[] ‘p2 la
165
xanthomas in FH homozygotes. It was also shown that the hypocholesterolemic effect of the drug is significantly increased when the patient follows a low-fat and low-calorie diet. The hypocholesterolemic effect of probucol is rather slow in its onset compared with the effect of cholestyramine or compactin. This is probably due to the relatively poor rate of absorption of the drug, as well as to a time lag in attaining equilibrium between plasma proteins and the body compartment where the drug is stored. This last could explain the difference in effectiveness of the drug in the 9-year-old boy who was given probucol immediately after IVA treatment and later at the steady state where he consumed the regular diet. Combined drug therapy with unabsorbable ion-exchange resin and either compactin [ 17,181 or probucol [ 191 is now thought to be the most valuable and reasonable treatment for the heterozygous form of FH. However, an extremely large dosage of compactin is necessary for the treatment of the homozygous form because the drug induces hydroxymethylglutaryl CoA reductase in this peculiar disease state where LDL receptors are completely lacking [20]. Plasmapheresis or plasma exchange is now more widely used for FH homozygotes [21,22]. Our present work and the work reported by Stein et al. [22] suggested that probucol is useful in preventing cholesterol rebound after plasma exchange, even if the effect is less than that of compactin at a very high dosage. The increase in triglycerides in homozygous cases of FH is in sharp contrast to the decrease observed in heterozygotes. It was reported that probucol lowers the activity of lipoprotein lipase [23,24] and also that the remnants are retained during treatment with probucol [25]. The delayed clearance of remnant lipoproteins caused by a deficiency in LDL receptor (B/E receptor) probably aggravated the situation in our homozygous cases. It is noteworthy that tendon xanthomas regressed after treatment with probucol. Cutaneous xanthomas are reabsorbed relatively easily; tendon xanthomas are generally more resistant. Whether or not this observation reflects on the vascular deposition of cholesterol can only be conjecture. However, in all patients under treatment with plasma exchange and probucol, there was a decrease in angina1 attacks and an improvement in the treadmill or MacMaster tests. References 1 Brown, MS. and Goldstein, J.L., Familial hypercholesterolemia - Genetic, biochemical and pathophysiologic considerations, Adv. Intern. Med., 20 (1975) 273-296. 2 Goldstein, J.L. and Brown, MS., The LDL receptor locus and the genetics of familial hypercholesterolemia, Ann. Rev. Genet., 13 (1979) 259-289. 3 Kane, J.P., Malloy, M.J., Tun, P. et al., Normalization of low-density lipoprotein levels in heterozygous familial hypercholesterolemia with a combined drug regimen, N. Engl. J. Med., 304 (1981) 25 I-258. 4 Ora, L., Olsson, A.G., Rossner, S. and Carlson, L.A., Cholestyramine, clofibrate and nicotinic acid as single or combined treatment of type IIa and IIb hyperlipoproteinemia, Postgrad. Med. J., 51 (1975) 76-81. 5 Moutafis, C.D., Myant, N.B., Mancini. M. and Oriente, P., Cholestyramine and nicotinic acid in the
166
6 7 8 9 10 11
12 13
14 15
16 17
18
19 20 21 22 23 24
25
treatment of familial hyperbetalipoproteinemia in the homozygous form, Atherosclerosis, 14 (1971) 247-258. Heel, R.C., Brogden, R.N., Speicht, T.M. and Avery, G.S., Probucol - A review of its pharmacological properties and therapeutic use in patients with hypercholesterolemia, Drug, 15 (1978) 409-428. LeLorier, J., DuBreuil-Quidoz, S., Lussier-Cacan, S., Huang, Y.S. and Davignon, J., Diet and probucol in lowering cholesterol concentrations, Arch. Intern. Med., 137 (1977) 1427- 1434. Riesen, W.F., Keller, M. and Mordasini, R., Probucol in hypercholesterolemia - A double blind study, Atherosclerosis, 36 (1980) 201-207. Enjalbert, M., Lussier-Cacan, S., DuBreuil-Quindoz, S., LeLorier, J. and Davignon, J., Usefulness of probucol in treating primary hypercholesterolemia, Can. Med. Ass. J., 123 (1980) 754-757. Miettinen, T.A., Huttunen, J.K., Strandberg, T., Naukkarinen, V., Mattila, S. and Kumlin, T., Lowered HDL cholesterol and incidence of ischemic heart disease, Lancet, ii (198 1) 478. Tedeschi, R.E., Taylor, H.L. and Martz, B.L., Clinical experience of the safety and cholesterol-lowering action of probucol. In: G. Noseda, B. Lewis and R. Paoletti (Eds.), Diet and Drugs in Atherosclerosis, Raven Press, New York, NY, 1980, p. 199-207. Burstein, M. and Scholnick, H.R., Lipoprotein-polyanion-metal interaction, Adv. Lipid Res., I1 (1973) 68-108. Kajikawa, T., Ishiki, R., Nakao, Y. et al., Determination of high-density lipoprotein cholesterol by heparin-Ca++ precipitation and enzymatic measurement, J. Jpn. Atheroscler. Sot., 9 (1981) 393-398 (Abstract in English). Yamamoto, A., Endo, A., Kitano, Y. et al., Two Japanese kindreds of familial hypercholesterolemia including homozygous cases, Jpn. J. Med., 17 (1978) 230-239. Harris, Jr., R.S., Gilmore, III, H.R., Bricker, L.A., Kiem, I.M. and Rubin, E., Long-term oral administration of probucol (DH-581) in the management of hypercholesterolemia, J. Amer. Geriat. Sot., 22 (1974) 167-175. Baker, S.G., Joffe, B.I., Mendelsohn, D. and Seftel, H.C., Treatment of homozygous familial hypercholesterolemia with probucol, S. Afr. Med. J., 62 (1982) 7-I 1, Kovanen, P.T., Bilheimer, D.W., Goldstein, J.L., Jaramillo, J.J. and Brown, M.S., A regulatory role for hepatic low density lipoprotein receptors in vivo in the dog, Proc. Nat. Acad. Sci. (USA), 78 (1981) 1194-1198. Yamamoto, A., Yamamura, T., Yokoyama, S., Sudo, H. and Matsuzawa, Y., Effect of combined drug regimen, cholestyramine and compactin, on heterozygous familial hypercholesterolemia, Int. J. Clin. Pharmacol. Ther. Toxicol., In press. Pasquali, R., Biso, P., Papenti, M. and Miichonda, N., Combined effects of probucol and cholestyramine in familial type II hyperlipoproteinemia, Lancet, i (1981) 1368. Yamamoto, A., Sudo, H. and Endo, A., Therapeutic effects of ML-236B in primary hypercholesterolemia, Atherosclerosis, 35 (1980) 259-266. Thompson, G.R., Plasma exchange for hypercholesterolemia - A therapeutic mode and investigative tool (Review), Plasma Ther., 1 (1980) 5- 15. Stein, E.A., Glueck, C.J., Wesselman, A. et al., Repetitive intermittent flow plasma exchange in patients with severe hypercholesterolemia, Atherosclerosis, 38 (1981) 149- 164. Miettinen, T.A., Mode of action of a new hypocholesterolemic drug (DH-581) in familial hypercholesterolemia, Atherosclerosis, 15 (1972) 163- 176. Strandberg, T., Kuusi, T., Tilvis, R. and Miettinen, T.A., Effect of probucol on cholesterol synthesis, plasma lipoproteins and the activities of lipoprotein and hepatic lipase in the rat, Atherosclerosis, 40 (1981) 193-201. Oppel, J.J. and Bahler, R., Ultracentrifugal study of metabolic effects of probucol - Plasma lipoproteins in patients with proven coronary artery disease, Artery, 10 (1982) 108- 130.