Effect of probucol treatment on lipoprotein cholesterol and drug levels in blood and lipoproteins in familial hypercholesterolemia

Fellin, Renato; Gasparotto, A; Valerio, G.; Baiocchi, Maria Rosa; Padrini, Roberto; Lamon, Stacy; Vitale, E.; Baggio, G.; Crepaldi, Gaetano

doi:10.1016/0021-9150(86)90032-8

Cited by 38 publications

(7 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The present results show a rapid increase of CETP activity during probucol treatment; this rise was found to be directly related to the plasma steady-state drug levels. Interestingly, six weeks after drug withdrawal, both plasma probucol levels and CETP activity were still elevated compared to baseline, thus confirming previous data on the very long (47 days) plasma halflife of the drug [34]. Taken together these findings strongly suggest a direct effect of probucol on the CETP, thus confirming preliminary reports showing increased CETP mass after drug treatment [35].…”

Section: Discussionsupporting

confidence: 88%

Probucol increases cholesteryl ester transfer protein activity in hypercholesterolaemic patients

Franceschini

Chiesa

Sirtori

1991

Eur J Clin Investigation

View full text Add to dashboard Cite

Probucol, a widely used lipid lowering drug, reduces both low- and high-density (LDL and HDL) lipoprotein levels and can induce a regression of tissue lipid deposits in both animals and man. The suggested mechanism(s) involve the prevention of LDL oxidative modifications and, possibly, an improvement in the reverse cholesteryl ester transport system. Probucol administration to 10 hypercholesterolaemic patients increased the activity of the cholesteryl ester transfer protein (CETP) by 50%. The rise of CETP activity was significantly related with the plasma steady-state drug levels (r = 0.51, P less than 0.005), thus suggesting that probucol may directly stimulate CEPT synthesis and/or release. Furthermore, CETP activity was inversely related with HDL-cholesterol levels, both in the whole series of 10 patients (r = -0.56, P less than 0.001) and, more so, in the single individuals (r between -0.77 and -0.97), thus suggesting that the reduction of plasma HDL-cholesterol levels is a direct consequence of CETP stimulation. These findings support the hypothesis that an improvement in the reverse cholesteryl ester transport is a major mechanism of probucol and that this may explain the drug induced plasma lipoprotein changes.

show abstract

Section: Discussionsupporting

confidence: 88%

Probucol increases cholesteryl ester transfer protein activity in hypercholesterolaemic patients

Franceschini

Chiesa

Sirtori

1991

Eur J Clin Investigation

View full text Add to dashboard Cite

show abstract

“…The percentage of probucol in LDL was 69.2% ± 11.0% in plasma. The mean plasma concentration of probucol in group B rabbits is just near the level of that in human patients who are treated with probucol for a long time with a standard administration schedule (16,34). The probucol level in LDL was significantly higher than in plasma, suggesting that high levels of this drug accumulate in lipoprotein particles.…”

Section: Resultsmentioning

confidence: 78%

Probucol prevents the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbit, an animal model for familial hypercholesterolemia.

Kita¹,

Nagano²,

Yokode³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

765

296

View full text Add to dashboard Cite

In this study, we questioned whether in vivo probucol could prevent the progression of atherosclerosis in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for familial hypercholesterolemia. At 2 months of age, eight WHHL rabbits were divided into two groups. Group A (n = 4) was fed standard rabbit chow for 6 months. Group B (n = 4) was fed standard rabbit chow containing 1% probucol for 6 months. At the end of the experiments, average plasma concentrations of cholesterol were 704 ± 121 mg/dl in group A and 584 ± 61 mg/dl in group B, respectively. The percentage of surface area of total thoracic aorta with visible plaques in group A versus group B was 54.2% ± 18.8% versus 7.0% ± 6.3%, respectively. What was noteworthy was that the percentage of plaque in the descending thoracic aorta was almost negligible (0.2% ± 0.2%) in group B rabbits compared to that in group A rabbits (41.1% + 20.2%). Low density lipoproteins (LDL) isolated from WHHL rabbits under treatment with probucol (group B) were shown to be highly resistant to oxidative modification by cupric ion and to be minimally recognized by macrophages. On the contrary, LDL from group A rabbits incubated with cupric ion showed a 7.4-fold increase in peroxides (thiobarbituric acidreactive substances) and a 4.3-fold increase in the synthesis of cholesteryl ester in macrophages compared to those of LDL from group B rabbits. Thus, probucol could definitely prevent the progression of atherosclerosis in homozygous WHHL rabbits in vivo by limiting oxidative LDL modification and foam cell transformation of macrophages.Familial hypercholesterolemia (FH) is one of the most common human genetic diseases. Homozygous FH patients have inherited allelic mutations in the gene specifying the low density lipoprotein (LDL) receptor located on the cell surface (1). In these patients, few or no functional LDL receptors are synthesized in the body. As a result, not only impairment of catabolism but also overproduction of LDL occurs in FH homozygotes, subsequently leading to a 6-fold to 8-fold increase in plasma LDL levels before birth (1-3). Elevation of plasma levels of LDL leads to characteristic xanthoma formation in tendons and skin and accelerated atherosclerosis (4). Symptomatic coronary atherosclerosis typically develops before the age of 20 years in homozygous FH patients (5). To protect FH patients against atherosclerosis including coronary artery disease, it is necessary to reduce the plasma levels of LDL to as normal a level as possible. In FH homozygotes, liver transplantation is the only treatment so far (6), and plasmapheresis and the portal-caval shunt operation are partially successful (5, 7). None of the antilipidemic drugs is effective in homozygous FH patients.The foam cell has been recognized as a characteristic feature of xanthomas in skin and tendons and also of the atheromas. Many foam cells in these lesions share properties characteristic of the macrophages. Therefore, the macrophage may be the progenitor of certain foam cel...

show abstract

“…that attained in the plasma of patients treated with 1.0 g/d of probucol (32,33), during copper-catalyzed oxidation. Once again, while the higher concentrations of probucol more effectively reduced LDL oxidation, they failed to preserve the endogenous antioxidants (Table III).…”

Section: Resultsmentioning

confidence: 98%

Preservation of the endogenous antioxidants in low density lipoprotein by ascorbate but not probucol during oxidative modification.

Jialal

Grundy²

1991

J. Clin. Invest.

208

View full text Add to dashboard Cite

Several lines of evidence indicate that the oxidative modification of low density lipoproteins (LDL) may provide an important link between plasma LDL and the genesis ofthe atherosclerotic lesion. Ascorbate is an important water-soluble, chainbreaking antioxidant in humans. Probucol, a lipid-soluble antioxidant drug has been shown to retard the progression of atherosclerosis. The aim of the present study was to compare the effects of probucol and physiologic levels of ascorbate on the oxidative modification of LDL in both a cell-free (2.5 ,M Cu++ in phosphate-buffered saline) and cellular system (human monocyte macrophages in Ham's F-10 medium). Both ascorbate and probucol inhibited the oxidative modification of LDL in both systems to a similar degree as evidenced by the thiobarbituric acid-reacting substance activity, electrophoretic mobility, and degradation by macrophages. However, whereas co-incubation with physiologic levels of ascorbate resulted in a substantial preservation of the a-tocopherol, y-tocopherol, and (3-carotene of the LDL, probucol in concentrations ranging from 10 to 80 ,M failed to protect these antioxidants. Thus, in addition to being as potent as probucol in inhibiting the oxidation of LDL, ascorbate in contrast preserves the endogenous antioxidants in the LDL. (J. Clin. Invest. 1991. 87:597401.)

show abstract

Effect of probucol treatment on lipoprotein cholesterol and drug levels in blood and lipoproteins in familial hypercholesterolemia

Cited by 38 publications

References 18 publications

Probucol increases cholesteryl ester transfer protein activity in hypercholesterolaemic patients

Probucol increases cholesteryl ester transfer protein activity in hypercholesterolaemic patients

Probucol prevents the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbit, an animal model for familial hypercholesterolemia.

Preservation of the endogenous antioxidants in low density lipoprotein by ascorbate but not probucol during oxidative modification.

Contact Info

Product

Resources

About