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PubMed2003

Optimizing probucol administration to preserve left ventricular compliance after reperfusion injury in the heterotopic rat heart isograft.

BACKGROUND: We investigated the optimal method of administering probucol to attenuate reperfusion-induced diastolic abnormalities in the left ventricle of the heterotopically transplanted rat heart isograft. METHODS: We assigned Lewis rats (n = 84) to 7 transplant groups. We arrested 42 hearts using coronary perfusion with hypothermic University of Wisconsin (UW) solution at 60 mm Hg and abdominally isografted the hearts. Neither donors nor recipients in the control group (C-C, n = 6) received probucol. Oral probucol (1% by weight in chow) was fed for 1 month before surgery to the donors only (OP-C, n = 6), the recipients only (C-OP, n = 6), or both (OP-OP, n = 6). We administered an intraperitoneal injection of probucol (300 mg/kg) in 3 ml oil 1 hour before surgery to the donors only (IP-C, n = 6), the recipients only (C-IP, n = 6), or both (IP-IP, n = 6). Transplanted hearts were reperfused for 15 minutes and re-arrested. We also arrested the control recipients' native hearts (native, n = 6). We measured post-mortem left ventricular compliance curves and myocardial water content. RESULTS: The most compliant grafts were in Groups IP-IP, OP-OP, and C-IP. All isograft groups had significantly less left ventricular compliance than did native hearts. Myocardial water content was significantly greater in controls than in natives, OP-OP, and OP-C. CONCLUSIONS: Pre-treatment with intraperitoneal probucol in cardiac isograft recipients combines optimal protection with simple administration when UW solution is used for both arrest and preservation. Further studies of the protective effect of probucol against reperfusion injury in large-animal models are warranted and should use intraperitoneal or intravenous injection in recipients.

Administration, Oral↗
PubMed1999

Effect of probucol on intracellular pH and proliferation of human vascular endothelial cells.

We investigated the effect of probucol on the intracellular pH ([pH]i) and proliferation of human umbilical vein endothelial cells (HUVEC), as well as their production of prostacyclin (PGI2). The addition of probucol produced a biphasic shift in [pH]i, with a brief initial acidification followed by a rapid alkaline shift. After pretreatment with EGTA, the initial decrease in [pH]i was abolished, and the subsequent increase was inhibited. After pretreatment with amiloride, only the increase of [pH]i was abolished. These results suggest that the probucol-induced increase of [pH]i was mainly dependent on Na+/H+ exchange and partly on extracellular Ca2+. In contrast, the addition of LDL produced a decrease of [pH]i. Under Ca2+-free condition, [pH]i was further decreased by LDL. In cells pretreated with amiloride, however, [pH]i was not further decreased by LDL. It was found that probucol promoted cell proliferation, and LDL inhibited cell proliferation. Addition of probucol also enhanced prostacyclin generation by HUVEC. This enhancement of PGI2 generation resulted from increased release of Ca2+ from the storage sites, due not only to increased production of inositol 1,4,5-triphosphate (IP3) but also to the increase of [pH]i. These findings may help to explain the antiatherosclerotic action of probucol.

Amiloride↗
PubMed2001

Hepatic cholesterol and bile acid synthesis, low-density lipoprotein receptor function, and plasma and fecal sterol levels in mice: effects of apolipoprotein E deficiency and probucol or phytosterol treatment.

We compared hepatic cholesterol metabolism in apolipoprotein (apo) E-knockout (KO) mice with their wild-type counterparts. We also investigated the effects of treatment with phytosterols or probucol on the activity of hepatic 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase (cholesterol synthesis), cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase (bile acid synthesis), and low-density lipoprotein (LDL) receptor function in this animal model of atherogenesis. These findings were then related to treatment-induced changes in plasma, hepatic, and fecal sterol concentrations. Mouse liver membranes have binding sites similar to LDL receptors; the receptor-mediated binding represents 80% of total binding and is LDL concentration-dependent. These binding sites have higher affinity for apo E-containing particles than apo B only-containing particles. Deletion of apo E gene was associated with several-fold increases in plasma cholesterol levels, 1.5-fold increase in hepatic cholesterol concentrations, 50% decrease in HMG-CoA reductase activity, 30% increase in cholesterol 7 alpha-hydroxylase and 25% decrease in LDL receptor function. Treatment of apo E-KO mice with either probucol or phytosterols significantly reduced plasma cholesterol levels. Phytosterols significantly increased the activity of hepatic HMG-CoA reductase, and probucol significantly increased cholesterol 7 alpha-hydroxylase activity. Neither treatment significantly altered hepatic LDL receptor function. Phytosterols, but not probucol, significantly increased fecal sterol excretion and decreased hepatic cholesterol concentrations. Plasma cholesterol lowering effects of phytosterols and probucol are due to different mechanisms: stimulation of cholesterol catabolism via increased bile acid synthesis by probucol and decreased cholesterol absorption by phytosterols. In the absence of apo E, hepatic LDL receptors could not be upregulated and did not contribute to the cholesterol lowering effects of either agent.

Animals↗
PubMed1998

Acute probucol treatment partially restores vasomotor activity and abnormal lipid metabolism whereas morphological changes are not affected in aorta from long-term STZ-diabetic rats.

The effects of acute probucol treatment on plasma lipids, lipid peroxides and vasomotor activity and structure of aorta were investigated in long-term streptozotocin (STZ)-diabetic rats. Treatment with probucol (300 mg/kg/day, i.o.) was initiated 10 weeks after the induction of diabetes and was continued for 2 or 3 weeks. Plasma cholesterol, triglyceride and thiobarbituric acid reactive substance (TBARS) levels were markedly increased in untreated diabetic rats, however, probucol treatment led to significant reductions in all of these characteristics in diabetic animals. Plasma glucose and insulin levels were similar between untreated and probucol-treated diabetic groups. STZ-diabetes impaired morphological integrity of aorta and caused significantly increase in contractile response to noradrenaline (NA). The percentage of endothelial response (PER), which was calculated in terms of the NA-induced maximum contractile response of aorta, as index of endothelial function, significantly decreased in untreated diabetic rats. Treatment of diabetic rats with probucol resulted in partial restorations in endothelial function and NA-induced contraction in aorta, whereas morphological changes were not affected. These observations suggest that the ability of acute probucol treatment to restore vessel functions may have important implications regarding the pathogenesis and treatment of diabetes and its complications.

Animals↗
PubMed1992

Probucol inhibits neointimal thickening and macrophage accumulation after balloon injury in the cholesterol-fed rabbit.

Restenosis is a frequent long-term complication after balloon angioplasty. Although smooth muscle cells form the major constituent of the occluding lesion, macrophage-derived foam cells are usually also present in high abundance. The latter have the potential to accelerate the rate of reocclusion because they elaborate many potent cytokines and growth factors, which may act to either recruit cells into the neointima or cause neointimal cell proliferation. Macrophage-derived foam-cell formation depends upon the uptake of modified low density lipoprotein via a scavenger receptor-mediated pathway. Foam-cell formation is accompanied by the release of smooth muscle cell mitogens and chemoattractants. We have examined the effects of probucol, a lipid-soluble antioxidant, in the balloon-catheterized carotid artery of the cholesterol-fed rabbit to evaluate the importance of oxidative processes in restenosis. After 5 weeks, serum cholesterol levels were 32% lower (P < 0.05) in rabbits fed 1% probucol with 2% cholesterol, compared with those receiving cholesterol alone. Probucol inhibited neointimal macrophage accumulation by 68% (P < 0.001), reduced absolute intimal size by 51% (P < 0.05), and reduced the intima/media thickness ratio by 51%. These inhibitory effects were directly related to serum probucol concentrations and appeared to be unrelated to probucol's hypocholesterolemic activity. These data suggest that reactive oxygen species may be involved in the intimal response to injury and that antioxidants, such as probucol, may be therapeutically useful as inhibitors of restenosis.

Animals↗
PubMed1999

Probucol improves symptoms and reduces lipoprotein oxidation susceptibility in patients with Raynaud's phenomenon.

OBJECTIVE: Reactive oxygen species have been implicated in the pathogenesis of inflammatory and vascular disease. We have undertaken a controlled trial to evaluate probucol, a synthetic antioxidant, as a potential therapy for Raynaud's phenomenon. METHODS: The study cohort included patients with systemic sclerosis (SSc; n = 20), primary Raynaud's phenomenon (n = 15) or 'autoimmune Raynaud's' (n = 5). Patients were allocated to receive either probucol (500 mg daily) or nifedipine (20 mg daily) for 12 weeks. Clinical and biochemical variables at baseline were compared with those at completion of treatment. Evaluation included assessment of Raynaud's attack frequency and severity by visual analogue scale, measurement of low-density lipoprotein (LDL) oxidation lag time, and plasma concentrations of cholesterol, triglyceride, vitamin E and vitamin C. RESULTS: There was a significant reduction of both the frequency and severity of Raynaud's attacks in the patients who received probucol, but not in the control group. LDL oxidation lag time, reflecting in vitro susceptibility to oxidation, was also increased by probucol therapy and serum cholesterol levels were significantly reduced. Similar changes were observed in both SSc- and non-SSc-associated Raynaud's cases. CONCLUSION: These data suggest that probucol may be useful for the symptomatic treatment of Raynaud's phenomenon and also reduces LDL oxidation susceptibility. Since oxidized lipoproteins may mediate vascular damage in SSc, the use of probucol could have additional disease-modifying benefits. Based upon the results of this pilot study, further evaluation of this novel form of therapy is warranted.

Anticholesteremic Agents↗
PubMedDate not supplied

Effects of probucol on hyperlipidemic patients with cardiac allografts.

Probucol, a well-tolerated new drug with moderate hypocholesterolemic effect in the general population, was evaluated in hypercholesterolemic (greater than 300 mg/dl) cardiac transplant recipients. Nine patients received probucol, 500 mg twice daily, in a single-blind, placebo-controlled trial lasting 20 weeks. Six patients responded with cholesterol falls of -20% (mean, -13.2%), and 1 patient showed minimal change. One patient developed cardiac rejection and was excluded, and another responded paradoxically and was returned to previous therapy. In 1 patient, probucol was readministered, and a similar favorable response occurred, which has been sustained for over 6 months. For the group completing the study, low-density lipoprotein (LDL) cholesterol fell by 15.4%, accounting for the major portion of overall change in plasma cholesterol. High-density lipoprotein (HDL) cholesterol also fell (-15.6%), and the LDL/HDL ratio was unchanged. Triglycerides and very low density lipoprotein cholesterol showed variable responses with no overall change. Probucol was universally well tolerated, without adverse clinical or laboratory effects. In conclusion, probucol may effect a moderate hypocholesterolemic response in hyperlipidemic recipients of cardiac transplantation, despite long-term maintenance therapy with corticosteroids. However, efficacy should be individually documented. The long-term effect of probucol on the natural history of coronary artery disease in these patients remains to be determined, particularly in view of its effects on HDL cholesterol.

Adult↗
PubMed1990

Effects of long-term treatment with probucol on serum lipoproteins in cases of familial hypercholesterolemia in the elderly.

The effect of probucol in lowering serum lipoprotein in young and middle-aged (YM) and elderly (E) patients with familial hypercholesterolemia were compared. Probucol at 1000 mg/day was administered orally to 37 YM patients and 14 E patients for an average of 10 months. Probucol treatment for this period caused significant reductions in the serum levels of total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol, and apoprotein AI, AII, B, and CIII in both groups. The decreases in the levels of total cholesterol, LDL-C, and apoprotein B were greater in the E group than in the YM group (total cholesterol: YM, -19.3%, E, -31.3% [P less than .001]; LDL-C: YM, -17.0%, E, -35.4% [P less than .001]; apoprotein B: YM, -12.3%, E, -28.1% [P less than .01]). The decreases in other parameters in the two groups were not significantly different. The serum probucol concentrations in the YM and E groups were not significantly different. No significant side effects were observed in any patient. Thus probucol reduced the serum level of LDL more in the E group than in the YM group, and did so without any increase in the serum concentration of the drug or in side effects, suggesting that probucol is safe and beneficial for use in elderly patients.

Administration, Oral↗
PubMedDate not supplied

Probucol, but not MaxEPA fish oil, inhibits mononuclear cell adhesion to the aortic intima in the rat model of atherosclerosis.

We have examined the influence of both dietary fish oil and probucol on monocyte adhesion to the aortic endothelium rats fed an atherogenic diet for 2 weeks. All rats were fed a low-fat diet supplemented with 4% cholesterol, 1% cholic acid, and 0.5% 2-thiouracil. In addition to the atherogenic diet, group 1 (FO; n = 20) received a dietary supplement of the fish oil concentrate MaxEPA (5% w/w); group 2 (CO; n = 20) received a supplement of a control oil with same polyunsaturated-monounsaturated-saturated fatty acid ratio as Max-EPA; and group 3 (PR; n = 20) received both the control oil supplement (5% w/w) and a 1% (w/w) supplement of probucol. Analysis of blood samples taken at 2 weeks revealed that both fish oil and probucol lowered total plasma cholesterol by 30% compared with the CO group. In addition, fish oil supplementation caused a significant decrease in cholesterol contained in the VLDL fraction while probucol supplementation caused a significant lowered cholesterol in the HDL fraction. Analysis of mononuclear cell adhesion to the aortic endothelium in vivo revealed that, fish oil had no significant effect probucol reduced adhesion by 40%. The results of this study suggest that probucol, but not fish oil, may inhibit the initiation of lesion formation in the rat model of atherosclerosis.

Animals↗
PubMed1987

Effect of probucol on hyperlipidemia in patients with nephrotic syndrome.

We have evaluated the effect of the antihyperlipidemic agent probucol on hyperlipidemia in patients with nephrotic syndrome. Twelve patients with long-standing nephrotic syndrome received 500 mg of probucol daily for 12 weeks. Serum total cholesterol, triglyceride, HDL-cholesterol and LDL-cholesterol were significantly lowered with probucol treatment. There were no differences in urine protein, serum total protein, serum albumin and renal function before and after probucol treatment. No drug-related side effects were observed during our study. These results indicated that probucol was effective against hyperlipidemia and free from side effects in patients with persistent nephrotic syndrome. The use of probucol is therefore suggested to be advisable when antihyperlipidemic treatment is required in some subgroups of nephrotic syndrome.

Adult↗
PubMed1992

Treatment of hyperlipidemia with probucol suppresses the development of focal and segmental glomerulosclerosis in chronic aminonucleoside nephrosis.

We have recently reported that a lipid-lowering agent, probucol, reduces proteinuria in puromycin aminonucleoside (PA)-induced nephrotic rats (PAN). In this study, we examined whether a long-term treatment of hyperlipidemia with probucol can suppress the development of focal and segmental glomerulosclerosis (FSGS) in chronic PAN. A chronic PAN model was made with repeated intraperitoneal injections of PA (initially 100 mg/kg body weight followed by 25 mg/kg 5 times at 2-week intervals). Two weeks after the first injection of PA, either normal rat chow with or without 1% probucol was given to the nephrotic rats for 10 weeks. Chronic PAN exhibited remarkable proteinuria, hypoalbuminemia and severe hyperlipidemia with all lipoprotein fractions increased. Probucol treatment significantly reduced the lipid concentration in all major lipoproteins, significantly reduced proteinuria and increased plasma albumin concentration. Plasma albumin inversely correlated with cholesterol or phospholipid in low-density and high-density lipoproteins, suggesting that the lipid-lowering effect of probucol may ameliorate the hypoalbuminemia associated with nephrosis. In light microscopic examination, various degrees of FSGS with tubulointerstitial lesions were observed in the renal cortex from chronic PAN. The degree of FSGS was scored from grades 1 to 4 according to severity. One half of the untreated PAN (4/8) was classified into grade 4 and the other into grades 2 or 3, whilst one half of treated PAN (4/8) was classified either into grade 1 or 2. The grading of FSGS correlated negatively with plasma albumin concentration. These results demonstrate that probucol is highly effective upon nephrotic hyperlipidemia and suggest that a long-term treatment of secondary hyperlipidemia can suppress progressive renal injury associated with chronic nephrosis.

Animals↗
PubMed1994

Probucol reduces renal injury in the ExHC rat.

To investigate the potential roles of oxidized lipoproteins and glomerular macrophages in the pathogenesis of lipid-induced glomerular injury, we examined the effects of administration of probucol on the development of renal injury in ExHC rats. ExHC rats are derived from the Sprague-Dawley strain and are highly susceptible to dietary hypercholesterolemic stimuli. We reported previously that ExHC rats fed a cholesterol-supplemented diet (HCD) develop proteinuria and characteristic glomerular lesions. These lesions include marked accumulation of numerous lipid-filled foam cells, which have a surface marker that identifies them as macrophages, within mesangial regions, as well as segmental clusters of foam cells that are associated with capsular adhesions, the destruction of glomerular tufts and glomerular sclerosis. ExHC rats were maintained on an HCD or on an HCD supplemented with 5% (wt/wt) probucol for 8 weeks. Probucol reduced the extent of renal injury, as evidenced by proteinuria and segmental glomerular lesions, in ExHC rats fed an HCD, in the absence of any significant reduction in plasma cholesterol levels. Both low-density lipoprotein and beta-very-low density lipoprotein isolated from the plasma of probucol-treated rats were found to be resistant to oxidative modification by cupric ions. Both the size and the number of foam cells within glomeruli in the probucol-treated rats were significantly reduced as compared to those of foam cells in the untreated rats. Probucol might reduce renal injury in ExHC rats by limiting the oxidative modification of lipoproteins and, subsequently, by restricting the foam cell transformation of macrophages within glomeruli and by inhibiting the recruitment of macrophages into glomeruli. The results of the present study may be interpreted to indicate that local glomerular oxidative modification of lipoproteins might occur in vivo, and both oxidized lipoproteins and glomerular macrophages may play important roles in the pathogenesis of lipid-induced glomerular injury.

Animals↗
PubMed1989

Intensive combination drug therapy of familial hypercholesterolemia with lovastatin, probucol, and colestipol hydrochloride.

Patients with familial hypercholesterolemia (FH) have had a life-long sustained elevation of low-density lipoprotein (LDL) cholesterol levels. Consequently, there is a need to maximally lower their elevated levels, and this usually requires lowering LDL levels more than 50%. Because no single hypolipidemic drug will consistently produce such degrees of lowering, combination drug therapy with two or even three agents is required to produce the desired degree of cholesterol lowering. A prospective trial was designed to determine if combination therapy using three hypolipidemic agents could effectively lower LDL levels in 17 severely affected FH subjects. Colestipol hydrochloride (10 g b.i.d.), probucol (500 mg b.i.d.), and lovastatin (20 or 40 mg b.i.d.) were given to each patient, in varying combinations, over a 25-month period. Lovastatin (40 mg/day) uniformly lowered LDL levels 36%. Probucol lowered LDL only 14% and in a variable manner. The combination of lovastatin and probucol lowered LDL no better than lovastatin alone. Lovastatin plus colestipol lowered LDL 52%; probucol added as a third agent produced no further lowering. Lovastatin (80 mg/day) plus colestipol lowered LDL 56%. Lovastatin increased high-density lipoprotein (HDL) cholesterol levels 6%, whereas probucol decreased HDL 29%. In all patients there was an effective lowering of LDL levels, ranging from 40% to 70%. Thus, lovastatin plus colestipol is an effective hypolipidemic regimen for producing marked decreases in LDL levels in FH subjects. The addition of probucol as a third hypolipidemic agent adds little to the therapeutic regimen as measured by lowering of LDL levels.

Cholesterol↗
PubMed1993

Probucol decreases neointimal formation in a swine model of coronary artery balloon injury. A possible role for antioxidants in restenosis.

BACKGROUND: Restenosis after percutaneous transluminal coronary angioplasty is the major limitation of the long-term success of this procedure. The process of restenosis is similar to an accelerated form of atherosclerosis. Thus, therapeutic interventions that limit the progression and initiation of atherosclerosis may be beneficial in the treatment of restenosis. One such intervention is the antioxidant drug probucol, which has demonstrated benefit in animal models of atherosclerosis. METHODS AND RESULTS: Twenty-six female domestic swine were divided into three study groups (control, n = 9; low-dose probucol, n = 9; high-dose probucol, n = 8) before oversized balloon injury of the left anterior descending and left circumflex coronary arteries. Probucol (1 g/d, low-dose group; 2 g/d, high-dose group) was administered 2 days before balloon injury and was continued until the swine were killed 2 weeks after balloon injury. Morphometric analysis of the injured arteries included the intimal area (square millimeters), maximal intimal thickness (millimeters), and residual lumen (ratio of luminal to intimal plus luminal area). Treatment with high-dose probucol significantly reduced neointimal formation compared with control animals (decreases of 36% in intimal area, P = .007; 20% in maximal intimal thickness, P = NS; and an increase of 15% in residual lumen, P = .02). CONCLUSIONS: The major finding of this study is that the antioxidant drug probucol reduces neointimal formation after oversized balloon injury in a swine model of restenosis. This suggests that active oxygen species may play a role in restenosis.

Animals↗
PubMed1994

Probucol promotes endogenous antioxidants and provides protection against adriamycin-induced cardiomyopathy in rats.

BACKGROUND: The potential usefulness of adriamycin (ADR) is restricted because of its cardiotoxic side effects. Since free radicals and lipid peroxidation are suggested to be involved in ADR cardiomyopathy, we examined the beneficial effects of probucol, a lipid-lowering drug with strong antioxidant properties. METHODS AND RESULTS: ADR was administered to rats in six equal intraperitoneal injections over a period of 2 weeks (cumulative dose of 15 mg/kg). After a 3-week posttreatment period, cardiomyopathy and congestive heart failure were characterized by ascites, congested liver, depressed cardiac function, elevated left ventricular end-diastolic pressure, and myocardial cell damage. Myocardial glutathione peroxidase (GSHPx) activity was decreased, and lipid peroxidation was increased. Probucol (cumulative dose, 60 mg/kg IP) was administered in six equal injections over a 2-week period on days alternating with ADR treatment. Probucol significantly attenuated the myocardial effects of ADR, improved left ventricular function, and lowered mortality as well as the amount of ascites. Treatment with probucol was also accompanied by an increase in myocardial GSHPx and superoxide dismutase activities, with a concomitant decrease in lipid peroxidation. CONCLUSIONS: These data provide evidence that ADR cardiomyopathy is associated with an antioxidant deficit. Improved cardiac function resulting from treatment with probucol may be related to the maintenance of the antioxidant status of the heart. The study suggests potential usefulness of antioxidant (probucol) therapy in ADR cardiomyopathy.

Animals↗
PubMed1995

Dietary probucol preserves endothelial function in cholesterol-fed rabbits by limiting vascular oxidative stress and superoxide generation.

Excess vascular oxidative stress and the local formation of oxidized LDL (ox-LDL) have been implicated in the development of impaired endothelium-dependent arterial relaxation in hypercholesterolemia and atherosclerosis. Dietary antioxidants limit LDL oxidation in vitro and treatment of cholesterol-fed rabbits with dietary antioxidants preserves endothelium-derived relaxing factor (EDRF) action. To investigate the mechanism(s) responsible for these observations, we examined EDRF action, vascular oxidative stress, and antioxidant protection in male New Zealand White rabbits using four dietary treatments. Animals consumed standard chow (chow group) or chow supplemented with: (a) 0.5% cholesterol (0.5% cholesterol group); (b) 1% cholesterol (1% cholesterol group); or (c) 1% cholesterol and 1% probucol (probucol group). After 28 d of dietary treatment, segments of thoracic aorta from the 0.5 and 1% cholesterol groups demonstrated impairment of acetylcholine-mediated endothelium-dependent arterial relaxation compared to chow-fed animals (57 +/- 11% and 45 +/- 9% vs 78 +/- 3%, respectively; P < 0.05). In contrast, vessels from the probucol group demonstrated normal relaxation to acetylcholine (83 +/- 5%). Plasma cholesterol levels and the extent of atherosclerosis were similar among all cholesterol-fed groups. Probucol treatment was associated a threefold increase in LDL resistance to copper-induced oxidative modification (P < 0.05) and a reduction in tissue lipid peroxidation (as assessed by thiobarbituric acid-reactive substances; P < 0.05) compared to animals fed cholesterol alone. Most importantly, both of these changes were strongly correlated with preserved EDRF action. Moreover, cholesterol feeding was associated with a dose-dependent increase in vascular superoxide generation and lysophosphatidylcholine content, both of which were prevented by probucol treatment. From these findings, we conclude that probucol, a lipid-soluble antioxidant, preserves EDRF action in cholesterol-fed rabbits in association with limiting vascular oxidative stress and superoxide generation.

Animals↗
PubMed1998

Control of plasma cholesterol-lowering action of probucol with various lipid carrier systems.

In order to explore the relationship between the pharmacokinetic properties and pharmacological actions of lipophilic drugs injected with lipid carrier systems, probucol was selected as a model drug with high lipophilicity, and the effect of disposition control on cholesterol-lowering activities was evaluated. Both large emulsion, with mean diameter of 280 nm, and long-circulating type small emulsion containing egg sphingomyelin with mean diameter of 100 nm, showed stable incorporation of probucol. The former produced rapid accumulation of probucol in the liver, while the latter demonstrated prolonged systemic circulation and gradual hepatic uptake. On the other hand, injection of a micellar solution with HCO-60 (polyoxyethylene hydrogenated castor oil) showed a rapid decrease in plasma concentration and a high hepatic uptake of probucol, similar to injections with serum, suggesting the rapid release of the drug from the micelles. However, probucol in a micellar solution showed higher cholesterol-lowering action than that in emulsion formulations. These results suggested that the pharmacological action of probucol in the liver might be affected by the uptake mode and sequential disposition in the organ, depending on the drug retention properties of the lipid carrier particles.

Animals↗
PubMed2003

Effects of candesartan and probucol on restenosis after coronary stenting: results of insight of stent intimal hyperplasia inhibition by new angiotensin II receptor antagonist (ISHIN) trial.

The purpose of this study was to determine whether candesartan and its combination with probucol reduce restenosis after coronary stenting. A total of 132 patients who successfully underwent stenting were randomly assigned to a control group (n=45), a candesartan group (8 mg daily, n=43), or a candesartan plus probucol group (+ probucol 500 mg daily, n=44). No differences in late loss were observed between the control and candesartan groups. In the candesartan plus probucol group, late loss was significantly smaller than in the control and candesartan groups (p=0.003, 0.015). The restenosis rate was 27% in the control group, 26% in the candesartan group (p>0.99), and 11% in the candesartan plus probucol group (p=0.104 vs the control group and p=0.103 vs the candesartan group). Intravascular ultrasound revealed no differences in stent area among the 3 groups, and no differences in lumen area or in intimal hyperplasia area between the control and candesartan groups. However, the intimal hyperplasia area in the candesartan plus probucol group was significantly less than that in the control and candesartan groups (p<0.001, p<0.001). This study demonstrated that candesartan failed to inhibit the neointimal hyperplasia and although the combination treatment did reduce neointimal hyperplasia, it did not statistically reduce the restenosis rate.

Aged↗