BACKGROUND AND OBJECTIVES: In a recent multicenter trial probucol was found to reduce stent restenosis by improving the lumen dimension. The probucol was administered for 2 weeks before, and 4 weeks after, stenting. The release of the drug at the site of a vascular injury, via polymer-coated stents, helps achieve an effective local concentration. The feasibility of a probucol stent coating in reducing in-stent restenosis was assessed. MATERIALS AND METHODS: The probucol loading and in vitro release were assessed using BiodivYsioTM stents, in a 50 mg/mL probucol solution. After being dip-coated with probucol (n=8), or a control (n=8) solution, the stents were implanted in 8 pigs. Angiography and histopathological analyses were performed 28 days later. RESULTS: The total probucol loading was 52+/-16 microgram/stent, with no release for up to 72 hours after loading. No pig died until sacrifice. On angiography, the reference and minimum lumen diameters showed no significant differences between the two groups, with similar diameters stenosis (8.7+/-3.68 vs. 13.3+/-4.18%, p=0.120). On histomorphometry, the injury scores, vessel, lumen and neointimal areas showed no significant differences between the groups, with similar areas of stenosis (23.1+/-12.39 vs. 25.2+/-8.22%, p=0.671). The degrees of re-endothelialization, inflammation and smooth muscle cell proliferation were not significantly different. CONCLUSIONS: Probucol can be loaded onto a polymer-coated stent, and does not release from the stent for up to 72 hours after loading. About 52 microgram probucol per stent does not reduce in-stent restenosis in porcine coronary arteries.
Angiography ; Antioxidants ; Constriction, Pathologic ; Coronary Disease ; Coronary Vessels ; Inflammation ; Myocytes, Smooth Muscle ; Probucol ; Stents* ; Swine ; Vascular System Injuries

PURPOSE: In adriamycin(ADR)-induced cardiomyopathy, several different mechanisms are suggested. However, little information is available regarding the role of apoptosis. In the present study, we examined the induction of apoptosis on ADR treatment and anti-apoptotic effects of probucol, a lipid-lowering drug, and we also studied the changes of bcl-2 expression in order to see the molecular mechanisms underlying the effect of probucol. METHODS: Cardiac myocytes were isolated from 3-day-old rats, and cultured in low(1 pM) or high doses(10pM) of ADR for 24 hours. Probucol(50 pM) was added 30 minutes before ADR administration. Apoptosis was determined by TUNEL staining, and bcl-2 expression was estimated by immunocytochemistry. RESULTS: The number of TUNEL-positive cells significantly increased in both groups treated with ADR. However, anti-apoptotic effect of probucol was evident only in low dose. In addition, the expression of bcl-2 was significantly increased only in the low-dose ADR treatment group and its expression was inhibited by pretreatment of probucol. CONCLUSION: These results suggest that apoptosis might play an important role in ADR-induced cardiotoxicity, and ADR-induced apoptosis was partially prevented by pretreatment of probucol. And ADR-induced apoptosis was not related with depression of bcl-2. Additionally, inhibition of bcl-2 gene expression of low-dose ADR treatment group by probucol suggests that another cell survival mechanism could be implicated in the action of probucol. (J Korean Pediatr Soc 2000;43:746-754)
Animals ; Apoptosis* ; Cardiomyopathies ; Cell Survival ; Depression ; Doxorubicin ; Genes, bcl-2 ; Immunohistochemistry ; In Situ Nick-End Labeling ; Myocytes, Cardiac* ; Probucol* ; Rats*

AIMTo study the pharmacokinetics and relative bioavailability of probucol inclusion complex capsule.

METHODSFollowing oral administration of a single dose of 250 mg of conventional tablet (formulation A, purchased from the market) and probucol inclusion complex capsule (formulation B, a new formulation for preclinical trial) to each of 6 healthy dogs in a randomized crossover design, the plasma levels of the active drug at different time points were determined by HPLC and the plasma concentration-time profiles of formulation A and B were obtained. The pharmacokinetic parameters as well as relative bioavailability were analyzed.

RESULTSThe concentration-time curves of formulation A and formulation B were found to fit a two-compartment open model. The Tmax values of formulation A and formulation B were (9.3 +/- 2.1) h and (9.3 +/- 2.1) h, the Cmax values were (1.5 +/- 1.0) microgram.mL-1 and (2.3 +/- 0.9) microgram.mL-1 and the AUC0-240 values were (85 +/- 56) microgram.h.mL-1 and (134 +/- 55) microgram.h.mL-1, respectively. The relative bioavailability of formulation B was found to be (198 +/- 90)% compared with formulation A. The results of variance analysis and two one-side t-test showed that there was significant difference between the two formulations in the AUC0-240.

CONCLUSIONThe high bioavailability by the inclusion of formulation B is attributed to the improvement of its water-solubility by the inclusion process and this is supposed to be a key factor for improving drug bioavailability.

Administration, Oral ; Animals ; Anticholesteremic Agents ; administration & dosage ; pharmacokinetics ; Biological Availability ; Capsules ; Dogs ; Female ; Probucol ; administration & dosage ; pharmacokinetics ; Random Allocation ; Tablets

BACKGROUND: Glomerular injury induced by angiotensin II (Ang II) may arise from its hemodynamic or non-hemodynamic actions including oxidative stress, or from such effects of Ang II acting in concert. The release of reactive oxygen species from podocytes may play a role in the pathogenesis of glomerular damage and proteinuria. METHODS: To investigate whether Ang II induces oxidative stress in vitro in glomerular epithelial cells (GEpC) and whether such oxidant stress may increase in vitro glomerular permeability model using cultured GEpC, we studied GEpC culture exposed to Ang II and antioxidant, probucol. For oxidative system assay, we measured the production of superoxide anion and hydrogen peroxide and the activity of superoxide dismutase (SOD). Scanning electron microscopy was performed on cells grown for one week on chamber slides. RESULTS: We found that in vitro permeability, which was prevented from probucol, increased significantly in media with 10-4 and 10-5 M of Ang II by 15.9% and 13%, respectively. Administration of the 10-5 M of Ang II significantly increased the superoxide anion productions by 39%, 61% and 30% at 1, 2 and 6 hours exposure time, respectively, compared to those of control and suppressed by probucol to control levels. At high concentration (10-5 M) Ang II suppressed the activity of SOD without affecting the production of hydrogen peroxide on the other hand, at low concentration (less than 10-5 M) Ang II showed reverse results. On ultrastructural examination, we could see the shortened and fused microvilli on GEpC surface by 10-5 M of Ang II, which change could be prevented by probucol. CONCLUSION: We could suggest that Ang II induces the generation of superoxide anion and the suppression of the activity of SOD, and subsequent oxidative stress leading to increase glomerular permeability by disruption of glomerular filtration barrier.
Angiotensin II* ; Angiotensins* ; Epithelial Cells* ; Glomerular Filtration Barrier ; Hand ; Hemodynamics ; Hydrogen Peroxide ; Microscopy, Electron, Scanning ; Microvilli ; Oxidative Stress* ; Permeability* ; Podocytes ; Probucol ; Proteinuria ; Reactive Oxygen Species ; Superoxide Dismutase ; Superoxides

BACKGROUND: AGE-induced oxidative stress is implicated in the development and progression of diabetic nephropathy. AGE also affect the GEC to increase their permeability, therefore, we investigate the possibility that AGE may induce oxidative stress and subsequent injury to GEC. METHODS: We cultured rat GEC on the AGE- or BSA-coated plate with high glucose (HG) to produce more pathophysiologic conditions similar to prolonged diabetic environment in vivo and measured the change of ROS and their anti-oxidants systems. We also evaluated the effects of probucol as an antioxidant on this system. RESULTS: The amount of superoxide anion slightly decreased on AGE condition without significance. However, the production of hydrogen peroxide was significantly enhanced by 10% on AGE-coated and HG condition compared to control (BSA-coated and 5 mM glucose) (p< 0.05) and hydroxyl radical have also showed similar increase on AGE-coated and HG condition by 10% above control (p< 0.01), and both increases were attenuated by probucol (both, p< 0.05). The activity of superoxide dismutase (SOD) was decreased by 10% on AGE-coated and HG condition (p< 0.05) and recovered by probucol partially. However, there were no significant changes on the activity of other anti-oxidant enzymes including catalase, glutathione peroxidase, and glutathione reductase. Therefore, glomerular epithelial injury presenting proteinuria may be provoked by hydrogen peroxide and subsequently increased hydroxyl radical induced by AGE and high glucose. CONCLUSION: We might assume that superoxide had been converted to hydrogen peroxide by consumptive SOD in the presence of AGE, and subsequently produced hydroxyl radical, which could be reversed by anti-oxidant, may induce diabetic glomerular epithelial injury and eventually proteinuria.
Animals ; Catalase ; Diabetic Nephropathies ; Epithelial Cells* ; Glucose ; Glutathione Peroxidase ; Glutathione Reductase ; Hydrogen Peroxide ; Hydroxyl Radical ; Oxidative Stress ; Permeability ; Probucol ; Proteinuria ; Rats* ; Reactive Oxygen Species* ; Superoxide Dismutase ; Superoxides

PURPOSE: The purpose of this experiment was to study the effects of Ox-LDL (oxidized low density lipoprotein) and Ox-VLDL (oxidized very low density lipoprotein) with or without probucol treatment on the proliferation of human vascular endothelial cells (EC) which were three dimensionally constructed vascular wall model. METHOD: The thiobarbituric acid reactive substance content of LDL and VLDL oxidized by incubation with copper irons was consistently greater than 10 nM malondialdehyde (MDA)/mg protein compared with less than 3 nM MDA/mg for unmodified lipoprotein immediately after isolation. On agarose gel electrophoresis, Ox-LDL and Ox-VLDL were shown to have greater cationic charge than unmodified lipoprotein. RESULT: In Ox-LDL stimulated ECs, the cellular enzymatic activity was markedly decreased in 50 mug/ml concentration of Ox-LDL and was protected by 10 nM probucol. And in Ox-VLDL stimulated ECs, the cellular enzymatic activity was markedly decreased in 25 and 50 mug/ml concentration of ox-VLDL and was not protected by 10 nM probucol. On scanning electron microscopy (SEM) and transmission electron microscopy (TEM), endothelial layers of control, unmodified LDL and unmodified VLDL groups showed similar appearance. But in Ox-LDL and Ox-VLDL groups, cellular edema, loosened cell-to-cell contact and loss of microvilli were shown on SEM, and marked cellular edema, distortion of cell membrane, loss of intracellular organelles and destruction of nulcleus were shown on TEM. And the protective effect of probucol was definite in Ox-LDL group but in 25 and 50 mug/ml concentration of Ox-VLDL group, there were no protective effects of probucol. CONCLLUSION: As a conclusion, three dimensionally constructed vascular wall model is to be a good experimental model for vascular research. And Ox-LDL and Ox-VLDL have toxic effects on vascular endothelial cell layer and its toxic effects are partially prevented by probucol.
Cell Membrane ; Copper ; Edema ; Electrophoresis, Agar Gel ; Endothelial Cells ; Humans ; Iron ; Lipoproteins* ; Malondialdehyde ; Microscopy, Electron, Scanning ; Microscopy, Electron, Transmission ; Microvilli ; Models, Theoretical ; Organelles ; Probucol

Apolipoprotein (apo) E deficient mouse can produce reproducible fixed stenotic primary atherosclerotic lesion, which reveals failure to remodel of vascular lumen, in the ascending aorta, external carotid, common carotid, iliac, femoral and popliteal arteries. To evaluate the effect of drugs in regarding to both prevention of primary atherosclerotic lesion and vascular remodeling, a systematic analysis of distribution of atherosclerotic lesions was undertaken in chow-fed, 9-momth-old apo E deficient mice, which was administrated drugs including asprin, methotrexate, probucol, sulodexide, diltiazem, cilazapril, trimetazidine, molsidomine, pentoxiphylline and Ginexin (R) for 7 month from 3 month-old. On gross and microscopic examination, formation of primary atheroscleotic lesions could be delated and/or prevented patially by effets of these drugs. On morphometric examination, failure to remodel forming vascular stenosis could not be seen, though relatively mild atherosclerotic lesion occured at vascular tree. These data suggest that the stenotic process in advanced atherosclerotic vessels can be delayed and/or prevented by several drugs including methotrexate, probucol, sulodexide, diltiazem, cilazapril, trimetazidine, molsidomine, pentoxiphylline and Ginexin (R) in vivo state.
Animals ; Aorta ; Apolipoproteins ; Apolipoproteins E* ; Atherosclerosis ; Cilazapril ; Constriction, Pathologic ; Diltiazem ; Humans ; Infant ; Methotrexate ; Mice ; Mice, Knockout* ; Molsidomine ; Popliteal Artery ; Primary Prevention ; Probucol ; Trimetazidine

BACKGROUND: Oxidative stress might be a role in atherosclerosis and increased intake of antioxidant appear to be protective and modify neointimal formation. An antioxidant and probucol prevents endothelial dysfunction and low density lipoprotein oxidation and also inhibits the secretion of cytokine by macrophages. We aimed 1) to study the effects of antioxidant (Vitamin C, E and probucol) supplementation on serum level of antioxidant status (TAS), P-selectin, MCP-1, IL-6 and IL-10 and 2) to investigate the effects of antioxidant intake on in-stent restenosis. METHODS: Total 90 patients were assigned to control or antioxidant group (probucol; 500 mg, vitamin C; 1,000 mg, vitamin E; 400 mg). We performed follow up coronary angiography in 35 patients of antioxidant group and 36 patients of control group after 6 months of coronary bare metal stent implantation. We counted the stenotic lesions more than 50% of implanted stent lumen as a restenosis by quantitative coronary angiography. The serum levels of total antioxidant status, P-selectin, MCP-1, IL-6 and IL-10 were measured. RESULTS: The serum levels of total antioxidant status was not elevated in antioxidant group. Antioxidant supplementation did not change the serum levels of P-selectin, MCP-1, IL-6 and IL-10. The 6-month angiographic in-stent restenosis rate was 27% versus 30% (p=NS) with an associated late loss of 0.76+/-1.01 mm versus 0.91+/-1.00 mm (p=NS) for antioxidant group and control group. The serum levels of total antioxidant status did not correlate with the restenosis or late loss after stent implantation. CONCLUSIONS: Vitamin C, E and probucol did not elevate the serum level of antioxidant status and could not prevent in-stent restenosis after bare metal stent implantation.
Antioxidants ; Ascorbic Acid ; Atherosclerosis ; Coronary Angiography ; Coronary Restenosis ; Cytokines ; Follow-Up Studies ; Humans ; Interleukin-10 ; Interleukin-6 ; Lipoproteins ; Macrophages ; Oxidative Stress ; P-Selectin ; Probucol ; Stents ; Vitamin E ; Vitamins

BACKGROUND: Tranilast is an anti-allergic drug that suppresses the release of cytokines. An antioxidant, probucol, prevents endothelial dysfunction and oxidation of low density lipoprotein and also inhibits the secretion of interleukin-1 by macrophages. In several studies, both the tranilast and probucol with multivitamins have been shown to decrease the frequency of angiographic restenosis after PCI. METHODS: We analyzed clinical events and restenosis at 6 months following percutaneous coronary angioplasty in 93 patients with 113 coronary arterial lesions after coronary stenting at Soonchunhyang University Hospital between Jan 2001 and Apr 2003. The patients were assigned to following three groups: 39 patients who didn't receive tranilast and antioxidants (control group, M 29, F 10, 61 +/- 10 years) ; 25 patients who received probucol (500 mg), vitamin C (1,000 mg), vitamin E (400 mg) (antioxidant group, M 19, F 6, 62 +/- 10 years) ; 29 patients who received tranilast (400 mg) (Tranilast group, M 18, F 11, 59 +/- 9 years). RESULTS: The restenosis per lesion between three groups was not different significantly (control group, 32.7%; antioxidant group, 26.7%; Tranilast group, 20.6%). At follow-up, minimal luminal diameter (MLD) was not different significantly between three groups (control group, 1.8 +/- 1.07 mm; antioxidant group, 2.1 +/- 1.18 mm; Tranilast group, 2.1 +/- 0.94 mm). Target lesion revascularization was lower in Tranilast group (3.4%) as compared with control group (25.6%) and antioxidant group (16%, p<0.05). CONCLUSION: Neither probucol combined with vitamin C and E nor tranilast did not improve significantly the angiographic restenosis rate. But tranilast had reduced the target lesion revascularization rate as compared with control group and antioxidant group.
Angioplasty ; Antioxidants ; Ascorbic Acid ; Cytokines ; Follow-Up Studies ; Humans ; Interleukin-1 ; Lipoproteins ; Macrophages ; Percutaneous Coronary Intervention* ; Phenobarbital ; Probucol* ; Stents ; Vitamin E ; Vitamins

BACKGROUND: An antioxidant, probucol, prevents endothelial dysfunction and low density lipoprotein oxidation and also inhibits the secretion of interleukin-1 by macrophages. These effects of probucol may result in decreased production of matrix metalloproteinases by smooth muscle cells and thus modify remodeling of the extracellular matrix. METHODS AND MATERIALS: We analyzed clinical events at 1 month and 6 months in 337 patients with 363 coronary arterial lesions after coronary stenting at Chonnam National University Hospital between January 1998 and May 1999. The patients were assigned to following four modalities: 500 mg of tilcipidine daily (Group I), 200 mg of cilostazol daily (Group II), 500 mg of probucol in addition to 500 mg of ticlipidine daily (Group III), and 500 mg of probucol in addition to 200 mg of cilostazol daily (Group IV). All patients received aspirin. RESULTS: Group I comprised of 149 (104 M, 45 F, 62+/-10 years), Group II 96 (73 M, 23 F, 60+/-10 years), Group III 50 (32 M, 18 F, 61+/-10 years), and Group IV 42 (32 M, 10 F, 62+/-10 years) patients. Clinical diagnosis was not different among four groups. Major adverse cardiac events, including myocardial infarction, cardiac death, and repeated intervention, at 1 month were 7 (4.7%) in Group I, 2 (2.1%) in Group II, 0 (0%) in Group III, 2 patients (4.8%) in Group IV, and those at 6 months were 29 (19.5%) in Group I, 17 (17.7%) in Group II, 9 (18.0%) in Group III, and 6 patients (14.3%) in Group IV. CONCLUSIONS: Probucol combined with aspirin and cilostazol has a tendency reducing the major cardiac events compared with aspirin and ticlopidine or cilostazol after stenting.
Aspirin ; Death ; Diagnosis ; Extracellular Matrix ; Humans ; Interleukin-1 ; Jeollanam-do ; Lipoproteins ; Macrophages ; Matrix Metalloproteinases ; Myocardial Infarction ; Myocytes, Smooth Muscle ; Probucol* ; Stents* ; Ticlopidine