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PubMed1998

Probucol inhibits neointimal formation in carotid arteries of normocholesterolemic rabbits and the proliferation of cultured rabbit vascular smooth muscle cells.

The proliferation of vascular smooth muscle cells (VSMCs) plays an important role in the formation of atherosclerotic lesions and restenosis after angioplasty. It has been suggested that probucol inhibits VSMCs proliferation, but this effect has not been directly demonstrated. In this study we investigated the effect of probucol on neointimal formation after balloon injury in normocholesterolemic rabbits and examined whether probucol could inhibit the proliferation of rabbit cultured VSMC stimulated by fetal bovine serum (FBS). Probucol inhibited the formation of neointima by about 63% 2 weeks after balloon injury. Probucol inhibited the increase in the number of cultured VSMCs and bromodeoxyuridine (BrdU) incorporation stimulated by 10% FBS in a dose-dependent manner. Also, 10% FBS stimulated the activities of mitogen-activated protein kinase (MAP kinase) and protein kinase C (PKC) in cultured VSMCs. Probucol inhibited these activities in a dose-dependent fashion. These results suggest that probucol may inhibit neointimal formation after balloon injury in normocholesterolemic rabbits by preventing the proliferation of VSMCs via inactivation of MAP kinase and PKC.

Animals↗
PubMed1996

Effect of probucol, an oral hypocholesterolaemic agent, on acute tobacco smoke inhalation in rats.

1. We hypothesized that probucol, an oral hypocholesterolaemic agent, can suppress the oxidant stress induced by acute tobacco smoke inhalation in rats. We determined lung tissue glutathione (reduced and oxidized), lipid peroxide, tocopherol and plasma elastase inhibitory capacity, ferroxidase activity and lipid peroxide in rats after inhalation of tobacco smoke. 2. Rats treated with the probucol diet for 3 days or 4 weeks equally showed no suppression of plasma elastase inhibitory capacity and ferroxidase activity compared with control rats after acute tobacco smoke inhalation, although both animals treated with probucol for 3 days or 4 weeks had pharmacologically effective concentrations of probucol to lower plasma cholesterol but plasma cholesterol in rats treated with probucol for 3 days was still in the normal range. 3. Probucol treatment for 4 weeks lessened tobacco smoke-induced suppression of lung tissue glutathione, attenuated tobacco smoke-induced increases in lung tissue lipid peroxide and did not alter lung tissue tocopherol compared with control (lungs). 4. These findings demonstrate that probucol, via its antioxidant ability, confers a protective effect on lung exposed to acute tobacco smoke inhalation.

Animals↗
PubMed1997

High-density lipoproteins from probucol-treated patients have increased capacity to promote cholesterol efflux from mouse peritoneal macrophages loaded with acetylated low-density lipoproteins.

To elucidate the anti-atherogenic effect of probucol, high-density lipoprotein (HDL) was isolated from probucol-treated patients (n = 14) and compared with that from control subjects (n = 12). The HDL obtained from probucol-treated patients was low in cholesteryl ester (CE) in comparison with that from control subjects (21.3 +/- 3.9 mol per cent vs. 27.6 +/- 3.2 mol% of total lipids. P < 0.001), and the peak diameters of patients' HDL were significantly smaller than those of control subjects on 4-30% non-denaturing polyacrylamide gradient gel electrophoresis (10.6 +/- 0.6 nm vs. 12.1 +/- 0.4 nm, P < 0.001). These data may be explained by the increased cholesteryl ester transfer protein (CETP) activities of probucol-treated patients (129 +/- 12% of control subjects, P < 0.001). The in vitro ability of HDL to remove CE from lipid-laden macrophages induced by incubation with acetylated low-density lipoprotein (Ac-LDL) was studied. The small and CE-poor HDL obtained from probucol-treated patients had a greater capacity to promote CE efflux from macrophages than did control HDL (59.8 +/- 6.9% vs. 44.2 +/- 5.4%, P < 0.01). Furthermore, the ability of HDL to promote cholesterol efflux correlated negatively with the CE content and particle diameter of HDL (r = -0.561 and r = -0.583 respectively; P < 0.01). When the inhibitory effect of HDL on the incorporation of [14C]-oleate into cellular cholesteryl ester was compared, the HDL from patients and control subjects inhibited CE formation to a similar extent. The enhanced ability of probucol-treated patients' HDL may, therefore, be involved in the acceleration of hydrolysis of the CE pool in macrophages. Taken together, we conclude that CETP plays a crucial role in making HDL more active in its anti-atherogenic function by reducing CE and making HDL smaller, and that probucol may enhance reverse cholesterol transport by activating CE transfer in vivo. The current study demonstrated, for the first time, that HDL modified by enhanced CETP activity in vivo is potentially anti-atherogenic.

Adult↗
PubMed2004

Probucol inactivates ABCA1 in the plasma membrane with respect to its mediation of apolipoprotein binding and high density lipoprotein assembly and to its proteolytic degradation.

Probucol has been shown to inhibit the release of cellular lipid by helical apolipoprotein and thereby to reduce plasma high density lipoprotein. We attempted to explore the underlying mechanism for this effect in human fibroblast WI-38. Probucol inhibited the apoA-I-mediated cellular lipid release and binding of apoA-I to the cells in a dose-dependent manner. It did not influence cellular uptake of low density lipoprotein, transport of cholesterol to the cell surface whether de novo synthesized or delivered as low density lipoprotein, and overall cellular content of cholesterol, although biosynthesis of lipids from acetate was somewhat increased. Probucol did not affect the mRNA level of ABCA1, and ABCA1 was recovered along with marker proteins for plasma membrane regardless of the presence of probucol. However, the protein level of ABCA1 increased, and the rate of its decay in the presence of cycloheximide was slower in the probucol-treated cells. ABCA1 in the probucol-treated cells was resistant to digestion by calpain but not by trypsin. We concluded that probucol inactivates ABCA1 in the plasma membrane with respect to its function in mediating binding of and lipid release by apolipoprotein and with respect to proteolytic degradation by calpain.

ATP Binding Cassette Transporter 1↗
PubMed2003

Effects of probucol on endothelial damage by 5-fluorouracil.

Cardiotoxicity is a serious side effect of cancer treatment with the commonly used drug 5-fluorouracil (5-FU). The pathophysiology of this is unclear. Experimental studies show a thrombogenic effect of 5-FU, secondary to a direct toxic effect on the endothelium, possibly mediated by radical generation. Probucol is a lipid-lowering drug with strong antioxidant properties. The aim of this study was to evaluate the possibility of using probucol treatment to protect against the toxicity of 5-FU on vascular endothelium of the central artery in the ears of rabbits. Five groups of rabbits were treated with 1) 5-FU, 2) saline, 3) probucol high-dose and saline, 4) probucol high-dose and 5-FU, 5) probucol low-dose and 5-FU. Damage to the arterial endothelium was evaluated by scanning electron microscopy. Damage to the endothelium in 5-FU + probucol-treated animals was minimal and comparable to that of the control group. Intima disruption or thrombus formation was seen with 5-FU only. The results of the study indicate that treatment with probucol prevents 5-FU-induced endothelial injury.

Animals↗
PubMed1980

Comparative ultrastructural study of rat hepatocytes after treatment with the hypolipidemic agents probucol, clofibrate, and fenofibrate.

Experimental findings are reported for two similarly conducted studies. One was designed to compared rat liver cell ultrastructure during and after 91 d of dosing with probucol, a hypocholesterolemic agent, and clofibrate, a hypolipidemic drug known to elicit marked alteration of rat hepatocellular morphology. The second was designed to similarly assess male rats after 28 d of treatment with the hypolipidemic agent fenofibrate. Diet mixes for these studies were prepared to attain dosage levels of approximately 500 mg/kg . d for probucol, 250 mg/kg . d for clofibrate, and 100 mg/kg . d for fenofibrate. Control rats were given untreated basal ration. Weekly adjustments in dietary concentrations were made in accordance with group mean food consumption and body weight changes. Probucol and clofibrate treatments produced statistically significant reductions in mean serum cholesterol levels of both sexes after 28 and 91 d of dosing. Only male rats were given fenofibrate, and they exhibited statistically significant cholesterol reductions after 28 d. Clofibrate and fenofibrate administration resulted in marked increases in liver weight/body weight ratios. Probucol had no statistically significant effects on liver weight/body weight ratios after 28 and 91 consecutive days of treatment. Light microscopy of liver sections stained with hematoxylin and eosin revealed an abnormal amount of cytoplasmic granularity within hepatocytes from rats given clofibrate and fenofibrate. The granules were identified by electron microscopy and cytochemistry as enlarged, proliferated peroxisomes--a known rat hepatocellular response to treatment with many hypolipidemic drugs. In addition, ultrastructural cytochemistry suggested reduced amounts of catalase in individual peroxisomes after clofibrate and fenofibrate dosing. Liver tissue from rats given probucol showed no abnormal cytoplasmic granularity and, ultrastructurally, no peroxisomal changes. Liver tissues from probucol-treated rats revealed features similar to those encountered in tissues from untreated control animals. It was concluded that the hypocholesterolemic response elicited by probucol treatment does not involve significant changes in rat liver cell morphology.

Animals↗
PubMed1991

Probucol reduces myocardial dysfunction during reperfusion after short-term ischemia in rabbit heart.

The effects of probucol, a lipophilic antioxidant, on the myocardial dysfunction (stunning) observed during reperfusion after 15-min ischemia in rabbit heart were studied. Rabbits received food with or without 1% probucol for 3 weeks. They were then anesthetized and prepared for recording of myocardial segment shortening, arterial blood pressure (BP), left ventricular pressure (LVP), rate of development of LVP (dP/dt), and a lead II ECG. Regional myocardial ischemia was produced by acute occlusion of the first marginal branch of the left coronary artery. Myocardial segment shortening was depressed after reperfusion in control rabbits. In comparison, myocardial segment shortening was significantly greater in probucol-treated rabbits than in control rabbits during reperfusion, indicating a beneficial effect. No hemodynamic or ECG changes measured could explain this difference. The number of premature ventricular contractions was reduced in the probucol-treated group, although the incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF) were not. Concentrations of probucol in serum and heart of five rabbits were 15.0 +/- 1.2 micrograms/ml and 17.5 +/- 2.5 micrograms/g (mean +/- SEM), respectively. Only probucol concentrations in the serum were positively correlated with the improvement in myocardial segment shortening (r = 0.91, p = 0.03). We conclude that a clinically relevant serum concentration of probucol reduces ischemia-induced myocardial stunning in the rabbit.

Animals↗
PubMed2003

Induction of NAD(P)H:quinone reductase by probucol: a possible mechanism for protection against chemical carcinogenesis and toxicity.

Dietary antioxidants protect laboratory animals against induction of tumours by a variety of chemical carcinogens. Among possible mechanism, protection against chemical carcinogenesis could be mediated via antioxidant-dependent induction of detoxifying enzymes, including quinone reductase and glutathione S-transferase (GSH transferase). Probucol is used cholesterol-lowering drug used in the clinic, with pronounced antioxidant effect that protect against chemical carcinogenesis and toxicity. In the present study we therefore examined the ability of probucol to induce activities of quinone reductase in the cytosolic fractions of various tissues of mice. Quinone reductase activity was increased significantly in 6 of 8 tissues examined from probucol-fed mice. The greatest proportionate increase, to 1.8 times control levels, was observed in liver. Probucol also increased quinone reductase activities of forestomach, heart, kidney, lungs and spleen. Quinone reductase is a major enzyme of xenobiotic metabolism that carries out obligatory two-electron reductions and thereby protects cells against toxicity of quinones. It is induced in many tissues coordinately with other enzymes that protect against electrophilic toxicity. The protective effects of probucol appear to be due, at least in part, to the ability of this antioxidant to increase the activities in rodent tissues of several enzymes involved in the non-oxidative metabolism of a wide variety of xenobiotics. The induction of such enzyme, quinone reductase by probucol suggests the potential value of this compound as a protective agent against chemical carcinogenesis and other forms of electrophilic toxicity. The significance of these results can be implicated in relation to cancer chemopreventive effects of probucol in various target organs.

Animals↗
PubMed2005

Processes involved in the site-specific effect of probucol on atherosclerosis in apolipoprotein E gene knockout mice.

OBJECTIVE: To elucidate processes by which the antioxidant probucol increases lesion size at the aortic sinus and decreases atherosclerosis at more distal sites in apolipoprotein E-deficient (apoE(-/-)) mice. METHODS AND RESULTS: Male apoE(-/-) mice were fed high-fat chow with 1% (w/w) probucol or without (controls) for 6 months, before aortic sinus, arch, and descending aorta were analyzed separately for lesion size and composition. Compared with control, probucol significantly increased lesion size by 33% at the sinus, but it inhibited atherosclerosis at the descending aorta by 94%. Sites where atherosclerosis was inhibited contained substantially fewer macrophages, less lipids (cholesterol and cholesteryl esters), and endogenous antioxidant (alpha-tocopherol), but not oxidized lipids, and the extent to which probucol metabolism occurred was increased. Compared with control, aortic sinus lesions of probucol mice contained a substantially increased content of extracellular matrix, but decreased total cell and macrophage density, comparable levels of lipids and alpha-tocopherol, and decreased concentrations of oxidized lipids (cholesteryl ester hydroperoxides, F2-isoprostanes, and 7-ketocholesterol). CONCLUSIONS: Probucol affects atherosclerosis in apoE(-/-) mice independent of the accumulation of arterial lipid oxidation products, thereby dissociating the 2 processes. Rather, probucol exerts antiinflammatory activity by decreasing accumulation of macrophages in lesions, and it promotes a more stable lesion composition at the aortic sinus.

Animals↗
PubMedDate not supplied

Probucol treatment affects the cellular composition but not anti-oxidized low density lipoprotein immunoreactivity of plaques from Watanabe heritable hyperlipidemic rabbits.

Use of the antioxidant probucol has been associated with a reduction in the development of atherosclerotic lesions in Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of familial hypercholesterolemia. In this study, atheromatous lesions from control or probucol-treated WHHL rabbits were probed with monoclonal antibodies to evaluate whether use of this drug either affected the presence or distribution of epitopes recognized by an antibody against oxidized low density lipoprotein or altered the cellular makeup of lesions. Although probucol-treated animals had much less aortic atherosclerosis than did controls, equivalent immunoreactivity for the anti-oxidized LDL antibody (OXL 41.1) was demonstrated in atherosclerotic lesions of both groups of animals, consistent with a role for oxidative modification of lipoproteins in atherogenesis in this animal model. Use of smooth muscle cell-specific (HHF-35) and macrophage-specific (RAM-11) antibodies demonstrated that lesions from probucol-treated animals were significantly smaller (p less than 0.01) and less cellular (p less than 0.05) than were control lesions. In addition, smooth muscle cells were the predominant cell type in lesions from probucol-treated animals, whereas macrophages predominated in lesions from controls (p less than 0.01). These findings are consistent with a reduction of monocyte/macrophage recruitment into or retention in lesions in probucol-treated animals, or with probucol-induced alterations in the production of growth factors or cytokines that might influence the cellular makeup of atherosclerotic lesions.

Animals↗
PubMed1992

Transport of HDL cholesterol esters to the liver is not diminished by probucol treatment in rats.

This study examined the relation of decreased high density lipoprotein (HDL) levels in probucol-fed rats and the transport of HDL cholesterol esters (CEs) to the liver. HDLs from both control rats and rats fed 1% probucol for 3 weeks were doubly labeled in their CE and apolipoprotein A-I moieties with intracellularly trapped tracers and then intravenously injected into probucol-fed or control rats for determination of plasma decay kinetics and sites of tracer uptake. Results for HDL from control and probucol-fed rats were not different. The fractional catabolic rate (FCR) of plasma HDL CE was significantly increased by probucol feeding (23%) so that mass transport of HDL CE through the plasma compartment was not significantly different from that in control rats. The plasma FCR for apolipoprotein A-I did not change. Similarly, the FCR for uptake of HDL CE by the liver increased on probucol feeding (20%), resulting in a near-normal rate of HDL CE mass uptake, whereas the FCR for HDL particle uptake (measured by apolipoprotein A-I uptake) did not change. Thus, the maintenance of near-normal HDL CE uptake by the liver was exclusively due to increased selective uptake (32%). To the extent that hepatic uptake of HDL CE mediates reverse cholesterol transport, that process was not significantly compromised in rats fed 1% probucol.

Animals↗
PubMed1992

Probucol increases the selective uptake of HDL cholesterol esters by Hep G2 human hepatoma cells.

A previous study in rats showed that even though probucol substantially lowers high density lipoprotein (HDL) levels, near-normal mass transport of HDL cholesterol esters (CE) to the liver is maintained by the induction of "selective" (direct) uptake of HDL CE. The present study describes a parallel result in cultured Hep G2 human hepatoma cells. Cells were preincubated in the presence or absence of probucol before measuring the uptake of doubly labeled HDL3 in the absence of probucol. Preincubation with probucol decreased the uptake of HDL3 particles (iodine-125-labeled N-methyltyramine cellobiose-apolipoprotein [125I-NMTC-apo] A-I uptake) but increased the uptake of [3H]cholesteryl oleyl ether in excess of 125I-NMTC-apo A-I (i.e., selective uptake) in a dose-dependent fashion. The reversibly cell-associated pool of CE tracer, a precursor for selective uptake, enlarged on probucol treatment, but the increase was not in proportion to the increase in selective uptake. HDL3 particle uptake decreased on probucol treatment. The decrease was evident after less than 20 minutes of probucol exposure and was maximal after 6 hours; in contrast, HDL3 CE selective uptake increased only after greater than 13 hours and had not reached a plateau after 20 hours. Thus, effects on particle uptake and selective uptake were dissociated in time.

Carcinoma, Hepatocellular↗
PubMed1994

Comparative study on the effect of low-dose vitamin E and probucol on the susceptibility of LDL to oxidation and the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbits.

The diet of Watanabe heritable hyperlipidemic (WHHL) rabbits was supplemented with a low dose (0.025% [wt/wt]) of the antioxidant vitamin E or probucol. The effect of 6 months of treatment on the susceptibility of low-density lipoproteins (LDLs) to oxidative modification and on established atherosclerotic lesions was studied. Vitamin E administration had no effect on plasma lipid levels; probucol supplementation decreased plasma total cholesterol. Vitamin E levels in plasma and LDL increased threefold in the course of treatment with this antioxidant. Six months of treatment with vitamin E and probucol increased the lag time of conjugated-diene formation of LDL subjected to in vitro oxidation by 54% (P < .001) and 51% (P = .019), respectively. In this LDL-oxidizability assay, only vitamin E reduced the maximal rate of conjugated-diene production (-24%, P < .001). Neither vitamin E treatment nor probucol therapy reduced the amount of thiobarbituric acid-reactive substances in plasma. Vitamin E treatment reduced the specific LDL apolipoprotein B-100 fluorescence (-10%, P = .035) compared with controls. Probucol was without effect on this index of in vivo LDL oxidation. At the end of the 6-month study, the mean +/- SD percentage area of aorta covered with plaques was 58.7 +/- 10.1% in control animals, 62.7 +/- 12.0% in the probucol-treated animals, and 48.9 +/- 13.8% in the animals treated with vitamin E; these differences were not significant. This study demonstrates that at this low dosage, vitamin E is a more effective antioxidant than probucol.

Animals↗
PubMed2003

Probucol promotes functional reendothelialization in balloon-injured rabbit aortas.

BACKGROUND: Probucol remains the only conventional drug that reduces restenosis after coronary angioplasty. Apart from its weak cholesterol-lowering effect, probucol has antioxidant properties, but it remains unclear how this drug inhibits restenosis. METHODS AND RESULTS: Aortic balloon-injured New Zealand White rabbits were fed 2% (wt/wt) cholesterol-enriched or normal chow, with 0.75% (wt/wt) probucol (P) or without (controls, C) for 6 weeks. Endothelial denudation of the abdominal aorta was performed at week 3 with a 3F Fogarty embolectomy catheter. The arteries were harvested after week 6 and analyzed for histology, lipids and antioxidants, and endothelial regeneration and function. Probucol significantly decreased aortic intima-to-media ratio (cholesterol-fed: C, 1.10+/-0.08 versus P, 0.70+/-0.10; normal: C, 0.89+/-0.02 versus P, 0.83+/-0.05; P<0.05) and the numbers of proliferating intimal smooth muscle cells and lowered serum cholesterol without altering the proportion of aortic lipids that was oxidized. Probucol promoted endothelial regeneration in the injured aorta in cholesterol-fed rabbits (25% increase in reendothelialization, P<0.05) and in those on normal chow (37% increase, P<0.01). This was associated with both improved endothelial function as assessed by enhanced aortic ring relaxation and cGMP production in response to acetylcholine and decreased intimal thickening. CONCLUSIONS: Probucol inhibits intimal thickening in balloon-damaged arteries of rabbits by promoting the regeneration of functional endothelium, without affecting the proportion of aortic lipids that was oxidized. This novel in vivo finding helps explain how probucol inhibits restenosis after coronary angioplasty and highlights potential new targets for therapeutic intervention.

Angioplasty, Balloon↗
PubMed1997

Paradoxical enhancement of atherosclerosis by probucol treatment in apolipoprotein E-deficient mice.

Dietary administration of probucol (0.5%, wt/wt) efficiently reduced total plasma cholesterol levels in apolipoprotein E-deficient mice (apoE-/-) by 40%, with decreases in high density lipoprotein (HDL) and apoAI by 70 and 50%, respectively. Paradoxically, however, aortic atherosclerotic plaques in the probucol-treated apoE-/- mice formed more rapidly than in the untreated apoE-/- mice, and the lesions were two to four times larger and more mature regardless of sex, age, and genetic background (P < 10(-)6). Histologically, lesions in probucol-treated mice contained increased fibrous materials and cells other than foam cells, and were commonly associated with focal inflammation and aneurysmal dilatation. Probucol treatment also accelerated lesion development in apoE+/- mice fed an atherogenic diet, indicating that the adverse effect is not dependent on the complete absence of apoE. Furthermore, mice lacking apoE and apoAI have plasma lipoprotein profiles very similar to the probucol-treated apoE-/- mice, but do not have accelerated plaque development. Thus, the enhanced atherosclerosis in the probucol-treated animals is unlikely to be caused by the reduction of HDL and apoAI levels. Our data indicate that a reduction in plasma cholesterol caused by probucol does not necessarily lead to an antiatherogenic effect.

Animals↗
PubMed2004

Probucol as a potent inhibitor of oxygen radical-induced lipid peroxidation and DNA damage: in vitro studies.

Probucol, a clinically used cholesterol lowering and antioxidant drug, was investigated for possible protection against lipid peroxidation and DNA damage induced by iron nitrilotriacetate (Fe-NTA) plus hydrogen peroxide (H2O2). Fe-NTA is a potent nephrotoxic agent and induces acute and subacute renal proximal tubular necrosis by catalyzing the decomposition of H2O2-derived production of hydroxyl radicals, which are known to cause lipid peroxidation and DNA damage. Fe-NTA is associated with a high incidence of renal adenocarcinoma in rodents. Lipid peroxidation and DNA damage are the principal manifestation of Fe-NTA induced toxicity, which could be mitigated by probucol. Incubation of renal microsomal membrane and/or calf thymus DNA with H2O2 (40 mM) in the presence of Fe-NTA (0.1 mM) induces renal microsomal lipid peroxidation and DNA damage to about 2.4-fold and 5.9-fold, respectively, as compared to control (P < 0.05). Induction of renal microsomal lipid peroxidation and DNA damage was inhibited by probucol in a concentration-dependent manner. In lipid peroxidation protection studies, probucol treatment showed a concentration-dependent inhibition (10-34% inhibition; P < 0.05) of Fe-NTA plus H2O2-induced lipid peroxidation as measured by thiobarbituric acid reacting species' (TBARS) formation in renal microsomes. Similarly, in DNA damage protection studies, probucol treatment also showed a concentration-dependent strong inhibition (36-71% inhibition; P < 0.05) of DNA damage. From these studies, it was concluded that probucol inhibits peroxidation of microsomal membrane lipids and DNA damage induced by Fe-NTA plus H2O2. However, because the lipid peroxidation and DNA damage studied here are regarded as early markers of carcinogenesis, we suggest that probucol may be developed as a cancer chemopreventive agent against renal carcinogenesis and other adverse effects of Fe-NTA exposure in experimental animals, in addition to being a cholesterol-lowering drug, useful for the control of hypercholestrolemia.

Animals↗
PubMed1989

Comparative study of bezafibrate and probucol in hyperlipidaemia.

Sixty out-patients diagnosed as having hyperlipidaemia, with a cholesterol level of greater than 200 mg/dl and/or a triglycerides level of greater than 200 mg/dl, took part in the trial. Patients were divided at random into two groups to receive pharmacological treatment plus diet; one group was given 500 mg probucol twice a day and the other group 200 mg bezafibrate twice or 3-times a day for an average treatment period of 60 days. The percentage changes in serum lipids, i.e. total cholesterol, triglycerides, HDL-cholesterol, and LDL-cholesterol, were evaluated by comparing the values before and at the end of treatment, and tolerability of the drug in use was evaluated from the appearance of adverse reactions and the ECG and blood pressure parameters. Whereas total cholesterol and LDL-cholesterol levels were reduced to a similar extent in both groups (cholesterol - 42% bezafibrate, 38.3% probucol; LDL-cholesterol - 30.8% bezafibrate, 26.5% probucol), triglycerides were reduced to a significantly greater extent (p less than 0.05) in the benzafibrate group (55.5%) than in the probucol group (24.0%). The most significant percentage change (p less than 0.005) was found with HDL-cholesterol; in the bezafibrate group, levels increased by 19.0% compared with a 11.8% reduction in the probucol group. Four (13.3%) patients on bezafibrate and 5 (16.7%) on probucol reported mild to moderately severe side-effects, mainly gastro-intestinal, but in no case was treatment interrupted, although benzafibrate dosage was temporarily reduced. ECG changes (prolongation of QTc) were recorded in 3 patients on probucol and these reverted to normal after the end of the trial.

Adult↗
PubMed1994

Probucol-induced QT prolongation and syncope.

We report a patient who experienced a reversible prolongation of the QT interval and episodes of syncope while receiving probucol. A 64-year-old woman experienced syncopal attacks 8 and 11 weeks after beginning probucol treatment (500 mg twice daily). The pre-treatment ECG showed a slight prolongation of the corrected QT interval (QTc) (0.46 sec). Her QTc increased to 0.62 sec 12 weeks after beginning probucol treatment and decreased to about the baseline value (0.48 sec) 6 weeks after treatment was discontinued. Probucol is known to prolong the QT interval. A long QT interval has been linked to an increased risk of ventricular arrhythmias, syncope or sudden death. However, clinical reports which causally relate probucol treatment to syncope are very rare. Although an ECG during the episodes of syncope was not available, this patient's syncope might be due to ventricular tachyarrhythmia associated with probucol-induced QT prolongation. This case emphasizes the need for careful evaluation of the QT interval before and during probucol treatment.

Atrial Fibrillation↗