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[The "duration of administration" factor in studies of clinical pharmacology of hypolipemic drugs].

Clinical pharmacological trials of lipid lowering drugs should first of all indicate the duration of interruption of previously used lipid lowering drugs. The duration of interruption should be at least 4 weeks for inhibitors of HMG CoA reductase, 6 weeks for a second generation fibrate or a resin and over 6 months for probucol. In order to obtain the maximum therapeutic effect, a 4 week treatment period is sufficient for a HMG CoA reductase inhibitor or a resin. On the other hand, this period is longer for a fibrate and a 6 week treatment period is to be preferred with this family of drugs. The efficacy of probucol on the lipid fractions can only be assessed after several months' therapy. In future, a more accurate classification of patients with respect to their physiopathology should provide a better evaluation of the comparative efficacy of the different lipid lowering drugs.

Clinical Trials as Topic↗

[Effect of xiongshao capsule on vascular remodeling in rabbit with experimental atherosclerosis].

OBJECTIVE: To study the effect of Xiongshao Capsule (XSC) on vascular remodeling in experimental atherosclerotic (AS) rabbits, and to explore the possible mechanisms. METHODS: Rabbit's fractional AS model was established by denuding and injuring the abdominal artery with 4F.Fogarty catheter, and followed with high cholesterol feeding. The animals were randomly divided into 8 groups, namely, the modeled group of 3 days, 2 weeks and 6 weeks after balloon injury (A, B and C); the single endothelium injury group (D), the probucol treating group (E), the low-dose and high-dose XSC treating group (F and G) and the normal control group (N). Except the rabbits in Group N and D, the other groups were all fed with high fat forage. Histopathological examination of abdominal aorta with the most obvious lesion was performed, and the changes of related vascular remodeling indexes after arterial injury were observed using computerized image analyzing system; the correlation analysis between progress of intimal proliferation and vascular remodeling were performed as well. RESULTS: Artery intimal proliferation progressed gradually as time went on, which was more significant in Group C as compared with that in Group B and D (P < 0.01). All the drugs could reduce the maximum intima thickness (MIT). Moreover, both high-dose XSC and Probucol profoundly decreased the intima area (IA), showing significant difference as compared with that in Group C (P < 0.01). The internal elastic laminal area (IELa), external elastic laminal area (EELa), minimum lumen diameter (MLD) and lumen area (LA) in Group A increased significantly, as compared with that in Group N (P < 0.01). At 6 weeks after balloon injury, with the further intimal thickening, IELa, EELa reduced contrarily, resulting in insufficient vascular compensation, lumen stricture and MLD reduction (P < 0.01). Improvement of MLD and LA was shown in all the drug treated groups, with significant difference in comparing with those in Group C (P < 0.01). CONCLUSION: Single endothelium injury may be one of the initiating elements of pathological vascular remodeling, which could be intensified by hyperlipemia. Intimal proliferation and vascular remodeling jointly participated in the pathological course of AS lumen stricture after endothelium injury. XSC plays its action in preventing and treating AS through inhibiting intimal proliferation after balloon injury and intervening pathological vascular remodeling.

Animals↗

[The use of antioxidants and antihypoxants for decreasing of LDL oxidation by macrophages and endothelial cells in ischemia and reperfusion of vascular wall].

Oxidative modification of LDL is a key factor in pathogenesis of atheroslerosis. In this work the effects of antioxidants (K-phenosan, probucol, and desferal) and antihypoxants (succinic acid, hypoxen, and deltaran) on the macrophage- and endothelial cell-mediated oxidation of LDL was studied. Electrophoretic mobility of LDL, the content of lipid peroxide products (TBARS and diene conjugates, DC) and cell viability were used as the indexes of LDL oxidation. The effectiveness of antioxidants as inhibitors of LDL oxidation decreased in the following order: desferal > probucol > K-phenosan, and antihypoxant ability was decreased in line: deltaran >> succinic acid (effect only in dose 40 mg/ml) >> hypoxane (no effect). The effect antioxidants on protection of cell viability (MP and EC) during ischemia reduced in the same order. The effectiveness of antihypoxant protection of MP viability, decreased in the following order: succinic acid > hypoxen >> deltaran. Macrophages added to 24 h ischemized EC + LDL in early reperfusion period decreased LDL EPM. This may apparently be attributed to selective uptake of oxidized LDL by MP.

Antioxidants↗

Relationship between free radicals produced by entamoeba histolytica and its proteases complex activity.

Entamoeba histolytica is a parasite which causes health problems and there has been many approaches to know what is the factor causing its pathogenicity. In the present work, we assayed if the production of free radicals by the amoeba, has a relationship with the proteases activity. When we test the DMSO action (free radicals quenching activity) the specific activity of the proteases complex of the parasite were affected also. At 33.3% (V/V) concentration of DMSO it was present a maximal decrease of the initial activity (about 46% decrease), for to a higher concentrations existing a trend to recuperate the original activity, suggesting that the free radicals are an important factor for the hydrolysis grade of the protein substrate. All the differences except those between 46.7 and 66.6%, were significantly different compared with the control without any addition. The effects of Probucol and Probucol plus DMSO, compared to those caused by Metronidazol (MZ). We can observe that the quenchers caused a decrease on proteases activity similar to that of MZ (which is an antiparasite drug) and it was of c.a. 58% of activity decrease. These data suggest that the action of both, free radicals and proteases complex of Entamoeba histolytica, can account for the pathogenicity of the parasite.

Animals↗

[Study of LDL receptors and response to lovastatin therapy in familial homozygotic hypercholesterolemia].

This study shows the results obtained with lovastatin as a combined therapy with probucol and cholestyramine on the lipid profile of two patients with homozygous familial hypercholesterolemia. Both have been diagnosed according to the clinical and biochemical criteria (tipe IIa hypercholesterolemia) as well as by the cholesterol or low density lipoprotein (LDL-C) receptor analysis. After the initial probucol and cholestyramine treatment we observed a drop of total cholesterol (T-C) of 41.7% and 46% as well as LDL-C of 51.6% and 49.3% in both patients. Respectively when lovastatin were associated an additional drop of T-C of 23.7%, LDL-C of 23.2%, high-density lipoprotein cholesterol (HDL-C) of 22.4% and the apoprotein B (Apo B) of 37% were obtained in one patient (receptor-defective) but no change in the lipid profile were obtained in the other patient (receptor-negative). No adverse effects were observed with this drug. This drug could be of help as a combined therapy in the treatment of homozygous familial hypercholesterolemia, even though the treatment of choice is the LDL-plasma feresis and/or liver transplantation. We expound the difficulties relate to LDL receptor study in homocygous receptor-negative patients.

Cholestyramine Resin↗

Rationale and management of hyperlipidemia of the nephrotic syndrome.

Hyperlipidemia is usually present in patients with the nephrotic syndrome. The most common lipid abnormality is hypercholesterolemia, although as the disorder progresses, hypertriglyceridemia may develop. Elevated plasma lipids have two potential vascular consequences, namely, atherosclerosis and progression of renal failure. Neither of these complications has been proven with certainty, but there is growing evidence to indicate that both may be long-term consequences of the nephrotic syndrome. Therefore, effective therapy of hyperlipidemia, particularly elevated cholesterol levels, is needed as a protection against these complications. Since nephrotic hypercholesterolemia frequently is severe, dietary therapy, although a valuable adjunct, will not normalize cholesterol levels in most nephrotic patients. Thus, if effective serum cholesterol lowering is to be achieved, drug therapy will be required. Bile acid-binding resins have been shown to lower cholesterol levels in nephrotic patients, but the decline in cholesterol concentrations is usually insufficient to produce a marked reduction in coronary risk. Nicotinic acid theoretically should be useful for treatment of nephrotic hyperlipidemia, but it has not been adequately tested. The new drugs that inhibit cholesterol synthesis, e.g., lovastatin, appear to be highly promising for treating elevations of both serum cholesterol and triglycerides in the nephrotic syndrome. However, testing of these drugs in this condition has been limited, and the possibility of significant side effects in an appreciable portion of patients has not been ruled out. Of particular concern is the development of severe myopathy that can produce myoglobinuria and acute renal failure. This side effect is relatively rare in patients without the nephrotic syndrome, but its prevalence in the latter condition has not been determined. The fibric acids will lower triglyceride levels in nephrotic patients, but they are not effective in lowering cholesterol levels; consequently, they probably have little role in the treatment of nephrotic hypercholesterolemia. Finally, the drug probucol will lower cholesterol levels in nephrotic patients, although not to desirable levels; still, probucol could prove useful in combination with other cholesterol-lowering drugs.

Humans↗

Multifactorial primary prevention of cardiovascular diseases in middle-aged men. Risk factor changes, incidence, and mortality.

In a randomized five-year multifactorial primary prevention trial of vascular diseases, hyperlipidemias, hypertension, smoking, obesity, and abnormal glucose tolerance of the high-risk test group (n = 612 men) were treated with dietetic-hygienic measures and hypolipidemic (mainly probucol and clofibrate) and antihypertensive (mainly diuretics and beta-blockers) agents. A matched high-risk control group (n = 610) and a low-risk control group (n = 593) were not treated. The program markedly improved the risk factor status, yet the five-year coronary incidence tended to be higher in the intervention group than in the control group (3.1% vs 1.5%), while the stroke incidence was significantly reduced (1.3% vs 0%). The coronary events tended to be accumulated in subgroups treated with beta-blocking agents or clofibrate, but there were few in those receiving probucol or diuretics. Thus, the intervention program significantly reduced development of stroke, but the occurrence of cardiac events was not prevented. Possible adverse drug effects offsetting the probable benefit of improved risk profile are not excluded.

Antihypertensive Agents↗

Carvedilol, a new vasodilating beta-adrenoceptor blocker, inhibits oxidation of low-density lipoproteins by vascular smooth muscle cells and prevents leukocyte adhesion to smooth muscle cells.

The present study was undertaken to assess the effect of carvedilol, a new vasodilating beta-adrenoceptor blocker with antioxidant activity, on the oxidation of low-density lipoproteins (LDL) by rat aortic smooth muscle cells (RASMC). LDL oxidation was assessed as thiobarbituric acid reactive substances (TBARS) formation and increase in electrophoretic mobility. Oxidized (ox) LDL-induced cytotoxicity was assessed as lactate dehydrogenase release (LDH) from cells and ox-LDL-enhanced adhesiveness of the RASMC for leukocytes was also determined. Carvedilol inhibited TBARS formation and LDH release from RASMC with IC50 values of 1.74 and 1.62 microM, respectively. Under the same conditions, the IC50 values of probucol and nicardipine were 2.33 and 5.60 microM, respectively, for inhibition of TBARS and 5.16 and 12.10 microM, respectively, for inhibition of LDH release; propranolol, atenolol, pindolol and labetalol, at concentrations up to 100 microM, had virtually no effect on either variable. RASMC-dependent ox-LDL stimulated the adhesive properties of RASMC for both monocytes and neutrophils in a concentration- and time-dependent manner, which were prevented when the RASMC were treated with carvedilol (IC50 2.07 microM for monocytes and 1.12 microM for neutrophils), whereas other beta blockers, at concentrations up to 30 microM, had only mild effects. The monoclonal antirat intercellular adhesion molecule-1 antibody partially inhibited ox-LDL-induced adhesion of RASMC for monocytes and neutrophils. Northern analysis demonstrated that ox-LDL induced intracellular adhesion molecule-1 messenger RNA expression on RASMC, which was inhibited by carvedilol and probucol via inhibition of LDL oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

Torsade de pointes and sudden death associated with diabetic autonomic diarrhoea--a case report.

A 68-year-old diabetic and hypertensive woman presented with chronic autonomic diarrhoea, syncope and palpitations which were associated with QT prolongation and recurrent episodes of torsade de pointes. She was on glibenclamide, indapamide and probucol (for type V hyperlipidaemia). Despite intravenous infusions of potassium, lignocaine and amiodarone, the unstable rhythm persisted. However, intravenous magnesium sulphate with small doses of intravenous propranolol terminated the torsade de pointes. She was stabilised but following discharge she relapsed, and upon re-admission, succumbed to intractable ventricular fibrillation. Early recognition and aggressive treatment of this condition is emphasised. Multiple aggravating factors ie autonomic diarrhoea resulting in severe potassium and magnesium depletion, kaliuretic effect of indapamide, probable QT prolongation associated with diabetic autonomic neuropathy and probucol; probable underlying coronary artery disease and heightened emotional and sympathetic discharge could have contributed to this very unstable ventricular arrhythmia and sudden death.

Aged↗

Potential emerging therapeutic strategies to prevent restenosis in the peripheral vasculature.

Despite the availability of antiplatelet and antithrombotic therapies, recent advances in catheter and stent technology and improved operator skill, restenosis remains the most frequent problem associated with percutaneous and surgical revascularization interventions for both coronary and peripheral arterial disease. Prevention of restenosis in the coronary vasculature has been demonstrated with cilostazol, trapidil, probucol, tranilast, nitric oxide donors, and clopidogrel. Given the similarities in revascularization procedures and in the pathophysiology of restenosis, it is possible that these results may be extrapolated to the setting of restenosis in the peripheral vasculature, making trials with these agents imperative. Several new agents have shown promising preliminary results for the prevention of restenosis in the peripheral vasculature, including cilostazol, low-molecular-weight heparins, and elastase. Several nonpharmacologic treatment modalities are also under study to prevent peripheral and coronary restenosis and have shown favorable initial results. These include endovascular radiation brachytherapy, arterial gene therapy, photoangioplasty, and several novel treatment delivery systems.

Animals↗

Role of cholesteryl ester transfer protein in reverse cholesterol transport.

Cholesteryl ester transfer protein (CETP) and apolipoprotein E (apo E) play important roles in reverse cholesterol transport in humans. CETP transfers cholesteryl ester (CE) from high-density lipoprotein (HDL) to other lipoproteins, mainly very low-density lipoprotein (VLDL) remnants, which provide a vehicle for the delivery of HDL-derived CE to the liver via apo E or B/E receptors. Using a sensitive and specific radioimmunoassay, we have demonstrated that plasma concentrations of CETP vary dependent on gender, the concentration and composition of plasma lipoproteins, and dietary cholesterol intake. Plasma CETP appears to increase as an adaptive response to increased peripheral flux of cholesterol. Probucol therapy results in a significant increase in plasma CETP concentration, which may explain, in part, the marked effect of this agent on HDL concentration and composition.

Apolipoproteins E↗

A simple luminescence method for detecting lipid peroxidation and antioxidant activity in vitro.

The excited carbonyl species formed during lipid peroxidation may transfer their energy to dye molecules containing heavy atoms such as rose bengal to produce excited singlet state dye molecules. The excited dye then emits photons to return to its ground state. The aim of the present study was to investigate the relationship between methemoglobin (metHb)-induced lipid peroxidation, rose bengal luminescence, and O2 consumption in a system containing 0-850 mu M phospholipid and 1 mu M metHb and 1 mu M rose bengal in Tris-HCl buffer, pH 7.4. The rapid rise in rose bengal luminescence was accompanied by a rapid rise in O2 consumption. Further, the luminescence of rose bengal could be quenched by alpha -tocopherol or probucol present in the phospholipid liposomes, with the latter being strikingly more effective than the former. This simple luminescence method is a useful practical approach to detect lipid peroxidation and determined antioxidant effects of water insoluble compounds in vitro.

Antioxidants↗

The effect of antioxidants on glycated albumin-induced cytotoxicity in bovine retinal pericytes.

Loss of retinal pericytes is the initial deficit in the early stage of diabetic retinopathy. Glycated albumin (GA) forms under hyperglycemic conditions and exists in the retinal blood vessels of diabetic patients with retinopathy. In this study, using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) reduction test, we investigated whether GA induces cytotoxicity in cultured bovine retinal pericytes, and whether the antioxidants, l-ascorbic acid, Trolox, and probucol, provide any protection from GA-mediated cytotoxicity. GA induced pericyte death in a dose-dependent manner. With increasing time, GA-induced cytotoxicity also increased despite no strict time dependence. Furthermore, this cell death was found to be mediated both by apoptosis, which was confirmed by apoptosis-specific fluorescent staining of nuclei and cell membranes, and mitochondrial damage, as elucidated by electron microscopy. All three antioxidants used in this study partially protected against GA-induced pericyte death, suggesting that oxidative stress plays a role in GA-induced pericyte death. The results indicate that GA induces cell death in cultured bovine retinal pericytes, and that certain antioxidants may reduce this cytotoxicity.

Animals↗

The relative roles of advanced glycation, oxidation and aldose reductase inhibition in the development of experimental diabetic nephropathy in the Sprague-Dawley rat.

Advanced glycation is an important pathogenic mechanism in the development of diabetic complications. However, other biochemical processes, such as the polyol pathway or lipid and protein oxidation which can interact with advanced glycation can also yield tissue fluorescence and may also be implicated in the genesis of diabetic microangiopathy. Aminoguanidine is an inhibitor of advanced glycation, but it is not known if all of its effects are mediated by this mechanism. The present study explores the relative contributions of aldose reductase, oxidative stress and advanced glycation on the development of aortic and renal fluorescence and urinary albumin excretion in streptozotocin diabetic rats. The study groups included non-diabetic (control), streptozotocin diabetic rats and diabetic rats receiving aminoguanidine, the anti-oxidants butylated hydroxytoluene and probucol and the aldose reductase inhibitor, ponalrestat. Serial measurements of glycaemic control and urinary albumin excretion were performed every 8 weeks. At 32 weeks, animals were killed, tissues removed and collagen extracted for measurement of fluorescence. Diabetic rats had increased fluorescence in aorta, glomeruli and renal tubules. Aminoguanidine prevented an increase in fluorescence at all three sites suggesting that diabetes-related tissue fluorescence is predominantly due to advanced glycation. Ponalrestat retarded fluorescence in aorta only and butylated hydroxytoluene attenuated fluorescence at the renal sites but not in the aorta. Diabetic rats had increased renal cortical sorbitol levels. Ponalrestat normalized renal cortical sorbitol levels but aminoguanidine did not affect this parameter. The only agent to decrease plasma thiobarbituric acid reactive substances was butylated hydroxytoluene. Diabetic rats developed albuminuria over the 32-week period.(ABSTRACT TRUNCATED AT 250 WORDS)

Albuminuria↗

Macrophages enhance binding of beta-VLDL and cholesterol ester accumulation in cultured aortic smooth muscle cells.

The effect of macrophages on the uptake of beta-very low-density lipoprotein (beta-VLDL) by smooth muscle cells (SMC) expressing different morphological phenotypes was examined in culture. The SMC were grown alone and in co-culture with macrophages for four days, then incubated with different concentrations of 125I-beta-VLDL for 3 h at 4 degrees C or with 75 ug/ml beta-VLDL for 24 h at 37 degrees C. The binding of beta-VLDL to SMC at 4 degrees C was enhanced in the presence of macrophages irrespective of the phenotype expressed by SMC. This occurred through modification of the lipoprotein, since binding of re-isolated macrophage-conditioned beta-VLDL to SMC was 12.5 times that of fresh beta-VLDL. This modified form of beta-VLDL competed with fresh beta-VLDL for binding to SMC. Binding was inhibited in the presence of probucol, suggesting that an oxidative mechanism may be involved. The presence of macrophages also enhanced the accumulation of beta-VLDL-derived cholesterol in SMC. While most of this is a consequence of the enhanced binding, macrophages may also act directly on SMC to increase cholesterol accumulation, since the activity of acid cholesterol ester hydrolase and neutral cholesterol ester hydrolase in SMC was reduced in the presence of macrophages.

Animals↗

Dieldrin-14C elimination from chickens.

A series of experiments was conducted with chickens contaminated with dieldrin-14C to find ways of accelerating the elimination of dieldrin from their bodies. The results of these experiments indicated that charcoal, imbiber beads, and the anion exchanges resins, Dowex XFS-4022 and Dowex SBR-C1, would not be useful agents for increasing the amount of dieldrin eliminated via feces (droppings) of chickens. Further, imbiber beads coalesced in the gizzard of the chickens and reduced their appetites. The anion exchange resin, cholestyramine, might be useful as gastrointestinal absorbant for increasing dieldrin elimination in chickens because it increased carbon-14 elimination in droppings, but its effect on carbon-14 residues in carcasses was not clear. We elected not to investigate this compound further. Probucol, investigated because it might alter gastrointestinal absorption or blood physiology that would affect dieldrin elimination, did not increase dieldrin elimination. Severe starvation was the only method investigated that clearly was useful for increasing dieldrin elimination because it increased carbon-14 elimination in droppings and reduced carbon-14 residues in carcasses.

Animals↗

Kinetics of photoperoxidation of arachidonic acid: molecular mechanisms and effects of antioxidants.

The kinetics of photoperoxidation of [1-14C]arachidonic acid (20:4n-6) at 1.32 mM was studied either with the unsaturated fatty acid alone or in the presence of 10 microM of antioxidants and/or inhibitors of eicosanoid metabolism. The photosensitizer used was meso-tetraphenylporphine. The time-course of the reactions was followed by ultraviolet spectral analysis, thiobarbituric acid reactivity and high-performance liquid chromatographic analysis of aliquots sampled every 15 min during the 4 h of irradiation. The kinetics of photoperoxidation of 20:4n-6 can be divided into three main successive steps: (i) monohydroperoxidation, characterized by the appearance of conjugated diene patterns and monohydroperoxidized 20:4n-6; (ii) secondary oxidation characterized by polyoxygenated products such as dihydroperoxidized 20:4n-6 possessing conjugated triene patterns; and (iii) the disappearance of conjugated patterns and the oxidative cleavage of the products of the two first steps into aldehydic molecules reacting with thiobarbituric acid. During the first 90 min of irradiation, the mechanism of monohydroperoxidation (step one) is purely or predominantly type II photoperoxidation involving only singlet oxygen. This step was inhibited by beta-carotene and by BW755C (3-amino-1-[3-trifluoromethylphenyl]2-pyrazoline). In contrast, the reactions involved in the second and third steps were predominantly type I photoperoxidation involving radical mechanisms. These latter steps were inhibited by beta-carotene, BW755C, vitamin E and probucol. Indomethacin and 5,8,11,14-eicosatetraynoic acid did not alter 20:4n-6 photoperoxidation. This in vitro model of lipid photoperoxidation allows the screening of antioxidants in accordance with their singlet oxygen quenching and/or free radical scavenging properties.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

Antioxidants and atherosclerosis: emerging drug therapies.

Inflammation has a fundamental role in mediating all stages of atherosclerotic disease. The key role of oxidation in linking lipids and inflammation to atherosclerosis is compelling and supported by experimental evidence. However, the relevance of the antioxidant hypothesis for the treatment of patients with atherosclerosis has not been definitively proven. Probucol has reduced post-percutaneous coronary intervention (PCI) restenosis and progression of carotid atherosclerosis in clinical trials. The antioxidant/vascular protectant AGI-1067 has also been effective at preventing atherosclerosis in all tested animal models. The nonintervened reference coronary segments of the PCI vessel demonstrated improvements with AGI-1067 in the Canadian Antioxidant Restenosis Trial-1 (CART-1), evidence supportive of a clinical effect on slowing atherosclerosis progression. Results of randomized trials with the "antioxidant" vitamins have been disappointing, but there are potentially important problems associated with their use, including their potential pro-oxidant effects. Two important trials that test the antioxidant/anti-inflammatory hypothesis are ongoing with AGI-1067: CART-2, which assesses its value for the reduction of both atherosclerosis progression in non-PCI vessels and post-PCI restenosis; and Aggressive Reduction of Inflammation Stops Events (ARISE), which is evaluating the effects of AGI-1067 on hard cardiovascular outcomes.

Antioxidants↗