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PubMed1987

[Indications for and the therapeutic action of hypolipidemic agents in patients with hyperlipoproteinemias].

Seventy three patients with hyperlipoproteinemia (HLP) type II and IV were divided into three groups and treated with different pharmaceuticals. The first group was treated with 300 mg Radecol daily, the second--with 750 mg Probucol and the third--with 600 mg Bezalip. Best results in the patients with HLP, type II A, as regards the effect on total cholesterol were obtained in those treated with Probucol, in type II B the results from the treatment with Radecol and Probucol are similar. In type IV HLP the reduction of triglycerides is best manifested in those treated with Bezalip. The tolerance and indications for the treatment of the patients with the three preparations are evaluated with a view to individualization of the medicamentous treatment.

Bezafibrate↗
PubMed1996

Inhibition of lipid hydroperoxidation of low density lipoprotein by the Ca(2+)-channel and alpha 1-adrenoceptor antagonist monatepil maleate.

The antioxidative effect of monatepil maleate (CAS 103379-03-9, AJ-2615), a new antihypertensive agent, was investigated by measuring its ability to inhibit copper-induced lipid hydroperoxidation of low density lipoprotein (LDL) and was compared with those of diltiazem (Ca(2+)-channel antagonist), prazosin (alpha 1-adrenoceptor antagonist), and probucol. The concentration of AJ-2615 required to inhibit copper-induced lipid hydroperoxidation of LDL by 50% (IC50) was 28 mumol/l. The IC50 values for diltiazem, prazosin, and probucol were > 1 mmol/l, > 1 mmol/l, and 17 mumol/l, respectively. These results indicate that AJ-2615 has the same potent antioxidative effect as probucol and suggest that a previously reported ability of AJ-2615 to inhibit the progression of atherosclerosis may be due to this antioxidative property. In addition, the dihydrodibenzothiepine ring of AJ-2615 may have an antioxidative functions.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1996

[Pharmacological correction of lipid peroxidation during hypoxia and possibility to enhance human resistance to high altitude by using preparations of the metabolic type of action].

In simulating acute hypoxic hypoxia with the participation of male volunteers, the authors investigated the antihypoxic and antioxidative activity of metabolic drugs (jakton, amtizole succinate, nootropil, probucol, and a mixture which consists of jakton, amtizole succinate, and probucol). The pharmaceuticals were shown to have heterodirectional effects on lipid peroxidative processes. Drugs having a pronounced antioxidative activity (such as probucol and the mixture) promotes oxygen utilization during hypoxia and posthypoxic reoxygenation chiefly by the oxygenase pathway. This rearrangement of oxygen utilization processes caused an increase in human high-altitude resistance. The use of the above drugs is a promising trend in the development of an adaptative response to hypoxia in persons engaged in hazardous jobs.

Adaptation, Physiological↗
PubMedDate not supplied

[The effect of phenol antioxidants on the development of alloxan diabetes in rats].

Experiments were conducted on an alloxan diabetes model to study the preventive effects of the phenol antioxidants ionol and probucol. Ionol showed a tendency towards inhibition of glycemia and free radical oxidation of lipids. Probucol effectively inhibited the development of glycemia, hyperlipidemia, and intensification of autooxidation in the vascular wall. On the grounds of the results it is concluded that inclusion of probucol into complex treatment of patients suffering from diabetes mellitus with vascular complications is expedient.

Alloxan↗
PubMed2001

Antioxidant compounds and Ca(2+) pathway blockers differentially protect against methylmercury and mercuric chloride neurotoxicity.

The effects of the environmental contaminants methylmercury (MeHg) and inorganic mercury (HgCl(2)) on cell viability, intracellular calcium concentration ([Ca(2+)](i)), and reactive oxygen species (ROS) generation were studied in rat cerebellar granule neuron cultures using fluorescent methods. MeHg exhibited an LC(50) (2.47 microM) tenfold lower than that of HgCl(2) (26.40 microM). To study the involvement of oxidative stress and Ca(2+) homeostasis disruption in mercury-induced cytotoxicity, we tested the neuroprotective effects of several agents that selectively interfere with these mechanisms. After a 24 hr exposure, the cytotoxic effect of both mercury compounds was reduced by thapsigargin, an inhibitor of endoplasmic reticulum Ca(2+)-ATPase; the Ca(2+) channel blocker flunarizine; and the Na(+)/Ca(2+) exchanger blocker benzamil. All these compounds decreased the mercury-mediated [Ca(2+)](i) rise. These results indicate that Ca(2+) influx through Ca(2+) channels and the Na(+)/Ca(2+) exchanger and Ca(2+) mobilization from the endoplasmic reticulum are involved in mercury-mediated cytotoxicity. The antioxidants probucol and propyl gallate reduced the HgCl(2) toxicity. Probucol and vitamin E partially inhibited the MeHg toxicity after a 24 hr period, whereas propyl gallate completely prevented this effect. Probucol slightly reduced ROS generation in methylmercury-exposed cultures and decreased mercury-mediated rise of [Ca(2+)](i). Propyl gallate abolished ROS generation and partially inhibited the increase of [Ca(2+)](i) induced by both mercury compounds. Propyl gallate also protected human cerebral cortical neuron cultures from the MeHg effect even after 72 hr of MeHg exposure, thus showing a long-lasting effect. Our data suggest that disruption of redox equilibrium and Ca(2+) homeostasis contribute equally to HgCl(2)-mediated toxicity, whereas oxidative stress is the main cause of MeHg neurotoxicity.

Amiloride↗
PubMed1999

Glucocorticoids, antioxidants and staurosporine modulate the adherence between monocytes and malaria infected erythrocytes.

OBJECTIVE AND DESIGN: Adherence interactions involving monocytes are important for cell-cell interaction as an integral component of immune function. The adherence of malaria parasitised red cells to monocytes was determined after monocytes were treated with dexamethasone, cortisol, ambroxol, danazol, probucol and staurosporine. MATERIALS: Human peripheral blood monocytes isolated by density gradient centrifugation and adherence to glass cover slips. METHODS: The adherence of malaria parasitised red cells to monocytes was determined after the monocytes were incubated for 24 h in the presence of each of the 6 drugs. RESULTS: The two glucocorticoids and staurosporine reduced the adherence of malaria infected erythrocytes to monocytes in a dose dependent manner at concentrations from 10(-10) M and above and ambroxol, danazol, and probucol at 10(-5) M. Staurosporine was the most effective of the drugs studied, completely abolishing adherence at 10(-6) M. CONCLUSION: The adherence of malaria infected erythrocytes to monocytes is reduced in response to glucocorticoids (dexamethasone and cortisol), anti-oxidants (probucol and ambroxol), danazol and staurosporine.

Anti-Inflammatory Agents↗
PubMed1989

Effect of hypolipidemic compounds on lauric acid hydroxylation and phase II enzymes.

Treatment of male Fischer 344 rats with various hypolipidemic drugs of different peroxisome proliferating potency (1-benzylimidazole, acetylsalicylic acid, clofibrate, tiadenol) led to an induction of liver lauric acid hydroxylase, whereas probucol, which is not a peroxisome proliferator, did not induce this enzyme. Activity of bilirubin UDP-glucuronosyltransferase was increased by all the compounds tested. The highest increase was observed after treatment with acetylsalicylic acid (2.3-fold). High correlation (r = 0.953) was observed between the activities of lauric acid hydroxylase and the corresponding activities of cytosolic epoxide hydrolase reported previously. The amount of microsomal epoxide hydrolase was not changed by any of the compounds. Whereas clofibrate and tiadenol decreased glutathione S-transferase activity with 1-chloro-2,4-dinitrobenzene as substrate, 1-benzylimidazole and probucol increased this activity. With 4-hydroxynonenal as a substrate qualitatively the same results were obtained with the exception that probucol did not affect the enzyme activity. When glutathione S-transferase activity was measured with cis-stilbene oxide as substrate only the more than five-fold increase after treatment with 1-benzylimidazole was significantly different from control values. Activity of dihydrodiol dehydrogenase was increased after treatment of rats with 1-benzylimidazole (1.5-fold), whereas application of tiadenol led to a decrease of enzyme activity. Feeding of male guinea pigs with clofibrate did not change the activity of peroxisomal beta-oxidation, cytosolic epoxide hydrolase or lauric acid hydroxylase. However, treatment with tiadenol caused an increase of these activities.

Animals↗
PubMed1994

SB 211475, a metabolite of carvedilol, a novel antihypertensive agent, is a potent antioxidant.

The antioxidant effects of SB 211475, a metabolite of carvedilol, a novel antihypertensive agent, were studied and compared with carvedilol and other antioxidants such as U78517F, U74500A and probucol. SB 211475 inhibited Fe(2+)-vitamin C-initiated lipid peroxidation, assessed as thiobarbituric acid reactive substance, in brain-homogenate with an IC50 of 0.28 microM. Under the same conditions, the IC50s of probucol, carvedilol, U74500A and U78517F were 50, 8.1, 0.71 and 0.16 microM, respectively. SB 211475 inhibited oxidation of human low density lipoprotein by mouse macrophages with an IC50 of 0.043 microM. In the same model, the IC50s of carvedilol, U78517F and probucol were 3.8, 0.15, and 0.80 microM, respectively. SB 211475 protected cultured bovine pulmonary artery endothelial cells against hydroxyl radical-initiated lipid peroxidation (IC50 = 0.15 microM) and cell damage (lactate dehydrogenase release, IC50 = 0.16 microM), and promoted cell survival with an EC50 of 0.13 microM. SB 211475 also protected endothelial cells against xanthine/xanthine oxidase-initiated cytotoxicity and protected rat cerebellar neurons from hydroxyl radical-mediated cell death (EC50 = 0.19 microM). Moreover, SB 211475 inhibited superoxide (O2-) release from human neutrophils stimulated by phorbol myristate acetate. These observations indicate that SB 211475 is a potent antioxidant and may potentially contribute to the therapeutic effects of carvedilol in vivo.

Adenosine Diphosphate↗
PubMed1993

A method to screen for the antioxidant effect of compounds on low-density lipoprotein (LDL): illustration with flavonoids.

We used a recently described anion-exchange chromatographic method (Vedie et al. J Lipid Res 1991;32:1359) to study the protective effect of potential inhibitors of low-density lipoprotein (LDL) oxidation mediated by cupric ion. By way of an example, we studied eight flavonoids (flavone, 3-hydroxyflavone, chrysin, galangin, fisetin, morin, quercetin, and myricetin) as well as three non-flavonoid antioxidants, butylated hydroxytoluene (BHT), probucol, and vitamin C, as reference compounds. Each compound was tested at various concentrations (1-100 microM). For flavonoid concentrations of 10 microM, an index was calculated as the (LDL control-flavonoid)/(LDL control-probucol) ratio, in which each term is expressed as the percentage of the most electronegative LDL fraction (fraction E). If the index is positive, the flavonoid inhibits LDL oxidation. A value > 1 (3-hydroxyflavone and galangin) means greater activity than probucol, whereas a value < 1 means lower activity (fisetin). If the index is around 0 (flavone and chrysin), the flavonoid is inactive. Finally, a negative value reflects possible prooxidant activity (morin, quercetin, and myricetin). Our results show that this chromatographic method can be applied to screening new pharmacological agents for activity against LDL oxidation.

Antioxidants↗
PubMed1998

Clinical efficacy and safety of cerivastatin in the treatment of heterozygous familial hypercholesterolemia.

Patients with heterozygous familial hypercholesterolemia are at especially high risk of premature coronary artery disease and usually require aggressive long-term lipid-lowering drug therapy to decrease plasma low-density lipoprotein (LDL) cholesterol concentrations to normal levels. In the present study, the lipid-lowering effects of cerivastatin in combination with cholestyramine and probucol were investigated in 20 patients with heterozygous familial hypercholesterolemia over a 20-week treatment period. After an initial 4-week treatment with once-daily 0.2 mg cerivastatin, serum total cholesterol and LDL cholesterol levels had decreased by a significant 22% and 25%, respectively (p <0.01). The addition of 8 g/day cholestyramine or 1 g/day probucol to ongoing cerivastatin therapy produced further significant reductions in total cholesterol of 16% and 16%, respectively, and in LDL cholesterol of 22% and 15%, respectively (p <0.01), over the 12-week combination therapy period. The potent lipid-lowering effects of combined treatment were accompanied by excellent toleration of study drugs. Only 2 patients experienced gastrointestinal side effects associated with cholestyramine therapy. There was no evidence of any abnormalities in creatine phosphokinase in either treatment group and only 2 patients exhibited minor increases in hepatic transaminases. This study has shown that cerivastatin can be safely combined with either cholesytramine or probucol to provide a safe and highly effective hypolipidemic treatment regimen for patients with heterozygous familial hypercholesterolemia.

Adult↗
PubMed1998

Regulation of monocyte to macrophage differentiation by antiglucocorticoids and antioxidants.

OBJECTIVE: Our purpose was to examine RU 486 and related compounds on monocyte to macrophage differentiation through scavenger receptors and cellular adhesion. STUDY DESIGN: Human monocytes were isolated, cultured, and treated with dexamethasone, levonorgestrel, RU 486, and other structurally related compounds alone or in combination. Macrophage scavenger receptor activity, inhibited by glucocorticoids and associated in the current literature with macrophage cellular adhesion, was determined in this study by counting the number of adherent cells after treatment. In addition, fluorescent-labeled acetyl-low-density lipoprotein uptake was determined as a function of scavenger receptor biologic activity. RESULTS: Dexamethasone, levonorgestrel (antiglucocorticoid only) and RU 486 (antiglucocorticoid and antioxidant) all significantly decreased adherent macrophages (4%, 52%, and 74% of control). Levonorgestrel, however, demonstrated a marked uptake of fluorescent-labeled scavenger receptor ligand. RU 486 and dexamethasone were antagonistic when combined (P < .001); levonorgestrel was less antagonistic but, however, still significant (P < .05). Reduced RU 486 (antioxidant but loses antiglucocortioid activity) decreased cellular adhesion, yet scavenger receptor function was enhanced. Both probucol (extracellular mechanism of action) and probucol analog (intracellular action) markedly up-regulated scavenger function, but once again a separation of adhesion from scavenger activity was noted. Vitamin E (antioxidant) and onapristone (antioxidant and antiglucocorticoid) had virtually little to no effect on adhesion and scavenger receptor activity. Finally, pyrrolidine dithiocarbamate, a potent oxygen-free radical quencher, was toxic to all cells examined. CONCLUSIONS: RU 486 is a known antiglucocorticoid with novel antioxidant properties first demonstrated by our laboratories. Levonorgestrel has antiglucocorticoid but no antioxidant activity. RU 486 antagonized the inhibitory effect of dexamethasone on scavenger receptor development, whereas levonorgestrel was stimulatory. A separation of scavenger receptor-induced cellular adhesion and scavenger receptor internalized ligand was demonstrated by (1) reduced RU 486, which loses its antiglucocorticoid activity but retains its antioxidant activity, and (2) probucol analog, which is chemically altered to allow intracellular entry. Glucocorticoids decrease the development of scavenger receptors, whereas antioxidants regulate inflammatory cytokines by intracellular mechanisms. It is therapeutically important to up-regulate scavenger receptor activity by antiglucocorticoids in the peritoneal cavity of women with endometriosis. However, because these mechanisms also induce inflammatory cytokines, a balance of antioxidants and antiglucocorticoids such as those demonstrated in the above study may prove beneficial.

Antioxidants↗
PubMed1998

Effect of antioxidant in endothelial cells exposed to oxidized low-density lipoproteins.

Antioxidants such as probucol and alpha-tocopherol have been shown to attenuate the oxidation of low-density lipoproteins (LDL) and atherosclerotic lesions in animal models of atherosclerosis. The purpose of this study is to determine the protection effect of antioxidants on endothelial cells when exposed to oxidized and native LDL. In a cell-free system, we found that probucol, alpha-tocopherol, and ascorbic acid inhibited copper-induced LDL oxidation by a dose-dependent fashion (from 1 microM to 10 mM). In porcine aortic endothelial cells, antioxidants alone did not change basal endothelin-1 (ET-1) secretion. When porcine aortic endothelial cells were exposed to LDL and oxidized-LDL, both of them stimulated ET-1 secretion dose-dependently, whereas oxidized-LDL elicited higher ET-1 secretion. However, probucol, alpha-tocopherol, and ascorbic acid did not prevent LDL or oxidized-LDL induced ET-1 secretion. Furthermore, nimodipine inhibited both of native and oxidized LDL induced ET-1 secretion. Since Ca2+ channel blocker reduced the elevation of induced ET-1 secretion, the [Ca2+]i is possibly involved for the regulation of ET-1 secretion. Our results suggest that antioxidants can only prevent the oxidation of LDL rather than oxidized and native LDL-induced ET-1 secretion in vascular endothelial cells. The increase in the [Ca2+]i of endothelial cells through the opening of voltage-dependent Ca2+ channels may be involved in the LDL-induced ET-1 release.

Animals↗
PubMed2003

A water-extract of the Korean traditional formulation Geiji-Bokryung-Hwan reduces atherosclerosis and hypercholesteremia in cholesterol-fed rabbits.

Geiji-Bokryung-Hwan (GBH), a drug preparation consisting of five herbs of Cinnamomi Ramulus (Geiji), Poria Cocos (Bokryun), Mountan Cortex Radicis (Mokdanpi), Paeoniae Radix (Jakyak) and Persicae Semen (Doin), is a traditional Korean herbal medicine that is widely used in the treatment of atherosclerosis-related disorders. A water extract of GBH was found to scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals and inhibit low-density lipoprotein (LDL) oxidation more effectively than probucol, a well-known commercially available antioxidant. In order to evaluate the anti-atherogenic potential of this medication, New Zealand White (NZW) rabbits were fed a normal diet for 12 weeks, a high cholesterol diet, a high cholesterol diet containing 1% probucol or a high cholesterol diet containing 5% water-soluble extract of GBH. Both GBH and probucol reduced plasma cholesterol levels. LDLs from the GBH-treated group were more resistant to Cu(2+)-induced oxidation and contained more vitamin E than LDLs from the high cholesterol diet group. Endothelial damage, determined at week 6, was reduced by 55% in the GBH group (P<0.01). GBH treatment reduced an atherosclerotic area in the abdominal aorta by 58% (P<0.05) and cholesterol deposition in the thoracic aorta by 55% (P<0.05). The severity of atherosclerosis in the GBH group was significantly reduced after an adjustment using cholesterol exposure as an index of the cholesterol-lowering effect. On the other hand, diet-induced hyperlipidemic rabbits were given water extract of GBH in doses of 50 (Group B) and 200 mg/kg (Group C) and compared with controls (Group A). At 40 days after intervention in groups A, B and C, total and LDL cholesterol levels were significantly lowered (P<0.01). LDL/high density lipoprotein (HDL) ratio was also significantly decreased (P<0.01). This study concludes that the reduction in atherosclerosis by GBH relies not only on its cholesterol-lowering effect but also more heavily on its antioxidant potential, which prevents endothelial damage and inhibits LDL oxidative modification in hypercholesterolemic animals.

Animals↗
PubMed1994

Reactive oxygen species in puromycin aminonucleoside nephrosis: in vitro studies.

We examined the role of reactive oxygen species (ROS) in puromycin aminonucleoside (PAN)-induced changes to glomerular epithelial cells (GECs) in vitro. Levels of superoxide anion (O2.-), hydrogen peroxide (H2O2) and hydroxyl radical (HO.) were measured in rat kidney-slice cultures containing PAN with or without antioxidants (allopurinol, probucol and alpha-tocopherol/ascorbic acid). GEC morphology was assessed after three days of culture using transmission (TEM) and scanning (SEM) electron microscopy. The effects of hypoxanthine on GEC ultrastructure was also assessed. O2.-, H2O2 and HO. were generated when PAN was added to kidney-slice cultures in Medium 199. TEM morphometry revealed that incubation with PAN (100 micrograms/ml) significantly (P < 0.05 at least) retarded the loss of GEC foot processes normally seen in vitro. When the hydrophobic antioxidants probucol or alpha-tocopherol/ascorbic acid, which scavenged/inhibited generation of O2.-, H2O2 and HO., were added to cultures containing PAN, the effect of PAN on foot processes was abolished. The TEM appearance of GECs now resembled that seen in control cultures. On the other hand, SEM revealed that probucol and alpha-tocopherol/ascorbic acid provided no protection against the changes induced by PAN in GEC cell bodies or major processes. Allopurinol provided no protection against the changes induced by PAN in GEC cell bodies, major processes or foot processes. The addition of hypoxanthine to kidney-slice cultures did not result in the generation of O2.-, H2O2 or HO., or alter GEC ultrastructure. These findings indicate that ROS play a role in PAN-induced alterations to GEC foot process architecture in vitro. However, the xanthine oxidase pathway does not appear to play a major role in generating ROS from PAN in vitro.

Animals↗
PubMed2003

Hypercholesterolemia is a prerequisite for puromycin inducible damage in mouse kidney.

BACKGROUND: The mouse, as opposed to the rat, is relatively resistant to the experimental nephrosis induced by puromycin aminonucleoside. The reason for this species specificity is not known. Apolipoprotein E (apoE)-deficient mice were used to determine whether hypercholesterolemia plays a role in inducing proteinuria. METHODS: Thirty-two mice were divided into normal and high cholesterol diet groups and then divided further into four subgroups: puromycin, puromycin+probucol, probucol and control. Urinary albumin of these mice was analyzed by nephelometry. The lipid peroxidation (LPO) end products malonyldialdehyde (MDA) and 4-hydroxynonenal (4-HNE) were detected by immunohistochemistry, and the expression level of the glomerular slit diaphragm protein, nephrin, was studied by immunohistochemistry and real time RT-PCR. RESULTS: Overt proteinuria was induced by puromycin only in the apoE knockout mice ingesting the high cholesterol diet. The staining intensities of MDA and 4-HNE were stronger in the glomeruli of proteinuric mice compared to glomeruli of non-proteinuric mice. When serum cholesterol levels were reduced by probucol, proteinuria decreased and fewer LPO end products were seen immunohistochemically. Three and eight days after puromycin injection the level of nephrin mRNA in the kidneys of proteinuric mice decreased in comparison to the controls. Puromycin-treated mice kidneys demonstrated a clearly reduced reactivity to the nephrin antibodies. CONCLUSIONS: Hypercholesterolemia, possibly via LPO, is a prerequisite for puromycin-inducible glomerular damage in the mouse. Furthermore, nephrin protein and mRNA levels appear to be candidate markers of glomerular damage in the mouse.

Animals↗
PubMed2001

Anti-atherogenic antioxidants regulate the expression and function of proteasome alpha-type subunits in human endothelial cells.

It has been proposed that phenolic antioxidants such as probucol exert their anti-atherogenic effects through scavenging lipid-derived radicals. In this study the potential for genomics to reveal unanticipated pharmacological properties of phenolic antioxidants is explored. It was found that two anti-atherogenic compounds, BO-653 and probucol, inhibited the expression of three alpha-type proteasome subunits, PMSA2, PMSA3, and PMSA4 in human umbilical vein endothelial cells. Here we report that both BO-653 and probucol caused not only inhibition of the mRNA levels of these three subunits but also inhibition of both the gene expression and protein synthesis of the alpha-type subunit, PMSA1. Other subunit components of the proteasome such as the beta-type subunits (PMSB1, PMSB7), the ATPase subunit of 19 S (PMSC6), the non-ATPase subunit of 19 S (PMSD1), and PA28 (PMSE2) were not significantly affected by treatment with these compounds. The specific inhibition of alpha-type subunit expression in response to these antioxidants resulted in functional alterations of the proteasome with suppression of degradation of multiubiquitinated proteins and IkappaBalpha. These results suggest that certain compounds previously classified solely as antioxidants are able to exert potentially important modulatory effects on proteasome function.

Antioxidants↗
PubMed1996

Protection of low density lipoprotein oxidation at chemical and cellular level by the antioxidant drug dipyridamole.

1. The oxidative modification of low density lipoprotein (LDL) is thought to be an important factor in the initiation and development of atherosclerosis. Natural and synthetic antioxidants have been shown to protect LDL from oxidation and to inhibit atherosclerosis development in animals. Synthetic antioxidants are currently being tested, by they are not necessarily safe for human use. 2. We have previously reported that dipyridamole, currently used in clinical practice, is a potent scavenger of free radicals. Thus, we tested whether dipyridamole could affect LDL oxidation at chemical and cellular level. 3. Chemically induced LDL oxidation was made by Cu(II), Cu(II) plus hydrogen peroxide or peroxyl radicals generated by thermolysis of 2,2'-azo-bis(2-amidino propane). Dipyridamole, (1-10 microM), inhibited LDL oxidation as monitored by diene formation, evolution of hydroperoxides and thiobarbituric acid reactive substances, apoprotein modification and by the fluorescence of cis-parinaric acid. 4. The physiological relevance of the antioxidant activity was validated by experiments at the cellular level where dipyridamole inhibited endothelial cell-mediated LDL oxidation, their degradation by monocytes, and cytotoxicity. 5. In comparison with ascorbic acid, alpha-tocopherol and probucol, dipyridamole was the more efficient antioxidant with the following order of activity: dipyridamole > probucol > ascorbic acid > alpha-tocopherol. The present study shows that dipyridamole inhibits oxidation of LDL at pharmacologically relevant concentrations. The inhibition of LDL oxidation is unequivocally confirmed by use of three different methods of chemical oxidation, by several methods of oxidation monitoring, and the pharmacological relevance is demonstrated by the superiority of dipyridamole over the naturally occurring antioxidants, ascorbic acid and alpha-tocopherol and the synthetic antioxidant probucol.

Antioxidants↗
PubMed1989

New horizons in combination drug therapy for hypercholesterolemia.

A modest number of hypolipidemic drugs are currently available, and their use as single agents frequently fails to adequately control patients with severe hypercholesterolemia. Combined-drug regimens afford the opportunity to maximize the cholesterol-lowering effects of drugs that have different mechanisms of action and, at the same time, minimize potential side effects. The bile acid sequestrants (cholestyramine and colestipol) enhance fecal sterol excretion and are nonsystemically acting; they have provided the cornerstone for the majority of the established combined-drug regimens. The most effective regimens have used bile acid sequestrants in combination with nicotinic acid, or more recently, lovastatin or simvastatin. Combinations in which fenofibrate, bezafibrate, or probucol have been used with cholestyramine or colestipol have also been shown to be useful although the low-density-lipoprotein-lowering effect of probucol appears quite variable. The use of low doses of bile acid sequestrants (4-8 g/day of cholestyramine or 5-10 g/day of colestipol) in combination with lovastatin, simvastatin, or probucol provides a therapeutic regimen that is usually well tolerated, shows additive lipid lowering, and is cost effective.

Anticholesteremic Agents↗