Probucol

Probucol is a lipid-lowering agent, but the results are not consistent with respect to LDL cholesterol. It lowers HDL cholesterol hence it is not the first drug of choice in therapy. The ability of probucol to correct atherosclerosis has been attributed to its antioxidant properties.77 The usual oral dose is 500 mg twice daily and is administered after food. Many experts use it as adjuvant therapy in familial hypercholesterolemia. The drug is well tolerated but causes GI side effects such as nausea and flatulence, headache, and dizziness. Patients taking probucol must be on a low-fat diet. Probucol should not be used in patients with recent myocardial infarction, and it should not be given to children or pregnant women. 

One of the first pharmacogenomic studies investigating lipid-lowering drags was published by Nestrack et al. in 1987 [29], describing that carriers of at least one apo E4 allele who received probucol showed the greatest cholesterol reduction in comparison to those without an apo E4 allele. These data were confirmed in a second study by Eto et al. [30]. 

Mutations within the SREBPs and the SREBP processing proteins (SCAP, SIP, S2P) have intensively been searched, especially in patients with familial hypercholesterolemia. So far, however, only four polymorphic sites within SCAP [38, 39], one within the promoter of SREBP-la [40], and five mutations in SREBP-2 [41] have been published. Yet, the impact of these polymorphisms and mutations on the response to statins has not been evaluated. 

Familial hypercholesterolemia (FH) is an autosomal dominantly inherited disease caused by mutations in the gene for the LDL receptor. Up to now more than 680 distinct mutations, distributed over the entire gene, have been described [42]. Heterozygous FH individuals express only half the number of functional LDL-r and, therefore, have a markedly raised plasma cholesterol and usually present with premature coronary artery disease. Homozygous FH individuals are more severely affected and may succumb before the age of maturity. The prevalence of heterozygous FH is approximately 1 in 500 in Caucasians. 

Apolipoprotein AI (apoAI) is the major apolipoprotein of HDL and plays an important role in the formation of mature HDL and the reverse cholesterol transport. HDL concentrations are largely determined by the rate of synthesis of apoAI in the liver. As a consequence deficiency of apoAI results in an almost complete absence of HDL and in accelerated atherosclerosis. In the promoter of the apoAI 

Apolipoprotein AIV (apo AIV) is produced in the intestine and is found in chylomicrons, VLDL and HDL. It may modulate enzymes involved in lipoprotein metabolism and may serve as a saturation signal [49]. In a study with 144 participants the apo AIV His360Glu polymorphism showed no significant effect on cholesterol lowering in response to statin therapy [50]. 

Chemical Name Bis(35-di-tert-butyl-4-hydroxyphenyl) acetone mercaptole Common Name — 

Trede Neme Manufecturer Country Year Introduced 

5-di-tert-butyl-4-hydroxyphenyl) acetone mercaptole, melting at 125°C to 126°C is prepared by employing 2,6-di-tert-butyl-4-mercaptophenol and acetone as starting materials. In one representative procedure, the 2,6-di-tert-butyl-4-mercaptophenol (47.5 g, 0.2 mol) is dissolved in methanol (50 ml) heated at a temperature of 50°C. A catalytic amount of concentrated hydrochloric acid (1 ml) is added, followed by acetone (5S g,0.1 mol). The temperature of the mixture rises to about 60°C, and is maintained at about 60°C to 65°C for 1.5 hours. The mixture is cooled, diluted with water and about 10 ml of aqueous sodium bicarbonate and extracted with ether. The ether extract is evaporated, and the product is obtained as a residue, which is recrystallized from ethanol and then from isopropanol to obtain the bis(3,5-di-tert-butyl-4-hydroxyphenyl) acetone mercaptole as a crystalline solid melting at about 125°Cto 126°C. 

In another representative procedure about 2.3 mols of 2,6-di-tert-butyl-4-mercaptophenol is dissolved in about 1,700 ml of methanol under a nitrogen atmosphere about 100 ml of concentrated hydrochloric acid and 1B0 ml of acetone are added, and the mixture is stirred and maintainedat a temperature of about 35°C to 50°C, for 1.5 hours. The mixture is then cooled to room temperature and filtered, and the bis(3,5-di-tert-butyl-4-hydroxyphenyl) acetone mercaptole product is collected as a colorless crystalline solid filter cake. The product is washed with water and aqueous sodium bicarbonate and purified by recrystallization from ethanol. 

Miller, C.S. U.S. Petent 2,608,507 August 26,1952 assigned to Sharp Dohme, Inc. 

Trade Name Manufacturer Country Year Introduced 

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Probucol. Probucol is an antioxidant that is effective in lowering LDL cholesterol. Whereas probucol was known to lower cholesterol after relatively simple clinical trials (160), its mechanism of action as an antioxidant in the treatment of atherosclerosis is quite novel. Probucol has been shown to have the abiUty to produce regression of atherosclerotic lesions in animal models (161). Probucol therefore represents a novel class of pharmaceutical agent for the treatment of atherosclerosis. This effect occurs mechanistically, in part, by preventing oxidation of LDL, a necessary step in foam cell formation. This antioxidant activity has been shown in laboratory experiments and its activity in lowering LDL cholesterol in human studies is well documented (162). 

Alprenolol HCl Bromelain Ciprofibrate Clortermine HCl Desonide Fenofibrate Flucloronide Flunisolide Fluocinonide Flurandrenolide Glucagon Gramicidin Hetacillin potassium I proniazid Kebuzone Methyltestosterone Niaprazine Probucol Relaxin Somatotropin Triamcinolone acetonide Acetonitrile... 

FRUEBis J, GONZALEZ v, siLVESTRE M and PALiNSKi w (1997) Effect of probucol treatment on gene expression of VCAM-1, MCP-1, and M-CSF in the aortic wall of LDL receptor-deficient rabbits during early sihsro genss.is, Arteriosclerosis, Thrombosis and Vascular Biology 17, 1289-302. 

In the case of a-tocopherol and probucol it is possible to demonstrate synergy between these antioxidants and the water-soluble antioxidant ascorbate in both model... 

Gotoh, N., Shimizu. K., Komuro, E., Tsuchiya, J., Noguchi, N. and Niki, E. (1992). Antioxidant activities of probucol against lipid peroxidations. Biochem. Biophys. Acta 1128, 147-154. 

Kalyanaraman, B., Darley-Usmar, V.M., Wood, J., Joseph, J. and Parathasarathy, S. (1992). Synergistic interaction between the probucol phenoxyl radical and ascorbic acid in inhibiting the oxidation of LDL. J. Biol. Chem. 267, 6789—6795. 

Carew, T.E., Schwenke, D.C. and Steinberg, O. (1987). Antiatherogenic effect of probucol unrelated to its hyper-cholesterolaemic effect evidence that antioxidants in vim can selectively inhibit low density lipoprotein degradation in macroph -rich fatty streaks slowing the progression of atherosclerosis in the WHHL rabbit. Proc. Natl Acad. Sci. USA 84, 7725-7729. 

Kita, T., Nagano, X., Yokode, M., Ishii, K., Kume, N., Ooshima, A., Yoshida, H. and Kawai, C. (1987). Probucol prevents the progression of atherosclerosis in Watanabe heritable hyperlipidaemic rabbits an animal model for hyper-cholesterolaemic. Proc. Natl Acad. Sci. USA 84, 5928-5931. 

Probucol treatment slows progression of atheroma In the Watanabe rabbit... 

Parthasarathy, S., Young, S.G., Witztum, J.L., Pittman, R.C. and Steinberg, D. (1986). Probucol inhibits oxidative modification of low density lipoprotein. J. Clin. Invest. 7, 641-644. 

Probucol, another di-r-butyl phenol, is an anti-atherosclerotic agent that can suppress the oxidation of low-density lipoprotein (LDL) in addition to lowering cholesterol levels. The antioxidant activity of probucol was measured, using EPR, with oxidation of methyl linoleate that was encapsulated in liposomal membranes or dissolved in hexane. Probucol suppressed ffee-radical-mediated oxidation. Its antioxidant activity was 17-fold less than that of tocopherol. This difference was less in liposomes than in hexane solution. Probucol suppressed the oxidation of LDL as efficiently as tocopherol. This work implies that physical factors as well as chemical reactivity are important in determining overall lipid peroxidation inhibition activity (Gotoh et al., 1992). 

The phenothiazines, chlorpromazine and promethazine, have been described as inhibitors of CCU-induced lipid peroxidation at relatively high concentrations in rat liver microsomes (Slater, 1968). Structural modifications of chlorpromazine were undertaken to try to increase antioxidant activity and maintain molecular lipophilicity. The 2-N-N-dimethyl ethanamine methanesulphonate-substituted phenothiazine (3) was found to be a potent inhibitor of iron-dependent lipid peroxidation. It was also found to block Cu -catalysed oxidation of LDL more effectively than probucol and to protect primary cultures of rat hippocampal neurons against hydrogen peroxide-induced toxicity in vitro (Yu et al., 1992). 

Nafenopin Pimetine Probucol Tibric Acid Treloxinate... 

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