Hypercholesterolemia isolated

The first generation of statins to be approved for the treatment of hypercholesterolemia was based upon the natural product compactin, an HMG-CoA reductase inhibitor originally isolated from cultures of Penicillium. The most widely prescribed of these first-generation statins are simvastatin (4, Fig. 12.2), marketed as Zocor , and pravastatin (5), marketed as Pravacol . Based in large part on the clinical effectiveness of these early... 

Hypocholesterolemic effects of soybean saponins have been dimonstrated. Isolated soybean saponins reduced diet-induced hypercholesterolemia in rats through an increase in bile acid excretion... 

Carreira has reported that the aldol addition reaction to fiiran 2-carboxaldehyde may be performed on preparative scale (0.5 mol) with as little as 0.5 mol % catalyst (Scheme 8B2.12) [30], The adduct is isolated as a crystalline solid with 94% ee a single recrystallization allows access to 122 with >99% ee. Ozonolytic cleavage of the furan unmasks a carboxyl function, providing acid 124. This acid has been used in a convergent synthesis of the amphotericin C ]-C3 polyol portion. Moreover, 124 has been utilized in the synthesis of a number of pharmacologically important structures such as HMG CoA reductase inhibitors for the treatment of hypercholesterolemia [34],... 

Lucas, E.A., Khalil, D.A., Daggy, B.P., and Arjmandi, B.H. 2001. Ethanol-extracted soy protein isolate does not modulate serum cholesterol in golden Syrian hamsters A model of postmenopausal hypercholesterolemia. J. Nutr. 131, 211-214. 

In the pathogenesis of nephrotic hyperlipidemia, both increased production and impaired catabolism of lipoproteins were demonstrated to play a role. Pathogenic mechanisms may be different in nephrotic patients with isolated hypercholesterolemia and in patients with combined hypercholesterolemia and hypertriglyceridemia (V6). 

Since Johann Lobstein first coined the term arteriosclerosis, or hardening of the arteries in 1833, to the Framingham Study which began in 1948 (42), to the isolation of mevastatin by Akira Endo in 1976 (43), and on to the publication of the Scandinavian Simvastatin Survival Study (4S) in 1994 (44), cholesterol levels have emerged as perhaps the most potent modifiable risk factor in the treatment of chronic ischemic heart disease. Genetic disorders such as homozygous familial hypercholesterolemia where severe atherosclerosis is present by early adolescence have helped clarify the importance of LDL cholesterol in the pathogenesis of atherosclerosis. 

Many attempts have been made to find cholesterol biosynthesis inhibitors for development as hypocholesterolemic agents. Microbial secondary metabolites have been used as valuable natural sources in the development of novel cholesterol biosynthesis inhibitors. Mevastatin and lovastatin were isolated from the fungi, Penicillium citrinum and Aspergillus terreus, respectively, as potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which is involved in the rate-limiting step of cholesterol synthesis in mammals. These findings have led to the development of statins , which are drugs of choice in the treatment of hypercholesterolemia. 

An important class of active agents that potently inhibit HMG-CoA reductase has evolved from extensive studies for microbial secondary metabolites. Since Brown and Goldstein have reported that the rate of cholesterol biosynthesis is determined by the activity of HMG-CoA reductase [19,20,21], this enzyme has been known to be a prime target for discovery of novel therapeutics against hypercholesterolemia. Several fimgal secondary metabolites were isolated as useful inhibitors of endogenous cholesterol biosynthesis and developed as commercially available hypolipidemics. Endo and Hasumi have extensively reviewed natural, semisynthetic and synthetic HMG-CoA reductase inhibitors in 1993 [22],... 

An isolated defect in bile acid production has been found so far only in familial hypercholesterolemia (62), though even in this entity cholesterol catabolism as a whole may be decreased. Essential hypercholesterolemics (11) and hypothyroid patients (11,89) also tend to have a low bile salt elimination, though the excretion of cholesterol as such appears to decrease, too, particularly in the latter condition. In the circumstances in which bile salt elimination is decreased as a result of decreased hepatic function, elimination of cholesterol as such is also reduced (11). Under these conditions, serum cholesterol apparently increases only when the amount of elimination is decreased more than the feedback mechanism(s) are able to suppress synthesis, i.e., when the production exceeds elimination. 

Acaterin (1), isolated from a culture broth of Pseudomonas sp. A92 by Endo and co-workers/ is one of the acyl-CoA cholesterol acyltransferase (ACAT) inhibitors that are expected to be effective for the treatment of atherosclerosis and hypercholesterolemia, and also has remarkable antitumor activity. Since the total synthesis of acaterin reported by Kitahara and co-workers, synthetic strategies based on the MBH reaction have more recently been reported for this molecule almost simultaneously by three different research groups. Franck and Figadere first reported the synthesis of racemic acaterin 1 by condensation of ot,(3-unsaturated y-lactone 2 (99% ee) and octanal via a DABCO-mediated MBH reaction (Scheme 5.1). Unfortunately, using chiral (S)-2 (99% ee) as a reactant. 

Weber, C., Erl, W., Weber, K. S., and Weber, P. C. (1997). HMG-CoA reductase inhibitors decrease CDllb expression and CDl lb-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J. Am. Coll. Cardiol. 30, 1212-1217. 

Numerous factors limited the efficiency of genetic reconstitution. First was the number of cells that were recovered from the liver specimen. A 250-gm liver specimen was resected, and from this only 3 billion hepatocytes were isolated for culture. A typical liver contains approximately 100 million hepatocytes per milliliter and thus the 250-gm specimen could have provided approximately 25 billion hepatocytes. Second, only 2 billion hepatocytes were viable, and only 20% of them expressed the LDL-R after transfection with the retrovirus. Even if these 400 million hepatocytes expressed the normal number of LDL receptors, they would have only the number of receptors typically found in 4 ml of liver. Since the average liver volume is slightly more 1600 ml [24], even if the methods were improved 100-fold, the result would be a LDL receptor levels that would still only be 25% of normal. Cholesterol metabolism is clearly sensitive to the number of LDL receptors since patients with one half the number of LDL receptors (heterozygotes for familial hypercholesterolemia) have markedly elevated levels of LDL cholesterol and develop premature atherosclerosis... 

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