Statins products

The antiinflammatory effects of statins likely result from their ability to inhibit the formation of mevalonic acid. Downstream products of this molecule include not only the end product, cholesterol, but also several isoprenoid intermediates that covalently modify ( pre-nylate ) certain key intracellular signaling molecules. Statin treatment reduces leukocyte adhesion, accumulation of macrophages, MMPs, tissue factor, and other proinflammatory mediators. By acting on the MHC class II transactivator (CIITA), statins also interfere with antigen presentation and subsequent T-cell activation. Statin treatment can also limit platelet activation in some assays as well. All these results support the concept that in addition to their favorable effect on the lipid profile, statins can also exert an array of antiinflammatory and immunomodulatory actions. 

It has been found that the 3-hydroxy-3-methylglutaryl-CoA (HMG CoA) inhibitors statins (atorvastatin, pravastatin, and cerivastatin), widely prescribed cholesterol-lowering agents, are able to inhibit phorbol ester-stimulated superoxide formation in endothelial-intact segments of the rat aorta [64] and suppress angiotensin II-mediated free radical production [65]. Delbose et al. [66] found that statins inhibited NADPH oxidase-catalyzed PMA-induced superoxide production by monocytes. It was suggested that statins can prevent or limit the involvement of superoxide in the development of atherosclerosis. It is important that statin... 

Ezetimibe interferes with the absorption of cholesterol from the brush border of the intestine, a novel mechanism that makes it a good choice for adjunctive therapy. It is approved as both monotherapy and for use with a statin. The dose is 10 mg once daily, given with or without food. When used alone, it results in an approximate 18% reduction in LDL cholesterol. When added to a statin, ezetimibe lowers LDL by about an additional 12% to 20%. A combination product (Vytorin) containing ezetimibe 10 mg and simvastatin 10, 20, 40, or 80 mg is available. Ezetimibe is well tolerated approximately 4% of patients experience GI upset. Because cardiovascular outcomes with ezetimibe have not been evaluated, it should be reserved for patients unable to tolerate statin therapy or those who do not achieve satisfactory lipid lowering with a statin alone. 

Dosingof selected agents by class fibrate (gemfibrozil 600 mg twice a day) niacin (1.5-3 g/day of immediate-release product) statin (simvastatin 10-40 mg/day if glomerular filtration rate [GFR] <30 mL/min, 20-80 mg/day if GFR >30 mL/min) bile acid sequestrant (cholestyramine 4-16 g/day). 

Bergeron S, Chaplin D, Edwards JH, Ellis BS, Hill CL, Holt-Tiffin K, Knight JR, Mahoney T, Osborne AP, Ruecroft G (2006) Nitrilase-catalyzed desym-metrization of 3-hydroxyglutaronitrile preparation of a statin side-chain intermediate. Org Proc Res Dev 10 661-665 Burns M, Weaver J, Wong J (2005) Stereoselective enzymic bioconversion of aliphatic dinitriles into cyano carboxylic acids. WO 2005100580 DeSantis G, Zhu Z, Greenberg W, Wong K, Chaplin J, Hanson SR, Farwell B, Nicholson LW, Rand CL, Weiner DP, Robertson D, Burk MJ (2002) An enzyme library approach to biocatalysis development of nitrilases for enantioselective production of carboxylic acid derivatives. J Am Chem Soc 124 9024-9025... 

Asymmetric hydrogenation of ketones is one of the most efficient methods for making chiral alcohols. Ru-BINAP catalysts are highly effective in the asymmetric hydrogenation of functionalized ketones,54,55 and this may be used in the industrial production of synthetic intermediates for some important antibiotics. The preparation of statine 65 (from 63b R = i-Bu) and its analog is one example (Scheme 6-28).56 Table 6-6 shows the results when asymmetric hydrogenation of 63 catalyzed by RuBr2[(R)-BINAP] yields threo-64 as the major product. 

Because HMG CoA reductase occurs before a branch point in the biosynthetic pathway, complete inhibition of the enzyme by cholesterol would necessarily deprive the cell of many other intermediates, some of which are important in cell growth and division. A group of drugs known as statins are widely used to reduce plasma cholesterol concentration by inhibiting HMG CoA reductase. Interest is now rising in the possible use of statins as anticancer drugs due to their impact on reducing the production of mediators of cell proliferation. 

Of the known classes of aldolase, DERA (statin side chain) and pyruvate aldolases (sialic acids) have been shown to be of particular value in API production as they use readily accessible substrates. Glycine-dependent aldolases are another valuable class that allow access to p-hydroxy amino acid derivatives. In contrast, dihydroxy acetone phosphate (DHAP) aldolases, which also access two stereogenic centres simultaneously,... 

Manzoni, M. and Rolhni, M., Biosynthesis and biotechnological production of statins by filamentous fungi and apphcation of these cholesterol-lowering drugs. Appl. Microbiol. Biotechnol., 2002, 58, 555-564. 

Hydroxy-3-methylglutaryl (HMG)-CoA reductase on the smooth endoplasmic reticulum (SER) is the rate-limiting enzyme. Insulin acth"ates the enzyme (dephosphorylation), and glucagon inhibits it. Mevalonate is the product, and the statin drugs competitively inhibit the enzyme. Cholesterol represses the expression o the HMG-CoA reductase gene and also increases degradation of the enzyme. 

Serajuddin et al. [19] reported that the degradation pathway of prevastatin sodium was directly linked to the micro-pH environment within the formulation. Under neutral conditions (pH 6.5), the statin formed two degradation products, a cyclic lactone and an internal hydroxyl rearrangement product. However, as the pH was increased to 9.9 with the incorporation of magnesium oxide into the blend, the only degradation mechanism involved the formation of the cleavage product, 2-methylpropanoic acid. This latter approach of increasing the... 

Endocrine effects Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Small declines in total testosterone with no commensurate elevation in LH have been noted with the use of fluvastatin. Pravastatin showed inconsistent results with regard to possible effects on basal steroid hormone levels atorvastatin, lovastatin, rosuvastatin, and simvastatin did not reduce basal plasma cortisol concentration or basal plasma testosterone concentration or impair adrenal reserve. Appropriately evaluate patients who display clinical evidence of endocrine dysfunction. Exercise caution when administering HMG-CoA reductase inhibitors with drugs that affect steroid levels or activity, such as ketoconazole, spironolactone, and cimetidine. 

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