Statins importance

Horsmans Y. Differential metabolism of statins importance in drug-drug interactions. Eur Heart J Suppl 1999 l(Suppl T) T7-T12. 

Rhabdomyolysis is disintegration and death of muscle cells (myocytes). It is an important but rare side effect of treatment with statins. 

Growing clinical data also points to the importance of IL-8 in atherogenesis. IL-8 has been found in atheromatous lesions from patients with atherosclerotic disease including carotid artery stenosis (103), CAD (118), abdominal aortic aneurysms (AAA) (103,104,114), and peripheral vascular disease (PVD) (104). Furthermore, studies using plaque explant samples have yielded more direct evidence for IL-8 involvement. Media from cultured AAA tissue induced IL-8-dependent human aortic endothelial cell (HAEC) chemotaxis (122). Homocysteine, implicated as a possible biomarker for CAD, is also capable of inducing IL-8 (123-125) by direct stimulation of endothelial cells (123,124) and monocytes (125). When patients with hyperhomocysteinemia were treated with low-dose folic acid, decreases in homocysteine levels correlated with decreases in IL-8 levels (126). Statins significantly decrease serum levels of IL-6, IL-8, and MCP-1, as well as expression of IL-6, IL-8, and MCP-1 mRNA by peripheral blood monocytes and HUVECs (127). Thus, IL-8 may be an underappreciated factor in the pathogenesis of atherosclerosis. 

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... 

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. 

The therapeutic class that uniquely exemplifies lactone prodrugs are the statins, i.e., the cholesterol-lowering agents that act by inhibiting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.34). This microsomal enzyme catalyzes conversion of HMG-CoA to mevalonate, an important rate-limiting step in cholesterol biosynthesis. Cholesterol synthesis occurs mainly... 

The most important class of cholesterol-lowering agents is the statins. These include lovastatin (Mevacor), simvastatin (Zocor), pravastatin (Pravachol), and atorvastatin (Lipitor), among others. These molecules work, in modest part, by inhibiting biosynthesis of cholesterol and, in larger part, by increasing the rate at which cholesterol is eliminated by the body. Let s have a look at this in more detail. 

The statins are an important class of cholesterol-lowering drugs... 

The important point for patients is not so much that plasma cholesterol decreases but that the clinical endpoints decrease nonfatal heart attacks, coronary artery disease deaths, surgery for coronary artery disease, and total mortality. Subsequent to the approval of statins based on reduction of plasma cholesterol levels, several large, controlled clinical trials have been carried out to establish the effects of statin use on these clinical endpoints. ... 

Statins are the most important class of cholesterol-lowering drugs. They are inhibitors of an enzyme on the route to synthesis of cholesterol. As a result, there is an increase of LDL receptors in the liver, the only important mechanism for elimination of cholesterol from the body. 

We synthesized the ketomethylene, , and hydroxyethylene,8, isosteres of a Leu-Ala dipeptide sequence in order to explore the importance of the two extra atoms in statine relative either to substrate or to the tetrahedral intermediate (Figure 1) in another aspartyl protease system. The compounds were synthesized by the routes outlined in Scheme I. This route was chosen so as to provide steric control at C-2 and C-5 of both 7 and 8 as well as to provide ready access to C-4 labeled analogs. Details of the synthesis have been described else-where.(23.24) Inhibitors were synthesized in which Leu-Ala dipeptide Isosteres replaced either Sta or Sta-Ala in known pepstatin analogs. Inhibition of porcine pepsin was determined using the reported spectrophotometric assay (Table I).(25)... 

Fluvastatin, launched in 1994, was the first S5mthetic HMG-CoA reductase inhibitor to be approved for the treatment of hypercholesterolemia. This statin was developed by Novartis (Sandoz), and it is marketed as a racemate under the trade name Lescol (Asberg and Holdaas, 2004). In laboratory studies, fluvastatin was shown to potently inhibit HMG-CoA reductase (IC50 = 8 nM) and effectively block cholesterol biosynthesis in hepatoc5de cells (IC50 = 52 nM) (Parker et al., 1990). Clinically, fluvastatin is prescribed less frequently than simvastatin, atorvastatin, or rosuvastatin, but it nevertheless remains an important medication for the treatment of hypercholesterolemia moreover, as the first completely S5mthetic statin to be approved, it offers a compelling synthetic story (Repic et al., 2001). 

Fig. 8. Most important steps in the biosynthesis of cholesterol. The reduction of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) to yield mevalonic acid is an important rate-limiting step and also the site of attack of the HMG-CoA-reductase inhibitors (statins).

Evidence-based pharmacotherapy provides a succinct appreciation of the benefits of a drug, but rarely takes into account the patient s quality of life. Eor instance, intensive statin therapy is recommended because it reduces the incidence of cardiovascular death (odds ratio 0.86), myocardial infarction (odds ratio 0.84), and stroke (odds ratio 0.82) however, the increased risks for any adverse event (odds ratio 1.44), for abnormalities on liver function testing (odds ratio 4.48), for elevations in CK (odds ratio 9.97) and for adverse events requiring discontinuation of therapy (odds ratio 1.28) are less often taken into account by the prescriber. This example emphasises that individualisation is of the utmost importance to keep an acceptable benefit/risk ratio (Clin Ther 2007 29 253-60). The benefits of evidence-based pharmacotherapy may be obtained whenever concordance/compliance of the patient is adequate. However, concordance rate is slightly higher than 30% for chronic conditions, such as hypertension (Curr Hypertens Rep 2007 9 184-9), indicating that the patient has to be educated about the use of drugs, and therapy has to be individualised. 

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