Of -statine

For ISIS 301012, a second-generation antisense inhibitor of apoB-100 in November 2006. Isis announced results from two Phase 2 clinical trials of ISIS 301012. In the first study repotted, patients with high cholesterol on stable doses of statins were treated with ISIS 301012 for 5 weeks. Patients who received 300 mg/week of ISIS 301012 in this study achieved a 51% reduction in LDL-cholesterol (LDL), a 42% reduction in total cholesterol (TC), and a 4l% reduction in triglycerides (TG) beyond the levels achieved with statins alone. 

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. 

Statins lower plasma cholesterol levels by inhibiting HMG-CoA reductase in the mevalonate pathway (Fig. 4). Some research has shown that certain statins (but not all) stimulate BMP-2 expression in osteoblasts, increase bone formation and mimic N-BP in that they inhibit bone resorption. The use of statins in osteoporosis is presently being investigated. 

HMG-CoA reductase inhibitors (statins). This effect has been suggested to account for some of the side effects of statins like myositis or rhabdomyolysis. 

Furthermore, there is some evidence for pleiotrophic effects (e.g., effects on hemostasis, vascular function, anti-inflammatory effects, and stabilizing effects on atherosclerotic plaques) of statins. The clinical relevance of this (and the potential difference between the various statins) is at present uncertain but subject to intense investigation. 

Mechanism of action of statins cholesterol synthesis pathway... 

HMG-CoA-Reductase Inhibitors. Figure 1 Mechanism of action of statins - cholesterol synthesis pathway. The conversion of acetyl CoA to cholesterol in the liver. The step of cholesterol biosynthesis inhibited by HMG-CoA reductase inhibitors (statins) is shown. 

The effect of statins on plasma lipids and lipoproteins is rapidly seen and fully achieved after 4-6 weeks of treatment. The effect persists unchanged during continued use for several years, but after stopping the diug, LDL-cholesterol rapidly increases to pretreatment levels. Treatment with statins is therefore usually continued indefinitely and not as a short-term cure. Finally, it is generally advisable to use the statins that have documented their efficacy in clinical trials (evidence-based medicine). 

Ray KK, Cannon CP (2005) The potential relevance of the multiple lipid-independent (pleiotropic) effects of statins in the management of acute coronary syndromes. J Am Coll Cardiol 46 1425-1430... 

Cholesterol Treatment Trialists (CTT) Collaborators (2005) Efficacy and safety of cholesterol-lowering treatment prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 366 1267-1278... 

Pasternak RC, Smith Jr, Bairey-Merz CN et al (2002) ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol 40 567-572... 

Liao JK, Laufs U. Pleiotropic effects of statins. Anna Rev Pharmacol Toxicol 2005 45 89-118. 

Cheung BM, Lauder IJ, Lau CP, Kumana CR. Meta-analysis of large randomized controlled trials to evaluate the impact of statins on cardiovascular outcomes. Br J Clin Pharmacol 2004 57 640-651. 

Montaner J, Chacon R Krupinski J, et al. Safety and efficacy of statins in the acute phase of ischemic stroke the mistics trial. Stroke 2004 35 293. 

Gertz K, Laufs U, Lindauer U, Nickenig G, Bohm M, Dirnagl U, Endres M. Withdrawal of statin treatment abrogates stroke protection in mice. Stroke 2003 34 551-557. 

Over the last decade, several studies in tens of thousands of patients have revealed that lowering cholesterol, specifically lowering LDL cholesterol with statins, is effective for both primary and secondary prevention of IHD-related events. Statins shown to decrease morbidity and mortality associated with IHD include lovastatin, simvastatin, pravastatin, and atorvas-tatin.22,23 A recent meta-analysis showed that the risk of major adverse cardiac events is reduced by 21% with the use of statins in patients at high risk for IHD-related events.23... 

There are now overwhelming data supporting the benefits of statins in patients with CAD in prevention of total mortality,... 

Compared with monotherapy, combination therapy is relatively unstudied in terms of the effects on CHD event reduction and may reduce patient compliance through increased side effects and increased costs. When used appropriately and with proper precautions, however, they are effective in normalizing lipid abnormalities, particularly in patients who cannot tolerate adequate doses of statin therapy for more severe forms of dyslipidemia. 

Agarwal R, Curley TM. The role of statins in chronic kidney disease. Am J Med Sci 2005 333 69-81. 

McCarey DW, Sattar N, Mclnnes IB. Do the pleiotropic effects of statins in the vasculature predict a role in inflammatory diseases Arthritis Res Ther 2005 ... 

Shovman O, Levy Y, Gilburd B, Shoenfeld Y. Antiinflammatory and immunomodulatory properties of statins. Immunol Res 2002 25(3) 271-285. 

It is worth noting here that inhibitors that interact with enzyme active site functionalities in ways that mimic the structure of covalent intermediates of catalysis can bind with very high affinity. This was seen in Chapter 1 with the example of statine-and hydroxyethylene-based inhibitors of aspartic proteases other examples of this inhibitor design strategy will be seen in subsequent chapters of this text. 

Blanco-Colio LM et al (2003) Anti-inflammatory and immunomodulatory effects of statins. Kidney Int 63 (1) 12—23... 

Greenberg, W.A., Varvak, A., Hanson, S.R. el ai (2005) Development of an efficient, scalable, aldolase-catalyzed process for enantioselective synthesis of statin intermediates. Proceedings of the National Academy of Sciences of the United States of America, 101, 5788-5793. 

Schonfeld G. Metabolic modes of action of statins in the hyperlipoproteinemias. Atherosclerosis 1998 141 203-207. 

The National Cholesterol Education Program considers ischemic stroke or TIA to be a coronary risk equivalent and recommends the use of statins in... 

A secondary goal is to reduce proteinuria and renal function decline seen with administration of statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors). 

Brower V (2003) Of cancer and cholesterol studies elucidate anticancer mechanism of statins. J Natl Cancer Inst 95(12) 844-846... 

Mueck AO, Seeeger H, Wallwiener D (2003) Effect of statins combined with estradiol on proliferation of human receptor-positive and receptor-negative breast cancer cells. Menopause 10(4) 332—336... 

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