Statin

The statins have achieved major importance as inhibitors of cholesterol biosynthesis and they are used in humans for the treatment of coronary disease. These compounds block isoprenoid formation by inhibiting the key enzyme, hydroxymethylglutaryl co-enzyme A reductase (HMGCoA reductase). This pathway is described in Chapter 5. The active form of the statins, in which the lactone ring is opened, has a formal resemblance to HMGCoA. This inhibition 

Biosynthetic experiments with variously labelled acetate units and [methyl- C] methionine established that the carbon skeleton of mevinolin was formed from nine acetate units, with the extra methyl group arising from methionine. The ester arose from two acetate units and a methionine. The oxygen atoms of the side chain at C-11, C-13 and C-15 were derived from the original acetate units whilst that at C-8 came from oxygen of the air. The cyclization reaction to form the bicyclic carbon skeleton may be a Diels-Alder cyclization (4.93 4.94). These are biosynthetically rather unusual. In the late stages of the biosynthesis, 4ot,5-dihydromonacolin L (4.95) is hydroxylated and dehydrogenated to form mevinolin. 

In the winter of 1507, there died at the Hospital Santa Maria Nuova in Florence an old man (il vecchio) (Fig. 5.134) who, shortly before his death, stated that in spite of his age, he felt no illness apart from a certain weakness. His age was one hundred years, more than double the statistical life expectancy at that time. 

Arteriosclerosis is one of the few internistic disease forms, the appearance of which can be demonstrated over many thousands of years. We owe this insight mainly to two circumstances favourable climatic conditions, and also the fact, that a number of ancient peoples wished their bodies not to be cremated or buried, but mummified and in this way preserved. [342] The disease is detectable by radiological investigations and dissection of mummies from Egypt, China 

136 English country doctor Caleb Hllller Parry (1755-1822). 

135 The autopsy of the body ofthe Ice-Man was not only the much-belated Investigation of a criminal case, but it also led to valuable information concerning the living conditions of men in the Neolithic period. 

Descriptions of some of the main secondary diseases following from arteriosclerosis have already been handed down to us from ancient times. Thus, one can find in the Hippocratic writings (Corpus Hippocraticum) indications of gangrene, stroke (apoplexia) and cardiac failure. But the explanation ofthe cause of such diseases first began in early modem times, when autopsies were carried out in increasing numbers to clarify the cause of death. 

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The statins lower cholesterol by inhibiting the en zyme 3 hydroxy 3 methylglutaryl coenzyme A reduc tase which is required for the biosynthesis of meva Ionic acid (see Section 26 10) Mevalonic acid is an obligatory precursor to cholesterol so less mevalonic acid translates into less cholesterol... 

The phenyl group became a practical protective group for carboxylic acids when Sharpless published a mild, effective one-step method for its conversion to a carboxylic acid. It has recently been used in a synthesis of the amino acid statine, where it served as a masked or carboxylic acid equivalent. ... 

The cholesterol-lowering agents called statins, such as simvastatin (Zocor) and pravastatin (Pravachol), are among the most widely prescribed drugs in the world. Identify the functional groups in both, and tell how the two substances differ. 

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. 

Statins (3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors)... 

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. 

Bone Metabolism. Figure 4 The mevalonate pathway. Interferences by statins and N-containing bisphosphonates are shown. 

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. 

Rate-limiting enzyme in cholesterol biosynthesis inhibition by statins results in reduction of plasma LDL-cholesterol levels. 

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. 

There are currently marketed four naturally derived statins (lovastatin, pravastatin, simvastatin, and rosuvas-tatin) and two synthetic statins (atorvastatin and fluvas-tatin). The structure of these statins is shown in Fig. 2. 

The individual statins differ with respect to their pharmacological properties, but in general the clinical consequences of this are limited, but may occasionally... 

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. 

Statins should not be used in pregnant women. If women with child-bearing potential are treated with statins efficient contraception should be secured. Statins should at present not be used in children unless they carry a very high risk of premature vascular-disease and in this case only by very experienced lipid specialists. 

Statins may reduce total cholesterol and LDL-cholesterol levels in plasma by 50-60%, reduce plasma... 

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). 

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