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JMSCR Vol||06||Issue||04||Page 1251-1260||April 2018 JMSCR Vol||06||Issue||04||Page 1251-1260||April 2018 www.jmscr.igmpublication.org Impact Factor (SJIF): 6.379 Index Copernicus Value: 71.58 ISSN (e)-2347-176x ISSN (p) 2455-0450 DOI: https://dx.doi.org/10.18535/jmscr/v6i4.203 Statins and Cholesterol: A Perspective Revisited Authors Dr Varshiesh Raina1, Dr Konika Razdan2 1Lecturer, Sanjeevni College of Nursing and Paramedical Sciences, Jammu, J & K 2VRDL, Department of Microbiology, Govt. Jammu Medical College, J & K Corresponding Author Dr Varshiesh Raina Over the past 36 years, the global market has emphasizing on the studies which will underpin witnessed a substantial demand for Statins. As a the risks associated with statins from cholesterol result Statins have proved to be a highly profitable point of view. and lucrative market in pharmaceutical sector. This rise in statin consumption has been mainly Discovery of Statins recognized due to its cholesterol lowering effect, As the evidence grew that the particularly, the low density lipoprotein (LDL) hypercholesterolemia is major risk factor for cholesterol in the body.[1] Increased levels of LDL coronary atherosclerosis, scientists across the are considered to be one of the major risk factor world began to unlock the pathway that was that predisposes heart patients towards heart involved in the biosynthesis of cholesterol. It was attack. Noticeably, heart disease is the number one around 1950s, when four biochemists—Konrad E. cause of death in U.S and, increasing, worldwide. Bloch, Feodor Lynen, John Cornforth and George A large number of placebo-controlled studies Popjak unveiled 30 enzymatic reactions critical showed that Statins can substantially reduce for cholesterol biosynthesis.[4] The cholesterol mortality in high risk patients, but no history of biosynthesis involves four stages and the third heart disease. The American Heart Association reaction in first stage (i.e., reduction of HMG- and the American College of Cardiology have CoA to mevalonate) governs the rate limiting step. provided guidelines wherein Statin treatment should be used for primary prevention of cardiovascular disease in adults with a 10-year risk of developing heart attack or stroke of 7.5% or more; LDL cholesterol ≥ 190 mg/dL or those with diabetes, age 40–75 with LDL-C 70– Around 1960s, the cholesterol pathway was 190 mg/dl.[2] The safety of statins became completed elucidated and at the Nobel Banquet in noticeable when cerivastatin was withdrawn Stockholm, December 10, 1964, the Bloch and worldwide in August 2001 as it caused fatal Lynen were honored with the Nobel Prize. This rhabdomyolysis.[3] In this review article we will be was the time when researchers in both academia Dr Varshiesh Raina et al JMSCR Volume 06 Issue 04 April 2018 Page 1251 JMSCR Vol||06||Issue||04||Page 1251-1260||April 2018 and industry began venturing into molecules that could target any step in cholesterol biosynthetic pathway. In 1959, Triparanol (which inhibited the final stage in the cholesterol synthetic pathway) was the first such candidate molecule that entered into the clinical trials in the U.S market; however it was withdrawn in 1960 because of the Structure similarities between HMG-CoA and numerous side effects like cataracts and Compactin accumulation of other sterols.[5] Around 1955, a In order to substantiate, the efficacy of Canadian pathologist Rudolf Altschul discovered Compactin, Akira along with his colleagues cholesterol lowering effect of nicotinic acid.[6] At performed some in-vitro and in-vivo Imperial Chemical Industries (ICI) laboratories in experiments.[11] Their in-vitro experiments with England, researchers synthesized Clofibrate and mammalian cells showed that at high many derivatives of clofibrate, called fibrates, that concentration of Compactin, the cells were unable showed cholesterol lowering properties and were to grow and died which was overcome by adding safe to use.[7] Unfortunately, the modes of action a small amount of mevalonate (the product of the of these synthetic derivatives were not well HMG-CoA reductase reaction). Surprisingly, the understood. Cholestyramine (a bile acid experiments also showed that cells treated with sequestrant) was introduced, which lowered Compactin responded by increasing endogenous plasma cholesterol by converting it to bile acids.[8] levels of HMG-CoA reductase activity. When the However, the Cholestyramine was not well rats were given Compactin repeatedly for 7 days, tolerated by all patients. One of the major no decrease in cholesterol levels was observed. drawbacks of these molecules reported so far was Strikingly, a single dose of Compactin in rats that none of them was effective in terms of safety decreased the serum cholesterol levels between 3 or efficacy. This refined the search to look for to 8 hours. Later on, they found, that in rat system molecules that could specifically block early steps the effect of Compactin was counteracted by of cholesterol biosynthetic pathway and display increased the amount of hepatic HMG-CoA better therapeutic properties. reductase. This suggested that Compactin was not In 1971, at Sankyo Research Laboratories, Tokyo, effective in rat system and as a result other animal Japan, a scientist named Akira isolated the first systems were studied which revealed some HMGCoA reductase inhibitor i.e., Citrinin, from interesting results. In hens, dogs and monkeys, the active culture broth of 3800 strains of fungi.[9] The Compactin showed promising results by Citrinin showed cholesterol lowering properties in decreasing plasma cholesterol by 50% after one experimental rat models but unfortunately, it was month. This indicated that Compact in can act as a toxic to the kidneys. The discovery of Citrinin new prototype in the list of cholesterol lowering opened a ray of hope to look for other molecules drugs. Thereafter, the Sankyo Research in culture broths of molds that might display Laboratories launched ‘Compact in Development cholesterol lowering properties. Fortunately, Project’ in 1976, which was headed by Akira Compact in (ML-236B) was isolated from active along with pathologists, pharmacologists, organic broth of Penicillium citrinum which was an chemists, toxicologists, and microbiologists. In extremely potent inhibitor of HMG-CoA collaboration with Akira Yamamoto, a physician reductase.[10] Further studies revealed that the at the Osaka University Hospital in Osaka, structure of Campactin was similar to HMG-CoA Sankyo conducted a Phase I and Phase II clinical and acted as a competitive inhibitor for HMG- trials in 1978, which reported significant efficacy CoA reductase. and better safety profile of Compactin. Dr Varshiesh Raina et al JMSCR Volume 06 Issue 04 April 2018 Page 1252 JMSCR Vol||06||Issue||04||Page 1251-1260||April 2018 Unfortunately, the Compactin was withdrawn were found to get more predisposed to high levels from market by Sankyo because at high doses of cholesterol.[17] (100 or 200 mg/kg/day) the dogs developed The word cholesterol is derived from two Greek lymphoma during a period of 2 years.[9] words – chole meaning bile and -ol meaning In 1979, Merck reported a statin named Mevinolin alcohol. It is a type of modified sterol that’s found which was isolated from the fungus in all cells of the body. Some of the major Aspergillus terreus.[12, 13] The Mevinolin was very functions of cholesterol in body are:[18] similar to Compactin in chemical structure. To build and maintain cell membranes and During same year Akira isolated another statin increases membrane packing [14] i.e., Monacolin K from Monascus ruber. Later Limit the permeability of the plasma on both of these Statins were found to be similar membrane to neutral solutes, sodium ions and renamed Lovastatin. The clinical benefits of and hydrogen ions. Lovastatin in Mabuchi’s report stimulated Merck Provide support to caveolae and clathrin- to conduct large-scale clinical trials in high risk coated pits in lipid rafts for conducting patients and long-term toxicity studies in dogs. In signaling processes. 1986, Lovastatin was given FDA approval and Provide insulation in myelin sheath for Merck became the first company to more efficient conduction of impulses. commercialize Lovastatin. After Lovastatin, six Serve as precursor molecule for the other statins i.e., 2 semi-synthetic statins synthesis of vitamin D and all steroid (pravastatin and simvastatin) and 4 synthetic hormones statins (atorvastatin, fluvastatin, pitavastatin and Secreted along with bile juice helps in [15] rosuvastatin) have been commercialized. It is emulsification of fats in intestine and estimated that around 30 million people absorption of fat-soluble worldwide are dependent on statins. vitamins, A, D, E, and K. Cholesterol and Its Association with Statins The cholesterol is transported in the blood by Since, the Statins were discovered; the cholesterol lipoproteins namely Low Density Lipoprotein has been presented in a very negative and vague (LDL), High Density Lipoprotein (HDL), very- manner. The people have started avoiding foods low-density lipoprotein (VLDL), intermediate- that contain cholesterol. It is totally a myth that density lipoprotein (IDL), chylomicrons and taking cholesterol rich foods are dangerous to chylomicrons remnants. These lipoproteins have a your heart and vessels. In fact, studies show that common structural feature which can be described the groups of people who had low levels of as a central hydrophobic core surrounded by a cholesterol in blood became atherosclerotic just hydrophilic
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