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 : 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 . 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 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 , 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was 190 mg/dl.[2] The safety of statins became completed elucidated and at the Nobel Banquet in noticeable when was withdrawn Stockholm, December 10, 1964, the Bloch and worldwide in August 2001 as it caused fatal Lynen were honored with the Nobel Prize.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, (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 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 and mammalian cells showed that at high many derivatives of clofibrate, called , 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 . 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 . 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 ( and ) and 4 synthetic hormones statins (, , and  Secreted along with bile juice helps in [15] ) 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 membrane. The cholesterol esters and [16] like the people who had high blood cholesterol. triglycerides form the hydrophobic core while as Also, there is no conclusive evidence that supports apolipoproteins, phospholipids and free the fact that too much animal fat and cholesterol cholesterol constitute hydrophilic membrane. in the diet promotes atherosclerosis or heart Below is the Table 1 which describes the major attacks. On contrary, sedentary habits, smoking, properties of these lipoproteins[19] hypertensive and mentally stressed individuals

Table 1: Types of Lipoproteins and associated properties Lipoprotein Density (g/ml) Size (nm) Major lipids Major apolipoproteins Chylomicrons <0.930 75-1200 Triglycerides Apo B-48, Apo C, Apo E, Apo A-I, A-II, A-IV Chylomicron Remnants 0.930- 1.006 30-80 Triglycerides Cholesterol Apo B-48, Apo E VLDL 0.930- 1.006 30-80 Triglycerides Apo B-100, Apo E, Apo C IDL 1.006- 1.019 25-35 Triglycerides Cholesterol Apo B-100, Apo E, Apo C LDL 1.019- 1.063 18- 25 Cholesterol Apo B-100 HDL 1.063- 1.210 5- 12 Cholesterol Phospholipids Apo A-I, Apo A-II, Apo C, Apo E

Dr Varshiesh Raina et al JMSCR Volume 06 Issue 04 April 2018 Page 1253

JMSCR Vol||06||Issue||04||Page 1251-1260||April 2018

From health perspective, doctors examine only effects or deficiencies which are outcome of LDL and HDL levels to conclude any risk towards cholesterol deficiency. atherosclerosis and cardiovascular disease (CVD). HDL (sometimes referred as good cholesterol) The cholesterol in LDL particles is sometimes acts like a maintenance crew that removes excess referred as bad cholesterol because it serves as a cholesterol from cells, and recycles it back to raw material for cholesterol plaques in walls of , which secretes it in the form of bile salts. arteries. Accumulation of cholesterol plaques in The antiatherogenic effect of HDL is determined atherosclerosis can lead to cardiovascular diseases by apo A-I component that induces cholesterol like coronary artery disease, cerebrovascular efflux from foam cell macrophages at atherogenic disease and peripheral arterial disease.[20] lesions.[25] HDL molecules also contain an enzyme Interestingly, LDL is the major transporter of known as paraoxonase, which protects the LDL cholesterol in the blood and LDL receptors molecules from oxidation.[26] There are several provide a gateway to transport cholesterol within reports which document direct co-relation the cells. When this gateway gets disrupted, the between the Statin therapy and increase in HDL LDL molecules can no longer be utilized by cells levels.[27, 28] However, there is not enough and wander in the blood, and in long run cause evidence that sheds light on association of atherosclerosis. It appears from here that LDL as antiatherogenic properties of increasing HDL. A such is not bad as long as LDL receptors are Meta analysis of Prospective Pravastatin Pooling functioning properly. In addition, it can also be Project, reported that there exists a negative argued that high level of LDL might serve as a association between HDL cholesterol and the risk marker for dysfunctional or low levels of LDL of coronary artery disease death and myocardial receptor. Worth to mention here, LDL is not just infarction, both in placebo-treated patients and in carrier of cholesterol but also serves as reservoir Pravastatin-treated patients.[29] In yet another to transport fats, vitamin D and fat soluble study named as Heart Protection Study, again a antioxidants.[21] The cholesterol present in outer negative association was found between HDL shell of LDL serves as a protective layer to cholesterol levels, HDL particle number, apoA-I prevent oxidation of fats in lipoproteins. levels and the risk of occlusive cardiovascular Moreover, it has been found that LDL cholesterol events; both placebo-treated individuals and also protects ApoB protein from attack of glucose simvastatin treated individuals.[30] It should be or fructose. Indeed, it is the oxidized and glycated noted that there is not any conclusive data that form of LDL molecules that have been found to shows significant association of statins with HDL accumulate at plaque sites and influence the cholesterol levels and CVD risk. In the diseases like diabetes.[22] The beneficial effects of Collaborative Atorvastatin Diabetes Study LDL were further evident from the fact that low (CARDS), no significant change was observed in levels of LDL can escalate problems such as HDL cholesterol and apoA-I levels, and moreover dementia and memory loss.[23] Earlier studies have neither any co-relation could be predicted for also indicated that there exists a strong link CVD risk in diabetic patients treated with between low LDL cholesterol levels and higher atorvastatin.[31] cancer risk.[24] Hence, all these studies indicate Several studies suggest that HDL cholesterol that LDL molecules are vital in certain biological efflux capacities might serve as a better biomarker processes and interfering with LDL synthesis by for atherosclerosis than HDL cholesterol levels. can limit bioavailibity of essential nutrients to However, Khera et al. work on almost 100 body cells. As statins work by lowering low patients treated with 10 mg atorvastatin, 40 mg density lipoprotein cholesterol, it is quite possible Pravastatin or 80 mg atorvastatin for 16 weeks that patients taking statins might experience side reported no effects of statin therapy on HDL

Dr Varshiesh Raina et al JMSCR Volume 06 Issue 04 April 2018 Page 1254

JMSCR Vol||06||Issue||04||Page 1251-1260||April 2018

cholesterol efflux capacities.[32] Two transporters sclerosis etc).[37] Most of the knowledge about a have been identified that play role in cholesterol molecule is gained through experimental studies efflux i.e., SR-B1 transporter utilized by and following are some of studies which have antiatherogenic HDL particles and ABCA1 dissected role of cholesterol in brain cells e.g., transporter utilized by pre-β-1 HDL. Upon transgenic mice over-expressing Cyp46 displayed treatment with statins like 40 mg rosuvastatin and increased expression of synaptic proteins and 80 mg atorvastatin it was observed that pre-β-1 improved spatial memory;[38] cholesterol depletion HDL levels decreased while as the large α-1 HDL impairs synaptic vesicle exocytosis in cultured particles increased.[33] Likewise, in type 2 diabetic neurons; cholesterol depletion impairs endocytosis patients, treatment with atorvastatin lowered the due to destabilization surface AMPA receptors;[39] amount of pre-β-1 HDL particles.[34] This in-turn cholesterol depletion impairs long-term leads us to the fact that statin therapy on potentiation due to destabilization surface NMDA transporter-specific cholesterol efflux needs to be receptors[40] etc. studied using more robust cellular models. The therapeutic application of Statins for the One of the major concerns that have challenged treatment of neurodegenerative diseases such as current therapeutic application of statins in Parkinson’s disease, Alzheimer’s disease, clinical therapeutics is that few patients receiving ischemic strokes multiple sclerosis and traumatic statin therapy fail to respond to treatment or brain injury has shown some controversial results. display statin tolerance. As a result they are The LEADe (Lipitor’s Effect in Alzheimer’s subjected to high doses of statin to achieve desired Dementia) study showed that 80 mg atorvastatin therapeutic effect which predisposes them to had no effect on mild to moderate AD patients.[41] adverse effects like brain diseases, liver injury, Likewise, the PROSPER (PROspective Study of muscle pain & damage, type-2 diabetes etc. Here Pravastatin in the Elderly at Risk) study reported we will shed some light on those side effects of no effect on cognition in patients given pravastatin statins which are associated with cholesterol. or placebo for a period of 3.5 years.[42] There is Cholesterol, statin and brain disease: however randomized clinical trials wherein it was Cholesterol is found abundantly in the brain and found that 10 or 40 mg of simvastatin for 6 constitutes almost 23% of total body cholesterol. months and 20 mg lovastatin for 6 months One of the interesting facts about the brain resulted in cognition impairment.[43] A study on cholesterol is that it is made locally and the blood mice also showed that administration of brain barrier does not allow circulating body atorvastatin orally for long-term precipitated cholesterol to enter central nervous system alterations in behavior and cognition[44] (CNS).[35] However, when the brain cholesterol Depending upon the medical history of patient, gets hydroxylated to 24S-hydroxycholesterol by studies show that statins reduced the risks of cytochrome P450 oxidase Cyp46a1, the latter ischemic strokes but worsened the risk of form of cholesterol can easily cross blood brain hemorrhagic strokes.[45] Other studies suggest that barrier and get metabolized in liver.[36] The statins can precipitate neuropathy like symptoms importance of cholesterol in brain is supported by in patients on statins.[46] It is generally presumed the fact that dyshomeostasis in cholesterol that chemical structure of statins can be cause biosynthetic pathways causes’ number of inherited behind the controversial results. Lipophilic statins diseases (like Niemann-Pick type C disease, can easily cross the blood brain barrier and Lemli–Opitz syndrome, , Rett directly affect brain cholesterol levels. syndrome, Huntington’s disease etc) and Cholesterol, statin and liver: Liver plays a vital neurodegenerative diseases (like Alzheimer’s role in regulating cholesterol levels within body disease, Parkinson’s disease, amyotrophic lateral through two ways: one by synthesizing cholesterol

Dr Varshiesh Raina et al JMSCR Volume 06 Issue 04 April 2018 Page 1255

JMSCR Vol||06||Issue||04||Page 1251-1260||April 2018

which is transported to body cells by lipoproteins transaminase at mild to moderate dosage. Two and other by sequestering cholesterol from body retrospective studies showed that statin therapy in the form of bile salts. The incidence of statin did not affect liver enzyme levels in patients induced liver injury is very low (almost 1%) and suffering from steatohepatitis and nonalcoholic the reported abnormalities include hepatitis (when fatty liver disease compared with patients not transaminase level is greater than 3 times the taking statins.[48] A study was conducted over a 5- upper limit of normal), autoimmune hepatitis–like year period which included 23,000 patients on syndrome (presence of autoantibodies like statins. It was found that only 0.1% patients had antinuclear antibody and antismooth muscle severe ALT levels and most importantly severity antibody), cholestatic pattern associated with was associated with -drug interactions.[49] jaundice.[47] Meta-analyses of randomized placebo Below Table 2 describes the relation between controlled trials reported that there occurred no statins and liver abnormalities[48] significant increase in liver enzymes like alanine

Table 2: Meta-analyses on long-term statin treatment and liver toxicity Meta-analysis Number of Total of Age Exposure to Treatment type and Liver function tests Conclusions studies subjects (years) study dosage (mg/day) abnormalities medication PPP Project 3 19.768 21–75 >5 years Pravastatin 40 Pravastatin: 0.9% Pravastatin was well Placebo: 1.0% tolerated, with no excess of liver function abnormalities de Denus S 13 49.275 55–75 From 48 Pravastatin 40 Statins 1.14% Only fluvastatin was weeks to 6.1 Lovastatin 30–45 Placebo 1.05% associated with a years Simvastatin 27–30 significant increase in the Fluvastatin 40–80 odds of having liver function tests abnormalities (1.13% vs. 0.29%) Alsheikh-Ali 23 75.317 55–75 From 0.9 to Lovastatin 20–80 High-dose: 271; Drug- and dose-specific AA treatment 6.1 years Simvastatin 20–80 Intermediate: 195; effects are more important arms Atorvastatin 10–80 Low-dose: 114 determinants of liver Pravastatin 40 (per 100,000 person- toxicity than magnitude of Fluvastatin 80 years for each 10% LDL-C lowering reduction in LDL-C) Dale KM 9 21.765 48–64 From 1 to 5 High dose: High-dose statin: 1.5% Higher intensity statin years Atorvastatin 80 Low-dose statin: 0.4% therapy significantly Simvastatin 40–80 increases the incidence of Lovastatin 76 transaminase elevation in Low dose: higher intensity Simvastatin 20–40 hydrophilic statins group Pravastatin 40 Atorvastatin 10 Lovastatin 4

Taking into account the anti-inflammatory and mammals namely glucocorticoids, anti-thrombotic effects property of statins, it is mineralocorticoids, and adrenal . These believed that statins may exert beneficial effects in can be further categorized as adrenal steroid reducing liver cancer, decreasing fibrosis or fatty hormones [like , and deposition and improvement of portal DHEA(s)] and non-adrenal steroid hormones (like hypertension. In a recent Cochrane meta-analysis, testosterone, progesterone and estradiol). The statins were found to improve serum precursor for all these steroid hormones is aminotransferase levels in NAFLD and NASH; cholesterol contained in low density lipoproteins. however no effect was observed on histological So theoretically speaking, statins should produce level and liver-related mortality and morbidity.[48] profound effect on steroid levels. However, Cholesterol, statins and steroid hormones: upcoming reports show that statins do not alter the There are three classes of steroid hormones in steroid hormones to the extent as expected. A

Dr Varshiesh Raina et al JMSCR Volume 06 Issue 04 April 2018 Page 1256

JMSCR Vol||06||Issue||04||Page 1251-1260||April 2018

Clinical report with Parvastatin showed that alone. Strikingly, vitamin D decreased the plasma although total and LDL cholesterol decreased levels of atorvastatin by 10%.[58] Only one study however there was no significant affect on levels claimed that statin decreased vitamin D levels by of steroid hormones or gonadotropins.[50] 21.4% in patients aged 60 and older.[59] So far, Similarly, no change in androgens or evidence regarding the association of statin and was observed in postmenopausal women in vitamin D has remained inconclusive due limited presence or absence of statin.[51] Schooling et al. data and conflicting results. Further randomized reported through meta-analysis of randomized controlled trials are warranted to make a direct controlled studies which involved both men and correlation. women that statins like rosuvastatin led to moderate decline in plasma testosterone levels. On Conclusion contrary, the plasma levels of gonadotropin and In conclusion we believe that a multicentered, ACTH showed a significant increase followed by placebo controlled, randomized and double no change in dehydroepiandrosterone sulphate and blinded trial with a large population should be cortisol.[52] A Cross-sectional study within the addressed to establish the risks associated with prospective population-based Rotterdam Study statins. One of the major concerns which revealed that statins significantly decreased serum physicians should consider about statins is total and non-SHBG-bound testosterone levels.[53] tolerability and safety during their clinical use and Additionally, a study conducted in mice showed clinicians should pay attention to it if encountered that Simvastatin treatment did not alter cholesterol and respond reasonably and quickly. The levels but aggravated the glucocorticoid pharmacokinetic and pharmacodynamic properties insufficiency associated with hypocholes- of the statins should be carefully assessed to terolemia.[54] elucidate drug interactions and safety profile in Cholesterol, statins and Vitamin D: The patients with hypercholesterolemia who are cholesterol also acts as a precursor for require long-term therapy. Overall, emphasis biosynthesis of vitamin D. In the presence of UV should be laid on risk-benefit balance of statin radiation 7-Dehydrocholesterol gets converts into during treatment. cholecalciferol--vitamin D3 in the human skin.[55] Vitamin D is very well known for calcium Financial support and sponsorship metabolism and upcoming reports have found Nil many more important roles like blood sugar Conflicts of interest regulation, mental health, the immune system There are no conflicts of interest. regulation and cancer prevention.[56] Thus, it will Contribution: *The authors have contributed not be wrong to say that statin might alter the equally. vitamin D levels and the functions associated. Surprisingly, randomized study showed that References rosuvastatin, atorvastatin, simvastatin and 1. Stancu C, Sima AJ. Statins: mechanism of lovastatin led to a significant rise in 25-hydroxy action and effects. Cell Mol Med 2001; vitamin D levels.[57] In contrast, fluvastatin had no 5:378-87. significant affect on vitamin D levels. The effect 2. Stone NJ et al. 2013 ACC/AHA guideline on of vitamin D on statins is quite interesting. A the treatment of blood cholesterol to reduce study claimed that patients which received atherosclerotic cardiovascular risk in adults: a vitamin D (800 IU/day) along with atorvastatin report of the American College of had apparently lower levels of total and LDL Cardiology/American Heart Association Task cholesterol as compared to patients on atorvastatin Force on Practice Guidelines. American

Dr Varshiesh Raina et al JMSCR Volume 06 Issue 04 April 2018 Page 1257

JMSCR Vol||06||Issue||04||Page 1251-1260||April 2018

College of Cardiology/American Heart 15. Peter HJ. Comparing HMG-CoA Reductase Association Task Force on Practice Inhibitors. Clin Cardiol 2003; 26:15-20. Guidelines. 16. Ravnskov U. Is atherosclerosis caused by Circulation 2014; 129:S1-45. high cholesterol? QJM: An Int Journal of 3. Davidson MH. Controversy surrounding the Med 2002; 95: 397-403. safety of cerivastatin. Expert Opin Drug Saf 17. Nicola M, Gabriele G, Stefano PC, Javier 2002;1:207-12. F, Federico M, Giulio A. Anxiety, Stress- 4. Bloch K. Summing up. Annu. Rev. Biochem Related Factors, and Blood Pressure in 1987); 56: 1–19. Young Adults. Front Psychol 2016; 7: 1682. 5. Daniel S, Joel A, Eugene B. Feigelson.Effects 18. Ira T. Cholesterol in health and disease. J Clin of triparanol (mer-29) on cholesterol Invest 2002; 110: 583-590. biosynthesis and on blood sterol levels in 19. Kenneth RF, Carl G. Introduction to Lipids man. J Clin Invest 1961; 40: 884–893. and Lipoproteins. Endotext book [Internet]. 6. Carlson LA. Nicotinic acid: the broad- 20. Brian A et al. Low-density lipoproteins cause spectrum lipid drug. A 50th anniversary atherosclerotic cardiovascular disease. 1. review. J Intern Med 2005;258:94-114. Evidence from genetic, epidemiologic, and 7. Fanny L, Bart S. Fibrates, glitazones, and clinical studies. A consensus statement from peroxisome proliferator-activated receptors. the European Atherosclerosis Society Arterioscler Thromb Vasc Biol 2010; 30: Consensus Panel. European Heart Journal 894–899. 2017; 38: 2459-2472. 8. Kohzo A, Yoshimasa A, Toshihiko I. Role of 21. Wadhera RK, Steen DL, Khan I, Giugliano bile acid sequestrants in the treatment of type RP, Foody JM. A review of low- 2 diabetes. World J Diabetes 2010; 1: 146– density lipoprotein cholesterol, treatment 152. strategies, and its impact on cardiovascular 9. Endo A. A historical perspective on the disease morbidity and mortality. J Clin discovery of statins. Proc Jpn Acad Ser B Lipidol 2016; 10: 472-89. Phys Biol Sci 2010; 86: 484–493. 22. Fernandez-Ruiz I. Atherosclerosis: Should we 10. Endo A, Kuroda M, Tsujita Y. ML-236A, redefine the normal LDL cholesterol range? ML-236B, and ML-236C, new inhibitors of Nat Rev Cardiol 2018; 15: 68-69. cholesterogenis produced by Penicillium 23. Low levels of good cholesterol linked to citrinum. J Antiobitics 1976; 29:1346–1348 memory loss, dementia risk. American Heart 11. Michael SB, Joseph LG. A tribute to Akira Association. ScienceDaily, 1 July 2008. Endo, discoverer of a “Penicillin” for 24. Low LDL cholesterol is related to cancer risk. cholesterol. Atherosclerosis 2004; 5: 13–16. American College of Cardiology. 12. Endo A. A historical perspective on the ScienceDaily, 26 March 2012. discovery of statins. Proc Jpn Acad. Ser B 25. Esin E, Necat Y, Ozgur A. High Density Phys Biol Sci 2010; 86: 484–493. Lipoprotein and it’s Dysfunction. Open 13. Bizukojc M, Ledakowicz S. A macrokinetic Biochem J 2012; 6: 78-93. modelling of the biosynthesis of lovastatin by 26. Aviram M, Rosenblat M, Bisgaier CL, Aspergillus terreus. J Biotechnol 2007; 130: Newton RS, Primo-Parmo SL, La-Du BN. 422–435. Paraoxonase inhibits high-density lipoprotein 14. Goswami S, Vidyarthi AS, Bhunia B, Mandal oxidation and preserves its functions. A T. A review on lovastatin and its production. possible peroxidative role for paraoxonase. J J Biochem Tech 2012; 4: 581-587. Clin Invest 1998; 101: 1581-1590.

Dr Varshiesh Raina et al JMSCR Volume 06 Issue 04 April 2018 Page 1258

JMSCR Vol||06||Issue||04||Page 1251-1260||April 2018

27. Philip JB, Gunnar B, Mike KP, Stephen JN. 34. Dallinga-Thie GM, van Tol A, Dullaart RP. Effect of statins on HDL-C: a complex Plasma pre beta-HDL formation is decreased process unrelated to changes in LDL-C: by atorvastatin treatment in type 2 diabetes analysis of the VOYAGER Database. J Lipid mellitus: Role of phospholipid Res 2010; 51: 1546-1553. transfer protein. Biochim Biophys Acta 2009; 28. Fergus MT, Peter J. Effects of Statins on 1791: 714-8. High-Density Lipoproteins: A Potential 35. Juan Z, Qiang L. Cholesterol metabolism and Contribution to Cardiovascular Benefit. homeostasis in the brain. Protein Cell 2015; Cardiovasc Drugs Ther 2008; 22: 321-338. 6: 254–264. 29. Sacks FM, Tonkin AM, Shepherd 36. Lange Y, Ye J, Strebel F. Movement of 25- J, Braunwald E, Cobbe S, Hawkins hydroxycholesterol from the plasma CM, Keech A, Packard C, Simes J, Byington membrane to the rough endoplasmic R, Furberg CD. Effect of pravastatin on reticulum in cultured hepatoma cells. J Lipid coronary disease events in subgroups defined Res 1995; 36: 1092-7. by coronary risk factors: the Prospective 37. Anchisi L, Dessì S, Pani A, Mandas A. Pravastatin Pooling Project. Circulation 2000; Cholesterol homeostasis: a key to prevent or 102: 1893-900. slow down neurodegeneration. Front Physiol 30. van Capelleveen JC et al. Association of 2013; 3: 486. High‐Density Lipoprotein‐Cholesterol Versus 38. Maioli S, Båvner A, Ali Z, Heverin M, Ismail Apolipoprotein A‐I With Risk of Coronary MA, Puerta E, Olin M, Saeed A, Shafaati Heart Disease: The European Prospective M, Parini P, Cedazo-Minguez A, Bjorkhem I. Investigation Into Cancer‐Norfolk Is It Possible to Improve Memory Function Prospective Population Study, the by Upregulation of the Cholesterol 24S- Atherosclerosis Risk in Communities Study, Hydroxylase (CYP46A1) in the Brain. PLoS and the Women's Health Study. J One 2013;8 :e68534. Am Heart Assoc 2017; 6: e006636. 39. Hering H, Lin CC, Sheng M. Lipid Rafts in the 31. Boekholdt SM. Levels and changes of HDL Maintenance of Synapses, Dendritic Spines, and cholesterol and apolipoprotein A-I in relation Surface AMPA Receptor Stability. J to risk of cardiovascular events among statin- Neurosci 2003; 23: 3262-71. treated patients; a meta-analysis. 40. Martin MG, Pfrieger F, Dotti CG. Cholesterol Circulation 2013; 128: 1504-12. in brain disease: sometimes determinant and 32. Khera AV, Cuchel M, De LL-M, Rodrigues frequently implicated. EMBO Rep 2014; 15: A, Burke MF, Jafri K, French BC, Phillips 1036-52. JA, Mucksavage ML, Wilensky RL, Mohler 41. Jones RW, Kivipelto M, Feldman H, Sparks ER, Rothblat GH, Rader DJ. Cholesterol L, Doody R, Waters DD, Hey-Hadavi efflux capacity, high-density lipoprotein J, Breazna A, Schindler RJ, Ramos H. The function, and atherosclerosis. N Engl J Med Atorvastatin/Donepezil in Alzheimer's 2011; 364: 127-135. Disease Study (LEADe): design and baseline 33. Ernst JS, Bela FA. Statins, cholesteryl ester characteristics. Alzheimers Dement 2008; 4: transfer protein inhibition, high density 145-53. lipoprotein particle metabolism and heart 42. Ford I et al. A Prospective Study of disease risk reduction. Pravastatin in the Elderly at Risk http://www.athero.org/commentaries/comm5 (PROSPER): Screening Experience and 19.pdf. Baseline Characteristics. Curr Control Trials Cardiovasc Med 2002; 3: 8.

Dr Varshiesh Raina et al JMSCR Volume 06 Issue 04 April 2018 Page 1259

JMSCR Vol||06||Issue||04||Page 1251-1260||April 2018

43. Bitzur R. Remembering Statins: Do Statins artery disease. Basic Clin Pharmacol Toxicol Have Adverse Cognitive Effects? Diabetes 2014; 114: 330-5. Care. 2016; 39: S253-9. 53. Keyser CE, Lima FV, Jong FH, Hofman 44. Schilling JM, Cui W, Godoy JC, Risbrough A, Rijke YB, Uitterlinden AG, Visser VB, Niesman IR, Roth DM, Patel LE, Stricker BH. Use of statins is associated PM, Drummond JC, Patel HH, Zemljic-Harpf with lower serum total and non-- AE, Head BP. Long-term atorvastatin binding globulin-bound testosterone levels in treatment leads to alterations in behavior, male participants of the Rotterdam Study. Eur cognition, and hippocampal biochemistry. J Endocrinol 2015; 173: 155-65. Behav Brain Res 2014; 267: 6–11. 54. Ouweneel AB, van der Sluis RJ, Nahon 45. Scheitz JF, MacIsaac RL, Abdul-Rahim JE, Van Eck M, Hoekstra M. Simvastatin AH, Siegerink B, Bath PM, Endres M, Lees treatment aggravates the glucocorticoid KR, Nolte CH. Statins and risk of poststroke insufficiency associated with hypocholeste- hemorrhagic complications. Neurology 2016; rolemia in mice. Atherosclerosis 2017; 261: 86: 1590-6. 99-104. 46. Brenton W. The implications of statin 55. Matthias W, Michael F. Holick. Sunlight and induced peripheral neuropathy. J Foot Ankle Vitamin D. A global perspective for health. Res 2011; 4: P57. Dermatoendocrinol 2013; 5: 51–108. 47. Manish T, Mark WR, Herbert LB. Statins and 56. Rathish N, Arun M. Vitamin D: The Liver Injury. Gastroenterol Hepatol (N Y). “sunshine” vitamin. J Pharmacol 2013; 9: 605-606. Pharmacother 2012; 3: 118–126. 48. Pastori D, Polimeni L, Baratta F, Pani A, Del 57. Miao H. Safety of statins: an update. Ther Ben M, Angelico F. The efficacy and safety Adv Drug Saf 2012; 3: 133–144. of statins for the treatment of non-alcoholic 58. Schwartz JB. Effects of vitamin D fatty liver disease. Dig Liver Dis 2015; 47: 4- supplementation in atorvastatin-treated 11. patients: a new drug interaction with an 49. Rossana MC, Luigi XC, Ronald BG, Eugene unexpected consequence. Clin Pharmacol RSchiff. Statins in the Treatment of Ther 2009; 85: 198-203. Dyslipidemia in the Presence of Elevated 59. Bischoff-Ferrari HA, Fischer K, Orav Liver Aminotransferase Levels: A EJ, Dawson-Hughes B, Meyer U, Chocano- Therapeutic Dilemma. Mayo Clin Proc 2010; Bedoya PO, Meyer OW, Ernst R, Schietzel 85: 349-356. S, Eberli F, Staehelin HB, Freystätter G, Roas 50. Bohm M, Herrmann W, Wassmann S, Laufs S, Theiler R, Egli A, Wilson NM. Statin Use U, Nickenig G. Does statin therapy influence and 25‐ Hydroxyvitamin D Blood Level steroid hormone synthesis? Z Kardiol 2004; Response to Vitamin D Treatment of Older 93: 43-8. Adults. J Am Geriatr Soc 2017; 65: 1267- 51. Peck A, Chaikittisilpa S, Mirzaei R, Wang 1273. J, Mack WJ, Hodis HN, Stanczyk FZ. Effect of statins on and lev els in postmenopausal women treated with est radiol. Climacteric 2011; 14: 49-53. 52. Krysiak R, Okopien B. The effect of aggressive rosuvastatin treatment on steroid hormone production in men with coronary

Dr Varshiesh Raina et al JMSCR Volume 06 Issue 04 April 2018 Page 1260