Name:	Simvastatin
Other Names:	Zocor®
Therapeutic Applications:	Oral antilipemic agent
Therapy Types:	Pharmaceutical small molecule
Mechanisms:	High affinity HMG-CoA reductase inhibitor
Development Status:	investigational in U.S.
FDA Phase:	Phase II/III
Primary Medical Role:	Simvastatin is a pro-drug, hydrolyzed in vivo to generate mevinolinic acid, an active metabolite that is structurally similar to HMG-CoA. This metabolite competes with HMG-CoA for binding HMG-CoA reductase, a hepatic microsomal enzyme. Simvastatin metabolites are high affinity HMG-CoA reductase inhibitors, reducing the quantity of mevalonic acid, a precursor of cholesterol. Simvastatin decreases total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B, while increasing HDL.
Pharmacological Role:	Apparently independent from its role in blocking HMG-CoA reductase, simvastatin affect beta amyloid metabolism by inhibiting both alpha and beta secretase activities in CNS. Statins also affect microglial activation as evidenced by reduced secretion of IL-6 from human microglial cell line CHME-3 (Lindberg et al., 2005).
Side Effects:	Simvastatin is generally well tolerated; side effects have been usually mild and transient in nature. Muscle problems (Pedersen & Tobert, 2004; Pedersen et al., 1996) can occur with simvastatin use. Myopathy is the only important, although rare (1 reversible case of myopathy of 4444 patients in S4 study) adverse effect of simvastatin; when severe, this can take the form of rhabdomyolysis which may lead to acute renal failure. Cognitive function may be slightly affected by simvastatin (Muldoon et al., 2004) manifest only as a failure to improve during 6 months treatment compared to placebo. Symptoms of hepatotoxicity including Creatine Kinase, liver enzymes, transaminase elevations occur with simvastatin treatment (Marz et al., 1999). Simvastatin may cause abdominal pain, constipation, flatulence, asthenia and headache.
Companies:	Merck & Co., Inc.
Notes:	Phase II clinical trial NCT00486044 (clinicaltrials.gov)is actively recruiting participants at University of Wisconsin, Madison. This record last updated Dec 22, 2008.

References

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Hoglund K, Wiklund O, Vanderstichele H, Eikenberg O, Vanmechelen E, Blennow K. Plasma levels of beta-amyloid(1- 40), beta-amyloid(1-42), and total beta-amyloid remain unaffected in adult patients with hypercholesterolemia after treatment with statins. Arch Neurol. 2004 Mar;61(3):333-7. Abstract

Sjogren M, Gustafsson K, Syversen S, Olsson A, Edman A, Davidsson P, Wallin A, Blennow K. Treatment with simvastatin in patients with Alzheimer's disease lowers both alpha- and beta-cleaved amyloid precursor protein. Dement Geriatr Cogn Disord. 2003;16(1):25-30. Abstract

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Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000 Oct;57(10):1439-43. Abstract

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