Simvastatin treatment

E4 carriers and patients with other genotypes were equally responsive to simvastatin treatment in terms of LDL cholesterol lowering [59]. 

Laaksonen R, Jokelainen K, Sahi T, Tikkanen MJ, Himberg JJ. Decreases in serum ubiquinone concentrations do not result in reduced levels in muscle tissue during short-term simvastatin treatment in humans. Clin Pharmacol Ther 1995 57(l) 62-6. 

Erythromycin should be administered slowly and at an appropriate dilution to avoid thrombophlebitis and a risk of prolonged QT interval. Erythromycin is an inhibitor of cytochrome P450 enzymes and concomitant administration with simvastatin is not recommended. Simvastatin treatment may be suspended or azithromycin substituted for erythromycin. 

Laaksonen, R., Jokelainen, K., Laakso, J., Sahi, T., Harkonen, M., Tikkanen, M.J., and Himberg, J.J. (1996). The effect of simvastatin treatment on natural antioxidants in low-density lipoproteins and high-energy phosphates and ubiquinone in skeletal muscle. Am J Cardiol 77 851-854. 

Krauss RM, Mangravite LM, Smith JD, Medina MW, Wang D, Guo X, Rieder MJ, Simon JA, Hulley SB, Waters D, Saad M, Williams PT, Taylor KD, Yang H, Nickerson DA, Rotter JI (2008) Variation in the 3 -hydroxyl-3 -methyl-glutaryl coenzyme a reductase gene is associated with racial differences in low-density lipoprotein cholesterol response to simvastatin treatment. Circulation 117 1537-1544... 

Sheu WH, Jeng CY, Lee WJ, et al. Simvastatin treatment on postprandial hypertriglyceridemia in type 2 diabetes melUtus patients with combined hyperUpidemia. MetaboUsm 2001 50 355—359. 

Johannesson M, Jonsson B, Kjekshus J, et al. Cost-effectiveness of simvastatin treatment to lower cholesterol levels in patients with coronary heart disease. Scandinavian Simvastatin Survival Study Group. N Engl J Med 1997 336 332-336. 

Soma, M R, Baetta, R., Bergamaschi, S., De Renzis, M.R., Davegna, C, Battaini, F, Fumagalli, R., Govoni, S. (1994) PKC activity in rat C6 glioma cells changes associated with cell cycle and simvastatin treatment. Biochem. Biophys. Res. Commn. 200, 1143-1149. 

In rodent stroke models, statin pretreatment has been shown to reduce infarct volumes and improve outcomes. Similarly, several clinical studies have shown that prior statin use reduced the severity of acute ischemic stroke and myocardial infarction. Recent studies indicate that beneftt can be achieved even when treatment is initiated after the onset of symptoms. In rodents, atorvastatin and simvastatin have been shown to reduce the growth of ischemic lesions, enhance functional outcome, and induce brain plasticity when administered after stroke onset. A retrospective analysis of the population-based Northern Manhattan Stroke Study (NOMASS) showed that patients using lipid-lowering agents at the time of ischemic stroke have a lower incidence of in-hospital stroke progression and reduced 90-day mortality rates. Retrospective analysis of data of the phase III citicoline trial showed... 

In an elegant paper, Gerdes et al. [59] examined whether the risk of death or a major coronary event in survivors of myocardial infarction (MI) was related to the apo E genotype and whether risk reduction brought about by simvastatin was different between genotypes. They analyzed 5.5 years of follow-up data of 966 Danish and Finish myocardial infarction survivors enrolled in the Scandinavian Simvastatin Survival Study and found that MI survivors with the apo E4 allele have a nearly 2-fold increased risk of death, and that treatment with simvastatin abolished excess mortality. They concluded that the effect of apo E4 may involve mechanisms unrelated to serum lipoproteins because... 

Treatment of Hypercholesterolemia Cholestyramine and other drugs that increase elimination of bile salts force the liver to increase their synthesis from cholesterol, thus lowering the internal level of cholesterol in the hepatocytes. Decreased cholesterol within the cell increases LDL receptor expression, allowing the hepatocyte to remove more LDL cholesterol from the blood. HMG-CoA reductase inhibitors such as lovastatin and simvastatin inhibit de novo cholesterol synthesis in the hepatocyte, which subsequently increases LDL receptor expression. 

Homozygous familial hypercholesterolemia-The recommended dosage is 40 mg/day in the evening or 80 mg/day in 3 divided doses of 20 mg, 20 mg, and an evening dose of 40 mg. Use simvastatin as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) in these patients or if such treatments are unavailable. 

Elderly In patients older than 70 years of age, the AUC of lovastatin, pravastatin, and simvastatin is increased. Pravastatin does not need dosage adjustment. The safety and efficacy of atorvastatin, rosuvastatin, and lovastatin extended-release in patients 70 years of age and older were similar to those of patients younger than 70 years of age. Elderly patients (65 years of age and older) demonstrated a greater treatment response in respect to LDL-C, total-C and LDL/HDL ratio than patients younger than 65 years of age. 

Children Atorvastatin, simvastatin, and lovastatin are indicated for treatment of patients 10 to 17 years of age with heterozygous familial hypercholesterolemia. Pravastatin is indicated for the treatment of patients 8 to 18 years of age with heterozygous familial hypercholesterolemia. Safety and efficacy have not been established for atorvastatin, simvastatin, and lovastatin in prepubertal patients and patients younger than 10 years of age. Safety and efficacy have not been established in patients younger than 8 years of age for pravastatin. Safety and efficacy have not been established in patients younger than 18 years of age for fluvastatin. Safety and efficacy of rosuvastatin have not been established in pediatric patients. 

Monitoring For lovastatin, perform LFTs before initiating therapy, at 6 and 12 weeks after initiation of therapy or after dose elevation, and periodically thereafter (approximately 6-month intervals). For rosuvastatin, fluvastatin, and atorvastatin, it is recommended that LFTs be performed prior to and at 12 weeks following both the initiation of therapy and any elevation in dose, and periodically (eg, semiannually) thereafter. For pravastatin and simvastatin, perform LFTs prior to the initiation of therapy, prior to elevation of dose, and when otherwise clinically indicated. For patients titrated to the 80 mg dose of simvastatin, perform LFTs prior to titration, 3 months after titration to the 80 mg dose, and periodically thereafter (eg, semiannually) for the first year of treatment. Pay special attention to patients who develop elevated serum transaminase levels. If transaminase levels progress. 

Renal function impairment For patients with severe renal insufficiency, do not start ezetimibe/simvastatin unless the patient has already tolerated treatment with simvastatin at a dose of 5 mg or higher. Exercise caution when ezetimibe/simvastatin is administered to these patients, and monitor them closely. Concomitant bile acid sequestrants Give ezetimibe/simvastatin either 2 hours or more before or 4 hours or more after administration of a bile acid sequestrant. Concomitant cyclosporine Exercise caution when initiating ezetimibe/simvastatin in the setting of cyclosporine. In patients taking cyclosporine, do not start ezetimibe/simvastatin unless the patient has already tolerated treatment with simvastatin at a dose of 5 mg or higher. Do not exceed 10 mg ezetimibe/10 mg simvastatin daily. 

The first generation of statins to be approved for the treatment of hypercholesterolemia was based upon the natural product compactin, an HMG-CoA reductase inhibitor originally isolated from cultures of Penicillium. The most widely prescribed of these first-generation statins are simvastatin (4, Fig. 12.2), marketed as Zocor , and pravastatin (5), marketed as Pravacol . Based in large part on the clinical effectiveness of these early... 

Fluvastatin, launched in 1994, was the first S5mthetic HMG-CoA reductase inhibitor to be approved for the treatment of hypercholesterolemia. This statin was developed by Novartis (Sandoz), and it is marketed as a racemate under the trade name Lescol (Asberg and Holdaas, 2004). In laboratory studies, fluvastatin was shown to potently inhibit HMG-CoA reductase (IC50 = 8 nM) and effectively block cholesterol biosynthesis in hepatoc5de cells (IC50 = 52 nM) (Parker et al., 1990). Clinically, fluvastatin is prescribed less frequently than simvastatin, atorvastatin, or rosuvastatin, but it nevertheless remains an important medication for the treatment of hypercholesterolemia moreover, as the first completely S5mthetic statin to be approved, it offers a compelling synthetic story (Repic et al., 2001). 

Simvastatin is also used in combination with nicotinic acid. It is found to be the most useful drug combination for the treatment of dyslipidemias associated with coronary artery disease. It is particularly effective in normalizing the lipid profiles of patients with familial combined dyslipidemia. 

Concomitant treatment with the CYP3A4 substrate simvastatin altered the mean AUC and mean Cmax of repaglinide by 2 and 27% respectively (64). 

Atorvastatin is an HMG Co-A reductase inhibitor. Pooled data from 21 completed and 23 continuing trials representing 3000 patient-years have shown that constipation, flatulence, dyspepsia, abdominal pain, headache, and myalgia occur in 1-3% of patients. Under 2% of atorvastatin-treated patients discontinued treatment because of an adverse event (1). Serious events in this review amounted to one patient with pancreatitis and one with cholestatic jaundice (1). There were no differences in adverse effects in 177 patients randomized for 52 weeks to either simvastatin or atorvastatin (2). 

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