Hypercholesterolemia treatment

Currently, there are a number of systemic and intestine-selective MTP inhibitors, including lomitapide (23, BMS-201038, AEGR-733), implitapide (24), JTT-130, SLx-4090, and R-256918 (latter three structures not disclosed) believed to be in active development [60]. In a meta-analysis of three Phase II clinical trials, lomitapide as monotherapy or in combination with ezetimibe, atorvastatin, or fenofibrate significantly reduced LDL cholesterol (up to 35% as monotherapy and 66% in combination with atorvastatin) and was well tolerated with less than 2% discontinuation due to abnormal liver function [61]. Lomitapide has also been granted orphan drug status for the treatment of homozygous familial hypercholesterolemia [59]. Results of a Phase II study of JTT-130 for type 2 diabetes are expected in August 2010 [59,60]. 

The principal use of niacin is for mixed hyperlipidemia or as a second-line agent in combination therapy for hypercholesterolemia. It is a first-line agent or alternative for the treatment of hypertriglyceridemia and diabetic dyslipidemia. 

Sirolimus is a potent immunosuppressive agent. To prevent thrombocytopenia and hypercholesterolemia, optimize efficacy, and reduce organ rejection, assays were developed to monitor concentrations of sirolimus in the whole blood of patients under treatment.40"12 Wallemacq et al.43 developed and validated a simple high-throughput HPLC-MS/MS method to routinely monitor sirolimus... 

Davidson, M. H., Dugan, L. D., Burns, J. H., Sugimoto, D., Story, K., and Drennan, K. (1996). A psyllium-enriched cereal for the treatment of hypercholesterolemia in children A controlled, double-blind, crossover study. Am. ]. Clin. Nutr. 63, 96-102. 

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. 

Hoglund, K., Wiklund, O., Vanderstichele, H., Eikenberg, O., Vamechelen, E., Blennow, K. (2004) Plasma levels of beta-amyloid(l-40), beta-amyloid(1 2), and total beta-amyloid remain unaffected in adult patients with hypercholesterolemia after treatment with statins. Arch. Neurol, 61, 333-337. 

There is considerable evidence that the form in which data is reported has an impact on the understanding of the results, and on the decisions, which are taken on the basis of the data. For example, Misselbrook and Armstrong report the results of an investigation in which hypertensive and matched nonhypertensive patients were offered treatment for chronic mild hypertension. They were provided information of the positive impact of the offered treatment on the likelihood of their suffering a future stroke. The information was presented in different formats, including RR and ARR. When the information of the benefit of treatment was given in the form of RR, 92% percent of patients responded that they would accept treatment. In contrast, when the same information was presented in the form of ARR only 75% patients reported that they would accept treatment. The confusion is not restricted to patients. Forrow et al report the results of a study in which physicians reported they were more likely to treat both hypertension and hypercholesterolemia when data were presented in the form of RR rather than ARR. 

Homozygous familial hypercholesterolemia - 10 to 80 mg/day. Use atorvastatin as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) in these patients or if such treatments are unavailable. 

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. 

Primary hypercholesterolemia/mixed dyslipidemia For the treatment of primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Frederickson Types lla and Mb) in the following Patients treated with lovastatin who require further TG-lowering or FIDL-raising who may benefit from having niacin added to their regimen patients treated with niacin who require further... 

Da Silva, V.B., Andrioli, W.J., Carvalho, I., Taft, C.A., Silva, C. Computer-aided molecular design of novel HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia. J. Theor. Comput. Chem. 2007, 6, 811-21. 

The choice of target cells is another point worthy of discussion. In some instances, this choice is pre-determined, e.g. treatment of the genetic condition familial hypercholesterolemia would require insertion of the gene coding for the low-density lipoprotein receptor specifically in hepatocytes. 

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). 

Treatment Plan Based upon the criteria for initiating drug therapy of hypercholesterolemia, the physician... 

For ethical reasons, children enrolled in these clinical trials have also received standard therapy of enzyme infusions, so the results of these studies have been difficult to interpret and are controversial. Nevertheless, there is some evidence that the ex vivo gene transfer approach may evoke a biological response relevant to the treatment of ADA deficiency. Such interpretations have stimulated efforts to use the ex vivo strategy for other monogenic disorders, such as familial hypercholesterolemia, hemophilia B, and Gaucher s disease. 

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