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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia
New England Journal of Medicine, Volume 356, No. 2, Year 2007
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Description
BACKGROUND: Patients with homozygous familial hypercholesterolemia have markedly elevated cholesterol levels, which respond poorly to drug therapy, and a very high risk of premature cardiovascular disease. Inhibition of the microsomal triglyceride transfer protein may be effective in reducing cholesterol levels in these patients. METHODS: We conducted a dose-escalation study to examine the safety, tolerability, and effects on lipid levels of BMS-201038, an inhibitor of the microsomal triglyceride transfer protein, in six patients with homozygous familial hypercholesterolemia. All lipid-lowering therapies were suspended 4 weeks before treatment. The patients received BMS-201038 at four different doses (0.03, 0.1, 0.3, and 1.0 mg per kilogram of body weight per day), each for 4 weeks, and returned for a final visit after a 4-week drug washout period. Analysis of lipid levels, safety laboratory analyses, and magnetic resonance imaging of the liver for fat content were performed throughout the study. RESULTS: All patients tolerated titration to the highest dose, 1.0 mg per kilogram per day. Treatment at this dose decreased low-density lipoprotein (LDL) cholesterol levels by 50.9% and apolipoprotein B levels by 55.6% from baseline (P<0.001 for both comparisons). Kinetic studies showed a marked reduction in the production of apolipoprotein B. The most serious adverse events were elevation of liver aminotransferase levels and accumulation of hepatic fat, which at the highest dose ranged from less than 10% to more than 40%. CONCLUSIONS: Inhibition of the microsomal triglyceride transfer protein by BMS-201038 resulted in the reduction of LDL cholesterol levels in patients with homozygous familial hypercholesterolemia, owing to reduced production of apolipoprotein B. However, the therapy was associated with elevated liver aminotransferase levels and hepatic fat accumulation. Copyright © 2007 Massachusetts Medical Society.
Authors & Co-Authors
Cuchel, Marina A.
United States, Philadelphia
University of Pennsylvania Perelman School of Medicine
Bloedon, Leanne Anne T.
United States, Philadelphia
University of Pennsylvania Perelman School of Medicine
Szapary, Philippe O.
United States, Philadelphia
University of Pennsylvania Perelman School of Medicine
Kolansky, Daniel M.
United States, Philadelphia
University of Pennsylvania Perelman School of Medicine
Wolfe, Megan L.
United States, Philadelphia
University of Pennsylvania Perelman School of Medicine
Sarkis, Antoine
Lebanon, Beirut
Hôtel-dieu de France Hospital
Millar, John S.
United States, Philadelphia
University of Pennsylvania Perelman School of Medicine
Ikewaki, Katsunori
Japan, Tokyo
The Jikei University School of Medicine
Siegelman, Evan S.
United States, Philadelphia
University of Pennsylvania Perelman School of Medicine
Gregg, Richard E.
United States, Seattle
Bristol-myers Squibb Pharmaceutical Research Institute
Rader, Daniel J.
United States, Philadelphia
University of Pennsylvania Perelman School of Medicine
United States, Philadelphia
Hospital of the University of Pennsylvania
Statistics
Citations: 480
Authors: 11
Affiliations: 5
Identifiers
Doi:
10.1056/NEJMoa061189
ISSN:
00284793
e-ISSN:
15334406
Research Areas
Maternal And Child Health
Noncommunicable Diseases