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Ezetimibe
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| Systematic (IUPAC) name | |
| (3R,4S)-1-(4-fluorophenyl)- 3-((3S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4- (4-hydroxyphenyl)-2-azetidinone |
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| Identifiers | |
| CAS number | |
| ATC code | C10 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C24H21F2NO3 |
| Mol. mass | 409.4 g.mol-1 |
| SMILES | & |
| Pharmacokinetic data | |
| Bioavailability | 35–65% |
| Protein binding | >90% |
| Metabolism | Intestinal wall, hepatic |
| Half life | 19–30 hours |
| Excretion | Renal 11%, faecal 78% |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status |
S4 (Au), POM (UK), ℞-only (U.S.) |
| Routes | Oral |
Ezetimibe (pronounced /ɛˈzɛtəmɪb/) is an anti-hyperlipidemic medication which is used to lower cholesterol levels. It acts by decreasing cholesterol absorption in the intestine. It may be used alone when other cholesterol-lowering medications are not tolerated, or together with statins (e.g. ezetimibe/simvastatin, marketed as Vytorin and Inegy) when cholesterol levels are unable to be controlled on statins alone. Ezetimibe was originally discovered by a team of four Schering-Plough research chemists: Drs. Stuart B. Rosenblum, Duane A. Burnett, John W. Clader and Brian A. McKittrick.
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Pharmacology
Ezetimibe localises at the brush border of the small intestine, where it inhibits the absorption of cholesterol from the diet. Specifically, it appears to bind to a critical mediator of cholesterol absorption, the Niemann-Pick C1-Like 1 (NPC1L1) protein on the gastrointestinal tract epithelial cells1 as well as in hepatocytes2. In addition to this direct effect, decreased cholesterol absorption leads to an upregulation of LDL-receptors on the surface of cells and an increased LDL-cholesterol uptake into cells, thus decreasing levels in the blood plasma.
Clinical use
Indications
Ezetimibe is indicated as an adjunct to dietary measures in the management of:
- Hypercholesterolaemia
- Homozygous sitosterolemia (phytosterolemia)3
On 9 June 2006, U.S. regulators approved the use of ezetimibe in combination with fenofibrate to treat mixed hyperlipidaemia.
Adverse effects
Common adverse drug reactions (≥1% of patients) associated with ezetimibe therapy include: headache and/or diarrhea. Infrequent adverse effects (0.1–1% of patients) include: myalgia and/or raised liver function test (ALT/AST) results. Rarely (<0.1% of patients), hypersensitivity reactions (rash, angioedema) or myopathy may occur.3
Dosage forms
Ezetimibe is available as 10 mg tablets in most markets. A combination preparation ezetimibe/simvastatin, which combines ezetimibe with a statin, is also available.
Clinical trial controversy
On January 14, 2008, it was reported in the New York Times that a clinical trial (ENHANCE trial) of Zetia that was designed to show that the drug could reduce the growth of fatty plaques in arteries instead resulted in growth of plaques. However, the growth noted was less than it would have been had the patients been on placebo alone. Merck and Schering-Plough completed the clinical trial in April 2006 and had initially planned to release the findings no later than March 2007. The companies missed several self-imposed deadlines, and in December 2007, finally agreed to publish the results "soon" after the delays were publicized in news reports.4
It should be recognized that the ENHANCE trial was not a clinical-outcome trial, but merely an imaging study. Formally, the American College of Cardiology (ACC) maintains that Zetia may be a reasonable option for patients who cannot tolerate a statin or cannot be controlled on a high dose statin. 5 Results from the trial have provoked three large clinical-outcome trials. The results from these trials will be presented in the next three to four years. However, a March 30th, 2008 meeting of the ACC resulted in negative press for drugs like Zetia as Yale University Cardiologist Harlan Krumholz and concurring colleagues called into question the efficacy of such drugs. 6 Krumholz' statements maintained that such pharmaceuticals should not be the first or even second option for prescribing doctors. Definitive conclusions of the efficacy and safety of Zetia can be made such a time when the results of more substantial and comprehensive trials are released, such as the upcoming IMPROVE-IT Trial which has an enrollment of 18000 patients and will report results in 2012.
Results of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial (ClinicalTrials.gov number, NCT00092677 [ClinicalTrials.gov] ) showed a potential increase in cancer in association with the use of these drugs together. (www.nejm.org September 2, 2008 (10.1056/NEJMe0807200). The actual significance has yet to be determined.
References
- ^ Garcia-Calvo M, Lisnock J, Bull HG, Hawes BE, Burnett DA, Braun MP, et al. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad Sci U S A 2005;102(23):8132-7. PMID 15928087
- ^ Temel, Ryan E., Tang, Weiqing, Ma, Yinyan, Rudel, Lawrence L., Willingham, Mark C., Ioannou, Yiannis A., Davies, Joanna P., Nilsson, Lisa-Mari, Yu, Liqing. Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concentration and is a target of ezetimibe J. Clin. Invest. 2007 0: JCI30060
- ^ a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
- ^ Berenson, A (2008-01-14). "Drug Has No Benefit in Trial, Makers Say", NY Times. Retrieved on 14 January 2008.
- ^ "ACC Statement on ENHANCE Trial", ACC (2008-01-15). Retrieved on 4 February 2008.
- ^ Carey, J (2008-03-31). "A Weak Prognosis for Vytorin and Zetia", Business Week. Retrieved on 1 April 2008.
See also
External links
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Wikipedia content modification information:
- This page was last modified on 4 November 2008, at 08:02.
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