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==Pharmacology== |
==Pharmacology== |
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{{see also|CETP inhibitor}} |
{{see also|CETP inhibitor}} |
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As [[High-density lipoprotein|HDL]] can alleviate atherosclerosis and other [[cardiovascular disease]]s, and certain disease states such as the [[metabolic syndrome]] feature low HDL, pharmacological inhibition of CETP is being studied as a method of improving HDL levels.<ref>{{cite journal |author=Barter PJ, Brewer HB Jr, Chapman MJ, Hennekens CH, Rader DJ, Tall AR |year=2003 |month=February |title=Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis |journal=Arterioscler Thromb Vasc Biol |volume=23 |issue=2 |pages=160–7 |pmid=12588754 |url=http://atvb.ahajournals.org/cgi/content/full/23/2/160 |doi=10.1161/01.ATV.0000054658.91146.64 |issn=1079-5642}}</ref> To be specific, in a 2004 study, the small molecular agent [[torcetrapib]] was shown to increase HDL levels, alone and with a [[statin]], and lower LDL when co-administered with a statin.<ref>{{cite journal |author=Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ |year=2004 |month=April |title=Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol |journal=N Engl J Med |volume=350 |issue=15 |pages=1505–15 |pmid=15071125 |url=http://content.nejm.org/cgi/content/full/350/15/1505 |doi=10.1056/NEJMoa031766 |issn=0028-4793}}</ref> Studies into cardiovascular endpoints, however, were largely disappointing. While they confirmed the change in lipid levels, most reported an increase in [[blood pressure]], no change in atherosclerosis,<ref>{{cite journal |year=2007 |month=March |title=Effect of torcetrapib on the progression of coronary atherosclerosis |journal=N Engl J Med |volume=356 |issue=13 |pages=1304–16 |pmid=17387129 |url=http://content.nejm.org/cgi/content/full/356/13/1304 |doi=10.1056/NEJMoa070635 |issn=0028-4793 |author1=Nissen Se, Tardif JC |author2=Investigators, Illustrate |last3=Nicholls |first3=Stephen J. |last4=Revkin |first4=James H. |last5=Shear |first5=Charles L. |last6=Duggan |first6=William T. |last7=Ruzyllo |first7=Witold |last8=Bachinsky |first8=William B. |last9=Lasala |first9=Gabriel P.}}</ref><ref>{{cite journal |year=2007 |month=April |title=Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia |journal=N Engl J Med |volume=356 |issue=16 |pages=1620–30 |pmid=17387131 |url=http://content.nejm.org/cgi/content/abstract/356/16/1620 |doi=10.1056/NEJMoa071359 |format=abstract |issn=0028-4793 |author1=Kastelein JJ, van Leuven SI |last2= |
As [[High-density lipoprotein|HDL]] can alleviate atherosclerosis and other [[cardiovascular disease]]s, and certain disease states such as the [[metabolic syndrome]] feature low HDL, pharmacological inhibition of CETP is being studied as a method of improving HDL levels.<ref>{{cite journal |author=Barter PJ, Brewer HB Jr, Chapman MJ, Hennekens CH, Rader DJ, Tall AR |year=2003 |month=February |title=Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis |journal=Arterioscler Thromb Vasc Biol |volume=23 |issue=2 |pages=160–7 |pmid=12588754 |url=http://atvb.ahajournals.org/cgi/content/full/23/2/160 |doi=10.1161/01.ATV.0000054658.91146.64 |issn=1079-5642}}</ref> To be specific, in a 2004 study, the small molecular agent [[torcetrapib]] was shown to increase HDL levels, alone and with a [[statin]], and lower LDL when co-administered with a statin.<ref>{{cite journal |author=Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ |year=2004 |month=April |title=Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol |journal=N Engl J Med |volume=350 |issue=15 |pages=1505–15 |pmid=15071125 |url=http://content.nejm.org/cgi/content/full/350/15/1505 |doi=10.1056/NEJMoa031766 |issn=0028-4793}}</ref> Studies into cardiovascular endpoints, however, were largely disappointing. While they confirmed the change in lipid levels, most reported an increase in [[blood pressure]], no change in atherosclerosis,<ref>{{cite journal |year=2007 |month=March |title=Effect of torcetrapib on the progression of coronary atherosclerosis |journal=N Engl J Med |volume=356 |issue=13 |pages=1304–16 |pmid=17387129 |url=http://content.nejm.org/cgi/content/full/356/13/1304 |doi=10.1056/NEJMoa070635 |issn=0028-4793 |author1=Nissen Se, Tardif JC |author2=Investigators, Illustrate |last3=Nicholls |first3=Stephen J. |last4=Revkin |first4=James H. |last5=Shear |first5=Charles L. |last6=Duggan |first6=William T. |last7=Ruzyllo |first7=Witold |last8=Bachinsky |first8=William B. |last9=Lasala |first9=Gabriel P. |last2=Tardif |last10=Tuzcu |first10=E. Murat |last11=Illustrate}}</ref><ref>{{cite journal |year=2007 |month=April |title=Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia |journal=N Engl J Med |volume=356 |issue=16 |pages=1620–30 |pmid=17387131 |url=http://content.nejm.org/cgi/content/abstract/356/16/1620 |doi=10.1056/NEJMoa071359 |format=abstract |issn=0028-4793 |author1=Kastelein JJ, van Leuven SI |last2=Van Leuven |first2=Michiel L. |last3=Burgess |first3=Leslie |last4=Evans |first4=Greg W. |last5=Kuivenhoven |first5=Jan A. |last6=Barter |first6=Philip J. |last7=Revkin |first7=James H. |last8=Grobbee |first8=Diederick E. |last9=Riley |first9=Ward A. |last10=Shear |first10=Charles L. |last11=Duggan |last12=Bots |first12=Michiel L. |last13=Radiance 1 |first13=Investigators}}</ref> and, in a trial of a combination of torcetrapib and [[atorvastatin]], an increase in cardiovascular events and mortality.<ref name=FDA2006>{{cite press release |title=Pfizer Stops All Torcetrapib Clinical Trials in Interest of Patient Safety |publisher=U.S. Food and Drug Administration |date=2006-12-03 |url=http://www.fda.gov/bbs/topics/news/2006/new01514.html}}</ref> |
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A compound related to torcetrapib, [[Dalcetrapib]] (investigative name JTT-705/R1658), was also being studied, but trials have since been ceased.<ref>{{cite journal |author=El Harchaoui K, van der Steeg WA, Stroes ES, Kastelein JJ |year=2007 |month=August |title=The role of CETP inhibition in dyslipidemia |journal=Curr Atheroscler Rep |volume=9 |issue=2 |pages=125–33 |pmid=17877921 |doi=10.1007/s11883-007-0008-5 |issn=1523-3804}}</ref> It increases HDL levels by 30%, as compared to 60% by torcetrapib.<ref>{{cite journal |author=de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Zwinderman AH, Posma JL, van Tol A, Kastelein JJ |year=2002 |month=May |title=Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study |journal=Circulation |volume=105 |issue=18 |pages=2159–65 |pmid=11994249 |url=http://circ.ahajournals.org/cgi/content/full/circulationaha;105/18/2159 |doi=10.1161/01.CIR.0000015857.31889.7B |issn=0009-7322}}</ref> Another CETP inhibitor under development is Merck's MK-0859 [[anacetrapib]], which in initial studies is not shown to increase blood pressure.<ref>{{cite news |author=Reuters|title=Merck announces its investigational CETP-Inhibitor, MK-0859, produced positive effects on lipids with no observed blood pressure changes | url=http://www.reuters.com/article/inPlayBriefing/idUSIN20071004163052MRK20071004 |publisher=Reuters, Inc. |date=2007-10-04 |accessdate=2007-11-04}}</ref> |
A compound related to torcetrapib, [[Dalcetrapib]] (investigative name JTT-705/R1658), was also being studied, but trials have since been ceased.<ref>{{cite journal |author=El Harchaoui K, van der Steeg WA, Stroes ES, Kastelein JJ |year=2007 |month=August |title=The role of CETP inhibition in dyslipidemia |journal=Curr Atheroscler Rep |volume=9 |issue=2 |pages=125–33 |pmid=17877921 |doi=10.1007/s11883-007-0008-5 |issn=1523-3804}}</ref> It increases HDL levels by 30%, as compared to 60% by torcetrapib.<ref>{{cite journal |author=de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Zwinderman AH, Posma JL, van Tol A, Kastelein JJ |year=2002 |month=May |title=Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study |journal=Circulation |volume=105 |issue=18 |pages=2159–65 |pmid=11994249 |url=http://circ.ahajournals.org/cgi/content/full/circulationaha;105/18/2159 |doi=10.1161/01.CIR.0000015857.31889.7B |issn=0009-7322}}</ref> Another CETP inhibitor under development is Merck's MK-0859 [[anacetrapib]], which in initial studies is not shown to increase blood pressure.<ref>{{cite news |author=Reuters|title=Merck announces its investigational CETP-Inhibitor, MK-0859, produced positive effects on lipids with no observed blood pressure changes | url=http://www.reuters.com/article/inPlayBriefing/idUSIN20071004163052MRK20071004 |publisher=Reuters, Inc. |date=2007-10-04 |accessdate=2007-11-04}}</ref> |
Template:PBB Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low-density (VLDL) or low-density lipoproteins (LDL) and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), and vice versa. Most of the time, however, CETP does a homoexchange, trading a triglyceride for a cholesteryl ester or a cholesteryl ester for a triglyceride.
The CETP gene is located on the sixteenth chromosome (16q21).
Rare mutations leading to increased function of CETP have been linked to accelerated atherosclerosis.[1] In contrast, a polymorphism (I405V) of the CETP gene leading to lower serum levels has also been linked to exceptional longevity [2] and to metabolic response to nutritional intervention.[3] However, this mutation also increases the prevalence of coronary heart disease in patients with hypertriglyceridemia.[4] The D442G mutation, which lowers CETP levels and increases HDL levels also increases coronary heart disease.[1]
Elaidic acid, a major component of trans fat, increases CETP activity.[5]
AsHDL can alleviate atherosclerosis and other cardiovascular diseases, and certain disease states such as the metabolic syndrome feature low HDL, pharmacological inhibition of CETP is being studied as a method of improving HDL levels.[6] To be specific, in a 2004 study, the small molecular agent torcetrapib was shown to increase HDL levels, alone and with a statin, and lower LDL when co-administered with a statin.[7] Studies into cardiovascular endpoints, however, were largely disappointing. While they confirmed the change in lipid levels, most reported an increase in blood pressure, no change in atherosclerosis,[8][9] and, in a trial of a combination of torcetrapib and atorvastatin, an increase in cardiovascular events and mortality.[10]
A compound related to torcetrapib, Dalcetrapib (investigative name JTT-705/R1658), was also being studied, but trials have since been ceased.[11] It increases HDL levels by 30%, as compared to 60% by torcetrapib.[12] Another CETP inhibitor under development is Merck's MK-0859 anacetrapib, which in initial studies is not shown to increase blood pressure.[13]
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
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Fatty acid |
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Hormone |
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Metal/element |
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Vitamin |
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Pigment |
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Other |
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Lipids: lipoprotein particle metabolism
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Lipoprotein particle classes and subclasses |
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Apolipoproteins |
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Extracellular enzymes |
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Lipid transfer proteins |
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Cell surface receptors |
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ATP-binding cassette transporter |
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