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When fatty substances such as cholesterol build up on the inner wall of the larger blood vessels, the result is atherosclerosis. In the heart, the resulting coronary artery disease can lead to a number of further problems, including myocardial or cerebral infarction, or peripheral vascular disease. The primary risk factor is a high level of blood cholesterol in its low density lipoprotein (LDLl form. High density lipoprotein (HDLl, however, takes cholesterol away from the tissues to the liver, and thus has a protective effect on the heart and circulation. Raising HDL levels is also thus desirable in the prevention of atherosclerosis.

The glycoprotein cholesterol ester transfer protein (CETPl is secreted from the liver and promotes the transfer of cholesteryl esters from the HDL form to LDL. It thus represents a novel target for therapeutic intervention in the prevention of atherosclerosis and Pfizer has developed the CETP inhibitor torcetrapib, which is now undergoing clinical investigation.

A randomised placebo-controlled multiple dose Phase I study has been carried out in 40 healthy subjects.' They were given 10, 30, 60 or 120mg of torcetrapib once a day, the highest dose twice a day or placebo for 14 days. As the dose increased so did both the extent and the duration of CETP inhibition. Dose-dependent increases in HDL cholesterol were also seen, with a reciprocal decrease in LDL cholesterol. It was well tolerated. A single blind placebocontrolled study was run in 19 subjects with low HDL cholesterollevels; nine were also given atorvastatin! All the subjects were given placebo for the first four weeks followed by 120mg torcetrapib once a day for four weeks. Six subjects not receiving atorvastatin were then given 120mg of the active twice a day for a further four weeks. HDL cholesterol was significantly increased by the drug at the end of each study period.

Two Phase II trials have also been carried out in patients with low HDL cholesterol levels.3 In the first, subjects were given 10, 30, 60 or 90mg doses of torcetrapib or placebo each day for eight weeks; a significant increase in HDL cholesterol was seen in all those given doses above 30mg. In the second trial, patients were also given atorvastatin, and again good increases in HDL cholesterol were observed in those given the higher doses. Significant decreases in LDL cholesterol were seen in both trials, but they were more homogeneous in those patients also given atorvastatin. Phase III trials of the drug in combination with atorvastatin are now under way.

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