Background: T3D-959 is a chemically unique, brain penetrant, dual PPAR delta/gamma agonist with 15-fold higher PPAR delta selectivity. Ubiquitous brain expression of PPAR delta, its critical role in regulating glucose and lipid metabolism, and the Alzheimer's disease (AD)-like phenotype of PPAR delta null mice motivated this study. Objective: To determine safety and tolerability of multiple doses of T3D-959 in subjects with mild to moderate AD, examine systemic and central drug pharmacology and in an exploratory manner, perform cognitive assessments. Methods: Thirty-four subjects with mild-to-moderate AD were orally administered 3, 10, 30, or 90 mg of T3D-959 daily for 14 days. There was no inclusion of a placebo arm. Safety and tolerability were monitored. Systemic drug pharmacology was examined via plasma metabolomics LC-MS-MS analysis, cerebral drug pharmacology via FDG-PET measures of changes in Relative CMRgl (R CMRgl, AD-effected regions relative to brain reference regions), and cognitive function assessed before and after drug treatment and again one week after completion of drug treatment, by ADAS-cog11 and the Digit Symbol Substitution Test (DSST). Results: T3D-959 was in general safe and well tolerated. Single point pharmacokinetics at the T max showed dose dependent exposure. Plasma metabolome profile changes showed dose-dependent systemic effects on lipid metabolism and metabolism related to insulin sensitization. Relative FDG-PET imaging demonstrated dose-dependent, regional, effects of T3D-959 on R CMRgl based on the use of multiple reference regions. ADAS-cog11 and DSST cognitive assessments showed improvements with possible ApoE genotype association and pharmacodynamics related to the mechanism of drug action. Conclusions: Exploratory data from this Phase IIa clinical trial supports further clinical investigation of T3D-959 in a larger placebo-controlled clinical study.

Female Wistar rats were given 5 mg of 7,12-dimethylbenz[a]anthracene (DMBA) and fed either a control diet (AIN), a 4% cholestyramine (CHST) diet, a 2% corn oil plus 18% coconut oil (saturated fat) diet, a 20% corn oil [unsaturated fatty acid (USF)] diet, or a USF + 4% cholestyramine (USF + CHST) diet. The mammary glands, tumors, livers, and sera were analyzed for lipids, de novo cholesterogenesis, and serum lecithin-cholesterol acyltransferase (LCAT) activity levels. Level and type of fat in the diet, DMBA, CHST, and length of feeding influenced the lipid composition of liver and mammary tissues. Stimulation of de novo cholesterogenesis in the mammary gland and depression in circulating LCAT activity levels correlated with the incidence and growth of mammary tumors, suggesting that stimulation of de novo cholesterogenesis plays an important role in mammary cancer development.

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Summary The promotion of 7,12-dimethylbenzanthracene (DMBA) induced mammary cancer in Wistar rats by a 4% cholestyramine (CHST) diet was investigated. The rats, 50 days of age, were divided into six groups. First two groups were given an intragastric dose of 0.8 ml of corn oil whereas the remaining four groups were given a single intragastric dose of 5 mg of DMBA dissolved in 0.8 ml of corn oil. After 1 week on laboratory chow the first two groups and two groups treated with DMBA were fed a control diet and the two remaining groups treated with DMBA were fed a 4% CHST diet. Half the animals were killed at 100 days and the remainder at 200 days. A detailed histologic examination of grossly normal mammary tissue as well as any tumour mass was made for each rat. The serum lipids were extracted and the individual neutral lipid composition was determined. In rats treated with DMBA and fed a 4% CHST diet, the incidence of malignant tumours increased by 5 fold, and the tumour weight by 12 fold. In addition, the serum total lipids, cholesterol esters and triglycerides decreased significantly when compared with rats fed a control diet. These results suggest that CHST diet promotes DMBA cholesterol levels by 12%, resulting in a 19% reduction in At 50 days of age, they were divided into 6 groups and deaths due to coronary heart disease (CHD). Based on these subjected to the following treatments: 4 animals each in studies it has been widely accepted that a reduction in the groups a and b were given a single intragastric dose of 0.8ml serum cholesterol levels will significantly reduce the risk of corn oil alone by a stomach tube; 5 animals in group c, 7 CHD in humans (Rifkind, 1986). While this conclusion may animals in group d, 6 animals in group e, and 10 animals in be warranted, some epidemiological studies have shown that group f were each given 5 mg of DMBA dissolved in 0.8 ml a reduction in serum cholesterol levels resulted in increased of corn oil. All the animals were fed laboratory chow (Allied incidence of all cancers and colon cancer in particular Mills Inc., Chicago, IL) for the next 7 days, then switched to (Graham 1984). Some scientists concluded that treatment semipurified diets (ICN Pharmaceuticals Inc. Cleveland, with cholestyramine increases the risk for cancer (Vitale & OH). The control semipurified diet (AIN) was prepared as Ross, 1985). If indeed CHST or low serum cholesterol levels recommended by the American Institute of Nutrition (Bieri increase the risk for cancer, the mechanism by which this is et al., 1977). This diet contained 50g sucrose, 20g casein, brought about is unknown. There are only three published 15g corn starch, 0.3g methionine, 5g cellulose, 5g corn oil, reportsa which showed conclusively that CHST promotes 1 g vitamin mixture, 3.5 g mineral mixture and 0.2 g choline. cancers in rats. Nigro et al (1973) showed that at 2% level A 4% CHST diet was prepared by substituting 4 g of pure in the dietn CHST promotes colon cancer in male Sprague-cholestyramine resin (Bristol-Meyers Company,...