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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Comparative hypolipidaemic and peroxisomal effects of ciprofibrate, clofibric acid, and their respective difluorocyclopropyl and 4-fluoro-substituted analogues in rat.

1. We investigated the biological activity of the difluoro analogue (WIN 36117) of ciprofibrate, a potent peroxisome proliferator, and re-examined the relative activity of clofibric acid and its 4-fluoro analogue (fluorofibric acid) in the rat. 2. Twenty-four hours after a single dose, ciprofibrate and WIN 36117 produced dosage-related reductions in plasma cholesterol (16-42 and 9-34% respectively) and triglycerides (14-32 and 9-22% respectively). However, a single dose of clofibric acid or fluorofibric acid produced hypocholesterolaemia only (32-58 and 9-29% reductions respectively). 3. After treatment for 7 days reductions in cholesterol were similar at all dosages of ciprofibrate (45% reduction, mean across groups) whereas the effects of WIN 36117, clofibric acid and fluorofibric acid were still dosage related (reductions of 21-44, 37-43 and 2-28% respectively). Hypotriglyceridaemia was produced by all compounds (ciprofibrate 36-50%, WIN 36117 14-36%, clofibric acid 18-48%, fluorofibric acid 6-28%). 4. After treatment for 14 days all compounds produced dosage-related decreases in plasma fibrinogen (ciprofibrate 18-33%, WIN 36117 7-11%, clofibric acid 13-26%, fluorofibric acid 7-15%). 5. Peroxisomal beta-oxidation activity was increased by WIN 36117 (4.8-fold) and fluorofibric acid (4.2-fold) although these increases were less than those produced by ciprofibrate (13.6-fold) and clofibric acid (7.0-fold). WIN 36117 and fluorofibric acid also produced smaller increases in peroxisome numbers, liver weight, and carnitine acetyl transferase activity and smaller decreases in glutathione S-transferase and glutathione peroxidase activities. 6. Maximal increases in peroxisomal beta-oxidation activity produced in cultured rat hepatocytes by WIN 36117 and fluorofibric acid were 58 and 72% of those produced by ciprofibrate and clofibric acid respectively. 7. These results indicate the difluoro and 4-fluoro analogues of ciprofibrate and clofibric acid are hypolipidaemic agents and peroxisome proliferators but with reduced potencies relative to the parent molecules.[1]

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