Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties.

Structure-guided lead optimization of recently described benzimidazolyl acetamides addressed the key liabilities of the previous lead compound 1. These efforts culminated in the discovery of 4-{(S)-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid 7g, a highly potent and selective FXR agonist with excellent physicochemical and ADME properties and potent lipid lowering activity after oral administration to LDL receptor deficient mice.

Fenofibrate and rosiglitazone lower serum triglycerides with opposing effects on body weight.

Activators of peroxisome proliferator activated receptors (PPARs) are effective drugs to improve the metabolic abnormalities linking hypertriglyceridemia to diabetes, hyperglycemia, insulin-resistance, and atherosclerosis. We compared the pharmacological profile of a PPARalpha activator, fenofibrate, and a PPARgamma activator, rosiglitazone, on serum parameters, target gene expression, and body weight gain in (fa/fa) fatty Zucker rats and db/db mice as well as their association in db/db mice. Fenofibrate faithfully modified the expression of PPARalpha responsive genes. Rosiglitazone increased adipose tissue aP2 mRNA in both models while increasing liver acyl CoA oxidase mRNA in db/db mice but not in fatty Zucker rats. Both drugs lowered serum triglycerides yet rosiglitazone markedly increased body weight gain while fenofibrate decreased body weight gain in fatty Zucker rats. KRP 297, which has been reported to be a PPARalpha and gamma co-activator, also affected serum triglycerides and insulin in fatty Zucker rats although no change in body weight gain was noted. These results serve to clearly differentiate the metabolic finality of two distinct classes of drugs, as well as their corresponding nuclear receptors, having similar effects on serum triglycerides.

Fenofibrate protects lipoproteins from lipid peroxidation: synergistic interaction with alpha-tocopherol.

One of the earliest steps of atherosclerotic plaque formation is an increase of circulating apolipoprotein B-containing lipoproteins which, after infiltrating the subendothelial space, undergo oxidative modification. Fenofibrate is an effective cholesterol- and triglyceride-lowering agent which has been shown to be beneficial in the treatment of atherosclerosis. Vitamin E, or alpha-tocopherol, is a powerful antioxidant which has been shown in a variety of studies to prevent lipoprotein peroxidation. The purpose of the present study was to investigate the effect of fenofibrate treatment, either alone or in combination with alpha-tocopherol, in reducing the susceptibility of lipoproteins to oxidative modification. Rats fed a normal diet were treated for up to 27 d with fenofibrate, either alone or in combination with equimolar doses of alpha-tocopherol. Combined VLDL (very low density lipoproteins) and LDL (low density lipoproteins) isolated after fenofibrate treatment were more resistant to copper-mediated oxidation, as assessed by conjugated diene formation. Lag time was prolonged up to 3.2-fold, while the maximal rate of diene production was significantly decreased by up to 2.2-fold. Treatment of rats with alpha-tocopherol alone at the selected dose had no significant effect on lag time, while the propagation rate was slightly decreased. Coadministration of fenofibrate with alpha-tocopherol prolonged the lag phase to a greater extent than fenofibrate alone, showing a synergistic interaction between the two compounds. Finally, the combination of fenofibrate and alpha-tocopherol was significantly more effective in modifying lipoprotein oxidation parameters than what was observed with alpha-tocopherol and bezafibrate or gemfibrozil. Thus, in addition to its well-established effects on lipoprotein concentrations and atherogenic parameters, fenofibrate reduces the susceptibility of VLDL and LDL to oxidative modification and exerts its action synergistically with alpha-tocopherol.

[Selective indications of skull radiography after head injury in children]. / Indications sélectives de la radiographie du crâne après traumatisme de la voûte chez l'enfant.

PURPOSE OF THE STUDY: Skull X-rays are systematically performed on children after head injuries in most hospitals. However, the discovery of a skull fracture as an isolated finding rarely warrants intervention. In february 1994, we stopped performing systematical skull X-rays in children after head injuries. We report the results of this experience. MATERIALS AND METHODS: Since February 1994, only children with possible skull penetration, depressed fracture, or presenting signs of basilar fracture had X-ray examination. Facial injuries were excluded in this study. In case of focal neurologic signs, neurosurgical consultation, or emergency CT examination, or both were performed. In case of change of consciousness at the time of injury or subsequently, the child was hospitalised for clinical observation for 48 hours, but no X-ray examination was performed. Children without any neurological signs or change of consciousness were discharged to their homes after they were given a head-injury instruction sheet, and if a second person could observe them for signs indicating that they belong to a higher risk group, but no X-ray examination was performed. RESULTS: An average of 241 children per month were presented at the Children Emergency Unit after head trauma. An average of twenty-one X-ray examinations per month were performed instead of 194/month before february 1994. This represented a decrease of 2000 X-ray examinations per year. There was no undiagnosed neurological complication, and the number of children staying in the hospital for clinical supervision did not increase. DISCUSSION: Skull radiographies only show fractures and do not afford visibility of either brain or blood to demonstrate an intracranial injury. The presence of a skull fracture without neurological abnormalities is of little significance. Harwood-Nash reported that 60 per cent of the children with extradural hematoma, 85 per cent of the children with subdural hematoma and 35 per cent of the children with brain damage did not have any associated skull fracture. Clinical examination is essential, and it would be a mistake to be reassured about the severity of a head trauma because skull X-rays are normal. CONCLUSION: Routine skull X-rays after head trauma are not justified either for financial or radioprotection reasons. In this study, more than half of the children were less than five years old and ran a higher risk of irradiation.