Drugs online research references
uniserv.ccr.rm.cnr.it
Bezafibrate belongs to the class of fibric acid derivatives usually used as antihyperlipidemia agents. From the biochemical point of view, these drugs show intriguing properties which leads one to think they may promote a differentiation process in tumour cells. This new pharmacological activity of fibrates could partially depend on the induction of an oxidative stress. To test this hypothesis, the effect of bezafibrate, as well as of clofibric acid and gemfibrozil, on growth, functional and cytochemical characteristics of human leukaemia-derived cell lines HL-60, U-937 and K-562 has been studied in some details. The results show that bezafibrate, gemfibrozil and clofibric acid, do induce differentiation in human myeloid leukaemia cell lines as indicated by several differentiation markers. Moreover fibrates, in dose dependent manner, significantly alter the cell cycle distributions, mainly leading to G0/G1 phase increment and G2/M phase reduction. The differentiating activity of fibrates could have significant implications both for the pharmacotoxicological profile of this class of compounds and for the pathophysiology of neoplastic disease.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10467352&dopt=Abstract
pasteur-lille.fr
Fibrates are widely used drugs which lower triglycerides and increase HDL concentrations in serum. Recent findings from our laboratory have shown that fibrates repress apolipoprotein (apo) CIII gene expression, an effect that explains partially the triglyceride-lowering activity of these drugs. The goal of the present study was to compare the effect of various fibrates on apo CIII gene expression in the human hepatoblastoma cell line HepG2. First, we demonstrate that the level of apo CIII secretion by HepG2 cells is controlled by serum factors whereas apo CIII mRNA levels are not and even increase under conditions when apo CIII secretion dramatically decreases. Twelve different fetal calf serum batches were tested during this study and apo CIII secretion in cell medium could only be detected with three of them. The effect of serum on apolipoprotein secretion was more pronounced for apo CIII whereas other apolipoproteins (apo E, apo B, apo AII and apo AI) were affected to a lesser extent. Under serum conditions allowing apo CIII secretion, treatment with the peroxisome-proliferator activated receptor (PPAR)alpha activators fenofibrate, gemfibrozil and Wy-14643 result in a marked lowering of apo CIII secretion and gene expression, this effect being most pronounced with Wy-14643. Comparison of the activity of a PPARgamma-specific ligand, the antidiabetic thiazolidinedione, BRL-49653 and a PPARalpha ligand Wy-14643 showed a marked decrease of apo CIII secretion and gene expression after activation of PPARalpha but not PPARgamma. In conclusion, fibrates down-regulate apo CIII gene expression in human HepG2 cells, most likely via PPARalpha but not via PPARgamma. However, these effects are only observed in HepG2 cells cultured under appropriate conditions.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10494028&dopt=Abstract
Clin Pharmacol Ther. 1991 Aug;50(2):208-14.
DNA polymorphisms of apolipoprotein B and AI/CIII genes and response to gemfibrozil treatment.
Aalto-Setala K, Kontula K, Manttari M, Huttunen J, Manninen V, Koskinen P, Frick HM.
Institute of Biotechnology, University of Helsinki, Finland.
Apolipoprotein B XbaI polymorphism and apolipoprotein AI/CIII SstI polymorphism have been found to be associated with variations in serum lipoprotein levels. We investigated whether these gene polymorphisms are involved in determining the lipid-modulating action of gemfibrozil. Of the 221 male subjects with hyperlipidemia studied, 121 responded well to the treatment with more than a 25% reduction in the non-high-density lipoprotein cholesterol level, whereas 100 were nonresponders. Among responders, but not nonresponders, homozygosity for the apolipoprotein B X2 allele (XbaI site present) and heterozygosity for the apolipoprotein AI/CIII S2 allele (SstI site present) were associated with elevated baseline serum low-density lipoprotein cholesterol and triglyceride levels, respectively. However, the hypolipidemic effect of gemfibrozil among the responders was independent of these gene polymorphisms. These data indicate that common polymorphisms of the apolipoprotein B and apolipoprotein AI/CIII gene loci influence serum lipid levels by mechanisms that are amenable to an intervention with gemfibrozil.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1678324&dopt=Abstract
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