Drugs online research references
Clin Chim Acta. 1997 Oct 31;266(2):173-83.
The priming effect of gemfibrozil on reactive oxygen metabolism of phagocytic leucocytes. An intriguing side effect.
Scatena R, Nocca G, De Sole P, Fresu R, Zuppi C, Giardina B.
Institute of Chemistry and Clinical Chemistry, Faculty of Medicine, Catholic University, Rome, Italy.
Gemfibrozil is an antihyperlipidaemia agent used in therapy to reduce the occurrence of coronary heart disease. Considering the biochemical and pharmacological peculiarities of this class of drugs, we investigated the influence of a single oral therapeutic dose of gemfibrozil on the reactive oxygen metabolism of phagocytic leucocytes. Analysis was carried out adopting a chemiluminescence assay. Results clearly indicate that gemfibrozil, acting as a primer, significantly enhances the induced reactive-oxygen-species (ROS) production by overall blood phagocytes (increment of Stimulation Index (SI) = +52% with respect to time 0 values; P < 0.01), by polymorphonuclear leucocytes (increment of SI = +28% with respect to control values; P < 0.01) and by monocytes (increment of SI = +83% with respect control values; P < 0.001), when these cells are stimulated by phorbol myristate acetate. This iatrogenic derangement of ROS metabolism could explain, at least in part, the occurrence of some side effects that occur in treatment with fibrates.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9437545&dopt=Abstract
Toxicol Appl Pharmacol. 1997 Dec;147(2):459-64.
Genotoxicity of acyl glucuronide metabolites formed from clofibric acid and gemfibrozil: a novel role for phase-II-mediated bioactivation in the hepatocarcinogenicity of the parent aglycones?
Sallustio BC, Harkin LA, Mann MC, Krivickas SJ, Burcham PC.
Department of Clinical Pharmacology, Queen Elizabeth Hospital, Woodville, South Australia.
Glucuronides formed from carboxylate-containing xenobiotics are more chemically reactive than most Phase II conjugates. However, while they have been shown to form protein adducts, their reactions with DNA have received little attention. We thus used the M13 forward mutational assay to assess the genotoxicity of acyl glucuronides formed from two widely used fibrate hypolipidemics, clofibric acid and gemfibrozil. Single-stranded M13mp19 bacteriophage DNA was incubated in pH 7.4 buffer for 16 h in the presence of 0, 1, 2.5, and 5 mM concentrations of each glucuronide as well as the respective aglycones. The modified DNA was then transfected into SOS-induced competent Escherichia coli JM105 cells and the transfection efficiency was determined after phage growth overnight at 37 degrees C. Significantly, both acyl glucuronides, but not the aglycones, caused a concentration-dependent decrease in the transfection efficiency of the DNA, with a greater than 80% decrease in phage survival produced by the 5 mM concentrations of the glucuronides. No increase in lacZa mutations accompanied the loss of phage survival. We propose that these genotoxic effects involve reactions with nucleophilic centers in DNA via a Schiff base mechanism that is analogous to the glycosylation of DNA by endogenous sugars. Since strand nicking is known to accompany such damage, we also analyzed glucuronide-treated pSP189 plasmids for strand breakages via agarose gel electrophoresis. Both clofibric acid and gemfibrozil glucuronides produced significant concentration-related strand nicking and exhibited over 10-fold greater reactivity than the endogenous glycosylating agent, glucose 6-phosphate. On the basis of these findings, the possibility that this novel bioactivation route participates in the carcinogenicity of the fibrate hypolipidemics deserves investigation.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9439741&dopt=Abstract
J Lipid Res. 1998 Jan;39(1):17-30.
A novel compound that elevates high density lipoprotein and activates the peroxisome proliferator activated receptor.
Bisgaier CL, Essenburg AD, Barnett BC, Auerbach BJ, Haubenwallner S, Leff T, White AD, Creger P, Pape ME, Rea TJ, Newton RS.
Department of Vascular and Cardiac Diseases, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
In the current studies we describe the effects of PD 72953 and related compounds on lipoprotein levels in chow-fed male rats. After 2 weeks, 10 mg/kg of PD 72953 daily was as effective as 100 mg/kg gemfibrozil for elevating HDL-cholesterol. At 100 mg/kg, PD 72953 further elevated HDL-cholesterol to 232% of control levels, and was associated with increased HDL size and plasma apoE (169% of control), despite no change in hepatic apoE mRNA. ApoA-I rose transiently (at 1 week), but by 2 weeks only apoE remained elevated. PD 72953 dose-dependently reduced plasma apoB, VLDL-cholesterol, LDL-cholesterol, and triglyceride. Hepatic apoC-III mRNA reduction parallelled triglyceride lowering. After 1 week, 30 and 100 mg/kg per day PD 72953 reduced plasma apo-CIII levels by 30 and 34%, and triglycerides by 60 and 83%, respectively. PD 72953 treatment had no effect on triglyceride production rates; however, 125I-labeled VLDL apoB disappearance was enhanced. We compared PD 72953 to a structurally similar diacid, PD 69405, that also reduced VLDL and LDL, but had no effect on HDL elevation. Compared to PD 72953, PD 69405 further accelerated 125I-labeled VLDL apoB disappearance, decreased triglyceride production, and elevated the ratio of post-heparin hepatic to lipoprotein lipase activity. Whole animal studies, transient transfection studies in HepG2 cells, and chimeric receptor studies in kidney 293 cells suggest that PD 72953 is a ligand for the peroxisomal proliferation activated receptor alpha (PPARalpha), and PPARgamma. Overall, PD 72953 may act through a peroxisomal proliferation activated receptor and result in plasma triglycerides and apoB-containing lipoprotein reduction, while also raising HDL cholesterol. Reduced apoC-III may allow triglyceride-rich remnants to more efficiently bind and present substrate to peripheral tissue lipoprotein lipase, and therefore allow enhanced shedding of remnant phospholipid surface for HDL production.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9469582&dopt=Abstract
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