Amelioration of oxidative stress in human endothelial cells by caffeic acid phenethyl ester (CAPE) and fluorinated derivatives (FCAPES) and pharmacokinetic characterization of CAPE and FCAPE in rats

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Amelioration of oxidative stress in human endothelial cells by caffeic acid phenethyl ester (CAPE) and fluorinated derivatives (FCAPES) and pharmacokinetic characterization of CAPE and FCAPE in rats

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dc.contributor.advisor Stavchansky, Salomon
dc.creator Wang, Xinyu, 1974 Aug. 12-
dc.date.accessioned 2008-08-29T00:05:37Z
dc.date.available 2008-08-29T00:05:37Z
dc.date.created 2007-12
dc.date.issued 2008-08-29T00:05:37Z
dc.identifier.uri http://hdl.handle.net/2152/3716
dc.description.abstract Tissue ischemia is a major cause of morbidity contributing to disease processes such as cardiovascular diseases, stroke, cancer, and traumatic injury and may lead to death. Failure to quickly reestablish flow to ischemic tissue results in tissue death. However, even timely return to normal flow has a downside in that the reintroduction of oxygen to ischemic tissue results in ischemia/reperfusion (I/R) injury that produces an oxidant stress. This pathological process requires new therapeutic strategies and agents to reduce the personal, social and economic loss. One of the most generally accepted mechanisms for the pathology of I/R injury is the production of the reactive oxygen species (ROS), suggesting antioxidants may ameliorate I/R injury. Caffeic acid phenethyl ester (CAPE), a plant derived polyphenolic compound, has been shown to protect organs from I/R induced damage in vivo, and this effect has been attributed to its antioxidant activity. To better understand the mechanism of CAPE protection, a model using menadione-induced oxidative stress in human endothelial cells to simulate I/R injury in vitro was developed. Gene expression analysis was performed with microarrays undergoing cytoprotection with CAPE. The dose-dependent cytoprotection of CAPE has been related to its induction of heme oxygenase-1 (HO-1). With the aim of improving the beneficial effect of CAPE and understanding structure activity relationship, six new catechol ring-fluorinated CAPE derivatives were synthesized and evaluated in the menadione-endothelial cell model. The data suggest good cytoprotective effects of CAPE and some analogues and indicate important structural features for cytoprotection. Further investigation of the mechanism of cytoprotection showed that cytoprotection profiles of CAPE and derivatives correlate better to their ability to induce HO-1 in human endothelial cells than free radical scavenging activity. One CAPE derivative (FCAPE) with cytoprotective effects similar to CAPE in vitro exhibited better stability in rat plasma. A validated ultra-performance liquid chromatography/tandem mass spectrometric method was developed that allowed for quantification of CAPE and FCAPE in plasma samples. Pharmacokinetic studies in male Sprague Dawley rats following intravenous bolus administration of 5, 10, and 20 mg/kg CAPE and 20 mg/kg FCAPE were performed. The results indicate that dose proportionality for CAPE does not exist in the dose range studied. Although the elimination half life was found not to be significant different between CAPE and FCAPE, significant difference was observed between the total body clearance of FCAPE and CAPE which may due to the difference in volume of distribution.
dc.format.medium electronic
dc.language.iso eng
dc.rights Copyright © is held by the author. Presentation of this material on the Libraries' web site by University Libraries, The University of Texas at Austin was made possible under a limited license grant from the author who has retained all copyrights in the works.
dc.subject.lcsh Oxidative stress--Prevention
dc.subject.lcsh Reperfusion injury--Prevention
dc.subject.lcsh Plant polyphenols--Therapeutic use
dc.subject.lcsh Endothelium
dc.title Amelioration of oxidative stress in human endothelial cells by caffeic acid phenethyl ester (CAPE) and fluorinated derivatives (FCAPES) and pharmacokinetic characterization of CAPE and FCAPE in rats
dc.description.department Pharmacy
dc.identifier.oclc 212411867
dc.identifier.recnum b69726930
dc.type.genre Thesis
dc.type.material text
thesis.degree.department Pharmacy
thesis.degree.discipline Pharmacy
thesis.degree.grantor The University of Texas at Austin
thesis.degree.level Doctoral
thesis.degree.name Doctor of Philosophy

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