Clinical Research Directory

Lipidomics Screening of Anti-inflammatory Drugs and Drug Candidates in Vitro - Part A

Sponsor: University of Pennsylvania

Summary

Cardiovascular complications of NSAIDs, selective for inhibition of COX-2, stimulated interest in microsomal prostaglandin E synthase-1 (mPGES-1) as an alternative drug target. Global deletion of mPGES-1 in mice suppresses PGE2 and augments PGI2 by PGH2 substrate rediversion. Unlike COX-2 inhibition or gene deletion, mPGES-1 deletion does not cause a predisposition to thrombogenesis and hypertension. However, cell-specific deletion of mPGES-1 reveals that the predominant substrate rediversion product amongst the prostaglandins varies by cell type, complicating drug development. We have developed an ultra performance liquid chromatography/ tandem mass spectrometry (UPLC-MS/MS) technique that allows the quantification of a wide range of lipids beyond the prostaglandin pathway (leukotrienes, anandamide and the 2-arachidonylglycerol cascades). This study is designed to examine different pathway interventions from the arachidonic acid cascade by anti-inflammatory compounds (with a focus on mPGES-1 inhibition) in whole human blood in vitro (Part A) and ex vivo (Part B). In Part A, whole human blood will be donated by healthy volunteers and treated with screening compounds in vitro (outside of the body). Experiments will be performed to measure an array of lipids in plasma and serum from pre-stimulated whole blood treated with a single or a combination of the test compounds. This study may reveal pathways previously unknown to be affected by the existing anti-inflammatory drugs and drug candidates, and will possibly suggest new indications and/or side effects.

Official title: Broad-spectrum Lipidomics Screening of Anti-inflammatory Drugs and Drug Candidates in In Vitro Human Whole-blood Assay (hWBA)

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