Tools for Investigating Functional Interactions Between Lipid-Derived Autacoids and Their Receptors

Lerner, Michael R.; Golovyan, Lina; Graminski, Gerard F.; Harris, Kristine; Huang, Liquan; Jayawickreme, Channa; Karne, Suresh; McClintock, Timothy S.; Potenza, Marc N.; Roby-Shemkovitz, A.; Quillan, M.J.

doi:10.1097/00045391-199604000-00005

Cited by 1 publication

(2 citation statements)

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“…They include aspirin, used in low doses for cardioprotection, and drugs such as ibuprofen and celecoxib, used for the relief of pain and inflammation (1). They target the prostaglandin (PG) G/H synthase enzymes, colloquially known as COXs (COX-1 and COX-2).…”

Section: Introductionmentioning

confidence: 99%

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A broad-spectrum lipidomics screen of antiinflammatory drug combinations in human blood

Mazaleuskaya¹,

Lawson²,

Li³

et al. 2016

JCI Insight

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Current methods of drug screening in human blood focus on the immediate products of the affected pathway and mostly rely on approaches that lack sensitivity and the capacity for multiplex analysis. We have developed a sensitive and selective method based on ultra-performance liquid chromatography–tandem mass spectrometry to scan the effect of drugs on the bioactive eicosanoid lipidome in vitro and ex vivo. Using small sample sizes, we can reproducibly measure a broad spectrum of eicosanoids in human blood and capture drug-induced substrate rediversion and unexpected shifts in product formation. Microsomal prostaglandin E synthase-1 (mPGES-1) is an antiinflammatory drug target alternative to COX-1/-2. Contrasting effects of targeting mPGES-1 versus COX-1/-2, due to differential substrate shifts across the lipidome, were observed and can be used to rationalize and evaluate drug combinations. Finally, the in vitro results were extrapolated to ex vivo studies by administration of the COX-2 inhibitor, celecoxib, to volunteers, illustrating how this approach can be used to integrate preclinical and clinical studies during drug development.

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Section: Introductionmentioning

confidence: 99%

“…PGs and other products of arachidonic acid (AA) metabolism are formed in pM to fM amounts, acting locally as evanescent mediators (1). Furthermore, the capacity of tissues or cells to form these compounds, collectively termed eicosanoids, greatly exceeds actual rates of biosynthesis in vivo.…”

Section: Introductionmentioning

confidence: 99%