Nonsteroidal anti-inflammatory drugs (NSAIDs) are consumed by tens of millions worldwide. Although they relieve pain and inflammation, we understand poorly their mechanism of action. They also cause serious gastrointestinal and cardiovascular adverse effects and are thought to have caused thousands of deaths. Despite enrolling more than 100,000 patients in randomized trials, we still do not know the NSAID of choice for patients with arthritis and heart disease or if NSAIDs differ in clinical efficacy. Here we propose a paradigm shifting, strategic approach to harvest benefit and manage risk by personalizing therapy with NSAIDs. Data from studies from yeast, mammalian cells, zebrafish, mice and humans will be integrated to develop signaling networks that reflect perturbation by model NSAIDs and that generate hypotheses ultimately addressed by prospective, randomized trials in humans. Our hope is that these iteratively refined models, progressively informed by human data, will lead to algorithms of incremental value to clinicians in the prediction of efficacy and adverse effects. This interdisciplinary strategy will deliver innovative tools and technologies, quantitative models and biomarkers of drug response and if successful will allow more rational prescription of NSAIDs to minimize risk and maximize benefit to individuals, creating a novel paradigm for the development and approval of drugs, the design of randomized trials and the treatment of chronic disease.

Public Health Relevance

Drugs are prescribed based on detection of large average signals of effectiveness and hazard. This proposal attempts to refine the use of nonsteroidal anti-inflammatory drugs so that they are used in patients individually most likely to benefit and least likely to suffer adverse effects.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZGM1)
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Srinivas, Pothur R
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University of Pennsylvania
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Dong, Liang; Zou, Hechang; Yuan, Chong et al. (2016) Different Fatty Acids Compete with Arachidonic Acid for Binding to the Allosteric or Catalytic Subunits of Cyclooxygenases to Regulate Prostanoid Synthesis. J Biol Chem 291:4069-78
Bender, Gunes; Schexnaydre, Erin E; Murphy, Robert C et al. (2016) Membrane-dependent Activities of Human 15-LOX-2 and Its Murine Counterpart: IMPLICATIONS FOR MURINE MODELS OF ATHEROSCLEROSIS. J Biol Chem 291:19413-24
Zemski Berry, Karin A; Murphy, Robert C (2016) Phospholipid Ozonation Products Activate the 5-Lipoxygenase Pathway in Macrophages. Chem Res Toxicol 29:1355-64
Mazaleuskaya, Liudmila L; Lawson, John A; Li, Xuanwen et al. (2016) A broad-spectrum lipidomics screen of antiinflammatory drug combinations in human blood. JCI Insight 1:
Sahu, Ravi P; Harrison, Kathleen A; Weyerbacher, Jonathan et al. (2016) Radiation therapy generates platelet-activating factor agonists. Oncotarget 7:20788-800
Martin, Sarah A; Brash, Alan R; Murphy, Robert C (2016) The discovery and early structural studies of arachidonic acid. J Lipid Res 57:1126-32
FitzGerald, Garret A (2016) ImPRECISION: Limitations to Interpretation of a Large Randomized Clinical Trial. Circulation :
Guo, Lili; Worth, Andrew J; Mesaros, Clementina et al. (2016) Diisopropylethylamine/hexafluoroisopropanol-mediated ion-pairing ultra-high-performance liquid chromatography/mass spectrometry for phosphate and carboxylate metabolite analysis: utility for studying cellular metabolism. Rapid Commun Mass Spectrom 30:1835-45
Xiang, Yaozu; Hwa, John (2016) Regulation of VWF expression, and secretion in health and disease. Curr Opin Hematol 23:288-93
Dong, Liang; Zou, Hechang; Yuan, Chong et al. (2016) Interactions of 2-O-arachidonylglycerol ether and ibuprofen with the allosteric and catalytic subunits of human COX-2. J Lipid Res 57:1043-50

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