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Potential for Developing Purinergic Drugs for Gastrointestinal Diseases

Ochoa-Cortes, Fernando PhD*; Liñán-Rico, Andromeda PhD*; Jacobson, Kenneth A. PhD; Christofi, Fievos L. PhD, AGAF*

Inflammatory Bowel Diseases:
doi: 10.1097/MIB.0000000000000047
Basic Science Review Articles
Abstract

Abstract: Treatments for inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), functional dyspepsia, or motility disorders are not adequate, and purinergic drugs offer exciting new possibilities. Gastrointestinal symptoms that could be targeted for therapy include visceral pain, inflammatory pain, dysmotility, constipation, and diarrhea. The focus of this review is on the potential for developing purinergic drugs for clinical trials to treat gastrointestinal symptoms. Purinergic receptors are divided into adenosine P1 (A1, A2A, A2B, A3), ionotropic ATP-gated P2X ion channel (P2X1–7), or metabotropic P2Y1,2,4,6,11–14 receptors. There is good experimental evidence for targeting A2A, A2B, A3, P2X7, and P2X3 receptors or increasing endogenous adenosine levels to treat IBD, inflammatory pain, IBS/visceral pain, inflammatory diarrhea, and motility disorders. Purine genes are also potential biomarkers of disease. Advances in medicinal chemistry have an accelerated pace toward clinical trials: Methotrexate and sulfasalazine, used to treat IBD, act by stimulating CD73-dependent adenosine production. ATP protects against NSAID-induced enteropathy and has pain-relieving properties in humans. A P2X7R antagonist AZD9056 is in clinical trials for Crohn's disease. A3 adenosine receptor drugs target inflammatory diseases (e.g., CF101, CF102). Dipyridamole, a nucleoside uptake inhibitor, is in trials for endotoxemia. Drugs for pain in clinical trials include P2X3/P2X2/3 (AF-219) and P2X7 (GSK1482160) antagonists and A1 (GW493838) or A2A (BVT.115959) agonists. Iberogast is a phytopharmacon targeting purine mechanisms with efficacy in IBS and functional dyspepsia. Purinergic drugs have excellent safety/efficacy profile for prospective clinical trials in IBD, IBS, functional dyspepsia, and inflammatory diarrhea. Genetic polymorphisms and caffeine consumption may affect susceptibility to treatment. Further studies in animals can clarify mechanisms and test new generation drugs. Finally, there is still a huge gap in our knowledge of human pathophysiology of purinergic signaling.

In Brief

Article first published online 21 May 2014.

Author Information

*Department of Anesthesiology, The Ohio State University Wexner Medical Center, Columbus, Ohio; and

Laboratory of Bioorganic Chemistry & Molecular Recognition Section, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD.

Reprints: Fievos L. Christofi, PhD, AGAF, Department of Anesthesiology, The Ohio State University Wexner Medical Center, 226 Tzagournis Medical Research Facility, 420 West 12th Avenue, Columbus, OH 43210 (e-mail: fedias.christofi@osumc.edu).

Current support from the National Institutes of Health on R01 DK093499; strategic initiative research funds from the Department of Anesthesiology & Wexner Medical Center at The Ohio State University to F. L. Christofi; R01 DK044179 11-15; DK04417915S and NCRR S10RR11434 to F. L. Christofi. Support for from “the NIDDK, NIH Intramural Research Program” to K. A. Jacobson for research in the Laboratory of Bioorganic Chemistry & Molecular Recognition Section, Bethesda, MD.

The authors have no conflicts of interest to disclose.

Received February 18, 2014

Accepted March 14, 2014

© Crohn's & Colitis Foundation of America, Inc.

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