A newly discovered enzyme inhibitor, identified by researchers originally looking for biological pest controls, may lead to pain relief for sufferers of arthritis and other inflammatory diseases, say researchers at the University of California, Davis. The finding, hailed by a noted inflammatory disease expert "as the most important discovery in inflammation in more than a decade," may also reduce side effects associated with the painkiller, Vioxx.
Lead author Kara Schmelzer, a post-doctoral researcher in principal investigator Bruce Hammock's lab, tested the novel compounds on rodents and found them to be as potent at a low-dose as Vioxx and Celebrex, but without the changes in blood chemistry linked to heart attacks. Vioxx and Celebrex belong to a class of drugs known as Cox-2 inhibitors. The enzyme targeted by the newly discovered inhibitors is also found in humans. (Enzymes are proteins that speed up chemical reactions.)
"The reason this is so exciting is that this is a novel way to reduce inflammation, with a combination therapy," Schmelzer said. "We're going after a new enzyme target, not going after the Cox-2 inhibitors."
Their research is reported in a paper entitled "Enhancement of Antinociception by Coadministration of Nonsteroidal Anti-Inflammatory Drugs and Soluble Epoxide Hydrolase Inhibitors," published in the current edition of Proceedings of the National Academy of Sciences.
"Our laboratory was initially interested in regulating the development of insect larvae," said Hammock, a distinguished professor of entomology and member of the National Academy of Sciences. The discovery switched the focus of the research from "pest control to pain control."
M. Eric Gershwin, chief of the Division of Rheumatology, Allergy and Clinical Immunology at the UC Davis School of Medicine and a distinguished professor of medicine, called the discovery "the most important discovery in inflammation in more than a decade." Gershwin, who was not affiliated with this study, is noted for his research on rheumatoid arthritis and other inflammatory diseases. His lab investigates the mechanisms leading to immunological alterations and autoimmunity.
As of 2004, physicians prescribed anti-inflammatory medication for more than 73 million patients. But many of the people suffer from pharmacological properties or side effects of the medications. Merck, the pharmaceutical company that manufactured and marketed Vioxx, a Cox-2 selective nonsteroidal anti-inflammatory drug (NSAID), voluntarily pulled the pain killer from the market in September 2004 due to safety concerns. A 12-month study, published in 2000, showed a four-fold increased risk of heart attacks. Merck hopes to replace it with another medication, Acoxia.
However, the class of drugs benefits millions of sufferers from inflammation and pain, Hammock said. The UC Davis study may mean a solution to the dilemma of whether to use the drugs.
"Combination therapies have long been used to treat inflammation while reducing side effects," Schmelzer wrote. She said the present study was designed to evaluate the therapeutic potential of combination treatment with NSAIDs and enzyme inhibitors (a previously undescribed soluble epoxide hydrolase inhibitor or sEHIs) in lipopolysaccharide (LPS)-challenged mice.
"We used LPS as an inflammatory agent, which is a component of some bacterial cell walls," said, co-author Steven Jinks. His laboratory examined the effects of these compounds in rodent inflammatory pain ehavior models. "Inflammatory mediators sensitize pain receptors and cause the animal to withdraw more quickly from a noxious stimulus, an indication of 'hyperalgesia' or heightened response to a painful stimulus. The sEH inhibitors reverse hyperalgesia and bring their withdrawal reaction back into the normal range.
Hammock said "these sEHIs are of similar or greater potency in reducing inflammation in rodents to Vioxx, but also when combined with Vioxx can dramatically reduce the concentrations of the Cox 2 inhibitor needed," Hammock said.
"The combination of Vioxx with the new sEHIs shifts blood chemistry toward the normal condition which may reduce the tendency toward blood clots," said UC Davis scientist Bora Inceoglu, a post-doctoral researcher and member of the research team.
The paper will be online at http://www.pnas.org/.
Schmelzer, Inceoglu and Hammock teamed with: In-Hae Kim, post-doctoral researcher in Hammock's lab; Steven Jinks, assistant adjunct professor, Department of Anesthesiology and Pain Medicine, UC Davis School of Medicine; Jason Eiserich, associate professor, Division of Nephrology, Department of Internal Medicine, UC Davis School of Medicine; and Lukas Kubala, former UC Davis post-doctoral researcher in Eiserich's lab.
Four UC Davis departments collaborated on the project: entomology, internal medicine, anesthesiology and pain medicine, and physiology and membrane biology, along with the UC Davis Cancer Research Center.
The work drew grant support from the National Institute of Environmental Health Sciences, Superfund Basic Research Program, and the Center for Children's Environmental Health and Disease Prevention, as well as a research award from the UC Davis Health Systems to Eiserich; a Paul F. Gulyassy Endowed Professorship to Eiserich and a UC Davis Department of Anesthesiology and Pain Medicine award to Jinks.
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