Basic metabolism studies lead to a treatment for laminitis in horses
By Sara Mishamandani
Hulahalla, a 4-year-old thoroughbred horse, was lame and a day away from being euthanized when University of California (UC), Davis veterinarian Alonso Guedes, D.V.M., Ph.D., made a call to UC Davis researcher Bruce Hammock, Ph.D. Guedes was interested in a compound that had been developed through NIEHS-funded Superfund Research Program (SRP) basic research. Testing in animal studies had demonstrated the safety of the compound, as well as its potential for inhibiting inflammation.
Within hours after Guedes administered the experimental drug, Hulahalla was back on her feet, the first sign she was recovering from laminitis, an agonizingly painful and usually terminal foot disease often seen in horses.
Today, one year after treatment, Hulahalla remains an active and healthy companion animal, and her example is inspiring continuing efforts to improve outcomes for other animals with laminitis.
Researchers at the UC Davis SRP, led by Hammock, had originally developed the compound to study basic catalytic mechanisms of an enzyme in the body and, in the process, found that the compound also relieved neuropathic pain and inflammation (see text box).
Making the call for treatment
The opportunity for the Hammock group to test the anti-inflammatory drug on larger animals presented itself through Guedes, who had been collaborating with the Hammock lab for several years. Laminitis is initiated by inflammation, progresses into severe inflammatory pain, and then into a chronic or neuropathic pain condition that leads to tissue destruction and often causes severe high blood pressure.
“In the United States, it is estimated that laminitis will strike 15 percent of horses during their lifetimes, and 75 percent of horses with laminitis will lose their lives,” said Guedes.
Hulahalla developed acute laminitis in both front feet. Veterinarians at UC Davis treated her with the standard of care for several days, but her condition deteriorated and she refused to stand. Guedes made an emergency call to Hammock, after obtaining compassionate permission to use the soluble epoxide hydrolases (sEH) inhibitor they had developed — the only option left, aside from euthanasia, to relieve the extreme pain and suffering.
Within three hours after clinicians administered the drug to Hulahalla, she was able to stand. Her pain level and blood pressure decreased progressively and, after three days, she could walk almost normally and her systolic blood pressure dropped significantly, from 200 to 110. After five days, Hulahalla was doing very well and no longer needed the sEH inhibitor. There has been no reoccurrence of laminitis or sign of adverse drug effects.
Bora Inceoglu, Ph.D., a collaborator of Guedes and Hammock, is working to move the compounds to the clinic for human diabetic and other neuropathic pain. “It is often hard to extrapolate from treatment of rodent models of pain to man,” said Inceoglu This mare was suffering from a real disease. Not only is it gratifying to save the life of Hulahalla, but she and other horses provide strong evidence that our success with treating neuropathic pain in rodents can be extrapolated to man.”
Moving the treatment forward
Since testing the compound with Hulahalla in 2011, four additional horses suffering from laminitis have been treated under a compassionate use protocol approved by the UC Davis Institutional Animal Care and Use Committee. That protocol allows animals to be treated with an experimental drug if no approved alternative treatment exists. Hulahalla experienced a complete remission that has lasted for more than a year, and three others have shown some improvement.
“The soluble epoxide hydrolase inhibitors are far more effective than any other commercial compound we have tried with pain models,” said former SRP graduate student Karen Warren, Ph.D.
“This is an unusual step for us to announce this so far in advance, but because euthanasia is often the only way to alleviate pain in severe laminitis, we felt that it was important to let the veterinarians and horse owners know that this compound has shown potential as a treatment,” said Guedes.
(Sara Mishamandani is a research and communication specialist for MDB Inc., a contractor for the NIEHS Superfund Research Program and Division of Extramural Research and Training.)
Starting from basic NIEHS research
Since its inception 25 years ago, SRP has supported the Hammock lab to study the role of epoxide hydrolases, enzymes that catalyze the opening of epoxide rings, to detoxify a variety of environmental chemicals.
Some epoxides are very reactive chemical compounds that form inside the body during the metabolism of drugs and environmental contaminants. Because of their reactivity, such epoxides can be potent mutagens, toxins, and carcinogens. Thus epoxide hydrolases offer significant protection against cellular injury, by transforming these harmful epoxides into less toxic and more water soluble compounds.
NIEHS-funded researchers led by Hammock discovered another soluble epoxide hydrolase (sEH), a new form of the enzyme that exists in the cell cytosol and degrades chemically stable fatty acid epoxides. To investigate the biological role of this enzyme, they created potent inhibitors. Inhibitors are commonly used to determine the location of the enzyme’s active site and to study factors that control enzyme activity.
Hammock and his team discovered that sEH is very good at converting fatty acid epoxides into diols, eliminating the epoxides from the body. However, some fatty acid epoxides of omega-3 and omega-6 can be very beneficial and have been found to reduce inflammation, inflammatory pain and, surprisingly, even chronic or neuropathic pain. They found that the potent inhibitors that they created to study sEH could be used in mouse and rat models as a drug to reduce inflammation and inflammatory pain more effectively than non-steroidal anti-inflammatory drugs (NSAIDs). They also began studying the use of the drug with horse enzymes, but had not yet used the drug in a horse or any other companion animal.
“It is very hard to tell where science will lead,” says Hammock. “We are hoping that the fundamental work supported by NIEHS on foreign compound metabolism will result in a treatment for devastating pain and inflammation in dogs and cats, as well as horses.”
A clinical trial to assess the drug’s safety and establish a tolerable dose for the compound is expected to begin in the spring. Further clinical trials would be needed to establish the drug’s effectiveness as a laminitis treatment.