This could be big. A discovery that “could eventually benefit millions of patients with chronic pain from trauma, diabetes, shingles, multiple sclerosis, or other conditions that cause nerve damage.” It’s all about bioactive lipids, key molecular signatures, and soluble epoxide hydrolase. Below, Professor Bruce Hammock, distinguished professor at the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, explains the discovery.
Q: Can you explain just how close the anatomy/neurology of diabetic rodents are to humans?
A: This is a very sophisticated and important question. It has proven hard to move compounds effective in mouse and rat models to humans. This could be because mice are physiologically very different than humans. We have addressed this issue by showing activity in mice and rats as well as horses, dogs, and cats. The fact that the compounds work in a variety of species builds confidence. It argues that with regard to neuropathic pain, different species—dogs, horses, humans, rats, etc—are similar. We also with Sphaera Pharma ran a clinical trial in India using a compound that is generally regarded as safe (GRAS) as a topical with human neuropathic pain. The results were very good with triclocarban, which is in products such as Dial Gold Soap and Safeguard Soap. Sphaera and Synthia Dermatech continue to work on this material. With animal health we are moving the compounds to the clinic for equine laminitis, which is a commonly terminal neuropathic pain. The other issue is using models. Models to test biochemical concepts are important in research but they are usually simplistic. To address this we have used numerous rodent models and found that the compounds work in all of them. We also are testing real patients but in this case the patients are companion animals and horses. Like man, the patients present not only with pain but hypertension, tissue destruction, and inflammation. The compounds reverse all of the symptoms.
Q. Your findings could benefit patients in chronic pain from nerve damage. What is the next step in your process to get this pain control out to the patients who need it?
A. We are taking several approaches. With companion animals we are starting to work with the FDA to design blind clinical trials. With man we are supported by a NIH Small Business Administration Grant and individual investors providing angel funding. With humans we are in 'IND enabling research.' We are carrying out the safety studies that will allow the compounds to be used in a Phase IA clinical trial. With triclocarban we are working to get this to patients by several routes. I wish we were moving faster on all fronts.
Q: What steered you and your research team to study neuropathic pain, and this aspect of neuropathic pain?
A: This work started as very fundamental research in developmental biology using insects as models. We found that the soluble epoxide hydrolase is highly conserved in evolution and asked its role in man and other mammals. We first found that inhibitors of the enzyme stabilize natural antihypertensive compounds called EETs and reduced blood pressure. We then found that they reduced inflammation and inflammatory pain. We tried neuropathic pain as an indication because it is so difficult to treat and were surprised to find that the enzyme soluble epoxide hydrolase inhibitor worked far better than drugs like gabapentin and Lyrica currently sold for neuropathic pain. Having failed to interest large pharma companies in this biology we started a small company EicOsis to move the inhibitors to the clinic for treating pain in both companion animals and man.
Q: What might be the side effects of blocking the compounds that cause endoplasmic reticulum stress?
A: An excellent question, and we do not know. We are working hard to answer this question. One can never prove a drug safe, only fail to prove it unsafe. It also is important to keep in mind that the only drugs without side effects are the ones that do not work. With all drugs we are pushing biology to the left or right trying to correct disease. As academics we are of course looking hard for serious side effects and have failed to find anything serious yet. However, there are certain to be side effects. With soluble epoxide hydrolase inhibitors we do avoid the bleeding ulcers and cardiovascular problems seen with NSAID drugs. We avoid the addiction problems seen with narcotics. We avoid the mobility impairment seen with gabapentin and pregabalin. But I feel certain we will find side effects.
Q: What do you think about the general state of pain management in the US today?
A: Others are better to answer this than me. I am not a clinician. There are sophisticated approaches integrating a number of techniques to manage pain. A great limitation is that the tool box we provide the physicians is relatively limited. I hope we can provide some more tools for that tool box. With over the counter drugs there are not good options for patients with neuropathic pain, either for companion animals or man. The situation becomes very bleak as we move to developing countries. In areas where diabetes and the resulting neuropathic pain is rampant, even the current marginally effective drugs are out of reach financially. Triclocarban is one of several approaches we are taking to get tools to developing countries.
Q: What is a dream project you hope to work on?
A: I have many dreams. I have spent my career focusing on chemical-biological interactions that involve natural chemicals such as omega 3 fats and drugs. I saw truly terrible pain when I was in the Army. It would be nice to provide a new tool to relieve this suffering.
Q: What brought you to the study of entomology and nematology?
A: A long-term interest in nature and biology. This was fostered by a wonderful Boy Scout Master who thought kids should be wandering in the woods, and a great biology teacher who provided a microscope to me in high school and said “Go discover.” The move to entomology was further stimulated when I realized that the big cause of human suffering in the world was starvation caused in part by insects eating crops. It was also stimulated by realizing that insect borne diseases dwarf cancer, heart disease, etc, in terms of human suffering. It is hard to know where science leads. In this case asking how caterpillars turn into butterflies led to a treatment for pain.
Q: As a professor, do you discuss your research with your students?
A: Yes we have 3 to 4 group meetings a week to discuss research. That is the fun part of science.
The Pain Reporter feels smarter now and hopeful that millions of people may benefit from this research. Many thanks to Professor Hammock and the team of researchers at UC Davis.
To read a Daily Dose synopsis of the research, with links to a press release and journal abstract, click here.