Friday, October 23, 2015

GWI Treatment Research Focusing on Anti-Inflammatory Treatments to Ease Pain, Fatigue

Editor's note:  Dr. Jarred Younger, featured in the news article below, is currently funded for Gulf War Illness treatment research by the Gulf War Illness Congressionally Directed Medical Research Program (CDMRP), within the U.S. Department of Defense.  Some of the anti-inflammatory treatments described in the article below are part of that funding.  

A Fiscal Year 2011 CDMRP-funded study (GW110044) by Dr. Younger and his research team at the University of Alabama at Birmingham found, "preliminary evidence that the immune system is involved in the pathophysiology of GWI."  

The publication of his study's results in a peer-reviewed medical journal further suggested, that immune profiling over time, "may be helpful in discovering targets for novel therapies in conditions such as GWI."

Dr. Younger's current treatment study, which builds on those findings and was funded by CDMRP using FY13 funds (GW130015), is, "designed to test nine plant-based compounds that may reduce inflammation and help those with GWI."  

According to the public abstract of the project:
"We believe that GWI is caused by inflammation in the brain. The inflammation results from overactive immune cells that are reacting to an unknown trigger. The chemicals released from the activated immune cells change the function of brain cells called neurons and cause pain, fatigue, cognitive problems, and other symptoms related to GWI. We believe that the best way to treat GWI is to administer anti-inflammatory agents. The idea is similar to how aspirin is used to reduce inflammation and swelling in the body, but common anti-inflammatory drugs do not cross into the brain easily. We are hoping to find plant-based compounds that can reach the brain and reduce inflammation."
"One of the main advantages of this study is that it tests compounds that are already available for human use. New drugs may take over 20 years, and millions of dollars, to go through the required regulations to be used in humans. In many cases, a treatment that works very well in animals fails to work at all in humans. During the time taken for drug development, patients continue to suffer. Individuals with GWI have already suffered for over 20 years and it is therefore essential that we test treatments and make them available as quickly as possible. We focus on treatments that allow us to skip animal testing and lengthy drug development. Individuals could take the treatments after the three-year study is completed. However, complete information about the effectiveness of the treatments may take up to 8 years to produce."
On a more technical basis, the project's concise, publicly available technical abstract describes the specific project aims:
Aim 1: To identify the most promising botanical microglia anti-inflammatories for the treatment of GWI. We will test nine botanical anti-inflammatory agents in a double-blind, placebo-controlled, crossover trial. Agents tested will include Resveratrol, Reishi Mushroom, Boswellia, Pycnogenol, Epimedium, Stinging Nettle, Luteolin, Fisetin, and Curcumin. We hypothesize that some of the tested agents will be significantly better than placebo at reducing pain, fatigue, and other symptoms associated with GWI. 
Aim 2 (exploratory): To identify biomarkers of GWI improvement. The second, exploratory, aim is to use machine learning algorithms to determine if blood-based inflammatory factors can serve as indicators of treatment response. Blood samples will be collected at baseline and during each treatment condition. Over 50 inflammatory and microglia-priming agents (e.g., IL-1beta, IL-1alpha, leptin, and eotaxin) will be quantified in the sera. Changes in symptoms in response to treatment will be tested for associations with changes in blood-based markers. We hypothesize that a positive clinical response to the tested agents will be associated with a reduction of inflammatory factors in blood sera. 
Impact: There are currently no accepted treatments that target GWI pathophysiology. There is a desperate and time-urgent need to identify adequate treatments. The development of promising botanical microglia-modulators would impact science and medicine in two ways. First, it would identify promising treatments that are immediately available to patients with GWI. Second, it would indicate new research directions for the diagnosis and treatment of GWI. We believe this screening approach gives us the best chance of being able to quickly translate research findings into clinical care. 


SOURCE:  CDMRP webpage, award outcomes search.


SOURCE:  Medical Xpress, Katherine Shonesy reporting, Oct. 22, 2015.


Solving the mysteries of fibromyalgia could help patients break free

October 22, 2015 by Katherine Shonesy

For 10 years, Gail De Sciose felt that pain controlled her activities, her schedule, her every move. She often found herself sprawled on the floor of her Birmingham home, sharp pains radiating down her neck, back, and hips. It was an abrupt change from the vibrant life she once led in New York City, where she had worked as a sales manager, traveled around the country, and volunteered at a local animal shelter.

"It felt like a hot poker being dragged across my body," De Sciose recalls. And the pain was accompanied by debilitating fatigue; De Sciose remembers falling asleep in the middle of conversations. "There were times I just couldn't function," she says. "I had to cancel theater tickets, vacations, and lunches with friends."
De Sciose is one of five million Americans and more than 200,000 Alabamians with fibromyalgia, a disorder characterized by widespread pain that has lasted at least three months and can't be attributed to any definitive cause. But a fibromyalgia diagnosis doesn't lead to a cure. For years after she had a name for her hot poker stabs, De Sciose remained in pain, and that's not unusual: The Centers for Disease Control and Prevention highlights studies showing that fibromyalgia patients rate their quality of life lower than patients with other chronic diseases, and are three-and-a-half times more likely to develop depression than those without the disorder.
Those responses could be on the verge of changing, however. At UAB, Jarred Younger, Ph.D., hopes to establish Alabama's first research and clinical care center specializing in fibromyalgia and related conditions, including  and Gulf War Illness. Already, research by Younger and his team in UAB's new Neuroinflammation, Pain, and Fatigue Lab has revealed possible underlying causes for the disorders and pointed to treatments that are helping to ease pain and fatigue—without side effects—in patients.
Younger's work "is really cutting-edge; it's groundbreaking," says David McLain, M.D., a Birmingham rheumatologist who treats the disease and often collaborates with UAB researchers. "He's responsible for opening up a whole new avenue of treatments, and it's fortunate he came to UAB."
A brainy solution
Younger, an associate professor recruited to the UAB College of Arts and Sciences Department of Psychology in 2014, became interested in fibromyalgia and chronic fatigue syndrome as a postdoctoral fellow at Stanford University's medical school. He had been studying pain more broadly when he realized how poorly understood these disorders were. 
"Patients are wholly affected," Younger says. "Some used to be athletes, some used to be business owners, and then their lives are taken over." Often, he points out, patients visit doctor after doctor, only to be told repeatedly that they're healthy—and that the pain or fatigue is all in their heads.
Younger, along with many other researchers and clinicians, believed otherwise. "I made it my mission to figure out what is wrong with these patients and how to treat them," he says.
As a Stanford postdoctoral fellow and faculty member, Younger spearheaded studies that surveyed immune molecules in the blood. He homed in on one particular protein called leptin, released by fat tissue, which appears in greater amounts in the blood of chronic fatigue patients. In fact, Younger could even gauge the day-to-day severity of a patient's symptoms just by tracking his or her leptin levels. These initial findings spurred him to continue investigating inflammatory immune molecules—and to start looking at the brain's role in the diseases.
Leptin has the ability to cross the blood-brain barrier and affect neural cells, causing pain and fatigue. But exactly how that happens remains a mystery. Younger thinks it has something to do with microglia, a type of immune cell found in the brain that normally helps to protect neurons.

Solving the mysteries of fibromyalgia could help patients break free
(Left to right) Graduate student Kelsey Campbell, postdoctoral student Joanne Lin, Ph.D., and Younger prepare a neuroimaging scan as part of research to develop a noninvasive tool for measuring brain temperature, which could diagnose neuroinflammation.

"Microglia defend our brain against everything," Younger explains. "When we get the flu, for instance, microglia are activated. These cells make us want to crawl into bed and do nothing—so our body can devote its resources to fighting off the flu."
In both fibromyalgia and chronic fatigue patients, Younger hypothesizes, the microglia are turned on when they're not supposed to be, causing fatigue or pain, a depressed mood, and cognitive dysfunction. At UAB, he is planning follow-up studies to help find evidence supporting this idea. He faces a crucial challenge, however: Currently, no methods are available to look directly at the activation or inflammation of microglia in living humans. But Younger and his colleagues are working on solutions, including specialized brain scans that measure the temperature of the brain or the presence of certain chemicals.
"It's only very recently that people are starting to explore what sensitizes microglia," Younger says. "The cells can be in a quiet, helpful state, or an active, warlike state." His findings, he hopes, will help reveal the difference.
Small gains, big impact
At the same time that Younger began studying the pathways underlying inflammation, he also started investigating alternative medicine and off-label treatments that had been used by patients with chronic fatigue and fibromyalgia. In 2009, he first reported the effectiveness of low-dose naltrexone—a drug normally used to treat opioid and alcohol addiction. Women who took 4.5 milligrams per day of the drug reported less pain throughout the weeks that they received it.
Interestingly, the naltrexone linked back to Younger's other studies: The drug is known to stop activated microglia from producing inflammatory chemicals.
De Sciose—who had resisted taking fibromyalgia drugs throughout the course of her disease because of the side effects that most can cause—heard about low-dose naltrexone from a friend in 2012, shortly after Younger published the results of his second, larger study on the drug. The science behind it seemed sound, she says, and Younger's studies had revealed few side effects. So she started taking a daily dose of naltrexone prescribed by her doctor.
"I didn't have any expectations; we hear so much about miracle drugs," De Sciose says. "But within the first two or three weeks, I stopped having that daily searing hot-poker pain. Then, a month later, different massage therapists told me that my muscles were feeling better."
Today, De Sciose wouldn't say she's cured of fibromyalgia—she still has to watch her activity levels to prevent flare-ups. But she can make plans again—lunch dates, theater tickets, and trips—without worrying that she'll end up sprawled on the floor every night. "Any small gain in pain reduction or quality of life is very important to me," she says.
Chain of Events
Younger's discoveries about leptin, microglia, and naltrexone have already begun to change the face of fibromyalgia and chronic fatigue research and treatment. But his work is just beginning, he says. "It's essential that we have a fuller understanding of what's wrong before we're able to find the best treatments," Younger says.
So while he's conducting further studies on low-dose naltrexone—as well as other compounds, including the spice curcumin, that are known to affect microglia—he's guiding the efforts of the Neuroinflammation, Pain, and Fatigue Lab toward uncovering the mechanisms behind the diseases. He would like to understand what triggers an increase in leptin production, what leptin activates, and what fires up microglia. He also wants to know how everything connects. "There's a chain of events, and we don't know where leptin falls in that chain," he says. "So we begin with one piece of the puzzle and start looking in both directions."
For patients, having any piece of the puzzle can be heartening. "These patients are not well understood," says McLain. "Their families and often their doctors think they're lazy or making up their symptoms. Being able to say, 'here's some of the science behind my illness' certainly makes them more hopeful."
Younger, too, is satisfied with the small bits of progress so far, but says that the treatment of chronic fatigue syndrome and  is a decade or two behind other inflammatory diseases. "Twenty years ago, rheumatoid arthritis absolutely wrecked people's bodies, and there wasn't a lot that could be done about it," he says. "Over time, researchers discovered the parts of the immune system that were involved, and that helped them develop better treatments."
If Younger's timeline holds true, then relief could be on the horizon for patients who must endure the pain, fatigue, and other symptoms every day. "I feel optimistic that I may wake up some day in the future and be able to feel even better and stronger than I do now as the result of a research finding and treatment to come," De Sciose says.
Quick facts about fibromyalgia and related diseases
  • Affect mainly women, though they can impact men and children.
  • Symptoms may include pain; fatigue; cognitive/memory problems; sleep disturbances; numbness and tingling; and sensitivity to temperature, noises, and light; among others.
  • There is no simple, specific test to diagnose these disorders. Physicians often talk with patients about  and fatigue severity and the presence of other symptoms.
  • Patients with  syndrome suffer daily, long-term, severe fatigue.
  • Gulf War Illness includes chronic, medically unexplained symptoms affecting veterans and civilians involved with military duty in the Persian Gulf region.

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