Aug. 16, 1999 Researchers at the University of Pennsylvania Medical Center have shown that a class of anti-diabetic agents currently on the market dramatically decreases the symptoms of inflammatory bowel disease in mice. Specifically, they discovered that these drugs inhibit the activation of a master regulator of the inflammatory response called NF-kappa B. Their research suggests that these compounds, called thiazolidinediones (TZDs), may be an effective new therapy for treating inflammatory bowel disease (IBD) in humans, a debilitating disorder that afflicts millions worldwide. The investigators present their findings in the August 15 issue of the Journal of Clinical Investigation.
The Penn team found that when they gave TZDs to mice with IBD, it significantly reduced the symptoms of the disease, as measured by a composite index of weight loss, diarrhea, and intestinal bleeding. After about a week of the treatment, there was an 80 percent improvement in the mice receiving TZDs. "We're excited about this because the mouse model in our study has been used for a long time to study treatments for inflammatory bowel disease, and many pharmacologic agents that are effective in humans with IBD are also effective in this animal model," says senior author Gary D. Wu, MD, an assistant professor of medicine.
Inflammatory bowel disease manifests itself in two ways -- one is limited to the colon, which is called ulcerative colitis. The other is Crohn's disease, which can involve the entire gastrointestinal tract. The total number of people in the United States that have either one of those diseases is approximately one million.
The Penn study focused on ulcerative colitis, which affects about 500,000 Americans. "IBD is a chronic disease with waxing and waning activity and is very debilitating in some patients," notes Wu. The symptoms in humans include abdominal pain, diarrhea, intestinal bleeding, nausea, and vomiting.
Many patients fail to respond to currently available therapies. Furthermore, some of the other drugs used to treat moderate to severe IBD, including steroids and other immune modulatory agents, can be toxic to the human system. "Because of this, we've been searching for more effective, safer oral treatments for ulcerative colitis," says Wu.
Using cell cultures, the researchers are also discovering how TZDs work on a molecular basis. By binding to PPAR-gamma, a nuclear hormone receptor, TZDs ultimately inhibit the action of NF-kappa B, a master regulatory molecule in the inflammatory response. PPAR-gamma is localized to the nucleus of cells found in several tissues of the body, including the cells lining the inside of the colon. When an activating molecule, such as a drug like TZD, migrates through the cell membrane and into the nucleus, it binds to PPAR-gamma. This complex, hypothesizes Wu and colleagues, then activates a gene that makes proteins which ultimately inhibit NF-kappa B and the inflammatory response.
Because of what is understood from studies in cell culture and now in animal models about the action of TZDs, the Penn Inflammatory Bowel Disease Center has just started enrolling patients in a clinical trial to see if the drugs will be an effective treatment for ulcerative colitis. They are using a new generation TZD drug called rosiglitazone (Avandia), which was released several weeks ago for the treatment of diabetes.
These studies were funded in part by grants from the National Institutes of Health.
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