Medication that both stimulates appetite and reduces metabolic rate

Scientists at Oregon Health & Science University, in collaboration with Neurocrine Biosciences Inc., have successfully tested a research medication that both stimulates appetite and reduces metabolic rate in preclinical trials.

Neurocrine, which developed the test medication for this research, is now developing a related medication that will likely be tested in patients suffering from a common, disease-related form of malnutrition and involuntary weight loss called cachexia. The results of the research are published in the current online edition of the journal Endocrinology.

"We've all seen AIDS and cancer patients who lose their appetites and suffer from involuntary weight loss. They lose muscle mass and become very frail as their disease progresses -- this is what we refer to as cachexia," explains Daniel Marks, M.D., Ph.D., a member of the OHSU Center for Weight Regulation and Associated Disorders and an assistant professor of pediatric endocrinology in the OHSU School of Medicine. "Cachexia is a very serious and currently untreatable disorder that can often impede the battle against the related disease. For instance, cancer patients who are malnourished due to cachexia cannot undergo intense chemotherapy simply because their bodies are too frail to handle it. If we can prevent cachexia and keep these patients from deteriorating physically, it gives them a greater chance of surviving the disease they are fighting."

This latest research breakthrough is based on earlier studies that demonstrated how a receptor on certain brain cells -- called the MC4 receptor -- can influence metabolism and appetite. Previous research involving mice demonstrated that when this specific cell receptor is blocked by delivering medications directly to the brain, the effects of cachexia are reversed. The animals' appetite and weight increase while their metabolic rate decreases. The next step in the research process, and the goal of this study, was to develop and test a medication that would have the same effect. This medication, and others in its class, have excellent oral absorption, which also enhances their appeal as drug candidates.

In this research, the scientists gave both normal mice and mice with a cachexia-like syndrome Neurocrine's orally-administered medication that blocks the MC4 receptor in the brain. In both cases, the animals' appetites increased and their metabolic rates decreased, ultimately resulting in the resumption of normal growth and accumulation of muscle mass. Researchers now hope to conduct clinical trials where both healthy human patients and those suffering from cachexia receive related oral medications to determine the drug's safety and effectiveness.

"We believe the results obtained in this collaborative study with OHSU will provide an important proof-of-principle for Neurocrine's small molecule MC4 receptor antagonist program in animal models relevant for cachexia," said Alan C Foster, Ph.D., Neurocrine Fellow and head of Neurocrine's neuroscience group. Neurocrine is a San Diego-based company that is developing medications related to weight regulation. "We hope to advance an optimized molecule into the first stages of human clinical testing later this year."

"While a lot of attention is paid to the country's obesity epidemic, researchers at OHSU also investigate the other side of weight regulation which is not as well-publicized -- extreme weight loss," said Roger Cone, Ph.D., director of the Center for the Study of Weight Regulation and Associated Disorders. "Cachexia and disorders like it can have extremely serious consequences on patients. This research not only provides hope for these patients, it is also provides another important piece of the puzzle in regards to the brain's control over weight regulation."

The Center for the Study of Weight Regulation and Associated Disorders is a new research institute at Oregon Health & Science University in which scientists and physicians work together to address the important basic and clinical questions surrounding weight regulation. Researchers at OHSU have been involved in a number of key weight regulation discoveries, including identification of specific cells in the brain that are crucial to weight control, and the possible connection between infant hormone exposure and lifelong weight issues. Another key role of the center is to provide a base of expertise for public (community) education, and serve as a source for continuing education in the treatment of weight-related disorders, such as obesity, diabetes, anorexia and cachexia.