Veterans Affairs

Drug candidate for chronic intestinal pseudo-obstruction

Easily administered, cost effective treatment for bowel evacuation in persons with spinal cord injuries or other neural disorders affecting the gastrointestinal tract

Medical & Biotechnology

Scientists at the VA have recently developed a two-drug combination to stimulate bowel movement in patients with spinal cord injury or other neural abnormalities affecting the gastrointestinal (GI) tract. The patented technology is available via patent license agreement to companies that would make, use, or sell it commercially.

Normal movement of stool through the colon depends on periodic contractions of the muscles in the wall of the colon that pushes the fecal matter in the direction of the rectum, which ultimately results in evacuation of the feces. These contractions normally are stimulated by nerves arising from the lower or sacral part of the spinal cord. The effects of these nerves on the colon are generally mediated by a substance called acetylcholine, which causes muscles in the wall of the colon to contract.

The neural control mechanisms of the GI tract are thought to be impaired, at least in part, in a number of diseases and medical conditions, including spinal cord injury, amyotrophic lateral sclerosis, spina bifida, multiple sclerosis, Parkinson’s disease and dementia, even though the colonic muscles remain intact and capable of responding to acetylcholine. As a result, persons afflicted with these conditions often experience difficulty with bowel functions, including the inability to initiate defecation, straining to defecate, or incomplete evacuation of feces. Because of the chronic nature of the underlying disease, the resulting bowel dysfunction is also chronic and may have a significant negative impact on the subject’s quality of life.

As an alternative to laxatives, enemas and other less pleasant approaches to bowel care, VA researchers have found that a combination of an acetylcholinesterase inhibitor, such as neostigmine, and an anticholinergic agent, such as glycopyrrolate, may be safely administered in repeated doses over a period of time in an on-going bowel care program for subjects with chronic intestinal pseudo-obstruction.

Neostigmine is a drug that has long been used by anesthesiologists to reverse the muscle paralysis artificially induced during surgery but it is not without risk. A known side effect is a bradycardia (slowing of the heart rate) which can become life-threatening and requires close cardiac monitoring in a clinical setting. To address this, the researchers have added glycopyrrolate – an anticholinergic agent, which blocks neurotransmission by acetylcholine but has only limited activity on the muscarinic receptors of the colon. Glycopyrrolate is used by anesthesiologists clinical settings and essentially on an emergency basis to counteract bradycardia caused by neostigmine.

The researchers have further found that this combination of an acetylcholinesterase inhibitor and an anticholinergic agent may be safely administered in repeated doses over a period of time in an on-going bowel care program for subjects with chronic intestinal pseudo-obstruction.

This technology is closely related to international patent application WO2017139794.

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