New research may ease strain on haemorrhoid sufferers
identified the existence of an enzyme that could be key to treating
chronic and severe disorders such as certain forms of constipation,
anal fissures and Hirschsprung's disease.
The identification of the enzyme Rho kinase (ROK) could form the basis of a new inhibitory drug that could join the market for gastrointestinal (GI) disorders, one of the largest and most important in the pharmaceutical industry, generating revenues of over $16bn (€12.8bn) in 2004.
Functional GI disorders, such as Irritable Bowel Syndrome (IBS), chronic diarrhoea, constipation and intestinal pain, are characterised by symptoms and not by a visible sign of disease or injury. Inflammatory GI disorders include Inflammatory Bowel Disease (IBD), Crohn's Disease and ulcerative colitis.
Researchers at the Jefferson Medical College of Thomas Jefferson University in Philadelphia have shown that the enzyme Rho kinase (ROK) plays an important role in maintaining tone of the internal anal sphincter (IAS), which is crucial for normal bowel functioning.
Working on a rat model, the researchers examined the effects of a ROK inhibitor, Y 27632, on the hypertensive IAS.
They performed a series of tests with varying doses of Y 27632, finding that the inhibitor caused a dose-dependent fall in the intraluminal pressures in the high pressure zone of the IAS tone. Similarly, the ROK inhibitor caused a fall in the IAS tone in in-vitro studies.
The team also showed that Rho kinase was present in high levels in smooth muscle cells of the IAS, demonstrating that Rho kinase inhibitors are potent smooth muscle inhibitors, causing direct smooth muscle relaxation.
"I would speculate that Rho kinase is not working properly in certain forms of rectum-anal incontinence," said Satish Rattan, professor of medicine in the Division of Gastroenterology and Hepatology at Jefferson Medical College of Thomas Jefferson University in Philadelphia.
"In the hypertensive sphincter, which is associated with numerous gastrointestinal disorders, Rho kinase is probably working overtime. Rho kinase inhibitors would have a role in therapy," he added.
Its long been known that when IAS tone is too high - or "hypertensive" - the result can be constipation, anal fissures and haemorrhoids.
The IAS is important for continence and is controlled autonomically (as is all smooth muscle), as opposed to the external sphincter, which as skeletal muscle is voluntary.
As a result, IAS dysfunction cannot be easily controlled, and treating a hypertensive IAS can be difficult.
Current treatments that have been devised include surgeons incising into the IAS with variable and limited outcomes.
Botox A has also been tried, as has nitroglycerin and calcium channel blockers with potential downsides to all of them.
"The next step in the work would be to try these kinds of tests in the hypotensive state of the IAS in animal models first, and then hopefully in humans with some of these conditions," concluded Rattan.
Rattan and his colleagues report their findings in July in the journal Gastroenterology.
