PHILADELPHIA, June 9 /PRNewswire/ -- New research published in the current issue of Gastroenterology identifies for the first time a molecular defect in the gastrointestinal (GI) tracts of patients with irritable bowel syndrome (IBS) that does not appear in those without the condition.
"IBS has long been classified as a purely psychosomatic condition," says GI expert Michael Gershon, M.D., professor and chairman, Department of Anatomy and Cell Biology, College of Physicians & Surgeons, Columbia University, New York. "Patients may have been treated solely for a condition that was supposedly 'all in their heads.' However, IBS is now associated with a very real abnormality in the gut and one that is as biochemical as any other."
Dr. Gershon, who collaborated on the research and authored "The Second Brain" about the independent operation of the gut by the enteric nervous system, says the discovery of a difference in the serotonin signaling function of the lining of the GI tract "should revolutionize the treatment of IBS."
The findings reinforce the critical role normal serotonin (5-HT) signaling plays in regulating GI function, pinpointing a difference in the way serotonin functions in certain cells lining the GI tract of IBS patients. This defect may underlie the clinical manifestations of IBS -- abdominal pain or discomfort, bloating, constipation and/or diarrhea -- that affect more than 40 million Americans.
Although serotonin generally is recognized as a chemical in the brain, only five percent of this naturally occurring neurotransmitter is found in the brain and central nervous system. The remaining 95 percent of serotonin resides in the cells lining the GI tract. In the gut, serotonin binds to 5-HT receptors on nerve cells, initiating intestinal movement. SERT (serotonin transporter), also found in cells lining the GI tract, initiate the uptake of serotonin by deactivating it when appropriate. Without this natural regulation, the mechanisms of digestion cannot function properly. In this study, patients with IBS were found to have decreased expression of SERT, which could lead to either over-stimulation of the gut (IBS with diarrhea) or receptor desensitization (IBS with constipation or IBS-C).
IBS is a common GI disorder affecting 15 to 20 percent of the U.S. population. It is a leading cause of workplace absenteeism, second only to the common cold, and costs the U.S. healthcare system an estimated $30 billion annually in direct and indirect costs. IBS is more prevalent in women, and patients spend approximately one out of every three days suffering with symptoms.
"The treatment of IBS has been extremely frustrating to physicians and patients alike," says Peter Moses, M.D., associate professor of Medicine and Director of Clinical Research in the Digestive Diseases, University of Vermont, and the study's co-lead investigator with Gary Mawe, Ph.D., professor of anatomy and neurobiology, University of Vermont. "We see our patients suffering. We know their problem is real. But until now, we have not been able to point to any specific physical difference in patients with IBS."
Dr. Gershon agrees, saying, "Functional diseases are a catch-all category for syndromes that cannot be explained by an anatomical or biochemical lesion. The definition of IBS as a 'functional disorder,' seems to imply that the problems experienced by IBS patients are somehow inferior to those with more 'serious' disorders, which are those associated with demonstrable anatomical or biochemical abnormalities. This is an unfair assessment, as the origins of IBS are clearly as biochemical as any other and its patients are equally deserving of compassion and the best treatment options available."
The research findings represent a major step forward into understanding the cause of chronic disorders of the gut, including IBS, according to the scientists. Dr. Moses says, "Six or seven new studies have been undertaken since we originally presented our research at the American College of Gastroenterology conference less than a year ago. In fact, even before our research started, new treatments that specifically address altered serotonin signaling were discovered, tested in clinical trials and approved for marketing. It is not uncommon to find drugs that work before knowing specifically how they address pathological conditions in the body."
Study Methods
The study examined tissue obtained from 43 healthy controls, 32 patients with IBS and 22 patients with inflammatory bowel disease (IBD). IBS patients were defined strictly using ROME II diagnostic criteria. Each biopsy was evaluated by five parameters: immunohistochemical staining, histological assessment, serotonin content, serotonin release and the measurement of mRNA encoding. The study also examined the molecular components of serotonin signaling, including the serotonin re-uptake system. Specifically, the investigators measured serotonin content, the endocrine cell number, serotonin release and presence of serotonin transporters (SERT). These regulatory molecules control the activity of serotonin within nerve endings in the GI tract to coordinate motility, visceral sensitivity and intestinal secretion.
Study Findings
In patients with both IBS and ulcerative colitis, the study found a significant decrease in serotonin content while the release of serotonin from endocrine (EC) cells was not significantly different compared to controls. In terms of the way the body inactivates serotonin signaling, or the serotonin re-uptake system, SERT mRNA and SERT immunoreactivity were markedly reduced in both patient populations compared to controls. This reduction is expected to decrease the capacity of epithelial cells to remove serotonin from intercellular space once it is released, thus increasing serotonin availability and ultimately causing abnormal bowel function.
"Now we have a perspective on molecular changes in the intestines of individuals with IBS that we did not have before. This is the first time we have been able to detect a sign of alterations in serotonin signaling in human subjects, and the data are very encouraging," said co-lead investigator Gary Mawe, Ph.D., professor of anatomy and neurobiology, University of Vermont.
The study was sponsored through a research grant from Novartis Pharmaceuticals Corporation, marketers of Zelnorm(R) (tegaserod maleate) for IBS with constipation. In addition to Moses and Mawe, members of the study team included Matthew Coates, Christine Mahoney, David Linden, Joanna Sampson and Eric Newton of the University of Vermont; Michael Gershon and Jason Chen of the Department of Anatomy and Cell Biology at Columbia University; Keith Sharkey of the Department of Physiology and Biophysics at the University of Calgary, and Michael Crowell of the Mayo Clinic, Scottsdale, Arizona.
About Zelnorm
Zelnorm is the first agent proven to provide women with relief from all three symptoms of IBS-C -- abdominal discomfort or pain, bloating and constipation, and it is the first in a novel class of drugs that act as an agonist at 5-HT4 (serotonin type 4) receptors. Zelnorm is indicated for the short-term treatment of women with IBS whose primary bowel symptom is constipation. The safety and effectiveness of Zelnorm in men have not been established.
In patients with IBS-C, Zelnorm has been shown to restore effectively deficient serotonin signaling by activating 5-HT4 receptors to increase GI motility in the gut. Zelnorm mimics the natural effects of serotonin, strengthening transmission in critical neural pathways, which normalizes impaired motility in the GI tract, inhibits visceral sensitivity (pain perception) and stimulates intestinal secretion of salts and water necessary in normal bowel function.
In IBS-C clinical trials, tolerability to Zelnorm was similar to placebo. The only adverse events reported significantly more often with Zelnorm than with placebo were headache (15 vs. 12 percent) and diarrhea (nine vs. four percent). The majority of patients reporting diarrhea had a single episode and in most cases, diarrhea occurred in the first week of treatment. Typically, diarrhea resolved with continued therapy. Serious consequences of diarrhea, including hypovolemia, hypotension, and syncope, have been reported in clinical studies (0.04 percent) and during marketed use of Zelnorm. In some cases, these complications have required hospitalization for rehydration.
Zelnorm was developed by Novartis, and is known internationally as Zelmac. It is approved in more than 55 countries for IBS-C. Approximately three million patients worldwide have been treated with Zelnorm for IBS-C. Zelnorm also is approved for use in chronic constipation in Mexico and Latin America. Zelnorm currently is being reviewed by the U.S. Food and Drug Administration for potential use in treating chronic constipation, and it is being studied as a potential treatment for other important GI disorders, including gastroesophageal reflux disease (GERD) and dyspepsia.
About Rome Criteria
Rome II is a classification system for all functional GI disorders agreed on by a multinational committee of specialists. The criteria defines IBS as at least 12 weeks or more, which need not be consecutive, in the preceding 12 months, of abdominal discomfort or pain that has two out of three features: symptoms relieved by defecation; onset of symptoms associated with a change in frequency of stool; the onset of symptoms associated with a change in stool consistency.
Forward-looking Statement
This release contains certain forward-looking statements relating to the Company's business, which can be identified by the use of forward-looking terminology such as "may," "encouraging," "potential," or similar expressions, or by discussions of strategy, plans or intentions. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results with Zelnorm to be materially different from any future results, performance or achievements expressed or implied by such statements. Specifically, there are no guarantees that the data described above will result in the commercial success of Zelnorm. Any such success can be affected by, among other things, uncertainties relating to product development, future clinical trial results, adverse regulatory actions or delays, government regulation generally, the ability to obtain or maintain patent or other proprietary intellectual property protection, competition in general and other risks and factors referred to in the Company's current Form 20-F on file with the Securities and Exchange Commission of the United States.
About Novartis
Novartis Pharmaceuticals Corporation researches, develops, manufactures and markets leading innovative prescription drugs used to treat a number of diseases and conditions, including central nervous system disorders, organ transplantation, cardiovascular diseases, dermatological diseases, respiratory disorders, cancer and arthritis. The company's mission is to improve people's lives by pioneering novel healthcare solutions.
Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG , a world leader in pharmaceuticals and consumer health. In 2003, the Novartis Group's businesses achieved sales of USD 24.9 billion and a net income of USD 5.0 billion. The Group invested approximately USD 3.8 billion in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ about 78,500 people and operate in over 140 countries around the world. For further information please consult http://www.novartis.com/ .
Contacts: Carrie Callahan Kevin Bannon Novartis Pharmaceuticals Corp. Ruder Finn (862) 778-7065 (212) 715-1621 carrie.callahan@pharma.novartis.com bannonk@ruderfinn.com John McInerney Ruder Finn (516) 606-3516 mcinerneyj@ruderfinn.com
Novartis
"IBS has long been classified as a purely psychosomatic condition," says GI expert Michael Gershon, M.D., professor and chairman, Department of Anatomy and Cell Biology, College of Physicians & Surgeons, Columbia University, New York. "Patients may have been treated solely for a condition that was supposedly 'all in their heads.' However, IBS is now associated with a very real abnormality in the gut and one that is as biochemical as any other."
Dr. Gershon, who collaborated on the research and authored "The Second Brain" about the independent operation of the gut by the enteric nervous system, says the discovery of a difference in the serotonin signaling function of the lining of the GI tract "should revolutionize the treatment of IBS."
The findings reinforce the critical role normal serotonin (5-HT) signaling plays in regulating GI function, pinpointing a difference in the way serotonin functions in certain cells lining the GI tract of IBS patients. This defect may underlie the clinical manifestations of IBS -- abdominal pain or discomfort, bloating, constipation and/or diarrhea -- that affect more than 40 million Americans.
Although serotonin generally is recognized as a chemical in the brain, only five percent of this naturally occurring neurotransmitter is found in the brain and central nervous system. The remaining 95 percent of serotonin resides in the cells lining the GI tract. In the gut, serotonin binds to 5-HT receptors on nerve cells, initiating intestinal movement. SERT (serotonin transporter), also found in cells lining the GI tract, initiate the uptake of serotonin by deactivating it when appropriate. Without this natural regulation, the mechanisms of digestion cannot function properly. In this study, patients with IBS were found to have decreased expression of SERT, which could lead to either over-stimulation of the gut (IBS with diarrhea) or receptor desensitization (IBS with constipation or IBS-C).
IBS is a common GI disorder affecting 15 to 20 percent of the U.S. population. It is a leading cause of workplace absenteeism, second only to the common cold, and costs the U.S. healthcare system an estimated $30 billion annually in direct and indirect costs. IBS is more prevalent in women, and patients spend approximately one out of every three days suffering with symptoms.
"The treatment of IBS has been extremely frustrating to physicians and patients alike," says Peter Moses, M.D., associate professor of Medicine and Director of Clinical Research in the Digestive Diseases, University of Vermont, and the study's co-lead investigator with Gary Mawe, Ph.D., professor of anatomy and neurobiology, University of Vermont. "We see our patients suffering. We know their problem is real. But until now, we have not been able to point to any specific physical difference in patients with IBS."
Dr. Gershon agrees, saying, "Functional diseases are a catch-all category for syndromes that cannot be explained by an anatomical or biochemical lesion. The definition of IBS as a 'functional disorder,' seems to imply that the problems experienced by IBS patients are somehow inferior to those with more 'serious' disorders, which are those associated with demonstrable anatomical or biochemical abnormalities. This is an unfair assessment, as the origins of IBS are clearly as biochemical as any other and its patients are equally deserving of compassion and the best treatment options available."
The research findings represent a major step forward into understanding the cause of chronic disorders of the gut, including IBS, according to the scientists. Dr. Moses says, "Six or seven new studies have been undertaken since we originally presented our research at the American College of Gastroenterology conference less than a year ago. In fact, even before our research started, new treatments that specifically address altered serotonin signaling were discovered, tested in clinical trials and approved for marketing. It is not uncommon to find drugs that work before knowing specifically how they address pathological conditions in the body."
Study Methods
The study examined tissue obtained from 43 healthy controls, 32 patients with IBS and 22 patients with inflammatory bowel disease (IBD). IBS patients were defined strictly using ROME II diagnostic criteria. Each biopsy was evaluated by five parameters: immunohistochemical staining, histological assessment, serotonin content, serotonin release and the measurement of mRNA encoding. The study also examined the molecular components of serotonin signaling, including the serotonin re-uptake system. Specifically, the investigators measured serotonin content, the endocrine cell number, serotonin release and presence of serotonin transporters (SERT). These regulatory molecules control the activity of serotonin within nerve endings in the GI tract to coordinate motility, visceral sensitivity and intestinal secretion.
Study Findings
In patients with both IBS and ulcerative colitis, the study found a significant decrease in serotonin content while the release of serotonin from endocrine (EC) cells was not significantly different compared to controls. In terms of the way the body inactivates serotonin signaling, or the serotonin re-uptake system, SERT mRNA and SERT immunoreactivity were markedly reduced in both patient populations compared to controls. This reduction is expected to decrease the capacity of epithelial cells to remove serotonin from intercellular space once it is released, thus increasing serotonin availability and ultimately causing abnormal bowel function.
"Now we have a perspective on molecular changes in the intestines of individuals with IBS that we did not have before. This is the first time we have been able to detect a sign of alterations in serotonin signaling in human subjects, and the data are very encouraging," said co-lead investigator Gary Mawe, Ph.D., professor of anatomy and neurobiology, University of Vermont.
The study was sponsored through a research grant from Novartis Pharmaceuticals Corporation, marketers of Zelnorm(R) (tegaserod maleate) for IBS with constipation. In addition to Moses and Mawe, members of the study team included Matthew Coates, Christine Mahoney, David Linden, Joanna Sampson and Eric Newton of the University of Vermont; Michael Gershon and Jason Chen of the Department of Anatomy and Cell Biology at Columbia University; Keith Sharkey of the Department of Physiology and Biophysics at the University of Calgary, and Michael Crowell of the Mayo Clinic, Scottsdale, Arizona.
About Zelnorm
Zelnorm is the first agent proven to provide women with relief from all three symptoms of IBS-C -- abdominal discomfort or pain, bloating and constipation, and it is the first in a novel class of drugs that act as an agonist at 5-HT4 (serotonin type 4) receptors. Zelnorm is indicated for the short-term treatment of women with IBS whose primary bowel symptom is constipation. The safety and effectiveness of Zelnorm in men have not been established.
In patients with IBS-C, Zelnorm has been shown to restore effectively deficient serotonin signaling by activating 5-HT4 receptors to increase GI motility in the gut. Zelnorm mimics the natural effects of serotonin, strengthening transmission in critical neural pathways, which normalizes impaired motility in the GI tract, inhibits visceral sensitivity (pain perception) and stimulates intestinal secretion of salts and water necessary in normal bowel function.
In IBS-C clinical trials, tolerability to Zelnorm was similar to placebo. The only adverse events reported significantly more often with Zelnorm than with placebo were headache (15 vs. 12 percent) and diarrhea (nine vs. four percent). The majority of patients reporting diarrhea had a single episode and in most cases, diarrhea occurred in the first week of treatment. Typically, diarrhea resolved with continued therapy. Serious consequences of diarrhea, including hypovolemia, hypotension, and syncope, have been reported in clinical studies (0.04 percent) and during marketed use of Zelnorm. In some cases, these complications have required hospitalization for rehydration.
Zelnorm was developed by Novartis, and is known internationally as Zelmac. It is approved in more than 55 countries for IBS-C. Approximately three million patients worldwide have been treated with Zelnorm for IBS-C. Zelnorm also is approved for use in chronic constipation in Mexico and Latin America. Zelnorm currently is being reviewed by the U.S. Food and Drug Administration for potential use in treating chronic constipation, and it is being studied as a potential treatment for other important GI disorders, including gastroesophageal reflux disease (GERD) and dyspepsia.
About Rome Criteria
Rome II is a classification system for all functional GI disorders agreed on by a multinational committee of specialists. The criteria defines IBS as at least 12 weeks or more, which need not be consecutive, in the preceding 12 months, of abdominal discomfort or pain that has two out of three features: symptoms relieved by defecation; onset of symptoms associated with a change in frequency of stool; the onset of symptoms associated with a change in stool consistency.
Forward-looking Statement
This release contains certain forward-looking statements relating to the Company's business, which can be identified by the use of forward-looking terminology such as "may," "encouraging," "potential," or similar expressions, or by discussions of strategy, plans or intentions. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results with Zelnorm to be materially different from any future results, performance or achievements expressed or implied by such statements. Specifically, there are no guarantees that the data described above will result in the commercial success of Zelnorm. Any such success can be affected by, among other things, uncertainties relating to product development, future clinical trial results, adverse regulatory actions or delays, government regulation generally, the ability to obtain or maintain patent or other proprietary intellectual property protection, competition in general and other risks and factors referred to in the Company's current Form 20-F on file with the Securities and Exchange Commission of the United States.
About Novartis
Novartis Pharmaceuticals Corporation researches, develops, manufactures and markets leading innovative prescription drugs used to treat a number of diseases and conditions, including central nervous system disorders, organ transplantation, cardiovascular diseases, dermatological diseases, respiratory disorders, cancer and arthritis. The company's mission is to improve people's lives by pioneering novel healthcare solutions.
Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG , a world leader in pharmaceuticals and consumer health. In 2003, the Novartis Group's businesses achieved sales of USD 24.9 billion and a net income of USD 5.0 billion. The Group invested approximately USD 3.8 billion in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ about 78,500 people and operate in over 140 countries around the world. For further information please consult http://www.novartis.com/ .
Contacts: Carrie Callahan Kevin Bannon Novartis Pharmaceuticals Corp. Ruder Finn (862) 778-7065 (212) 715-1621 carrie.callahan@pharma.novartis.com bannonk@ruderfinn.com John McInerney Ruder Finn (516) 606-3516 mcinerneyj@ruderfinn.com
Novartis
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