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Pharmaceutical
      #13949 - 07/14/03 01:50 PM
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All articles related to gastrointestinal pharmaceutical research should be posted here.



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Combined use of SSRIs and NSAIDs increases the risk of GI adverse effects new
      #13977 - 07/14/03 03:15 PM
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British Journal of Clinical Pharmacology
Volume 55 Issue 6 Page 591 - June 2003
doi:10.1046/j.0306-5251.2002.01770.x

Combined use of SSRIs and NSAIDs increases the risk of gastrointestinal adverse effects

Jeroen C. F. de Jong, Paul B. van den Berg, Hilde Tobi & Lolkje T. W. de Jong - van den Berg

Aims To investigate the relationship between the use of antidepressants with or without NSAIDs and the risk of gastrointestinal side-effects.

Methods This was a population-based cohort study. Medication data of 180 000 patients from 16 pharmacies in The Netherlands were studied. The subjects were a group of 15 445 new users of antidepressants with or without NSAIDs. A review of patient profiles for cases of gastrointestinal adverse effects caused by first time use of antidepressants with or without NSAIDs was carried out. The number of first prescriptions for peptic ulcer drugs (Anatomical Therapeutic Chemical classification A02B) in the period from day 2 after starting antidepressants with or without NSAIDs until 10 days after the last dose was the main outcome measure.

Results In the reference group of 619 new users of nonselective antidepressants (TCAs), the incidence of first prescriptions for peptic ulcer drugs was 0.051 (95% confidence interval 0.021, 0.105). The use of SSRIs (n = 1181) caused a slightly higher incidence rate ratio (IRR) of 1.2 (0.5, 2.8). The combined use of SSRIs and NSAIDs (n = 86) increased the IRR to 12.4 (3.2, 48.0). In contrast, the combination of nonselective antidepressants and NSAIDs (n = 74) increased the IRR to 2.5 (0.3, 20.3).

Conclusions SSRIs increase the risk of gastrointestinal adverse effects in first time users as compared with nonselective antidepressants. The combined use of SSRIs and NSAIDs strongly increases the risk of gastrointestinal adverse effects and should be avoided. The combination of nonselective antidepressants and NSAIDs does not have this effect.

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Use of Antidepressants in the Treatment of IBS? new
      #13991 - 07/14/03 03:58 PM
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Gastroenterology Ask the Expert

Use of Antidepressants in the Treatment of IBS?

Posted 04/08/2003 from Medscape Gastroenterology


Question
When is it recommended to start antidepressant therapy in patients with irritable bowel syndrome (IBS)? Which is the preferred approach: tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRIs)?

Amir Belson, MD

Response
from Yehuda Ringel, MD, 04/08/2003

The treatment approach in patients with IBS is usually guided by the predominant symptoms (ie, pain, diarrhea, or constipation) as well as the severity of the disorder.

Most patients with IBS have mild and infrequent symptoms with no, or only little, associated disability. These patients do not usually need antidepressants. Reassurance, education, recommendations for dietary changes, and short-term symptomatic treatment are sufficient in most of these cases. Patients who have moderate or severe symptoms that considerably affect their daily activities and quality of life may require additional pharmacologic treatments, including psychopharmacologic (eg, antidepressants) and/or psychological and behavioral therapies.[1]

The rationale for the use of antidepressants in IBS is the coexistence of psychological disturbances, particularly in patients with more severe symptoms who seek medical care, and their effect/action on reducing gut sensation. The latter neuromodulatory analgesic effect of these agents is unrelated to their psychotropic effects. Thus, antidepressants can be used in IBS patients with or without psychiatric comorbidity (eg, depression, anxiety).

A recent meta-analysis of 12 studies concluded that antidepressants are effective in IBS patients. On average, 3.2 patients need to be treated to achieve 1 positive response in a patient's symptoms.[2] Tricyclic antidepressants have been best studied in IBS patients with pain and diarrhea. Low doses of desipramine (50-100 mg) or amitriptyline (25-75 mg) appear to be effective in controlling IBS symptoms in these patients. Although data on SSRIs are still limited, the current information suggests a beneficial effect. SSRIs may be preferred in older patients or in those with constipation because they have little or no anticholinergic effects.[1]

Long-term adverse effects are common with antidepressant treatment and relate to the anticholinergic, serotonergic, sedative antihistaminic, and alpha-adrenergic effects. These effects must be considered in choosing the treatment approach. In addition, because psychotropic agents also affect intestinal motility,[3] the patient's bowel function should also be considered when selecting an antidepressant medication.

Finally, because the disorder is multidetermined, it is important to view medication therapy as part of a more comprehensive management plan in the setting of IBS.[4]



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References
Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology. 2002;123:2108-2131. Abstract
Jackson JL, O'Malley PG, Tomkins G, Balden E, Santoro J, Kroenke K. Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis. Am J Med. 2000;108:65-72. Abstract
Chial HJ, Camilleri M, Burton D, Thomforde G, Olden KW, Stephens D. Selective effects of serotonergic psychoactive agents on gastrointestinal functions in health. Am J Physiol Gastrointest Liver Physiol. 2003;284:G130-G137. Abstract
Ringel Y, Drossman DA. Psychosocial factors in functional gastrointestinal disorders: Toward a more comprehensive understanding and approach to treatment. Medscape Conference Coverage, Digestive Disease Week 2001; Medscape Gastroenterology, 2001. Available at: http://www.medscape.com/viewarticle/418547 Accessed April 3, 2003.
About the Panel Members
Yehuda Ringel, MD, Assistant Professor, Department of Medicine, University of North Carolina at Chapel Hill; Attending Physician, Department of Digestive Diseases and Nutrition, University of North Carolina Hospitals, Chapel Hill



Medscape Gastroenterology 5(1), 2003. © 2003 Medscape

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Antidepressants in the Treatment of IBS and Other Functional GI Disorders new
      #14338 - 07/18/03 12:20 PM
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Use of Antidepressants in the Treatment of irritable Bowel Syndrome and Other Functional GI Disorders

Christine B. Dalton, PA-C
Laura A. Keeter, MSIV
Douglas A. Drossman. MD

Your doctor has recommended the use of antidepressants for your symptoms from irritable bowel syndrome (IBS) or another functional G.I. disorder. You may have questions and concerns about the use of these medications. The following information should help answer some of these questions.

Click here for the full article from UNC:

http://www.med.unc.edu/medicine/fgidc/antidepressentsandibs.htm



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Hypersensitivity and hyperreactivity in IBS: opportunity for drug discovery new
      #14349 - 07/18/03 12:39 PM
HeatherAdministrator

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Dig Dis. 1999;17(2):90-9. Related Articles, Links


Hypersensitivity and hyperreactivity in the irritable bowel syndrome: An opportunity for drug discovery.

Sanger GJ.

Department of Neuroscience Research, SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK. Gareth_J_Sanger@sbphrd.com.uk

The gastrointestinal tract of many patients with irritable bowel syndrome (IBS) is hypersensitive to different stimuli. The mechanisms of this hypersensitivity are unclear, but could involve enteric, visceral afferent/efferent, spinal and/or central nervous systems. Such complexity, the absence of animal models or anatomical, molecular or genetic markers of IBS, means that it is difficult to create new types of drugs which specifically treat the condition of IBS. To help in this process, current pre-clinical and early-clinical approaches are evaluated in terms of their ability to intervene within the gut-spinal cord/brain axis and inhibit gastrointestinal 'hypersensitivity' and 'hyperreactivity'. Thus, by developing a rational process the pharmaceutical industry may better understand how to design truly effective drugs for the treatment of IBS.

Publication Types:
Review
Review, Academic

PMID: 10545714 [PubMed - indexed for ME web page DLINE]


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Pain Relievers and Intestinal Disorders new
      #20928 - 09/16/03 04:20 PM
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Pain Relievers and Intestinal Disorders

Chris Woolston
CONSUMER HEALTH INTERACTIVE

• Why are NSAIDs hard on the stomach?
• Who is at risk for NSAIDs-related intestinal trouble?
• What are the symptoms of NSAIDs-related stomach trouble?
• What is the treatment for NSAIDs-related stomach trouble?
• Can NSAIDs-related stomach trouble be prevented?



Ever since aspirin hit the market in the late 1800s, it has been a fixture in medicine cabinets everywhere -- and for good reason. It erases headaches, soothes arthritis, lowers fevers, helps prevent heart disease, and may even ward off some types of cancer. If it were discovered today, doctors would hail it as a medical breakthrough.

But for some people, aspirin has a serious downside -- especially if taken regularly. At the same time it's easing your pain, it could be giving you an ulcer. Aspirin is just one of many painkillers known as nonsteroidal anti-inflammatory drugs (NSAIDs), which can cause serious damage to your digestive system. Other members of the NSAID class include the over-the-counter pain relievers ibuprofen and naproxen and at least 15 prescription drugs.

According to the American College of Gastroenterology, up to 60 percent of the approximately 14 million patients with arthritis who consume NSAIDs regularly will develop side effects related to the drugs. Although most are minor, side effects may include stomach ulcers, bleeding, holes in tissue, and even death.

The danger is real. According to a report in the May 2001 issue of Postgraduate Medicine, more than 100,000 Americans are hospitalized each year with intestinal trouble caused by aspirin and other NSAIDs. Only a small percentage of cases are fatal, but it's enough to make NSAIDs-related stomach trouble the 15th most common cause of death in the United States, ahead of asthma, cervical cancer, and Hodgkin's disease.

Why are NSAIDs hard on the stomach?
The drugs cause ulcers by interfering with the stomach's ability to protect itself from stomach acids, according to the National Digestive Diseases Information Clearinghouse. "Normally the stomach has three defenses against digestive juices: mucus that coats the stomach lining and shields it from stomach acid, the chemical bicarbonate that neutralizes stomach acid, and blood circulation to the stomach lining that aids in cell renewal and repair," the clearinghouse explains. "NSAIDs hinder all of these protective mechanisms, and with the stomach's defenses down, digestive juices can damage the sensitive stomach lining and cause ulcers."

How do NSAIDS undermine the stomach's defenses? All but the newest block an enzyme called cyclooxygenase 1, or COX-1. This enzyme helps prevent ulcers by enhancing blood flow to the stomach and increasing the production of protective mucous. If there's a shortage of COX-1, your stomach may not develop its usual protective lining, making it more vulnerable to attack by stomach acid.

In most cases, the damage is minor and your stomach heals completely about five days later. Still, regular doses can cause dyspepsia, lingering pain, or discomfort in the stomach. And if your stomach doesn't heal quite as quickly as it should, you could easily develop an ulcer or serious internal bleeding.

Who is at risk for NSAIDs-related intestinal trouble?
The typical person with NSAIDs-related intestine problems is an arthritis sufferer who takes several pills every day. For some people, however, just one pill each day can be enough to cause trouble. Older people are especially prone to complications of NSAIDs. The risk climbs if you have a history of ulcers, if you're currently taking corticosteroids or anticoagulants, or if you have a serious illness such as cancer or cirrhosis.

There's some evidence that smoking and drinking can also increase the likelihood of an NSAIDs-induced ulcer. According to the American Family Physician, alcohol consumption can also increase the risk for major bleeding in the upper GI tract, which includes the esophagus (or gullet), the stomach, and the beginning of the small intestine. In a study of more than 1,200 patient admitted for upper GI bleeding, researchers found that those who drank heavily and used aspirin or ibuprofen regularly had a much higher relative risk of intestinal bleeding. What's more, this was true even for people who were taking low-dose aspirin. (Because NSAIDs cause system-wide effects, even "enteric-coated" aspirins can cause ulcers.)

What are the symptoms of NSAIDs-related stomach trouble?
NSAIDs can inflict serious damage before they ever cause any symptoms. As reported in Postgraduate Medicine, more than 80 percent of patients hospitalized with serious complications of NSAIDs never notice any warning signs.

For some patients, mild stomach discomfort (dyspepsia) and nausea may be an early sign of trouble. If an ulcer develops, you may feel a gnawing, burning pain in your abdomen. The pain usually comes and goes. You may also feel nauseous and lose your appetite. If the ulcer causes internal bleeding, you may become tired and anemic and your stools may turn black or tarry. If you notice these symptoms, you should make an appointment with your doctor right away.

If the bleeding is severe, you could start vomiting bright-red blood and go into shock. Obviously, these are signs of a medical emergency: Call 911 or have someone drive you to an emergency room immediately.

What is the treatment for NSAIDs-related stomach trouble?
For most people, giving up NSAIDs is the key to treatment. If it's impossible to quit, you'll have to at least lower the dose. Either way, your stomach will quickly begin to heal. If you have an ulcer, your doctor might speed the recovery by prescribing acid-blocking drugs, proton-pump inhibitors, or other medications. If you are infected with Helicobacter pylori, a bacterium that can irritate the stomach and cause ulcers, your doctor will prescribe antibiotics to wipe out the germs.

If you have serious internal bleeding or a hole in your stomach or intestine, you'll need treatment that may include endoscopy or surgery.

Can NSAIDs-related stomach trouble be prevented?
One way to avoid NSAIDs-related stomach trouble is to avoid NSAIDs. If you have osteoarthritis, for example, you may be able to control the pain with acetaminophen (Tylenol) and capsaicin creams along with physical therapy and exercise. You might want to ask your doctor about complementary medicine, too: Some research indicates that fish oil supplements might ease inflammation in people with arthritis, for instance, and certain herbs, self-hypnosis, biofeedback, and other alternative therapies may also prove beneficial. Whatever alternative methods you explore, however, be sure to discuss these options with your doctor.

For many people, though, giving up NSAIDs isn't the best option. Other pain relievers may not be up to the task, and when it comes to preventing heart attacks, aspirin is in a class by itself.

Practically everyone can safely take an NSAID every now and then, but you should talk to your doctor before making it a regular habit. Let your doctor know all the other prescription drugs, herbs, and over-the-counter supplements you're taking, as well as how much alcohol you drink on a regular basis. If your doctor believes the benefits of NSAIDs outweigh the risks, you can proceed with caution.

If you do start an NSAID routine, think small. For instance, a single baby aspirin (about 80 milligrams) every day can give you strong protection against heart disease with relatively few side effects. Whatever your reason for taking an NSAID, your doctor can help you find the lowest effective dose.

Some NSAIDs are more dangerous than others. If you need a prescription NSAID to fight pain, ask your doctor if youąre at high risk for stomach trouble. If so, you should take less harsh drug such as nabumetone (Relafen) or etodolac (Lodine) instead of more problematic drugs such as ketorolac tromethamine (Toradol) or meclofenamate sodium (Meclomen).

If you suffer from rheumatoid arthritis or osteoarthritis, the newest generation of NSAIDs may be somewhat safer. These drugs, which include celecoxib (Celebrex) and rofecoxib (Vioxx), specifically target the COX-2 enzyme, a major player in pain and inflammation. (The new drugs can also block the Cox-1 enzyme, but to a far smaller extent than traditional NSAIDs). According to a report in the January 8, 2001 issue of the American Journal of Medicine, these drugs don't appear to raise the risk of ulcers. And compared with other NSAIDs, celecoxib and rofecoxib are less likely to cause dyspepsia.

If you regularly take a traditional NSAID and are at high risk for ulcers, your doctor may prescribe a medication to protect your stomach. The drug misoprostol (Cytotec) has been shown to slightly reduce the rate of ulcers in long-term NSAID users. However, the minor benefit is coupled with a high incidence of diarrhea and other side effects. Proton-pump inhibitors, such as omeprazole (Prilosec) have also been shown to protect against ulcers in NSAID users, without frequent side effects.

-- Chris Woolston, M.S., is a health and medical writer with a master's degree in biology. He is a contributing editor at Consumer Health Interactive, and was the staff writer at Hippocrates, a magazine for physicians. He has also covered science issues for Time Inc. Health, WebMD, and the Chronicle of Higher Education. His reporting on occupational health earned him an award from the northern California Society of Professional Journalists.

References

Alcohol and NSAIDs increase risk for upper GI bleeding. Karl E. Miller, American Family Physician. May 1, 2000.

American College of Gastroenterology. Effects of NSAIDs on the upper
gastrointestinal tract. www.acg.org/phyforum/gifocus/2eiv.html

Emery P. Cyclooxygenase-2: A major therapeutic advance? American Journal of
Medicine. January 8, 2001. 110(1A): 42S-45S.

Graumlich JF. Preventing gastrointestinal complications of NSAIDs.
Postgraduate Medicine. May 2001. 109(5): 117-128.

NSAIDs and Peptic Ulcers. National Digestive Diseases Information Clearinghouse. www.niddk.nih.gov/heath/disgest/summary/nsaids/

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Evaluation of drug treatment in irritable bowel syndrome new
      #22096 - 09/30/03 12:52 PM
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British Journal of Clinical Pharmacology
Volume 56 Issue 4 Page 362 - October 2003
doi:10.1046/j.1365-2125.2003.01966.x

Evaluation of drug treatment in irritable bowel syndrome
Nicholas J. Talley

The irritable bowel syndrome (IBS) remains a therapeutic challenge in part because of the limited understanding of the pathophysiology. The placebo response rate varies in randomized controlled trials from 20 to 70%, and can persist for up to at least 1 year. Anticholinergic and antispasmodic agents are of questionable benefit in IBS despite positive meta-analyses of poor quality trials. A meta-analysis concluded that the tricyclic antidepressants were superior to placebo in IBS, although the individual trial results were variable. Selective serotonin reuptake inhibitors are of uncertain benefit. Laxatives are used for constipation but probably poorly control the IBS symptom complex. Loperamide is superior to placebo in improvement of diarrhoea but not abdominal pain in IBS. Tegaserod is a well- tolerated aminoguanidine indole derivative of serotonin that is a partial 5HT4-receptor agonist with prokinetic properties; a therapeutic gain over placebo of 5% to 15% has been observed in constipation-predominant IBS in females. Alosetron is a 5HT3-receptor antagonist that is efficacious in females with diarrhoea-predominant IBS, with a 12% to 17% therapeutic gain; the risk of ischaemic colitis is 1 in 350, with very severe constipation occurring in about 1 in 1000. Optimizing study design remains a challenge in IBS. New visceral analgesic and motility modifying agents, as well as anti-inflammatory agents are in trials, and hopefully additional efficacious therapeutic options for patients with IBS will soon emerge.

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Step-down dosage of PPI drugs for hearburn new
      #22106 - 09/30/03 01:26 PM
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Step-down from multiple- to single-dose proton pump inhibitors (PPIs): a prospective study of patients with heartburn or acid regurgitation completely relieved with PPIs

John M. Inadomi a,b,c * , Lisa McIntyre a , Latoya Bernard a and A. Mark Fendrick c
Received: 9/12/2002. Accepted: 5/12/2003.

Abstract

Objectives
Management costs for gastroesophageal reflux disease are high because of the expensive medications used for maintenance therapy. Previous studies have illustrated the success of step-down from proton pump inhibitors (PPIs) to less-expensive therapy once symptoms have abated. This study was conducted to determine whether patients requiring greater than single-dose PPI for initial symptom resolution could be stepped-down to single-dose PPI and whether this intervention decreased costs or adversely affected quality of life.


Methods


Consecutive patients in whom greater than single-dose PPI had completely alleviated reflux-type symptoms (heartburn or acid regurgitation) were recruited through the use of pharmacy records of PPI prescriptions. Eligible subjects completed baseline demographic information and quality-of-life surveys and were stepped-down to single-dose PPI (lansoprazole 30 mg or omeprazole 20 mg daily). Follow-up continued for 6 months or until subjects reported recurrence of reflux-type symptoms, at which point PPIs were reinstituted at the dose that had originally alleviated the subjects' symptoms. The primary outcome was the proportion of subjects in whom step-down was successful, defined as no recurrence of reflux-type symptoms on single-dose PPI.


Results


A total of 117 subjects enrolled in the study; all were followed to the primary endpoint. 79.5% did not report recurrent symptoms of heartburn or acid regurgitation during the 6 months after step-down to single-dose PPI. Logistic regression revealed that longer duration of PPI use before study enrollment was associated with greater likelihood of symptom recurrence with step-down. Although quality of life was not significantly altered, dyspepsia (excluding reflux-type symptoms) increased. Overall costs of management were reduced.


Conclusions


The majority of patients rendered asymptomatic on greater than single-dose PPI might be subsequently stepped-down to single-dose therapy without recurrence of reflux-type symptoms. This intervention can decrease management costs without adversely affecting quality of life.

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FDA Orders Novartis To Pull Zelnorm Ads new
      #22768 - 10/07/03 11:25 PM
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FDA Orders Novartis To Pull Zelnorm Ads

June 30, 2003

WASHINGTON (AP) -- The government says an ad campaign implies a drug for irritable bowel syndrome works far better than it really does, and ordered Zelnorm's maker to stop the advertising.

The Food and Drug Administration cited ads by Novartis Pharmaceuticals that pictured a smiling woman and said, "Novartis and Gloria ended 30 years of debilitating abdominal pain, bloating and constipation in just three days."

While the ad doesn't mention Zelnorm's name, it discussed a "treatment from Novartis" that is "beating IBS."

The ad implies Zelnorm cured Gloria and could help millions of women when in fact it's not a cure, doesn't work in just three days, and helps only a very small proportion of patients, FDA officials wrote Novartis on Friday in ordering such ads to immediately cease.

"The ads are messages of hope based on true patient experiences," that let people know they should ask doctors about new treatments, said Novartis spokesman Greg Baird.

The ads run periodically and aren't running now, but Novartis will discuss FDA's concerns with agency officials, he said.

Zelnorm was approved last summer to treat women with one form of irritable bowel syndrome, the type associated with constipation. In studies FDA stressed at the time, patients fared only a little better -- 5 percent to 10 percent better -- when taking Zelnorm than when taking dummy pills.

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Measuring Treatment Effects in IBS Trials new
      #24040 - 10/20/03 03:30 PM
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American College of Gastroenterology 68th Annual Scientific Meeting

Baltimore, Wednesday, October 15, 2003

Measuring Treatment Effects in IBS Trials

There is no single therapeutic approach to IBS. Most patients (ie, those with mild symptoms and minimal impairment) with IBS can be managed at a primary-care level. Fewer than 25% of patients with IBS have more severe symptoms with significant lifestyle impairment requiring management by a gastroenterologist, and 5% of patients with IBS have such severe and incapacitating symptoms that they require referral to a center with multispecialty capability.[9] Goals of therapy should focus on symptom management rather than cure.

It would seem intuitive that investigators performing therapeutic trials for IBS would measure changes in individual IBS symptoms, such as abdominal pain, bloating, and bowel habit satisfaction in order to determine therapeutic efficacy. Reliance on changes in individual symptoms, however, may not be as sensitive an endpoint as global IBS symptom relief, likely due to the nonspecific, variable, and subjective complaints that are common with IBS.

Dunger-Baldauf and colleagues[10] presented data from a large Nordic trial assessing tegaserod for treatment of IBS symptoms in 647 patients (83% women) with nondiarrhea-predominant disease. These investigators examined the primary outcome variable -- global IBS symptom relief -- relative to changes in the individual symptoms of IBS. They demonstrated that global relief is responsive to changes in the individual symptoms of IBS and is therefore appropriate as a primary outcome of IBS therapy trials. This is an important concept because trials that show improvement in individual IBS symptoms may not translate into overall improvement of the patient with IBS. Clinicians examining IBS therapy trials should look for this outcome.

9. Drossman DA, Thompson WG. The irritable bowel syndrome: review and a graduated, multicomponent treatment approach. Ann Intern Med. 1992;116:1009-1016.

10. Dunger-Baldauf C, Nyhlin H, Ruegg P, et al. Subject's global assessment of satisfactory relief as a measure to assess treatment effect in clinical trials in irritable bowel syndrome (IBS). Am J Gastroenterol. 2003;98:S269.[Abstract #809]



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SOLVAY presses ahead with cilansetron, a new IBS drug new
      #27742 - 11/18/03 03:43 PM
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29-10-2003 ŕ 08:01:00

SOLVAY presses ahead with cilansetron registrations following favorable phase III clinical findings

SOLVAY announces today that headline results from the first two large placebo-controlled phase III efficacy studies show convincing evidence for the patient benefits of cilansetron, a novel drug developed by the Group's PHARMACEUTICALS subsidiaries for the treatment of Irritable Bowel Syndrome with predominantly diarrhea (IBS-D). In view of favorable clinical findings, SOLVAY will expedite compilation of registration dossiers for major territories, beginning with submissions in Europe and the United States in the first quarter of 2004. Registration submissions in other territories will follow.

SOLVAY is running a full phase III clinical program with cilansetron, a 5HT3 antagonist for the treatment of Irritable Bowel Syndrome with predominantly diarrhea. Together with our preferred-provider QUINTILES, more than 4,000 patients have been entered into phase III clinical studies. Cilansetron was created by SOLVAY's own in-house drug-discovery efforts. In two Phase II placebo controlled clinical studies and two Phase III placebo controlled clinical studies conducted in the US, Europe and other countries, cilansetron has shown clinical benefits in both males and females.

IBS is a frequently encountered troublesome condition, characterized by abdominal pain, bloating and altered bowel habits. IBS has a significantly negative impact on quality-of-life for the large populations of men and women suffering from it.

SOLVAY is an international chemical and pharmaceutical Group with headquarters in Brussels. It employs more than 30,000 people in 50 countries and had consolidated sales in 2002 of EUR 7.9 billion, generated by four sectors of activity: Pharmaceuticals, Chemicals, Plastics and Processing. The Group's pharmaceuticals subsidiaries employ 7500 people and have a good research and development pipeline, with several projects alongside cilansetron currently in phase III/II testing; bifeprunox for schizophrenia (together with Lundbeck), tedisamil for atrial fibrillation and cetrorelix for endometriosis, myoma and benign prostatic hypertrophy just to mention a few. SOLVAY is listed in the Euronext 100 index of top European companies. For further information please consult: www.solvay.com


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Clinical Trial Guidelines for Pharmacological Treatment of IBS - Pharmacological Options new
      #29621 - 12/01/03 05:55 PM
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Pharmacological Options

Pharmacological options aim to control irritable bowel syndrome symptoms, bowel alterations and abdominal pain with drugs mainly targeted to the gastrointestinal tract or the central nervous system.

The majority of the available drugs have been tested and are used in the management of individual symptoms, and not to control the whole range of symptoms inherent in the complex irritable bowel syndrome. Loperamide has been shown to be effective in the control of functional diarrhoea, and osmotic and contact laxatives and polyethylene solution in the control of functional constipation. These agents, however, have no effect on, or may even aggravate, other symptoms, such as pain and bloating.[49,50] In addition, their use is indicated only as a symptomatic, on-demand treatment in selected patients, as their effect may be unpredictable or even undesirable in the majority of irritable bowel syndrome patients who present with an alternating bowel pattern.

The smooth muscle relaxants, cimetropium bromide, pinaverium bromide, octilonium bromide, trimebutine and mebeverine, have been shown to be more effective than placebo in three meta-analyses.[41,51,52] On average, the global symptom improvement with myorelaxants exceeded that of placebo by 22%. However, the benefit was due essentially to their effect on abdominal pain and abdominal distension (18% and 14% over placebo, respectively) with no effect on bowel alterations.[52]

Besides being of limited value, the therapeutic benefit of myorelaxants was demonstrated in clinical trials that were hampered by methodological problems. The trials were performed in non-homogeneous groups of patients who presented with different types of functional bowel alterations and were not selected on the basis of standardized irritable bowel syndrome symptom-based criteria.

Psychotropic drugs, mainly low-dosage tricyclic antidepressants, have been used in non-constipated irritable bowel syndrome patients with abdominal pain as the chief complaint. A meta-analysis based on a few uncontrolled trials indicated that they were useful in about one-third of patients.[53] However, their efficacy has not been assessed in randomized, double-blind, placebo-controlled trials.*

*After submission of this article, a randomised, double-blind, placebo-controlled trial has been published showing that the tricyclic antidepressant desipramine may be effective in clinical subgroups of patients with functional bowel disorders (Drossman DA, Toner BB, Whitehead WE, et al. Gastroenterology 2003; 125: 19-31.

http://www.medscape.com/viewarticle/463164_5

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Renzapride Improves Symptoms in Constipation-Predominant Irritable Bowel Syndrome new
      #29628 - 12/01/03 06:14 PM
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UEGW: Renzapride Improves Symptoms in Constipation-Predominant Irritable Bowel Syndrome
By Adrian Burton

MADRID, SPAIN -- November 4, 2003 -- Renzapride, a new 5-HT4 agonist/5-HT3 antagonist, relieves the symptoms of constipation-predominant irritable bowel syndrome (C-IBS), increasing bowel movement frequency and softening stools.

Dr. Nicholas Meyers, Development Manager for Alizyme Therapeutics Ltd, Cambridgeshire, United Kingdom, reported the results here November 3rd at the 11th United European Gastroenterology Week.

Irritable bowel syndrome is a common disease, the symptoms of which may include constipation, diarrhoea or both. "There really are no suitable treatments for irritable bowel syndrome [in Europe]," explained Dr. Meyers. "By and large, the sort of treatments people can buy over the counter such as peppermint oil don't really work. So we need more active drugs."

In this large, placebo controlled, double blind Phase IIb trial that enrolled 510 patients with C-IBS, 125 received 1 mg of renzapride, 125 other patients received 2 mg of the drug, and 135 received 4 mg of renzapride, while 125 received placebo. Treatment was dosed every day for 12 weeks.

Patients kept diaries to record their perceived response to treatment in terms of pain or discomfort relief, and recorded their frequency of bowel movements and the consistency of their stools.

The 4-mg/day dose significantly increased the frequency of bowel movements from a mean of 0.9 to 1.7 in Week 1, decreasing after that time, but remaining significant during Weeks 1 through 4 (P < .0001) and through to the end of the study (P < .0046). The same dose also improved stool softness (from a baseline of 0.2 on an arbitrary softness scale to over 0.5 in Weeks 1 through 4 (P < .0048), and to just under 0.5 during weeks 5-12 (P < .016).

When analysed alone, the female population showed slightly better results.

Adverse events at the effective 4-mg/day dose were diarrhoea in 25.2% of patients and headache in 17.8%. The rate of serious adverse events was 1.6% for all patients taking renzapride compared to 2.4% for those taking placebo.

"We hope to be reporting the effects of renzapride in mixed-symptom patients in May [2004]," explained Dr. Meyers. "But the main message here is that [renzapride] 4 mg/day seems to work very well for C-IBS patients."


[Study title: Efficacy and Safety of Renzapride in Patients With Constipation-Predominant IBS: A Phase IIb Study in the UK Primary Healthcare Setting. Abstract Mon-G-161]

http://www.docguide.com/news/content.nsf/news/8525697700573E1885256DD4004D8FD7

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Zelnorm Warning Issued by FDA new
      #69080 - 05/10/04 01:01 PM
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Zelnorm Warning Issued by FDA

On April 28, 2004, the Food and Drug Administration (FDA) announced the addition of serious new risk information to the health professional labeling for Zelnorm. The specific revisions include:

a new warning about the serious consequences of diarrhea associated with the medication

a new precaution about ischemic colitis and other forms of intestinal ischemia (reduced blood flow to the intestines)

changes to the adverse reactions section describing post-marketing reports

new information in the "Information for the Patient" leaflet

The new warning states: "Serious consequences of diarrhea, including hypovolemia, hypotension and syncope have been reported in the clinical studies and during marketed use of Zelnorm. In some cases, these complications have required hospitalization for rehydration. Zelnorm should be discontinued immediately in patients who develop hypotension or syncope. Zelnorm should not be initiated in patients who are currently experiencing or frequently experience diarrhea."

"The FDA currently has 21 reports of diarrhea so severe that it caused such complications as low blood pressure and fainting. Sixteen patients required hospitalization," said the FDA's Dr. Robert Justice.

The new precaution on ischemic colitis states: "Ischemic colitis, and other forms of intestinal ischemia, have been reported in patients receiving Zelnorm during marketed use of the drug. A causal relationship between Zelnorm use and these events has not been established. Placebo-controlled clinical trials of 7,000 patients for 3-month duration showed no cases of these events, and would suggest the rate of these events is low. Zelnorm should be discontinued immediately in patients who develop symptoms of ischemic colitis, such as rectal bleeding, bloody diarrhea or new or worsening abdominal pain. Patients developing these symptoms should be evaluated promptly and have appropriate diagnostic testing performed. Treatment with Zelnorm should not be resumed in patients who develop findings consistent with ischemic colitis."

"Since Zelnorm went on sale in 2002, the FDA has received 20 reports of ischemic colitis, plus three reports of a similar intestinal problem," Justice said. "Fourteen patients were hospitalized. Four died, although they had numerous other serious medical conditions."

Consumer watchdog Sidney Wolfe said Zelnorm is too dangerous to stay on the market and only slightly more effective than a placebo. He had urged the FDA not to approve the drug in the first place.

"If a drug is actually more dangerous than a placebo and not much more effective, it is a very bad trade-off," Wolfe, head of Public Citizen's Health Research Group, said in an interview.

Under the post marketing experience heading in the adverse reactions section, the labeling now states: "Voluntary reports of adverse events occurring with the use of Zelnorm include the following: ischemic colitis, mesenteric ischemia, gangrenous bowel, rectal bleeding, syncope, suspected sphincter of Oddi spasm, bile duct stone, and cholecystitis with elevated transaminases. Because these cases are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. No causal relationship between these events and Zelnorm use has been established. Hypokalemia secondary to diarrhea has also been reported."

The new patient information advises patients who get new or increased stomach pain or blood in their stools to stop taking Zelnorm right away and to immediately contact their doctor to determine if they may have a serious problem. In addition, the new labeling advises patients to stop taking Zelnorm and to call a doctor right away if they experience diarrhea that leads to lightheadedness, dizziness or fainting. In conjunction with today's FDA announcement, the manufacturer of Zelnorm, Novartis Pharmaceuticals Corporation of East Hanover, N.J., has issued a letter to health professionals to highlight the labeling changes.

http://www.helpforibs.com/footer/zelnorm.asp#warning

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Fears cause low sales of Lotronex new
      #69103 - 05/10/04 01:46 PM
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Glaxo seeks fewer barriers to Lotronex

By Lisa Richwine

ROCKVILLE, Md., May 5 (Reuters) - Limits put in place to minimize potentially deadly risks from an irritable bowel drug may be discouraging too many seriously ill patients from using it, maker GlaxoSmithKline Plc <GSK.L> said on Wednesday.

Glaxo pulled Lotronex off the market in November 2000, eight months after its debut, because of dozens of reports of users suffering severe constipation or ischemic colitis, inflammation of the large bowel caused by reduced blood flow. At least five patients died from those complications.

The medicine was re-introduced in November 2002, with restrictions, in order to provide access to patients with severe forms of the disease and few options.

Doctors are encouraged to report side effects and sign a form saying they have told a patient about risks. Patients also are asked to sign a consent form.

The program may have frightened away some patients and burdened doctors, said Craig Metz, GlaxoSmithKline vice president for U.S. regulatory affairs.

"We are going to look for ways to make this less onerous" while maintaining safeguards, Metz told a Food and Drug Administration advisory committee.

About 10,000 patients, a far lower number than expected, received at least one Lotronex prescription from November 2002 through December 2003, Metz said. Only between 10 percent and 20 percent of patients got refills.

At least 111,000 patients may have severe cases of irritable bowel syndrome and could benefit from the drug, GSK officials said.

Some FDA panel members said the program was working by discouraging many patients from using the medicine.

"That is what the point is," said Robyn Shapiro, professor of bioethics at the Medical College of Wisconsin.

The FDA believes the risk reduction program has been successful but will work with the manufacturer to identify overly restrictive barriers to drug access, said Dr. Robert Justice, head of the FDA's gastrointestinal drugs division.

No drug-related deaths were reported between November 2002 and February 2004, GlaxoSmithKline said. Eight cases of ischemic colitis, a potentially fatal reduction of blood flow to the colon, were recorded, as well as 5 cases of severe complications from constipation.

Consumer watchdog Dr. Sidney Wolfe said the restrictions had failed to adequately protect patients. He said the drug should once again be withdrawn, and a tightly controlled research program set up for seriously ill patients, he said.

GlaxoSmithKline has said it does not expect Lotronex to significantly impact the giant London-based drug maker's finances.

Irritable bowel syndrome, or IBS, causes alternating bouts of constipation and diarrhea as well as abdominal pain and sometimes incontinence. Severe cases can be debilitating.

Lotronex is the only prescription drug approved for treating women with IBS whose main symptom is diarrhea.

Copyright 2004, Reuters News Service

http://www.forbes.com/business/healthcare/newswire/2004/05/05/rtr1360714.html

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Irritable bowel syndrome helped by Paroxetine, a drug for depression new
      #69116 - 05/10/04 02:15 PM
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Irritable bowel syndrome helped by Paroxetine, a drug for depression

08 May 2004

Paroxetine, a drug commonly used to treat depression, can improve symptoms in people with irritable bowel syndrome (IBS), according to a study in the May issue of the American Journal of Gastroenterology. In a randomized double-blind, placebo-controlled study, researchers at the University of Pittsburgh School of Medicine found that the drug relieved some symptoms of IBS and improved the well-being of people with IBS.

"This study points out the benefits of this drug as a potential new and improved treatment for IBS, a disease that is very difficult for physicians to manage," said George Arnold, M.D., F.A.C.P., clinical professor of medicine at the University of Pittsburgh School of Medicine and principal investigator in the study.

IBS is a chronic gastrointestinal disorder that affects 14-24 percent of women and 5-19 percent of men in western populations and is characterized by abdominal pain, altered bowel habits and abdominal bloating. It generally has been treated with high-fiber diet, drugs or both.

The study found that the percentage of participants experiencing an improvement in overall well-being was significantly greater (63.3 percent) in the paroxetine group than the placebo group (26.3 percent). The percentage of participants experiencing an improvement in bowel movements was significantly greater in the paroxetine recipients (58.6 percent) than the placebo recipients (32.4 percent). There was a significant improvement in food avoidance and work function for those on paroxetine. There was no significant improvement in abdominal pain or bloating between the paroxetine and placebo groups.

"This study showed that in absence of depression, paroxetine helped irritable bowel syndrome," said Dr. Arnold. "This is a medicine that has been in use for some years and is safe with no long term side effects, which is a problem with current medications for IBS."

The effectiveness of paroxetine, a selective serotonin reuptake inhibitor (SSRI), has been reported in case reports but not in controlled studies. SSRIs are considered first line treatments in psychiatric illnesses such as major depression and generalized anxiety disorder, which are found in 50 to 90 percent of patients with IBS, according to Dr. Arnold, who is a gastroenterologist at the University of Pittsburgh Medical Center's (UPMC) Shadyside Hospital.

The two-part clinical study enrolled a total of 110 participants with IBS. Group one consisted of 98 participants who at enrollment were consuming a low-fiber or average-fiber diet, who were then put on a high-fiber diet. In this group, 26 percent reported an overall improvement in well-being. Abdominal pain and bloating decreased in 22 percent and 26 percent of participants respectively.

Group two consisted of 12 participants who at enrollment were already consuming a high-fiber diet plus the 69 participants from group one who reported an inadequate response to the high-fiber diet. Group two participants continued to consume their high-fiber diet throughout the study and were randomized to receive a 12-week course of either paroxetine or a placebo.

All participants began with a dosage of paroxetine of 10 mg/day. Participants who experienced improvement in their condition were instructed to continue at the same dosage while those who experienced no improvements were instructed to increase their dosage.

Because SSRIs have a well-recognized effect on depression, the researchers also performed a separate analysis of participants and showed that the improvement in well-being held true for non-depressed patients taking paroxetine.

Also participating in the study were Gary Tabas, M.D., Mary Beaves, R.N., Jiping Wang, M.D., Paul Friday, Ph.D. and Houssam Mardini, M.D.

The study was funded by the Competitive Research Fund of the Shadyside Hospital Foundation of Pittsburgh.

ADDITIONAL CONTACT:

Jocelyn Uhl
PHONE: 412-647-3555
FAX: 412-624-3184
E-MAIL:
UhlJH@upmc.edu

Contact: Frank Raczkiewicz
RaczkiewiczFA@upmc.edu
412-647-3555
University of Pittsburgh Medical Center

http://www.medicalnewstoday.com/index.php?newsid=8065



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Pharmaceutical companies funding a number of studies into IBS in the UK new
      #73257 - 05/25/04 12:00 PM
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Researchers at The University of Nottingham, England have picked up almost Ł1 million in funding for a number of studies into a painful and distressing bowel condition that will affect up to one in 10 of the population at some time or another.

The team in the Division of Gastroenterology at the University, led by Professor Robin Spiller, are looking at various aspects of Irritable Bowel Syndrome (IBS) in a bid to increase our understanding of the mechanisms that underpin the condition and to develop new treatments for patients.

They have received Ł434,563 in funding from the drug company GlaxoSmithKline for a study examining evidence for inflammation of the gut in IBS patients. It is believed that some IBS patients may have a genetic predisposition to this kind of inflammation, which is usually associated with other bowel disorders such as Crohn's disease and ulcerative colitis. Often these patients have to undergo many tests that turn out to be unnecessary before being correctly diagnosed with IBS.

Another aspect of the study is examining why as many as one in 10 people who suffer from severe Campylobacter food poisoning may go on to develop IBS. The study will be comparing people who have had a Campylobacter infection and developed IBS with those who have made a complete recovery to get a clearer idea of why some patients are at a greater risk.

Further research into inflammation in the gut in IBS may lead to new methods of identifying patients who would respond well to drugs not traditionally used for the treatment of bowel conditions but which are successfully used in the treatment of asthma.

The researchers have also received Ł172,914 from NovartisPharma and Ł360,000 from the Biotechnology and Biological Sciences Research Council to look at the role of serotonin in IBS. Serotonin is a ubiquitous signalling molecule used throughout the brain and gut to transmit impulses. The over-production of serotonin can cause vomiting and diarrhoea and part of the study is looking at whether serotonin levels can be altered by introducing different molecules into the system.

The researchers are seeking patients with IBS to take part in the study and anyone interested should contact Marguerite Richards on 0115 924 9924 ext 36804 or ext 44970 or by e-mail at marguerite.richards@nottingham.ac.uk

http://www.news-medical.net/view_article.asp?id=1439

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Therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome new
      #76331 - 06/04/04 03:54 PM
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Neuroendocrinol Lett. 2004 Feb-Apr;25(1-2):31-9.

Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?

Russo EB.

GW Pharmaceuticals, 2235 Wylie Avenue, Missoula, MT 59802, USA. erusso@montanadsl.net

OBJECTIVES: This study examines the concept of clinical endocannabinoid deficiency (CECD), and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis. METHODS: Available literature was reviewed, and literature searches pursued via the National Library of Medicine database and other resources. RESULTS: Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia. Cannabinoids have similarly demonstrated the ability to block spinal, peripheral and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, IBS and related disorders. The past and potential clinical utility of cannabis-based medicines in their treatment is discussed, as are further suggestions for experimental investigation of CECD via CSF examination and neuro-imaging. CONCLUSION: Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.

PMID: 15159679 [PubMed - in process]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15159679

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The Relationship among Previous Antimicrobial Use and H. Pylori Infections new
      #83746 - 06/27/04 01:33 PM
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By Greg Arnold, June 3, 2004, Abstracted from "The Relationship among Previous Antimicrobial Use, Antimicrobial Resistance, and Treatment Outcomes for Helicobacter pylori Infections" in The Annals of Internal
Medicine 2003, Volume 139, pp. 463-469

The use of antibiotics has resulted in an "arms race" between man and Nature. With Nature adapting to antibiotics by mutating and becoming antibiotic-resistant, formation of "superbugs" is now commonplace, so much so that many experts are even discouraging the use of antibacterial soaps for they are ineffective at preventing bacterial infections(2) and may contribute to the "superbug" explosion.

A chronic bacterial infection in people is Helicobacter pylori, the cause of peptic ulcers. It is estimated that one in ten Americans develop a peptic ulcer at some time in his or her life. H. pylori weakens the protective mucous coating of the stomach and duodenum, which allows acid to get through to the sensitive lining beneath, irritating the lining and causing the ulcer. H. pylori is able to survive in stomach acid because it secretes enzymes that neutralize the acid. This mechanism allows H. pylori to make its way to the "safe" area--the protective mucous lining. Once there, the bacterium's spiral shape helps it burrow through the lining.(1)

Now it appears that antibiotic use makes it harder to get rid of peptic ulcers, according to a new study in the Annals of Internal Medicine. Not knowing the relationship between previous antimicrobial treatments and infection with drug-resistant H. Pylori, researchers sought to determine whether previous antibiotic use causes antibiotic
resistance of H. Pylori.

Conducting a retrospective cohort analysis of adults recruited sequentially from a clinical practice, researchers studied 125 adults with an H. Pylori infection in a referral hospital in Anchorage, Alaska. They reviewed antibiotic use in the 10 years before H. Pylori infections occurred and found that 120 of the 125 patients (96%) had
H. Pylori that was resistant to two of the more common antibiotics, clarithromycin and metronidazole.

The researchers concluded, "previous use of macrolides and
metronidazole is associated with H. Pylori resistant to these antimicrobial agents. Clarithromycin resistance is associated with a greater risk for failure with larithromycin-based treatments."

Instead of using antibiotics, a much more viable option for peptic ulcer sufferers is through probiotic supplementation, recently reviewed to be effective as an adjunctive treatment for H. Pylori infection.(3)

References:

1 National Digestive Diseases Information Clearninghouse (NDDIC)
Website: "H. Pylori and Peptic Ulcer"
<http://digestive.niddk.nih.gov/ddiseases/pubs/hpylori/>

2 Larson EL. Effect of antibacterial home cleaning and handwashing
products on infectious disease symptoms: a randomized, double-blind
trial. Annals of Internal Medicine 2004; 140(5): 321-9

3 Hamilton-Miller JM. The role of probiotics in the treatment and
prevention of Helicobacter pylori infection.

Internationals Journal
of Antimicrobial Agents 2003; 22(4): 360-366




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New Risk Information on Zelnorm for IBS for Women new
      #88761 - 07/11/04 02:18 PM
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New Risk Information on Zelnorm for IBS for Women

11 Jul 2004

New risk information will now appear in the labeling for the drug Zelnorm, or tegaserod maleate. This medication is used for the short-term treatment of women with irritable bowel syndrome whose primary bowel symptom is constipation.

The new labeling will contain a warning about the serious consequences of diarrhea in these patients, including hypovolemia, hypotension and syncope. The labeling also warns that patients on Zelnorm who develop hypotension or syncope should stop taking the drug. And patients who have or frequently experience diarrhea should not be started on Zelnorm.

The labeling will also contain a new precaution on ischemic colitis in patients receiving Zelnorm. Although a causal relationship has not been established, the drug should be discontinued immediately if the patient develops symptoms of ischemic colitis. These include rectal bleeding, bloody diarrhea, or new or worsening abdominal pain.

The new information will also be incorporated in a revised leaflet for patients.

Additional Information:

All about Zelnorm for IBS: http://www.helpforibs.com/footer/zelnorm.asp

MedWatch Safety Alerts – Zelnorm (tegaserod maleate)
http://www.fda.gov/medwatch/SAFETY/2004/safety04.htm#zelnorm

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On the Relationship Between Colon Ischemia, Irritable Bowel Syndrome, and Serotonergic Therapy of Irritable Bowel Syndrome new
      #115459 - 10/24/04 07:10 PM
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From Medscape Gastroenterology

Irritable Bowel Syndrome Expert Column
On the Relationship Between Colon Ischemia, Irritable Bowel Syndrome, and Serotonergic Therapy of Irritable Bowel Syndrome
Posted 09/24/2004

Lawrence J. Brandt, MD

Introduction and Context
The Problem
Colon ischemia and irritable bowel syndrome (IBS) are 2 common gastroenterologic disorders that, until recently, were thought to occur independently in very different populations. We know now, however, that there is a complex association between the 2: (1) colon ischemia appears to be more common in the IBS patient than was recognized previously; and (2) there is concern that the newly developed serotonin receptor agonists or antagonists may increase the risk of colon ischemia, and serotonergic signaling may be abnormal in patients with colitis. This review highlights some of the relationships between colon ischemia, IBS, and therapy for IBS.

IBS -- Pathophysiology and Clinical Presentation
IBS is a disorder that is diagnosed by various symptom-based criteria, such as the Manning, Rome, and Rome II criteria. IBS lacks any biologic, physiologic, structural, or serologic marker, and so diagnosis is symptom-based. Symptoms typically include abdominal discomfort or pain, bloating, diarrhea, fecal urgency, and constipation. Symptoms may change with time, and patients who have diarrhea or constipation as a major part of their illness may evolve to the opposite bowel habit or develop a pattern in which they alternate between the 2. IBS must never be considered as the explanation for rectal bleeding, bloody diarrhea, weight loss, fever, constitutional symptoms, or anemia, and in the presence of these "alarm" symptoms or signs, organic disease must be excluded using conventional stool tests, endoscopic, and radiologic examinations. For the IBS patient without alarm symptoms, the routine use of these tests is not recommended, although for patients with IBS and diarrhea, serologic testing for celiac sprue may be appropriate and cost-effective.[1,2] Of course, screening tests for colon cancer are recommended for all patients 50 years of age or older, including those with IBS.

Colon Ischemia -- Pathophysiology and Clinical Presentation
Colon ischemia generally presents in individuals older than 55 years, a population considerably older than that typically affected by IBS. The known causes of colon ischemia are many, but in the usual case, no definitive cause is found; most episodes of colon ischemia are thought to be caused by brief periods of localized nonocclusive ischemia. The acute onset of mild, lower abdominal pain accompanied or followed by diarrhea, rectal bleeding, or bloody diarrhea is typical. Most patients with colon ischemia have spontaneous resolution of symptoms within several days. Computed tomography of the abdomen usually shows segmental thickening of the colon, although this is not a specific finding. Colonoscopy, if performed within the first 24-48 hours, usually will show submucosal hemorrhage or edema in a segmental pattern (ischemic colopathy). If the examination is repeated within a few days after the onset of symptoms, it will show the disease process to have evolved into a segmental (ischemic) colitis pattern with ulceration and even pseudopolyp formation, an appearance that may mimic inflammatory bowel disease or infectious colitis; biopsy usually is nonspecific, with only infarction and ghost cells pathognomonic of ischemic injury. In general, mesenteric angiography is not used to evaluate patients suspected of having colon ischemia, because by the time of presentation, colonic blood flow usually has normalized.

It is important for primary care practitioners to be aware of colon ischemia because it is a common cause of bloody diarrhea in the elderly and can be seen in patients of all ages, especially those who have a coagulation disorder, systemic illness associated with vasculitis, or those with IBS. Moreover, colon ischemia can mimic or be mimicked by infectious colitis or inflammatory bowel disease. Most patients who develop colon ischemia do well with conservative management. For the patient who continues to have symptoms for more than 2 weeks, referral to a gastroenterologist is recommended because it is likely that these individuals will have a complicated course.




--------------------------------------------------------------------------------

Section 1 of 6 Next Page: Issues in Epidemiology


Lawrence J. Brandt, MD, Chief of Gastroenterology, Montefiore Medical Center, Bronx, New York; Professor of Medicine and Surgery, Albert Einstein College of Medicine, Bronx, New York


Disclosure: Lawrence J. Brandt, MD, has served as an advisor or consultant for Novartis, GlaxoSmithKline, Solvay, and TAP. He has also disclosed he is on the speakers bureau for AstraZeneca.

Medscape Gastroenterology 6(2), 2004. © 2004 Medscape


Continue reading this article here http://www.medscape.com/viewarticle/488174_2

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Irritable Bowel Syndrome Medications Side Effects Survey new
      #120323 - 11/09/04 02:04 PM
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Irritable Bowel Syndrome Medications Side Effects Survey.

Journal of Clinical Gastroenterology. 38(9):776-781, October 2004.

Lembo, Anthony MD

Abstract:
Objectives: This study was conducted to determine the frequency and severity of side effects (SEs) experienced during treatment with standard medications used to treat patients with irritable bowel syndrome (IBS) with constipation (IBS-C).

Methods: In January of 2002, 668 subjects responded to a survey addressed to an online panel of 25,000 physician-diagnosed IBS sufferers. Of the survey respondents, 504 had constipation as a predominant bowel habit (median age 45 years, and 88% were women). Respondents answered questions about the therapies they used to relieve their IBS symptoms and about any SEs they experienced while taking these therapies; they were also asked to rate their satisfaction with their current/past medications. To gauge IBS impact, respondents were also asked about the number of times they either visited or called their health-care provider about their IBS symptoms and approximately how many days of work or school they missed because of their IBS symptoms.

Results: Subjects reported having tried an average of 3.9 +/- 3.3 medications for their IBS-C symptoms with virtually all subjects (99%) having tried at least 1 medication. Subjects reported an average of 3.3 +/- 2.7 SEs. Nearly three quarters reported discontinuing treatment because of SEs, and many sought medical help or missed work, school, or social activities because of SEs.

Conclusions: Traditional therapies for IBS-C, including laxatives, fiber, and stool softeners, are associated with SEs that negatively affect the lives of IBS sufferers.

(C) 2004 Lippincott Williams & Wilkins, Inc.


http://www.mdlinx.com/GILinx/thearts.cfm?artid=1087190&specid=13&ok=yes

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Efficacy and Safety of Alosetron in Men with Diarrhea-Predominant IBS new
      #152021 - 02/19/05 05:56 PM
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The American Journal of Gastroenterology
Volume 100 Issue 1 Page 115 - January 2005
doi:10.1111/j.1572-0241.2005.40365.x


A Dose-Ranging, Phase II Study of the Efficacy and Safety of Alosetron in Men with Diarrhea-Predominant IBS

Lin Chang, M.D.1, Vanessa Z. Ameen, M.D.1, George E. Dukes, Pharm.D.1, David J. McSorley M.S.1, Eric G. Carter, M.D., Ph.D.1, and Emeran A. Mayer, M.D.1
BACKGROUND: A randomized, double blind, placebo-controlled dose-ranging study was conducted to assess the efficacy of alosetron in men with diarrhea-predominant irritable bowel syndrome (IBS).

METHODS: Six hundred and sixty-two men were randomized to treatment with alosetron 0.5, 1.0, 2.0, 4.0 mg, or placebo twice daily for 12 wk, followed by a 4-wk posttreatment period. Adequate relief of IBS pain and discomfort during week 512 of the treatment phase was the primary endpoint; secondary endpoints included bowel urgency, stool frequency, and consistency, incomplete evacuation, bloating, and abdominal pain or discomfort.

RESULTS: Subjects ranked urgency and abdominal pain as their most bothersome IBS symptoms. The average rate of adequate relief during week 512 was significantly higher in the alosetron 1.0 mg twice-daily group compared to placebo (53%vs 40%, p= 0.04), and all doses of alosetron significantly reduced stool consistency scores (p< 0.001) indicating firmer stools. No significant effects of alosetron were seen with regard to urgency, number of bowel movements, bloating, and incomplete evacuation. Constipation was the most common adverse event and occurred in a dose-related manner among subjects receiving alosetron, 9% (0.5 mg twice daily), 15% (1.0 mg twice daily), 11% (2.0 mg twice daily), and 21% (4.0 mg twice daily). No serious adverse events of constipation were reported. One subject in the 0.5 mg twice-daily group had an episode of rectal bleeding suggestive of a possible diagnosis of ischemic colitis.

CONCLUSIONS: Alosetron 1 mg twice daily provided adequate relief of IBS pain and discomfort, and improved stool consistency in men with diarrhea-predominant IBS.

http://www.blackwell-synergy.com/links/doi/10.1111/j.1572-0241.2005.40365.x/abs/


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Clinical Response to Tricyclic Antidepressants in Functional Bowel Disorders not Related to Dosage new
      #164750 - 03/28/05 01:32 PM
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The American Journal of Gastroenterology
Volume 100 Issue 3 Page 664 - March 2005
doi:10.1111/j.1572-0241.2005.30375.x


Clinical Response to Tricyclic Antidepressants in Functional Bowel Disorders is not Related to Dosage

Albena Halpert, M.D.1, Christine B. Dalton, P.A.-C.1, Nicholas E. Diamant, M.D.1, Brenda B. Toner, Ph.D.1, Yuming Hu, Ph.D.1, Carolyn B. Morris, Ph.D.1, Shrikant I. Bangdiwala, Ph.D.1, William E. Whitehead, Ph.D.1, and Douglas A. Drossman, M.D.1

BACKGROUND: As shown in the per protocol analysis of a recent randomized, controlled trial, when tolerated, Desipramine (DES) is effective over placebo (PLA) in treating moderate-to-severe functional bowel disorders (FBD). Clinical experience suggests that the benefit from tricyclic antidepressants (TCA) in FBD can be achieved at doses lower than those used to treat major depression. Within psychiatry, when using higher dosage of TCAs, plasma levels can be used to adjust daily dosage to optimize a treatment response. However, in FBD, it is not known whether plasma levels at the lower dosage are similarly related to a clinical response.

AIM: To determine in treating FBD, whether DES blood levels or dose taken can predict a clinical response.

METHODS: As part of a study of 12 wk of antidepressant and psychological treatment in 431 patients with FBD at UNC and U of Toronto, we studied those participants who completed treatment (per protocol analysis) taking DES (N = 97, dose 50150 mg/day) or pill placebo (PLA) (N = 55 13 pills/day). The primary outcome measure was defined as a composite score (Satisfaction with Treatment, McGill Pain Questionnaire, Global Well-being, and IBS-QOL). The composite score was correlated with: (i) DES plasma levels at week 6, and (ii) number of pills taken over the duration of the 12-wk treatment period. In addition, we also compared DES dose with DES plasma levels.

RESULTS: There was a modest correlation between mean DES dose at weeks 5 and 6 and DES blood level at week 6 (R = 0.2 p< 0.07). However, there were no significant correlations between the composite score either with DES dose or with DES blood levels.

CONCLUSIONS: Detectible blood levels of DES are associated with a clinical response in FBD. However, with dosages up to 150 mg, there is no relationship between total dose or plasma level and the clinical response.

http://www.blackwell-synergy.com/links/doi/10.1111/j.1572-0241.2005.30375.x/abs/

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Zelnorm Associated With Rare Cases of Severe Diarrhea, Ischemic Colitis new
      #173169 - 04/24/05 03:48 PM
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Zelnorm Associated With Rare Cases of Severe Diarrhea, Ischemic Colitis


Yael Waknine

April 29, 2004 — The U.S. Food and Drug Administration (FDA) and Novartis notified healthcare professionals on April 26 of revisions to the warnings and precautions sections of labeling for tegaserod maleate (Zelnorm). The warning refers to serious consequences of diarrhea (including hypovolemia, hypotension, and syncope) that occurred both during clinical trials and during marketed use, in some cases requiring hospitalization.

Tegaserod maleate is a serotonin 5-HT4 receptor partial agonist, indicated for the short-term treatment of women with irritable bowel syndrome whose primary bowel symptom is constipation.

According to the FDA, tegaserod maleate should be discontinued in patients who develop hypotension or syncope. It should not be initiated in patients who frequently experience or are currently experiencing diarrhea.

The precaution refers to rare cases of ischemic colitis and other forms of intestinal ischemia that have been reported during marketed use of tegaserod maleate, although no causal relationship has been established.

The FDA recommends discontinuation of the drug in patients who develop symptoms of ischemic colitis such as rectal bleeding, bloody diarrhea, or new/worsening abdominal pain. These patients should be evaluated promptly and treatment with tegaserod maleate should not be resumed if a diagnosis of ischemic colitis is confirmed.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of tegaserod maleate to Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, or call 1-888-669-6682, or via the Internet at http://www.novartis.com.

Alternatively, this information may be reported to the FDA's MedWatch safety information and adverse event reporting program by calling 1-800-FDA-1088, by fax at 1-800-FDA-0178, or via the Internet using Form 3500 at http://www.fda.gov/medwatch/index.html.

Reviewed by Gary D. Vogin, MD

Yael Waknine is a freelance writer for Medscape.

http://www.medscape.com/viewarticle/474771

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Rationale for Using Serotonergic Agents to Treat Irritable Bowel Syndrome new
      #177497 - 05/08/05 06:21 PM
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From American Journal of Health-System Pharmacy

Rationale for Using Serotonergic Agents to Treat Irritable Bowel Syndrome

Danial E. Baker

Abstract and Introduction
Abstract
Purpose: The role of serotonin in gastrointestinal (GI)-tract functioning, the pharmacologic rationale for using serotonergic agents in the treatment of irritable bowel syndrome (IBS), and clinical experience with novel serotonergic agents are described.
Summary: IBS is a common multisymptom disorder that is associated with a high socioeconomic burden. The goal of treatment is to provide rapid and sustained global relief of the multiple symptoms of IBS with a single, effective, well-tolerated agent. Traditional treatment options target single symptoms, and many patients are dissatisfied with the level of relief achieved and adverse effects. Research has revealed that serotonin is involved in three major actions in the gut: (1) mediating intestinal motility, (2) mediating intestinal secretion in the GI tract, and (3) modulating perception in the bowels. Serotonin is also a vital link in the brain-gut axis. Alterations in key elements of serotonin signaling have been demonstrated in patients with IBS. Tegaserod, a selective serotonin type 4 (5-HT4)-receptor partial agonist, is indicated for use in women with IBS whose primary bowel symptom is constipation. Alosetron, a 5-HT3-receptor antagonist, is indicated for use in women with severe diarrhea-predominant IBS in whom traditional therapies have failed. The clinical usefulness of several other serotonergic agents for IBS is being investigated.
Conclusion: The use of serotonergic agents in patients with IBS is based on the critical role that serotonin plays in the maintenance of normal gut function and brain-gut communication. Pharmacologic therapies targeting specific serotonin receptors represent an important step in the management of IBS.

Introduction
Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder characterized by abdominal pain or discomfort and altered bowel habits.[1] Traditional treatment options for patients with IBS target single symptoms, are often ineffective, and can cause bothersome adverse effects in some patients.[2] During the past two decades, important research strides have enhanced our understanding of the underlying pathophysiology of IBS. The understanding of the critical role that serotonin plays in maintaining normal GI-tract function (e.g., motility, secretion, and sensation) and of the vital link between serotonin and the enteric nervous system (ENS), the autonomic nervous system (ANS), and the central nervous system (CNS)[3] has resulted in the development of several serotonergic agents as potential therapies for IBS.[1,4]

Two serotonergic agents currently have FDA-approved labeling for use in the treatment of IBS: tegaserod maleate, a selective serotonin type 4 (5-HT4)-receptor partial agonist indicated for women with IBS whose primary bowel symptom is constipation (IBS-C),[5] and alosetron hydrochloride, a 5-HT type 3 (5-HT3)-receptor antagonist indicated for women with severe IBS with diarrhea (IBS-D) in whom traditional therapies have failed to provide adequate relief.[6] Other serotonergic agents are currently in development.

This article discusses the role of serotonin in GI-tract functioning, the pharmacologic rationale for using serotonergic agents in the treatment of IBS, and clinical experience with novel serotonergic agents.



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Section 1 of 10 Next Page: Review of IBS

Click here to continue reading this study:

http://www.medscape.com/viewarticle/503569?src=mp



Danial E. Baker, Pharm.D., FASCP, FASHP, is Associate Dean, Clinical Programs; Director, Drug Information Center; and Professor of Pharmacotherapy, Department of Pharmacotherapy, College of Pharmacy, Washington State University, Spokane, WA


Am J Health-Syst Pharm. 2005; 62 (7): 700-711. ©2005 American Society of Health-System Pharmacists



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Clinical pharmacology of new motility promoting agents new
      #180696 - 05/22/05 06:33 PM
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Neurogastroenterology and Motility
Volume 0 Issue 0 - May 2005
doi:10.1111/j.1365-2982.2005.00675.x


Basic and clinical pharmacology of new motility promoting agents

j. j. galligan* & s. vanner*
Department of Pharmacology and Toxicology and The Neuroscience Program, Michigan State University, East Lansing, MI, USA

Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada

Abstract

Recent research has provided new information about drugs that could be used to treat functional motility disorders. Promotility drugs accelerate gastric emptying or colonic transit and these properties may contribute to their efficacy in treating symptoms associated with gastroparesis, functional dyspepsia or constipation. 5-Hydroxytryptamine4 receptors are targets for drugs (tegaserod, renzapride) that treat symptoms in constipated irritable bowel syndrome patients and in gastroparesis. Drugs acting at motilin (erythromycin) and cholecystokinin-1 (dexloxiglumide) receptors accelerate gastric emptying. Dexloxiglumide might be useful in the treatment of functional dyspepsia particularly that associated with lipid intake.

Alvimopan is a -opioid receptor antagonist that does not cross the blood brain barrier. Alvimopan is effective in treating postsurgical ileus and perhaps opiate-induced bowel dysfunction. Successes and failures of recent efforts to develop promotility agents revealed opportunities and challenges for developing new promotility drugs. The pharmacological properties of partial agonists might be exploited to develop effective promotility drugs. However, opposing actions of promotility agents on motility (increased contraction vs decreased accommodation) limit the clinical efficacy of drugs with these opposing actions. Selection of appropriate patient populations for evaluation of new drugs is also critical.

http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2982.2005.00675.x?cookieSet=1

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FDA revisions to safety labeling for Lotronex (alosetron ) new
      #180699 - 05/22/05 06:46 PM
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The U.S. Food and Drug Administration approved in February revisions to safety labeling to advise that use of alosetron HCl has been associated rarely with serious gastrointestinal tract adverse events and concomitant administration of alosetron HCl and fluvoxamine is contraindicated; caspofungin acetate should be administered concomitantly with cyclosporine only in those patients for whom the potential benefit outweighs the potential risk of elevated liver enzyme levels; the atenolol component of atenolol-chlorthalidone tablets is associated with a risk of clinically significant bradycardia in neonates born to mothers receiving the fixed-dose combination drug at parturition or while breast-feeding.

Alosetron (Lotronex) Associated Rarely With Serious Gastrointestinal Adverse Events

On Feb. 18, the FDA approved revisions to the safety labeling for alosetron HCl tablets (Lotronex, made by GlaxoSmithKline) to advise of contraindications and warnings associated with its use.

Concomitant use of alosetron with fluvoxamine is contraindicated. Fluvoxamine is a known strong inhibitor of CYP1A2 that has been shown in clinical studies to increase mean alosetron plasma concentrations by approximately sixfold and prolong its half-life by approximately threefold.

The FDA warns that use of alosetron has been associated with infrequent reports of serious gastrointestinal tract adverse events such as ischemic colitis and complications of constipation. Some of these events have occurred without warning and have resulted in hospitalization, but rarely have resulted in blood transfusion, surgery, or death.

Serious complications of constipation, including obstruction, ileus, impaction, toxic megacolon, and secondary bowel ischemia, have been reported in alosetron clinical trials and during postapproval use. Intestinal surgery, including colectomy, has been required in some cases. Postmarketing reports have also included rare incidences of perforation and death.

In clinical trials, constipation-related adverse events resulted in a discontinuation rate of approximately 10% among alosetron recipients (overall incidence rate for patients is about 0.1%; 1 per 1,000 patients).

The FDA notes that the risk of serious complications of constipation may be increased in patients who are elderly, debilitated, or concurrently receiving medications that reduce gastrointestinal motility.

Alosetron therapy has also been associated with rare reports of ischemic colitis in clinical trials and during postapproval use.

In clinical trials, the cumulative incidence of ischemic colitis was 0.2% in women receiving alosetron for three months (2 per 1,000 patients; 95% confidence interval [CI], 1 - 3) and 0.3% after six months of therapy (3 per 1,000 patients; 95% CI, 1 - 4). According to the FDA, these data from controlled studies are insufficient to estimate the incidence of ischemic colitis in patients receiving alosetron therapy for longer than six months.

Alosetron is indicated for the treatment of chronic, severe, diarrhea-predominant irritable bowel syndrome in women who have not responded adequately to conventional therapy.

http://www.medscape.com/viewarticle/504287

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Acute Hepatitis Associated With Lotronex new
      #198982 - 07/24/05 02:37 PM
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Acute Hepatitis Associated With Alosetron (Lotronex(R)).

Journal of Clinical Gastroenterology. 39(7):641-642, August 2005.

Turgeon, D Kim MD; Tayeh, Nadia BS; Fontana, Robert J MD

Abstract:
Alosetron hydrochloride (Lotronex(R), GlaxoSmithKline, Inc) is a safe and effective agent for selective patients with severe irritable bowel syndrome when prescribed as recommended. We describe the first reported case of acute liver injury in a 39-year-old white woman who developed symptomatic hepatitis 28 days after starting alosetron. All other competing causes of acute hepatitis were excluded by radiologic and laboratory studies and the liver injury resolved after drug discontinuation. Although the mechanism of alosetron hepatotoxicity is unknown, metabolic idiosyncrasy is suspected since the drug is known to be extensively metabolized by cytochrome-P450 enzymes. Clinicians prescribing alosetron should be aware of this potential side effect if unexplained abdominal pain, jaundice,or abnormal liver biochemistries are encountered in a treated patient.

(C) 2005 Lippincott Williams & Wilkins, Inc.

http://www.mdlinx.com/GILinx/thearts.cfm?artid=1269472&specid=13&ok=yes

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Lack of Lasting Effectiveness of Miralax Laxative Treatment of Constipation. new
      #203375 - 08/07/05 04:18 PM
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Lack of Lasting Effectiveness of Miralax Laxative Treatment of Constipation.

Journal of Clinical Gastroenterology. 39(7):600-602, August 2005.

Tran, Lily C MD; Di Palma, Jack A MD

Abstract:
Purpose: PEG 3350 (MiraLax, Braintree Laboratories Inc., Braintree, MA) 17 g daily has been shown to be safe and effective in a 14-day trial for constipation. This present investigation was designed to extend the treatment and safety experience with PEG 3350 and to evaluate any lasting effectiveness during a 30-day post-treatment observation period.

Methods: Study subjects met Rome II criteria for constipation and reported <3 bowel movements a week. They were treated with PEG 3350 17 g daily for 14 days. Treatment efficacy was defined by resolution of constipation symptoms as determined by the Rome II and stool frequency definitions during the treatment period.

Results: Fifty healthy constipated subjects formed the study group. There were 42 females and 8 males. Mean age was 52 +/- 15.5 years (+/-SD). Symptom duration was 22.6 +/- 16.7 months (+/-SD). At baseline, all had <3 bowel movements a week and met Rome II criteria. Two were lost to follow-up. Two took enemas or laxatives and 2 discontinued active treatment because of "gas" and were considered treatment failures. At the end of 14 days, 40 of 48 (83.3%) had >3 stools in the last week and no longer met Rome criteria. Thirty-two of 45 (71.1%) reported satisfaction with the first bowel movement after initiating treatment. Thirty days after active treatment, 29 of 47 (61.7%) responded that they needed laxative treatment.

Conclusion: PEG 3350 relieved constipation in most treated study subjects. During a 30-day post-treatment observation period, 29 of 47 (61.7%) had additional constipation treatment interventions.

(C) 2005 Lippincott Williams & Wilkins, Inc.


http://www.mdlinx.com/GILinx/thearts.cfm?artid=1291584&specid=13&ok=yes


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Octreotide May Be Effective in Treatment of Nonconstipated IBS new
      #230157 - 12/08/05 12:31 PM
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Octreotide May Be Effective in Treatment of Nonconstipated IBS

Laura Gater

May 24, 2005 (Chicago) — Octreotide reduces abdominal complaints and improves stool consistency, suggesting that it may be beneficial in nonconstipated irritable bowel syndrome (IBS), according to findings presented here at Digestive Disease Week 2005.

The study examined the effect of a slow-release preparation of octreotide (Sandostatine LAR) on rectal sensitivity and symptoms in nonconstipated IBS patients. Previous research by Hasler and colleagues published in the March 1994 issue of the Journal of Pharmacology and Experimental Therapeutics determined that acute administration of octreotide inhibits afferent responses to rectal distension and possesses an antihyperalgesic effect in IBS, according the findings of Schwetz and colleagues in the January 2004 issue of Alimentary Pharmacology & Therapeutics. It was unknown if prolonged octreotide treatment would improve gastrointestinal tract symptoms and reduce visceral sensitivity. In fact, the eight-week treatment with octreotide compared with placebo did significantly increase patients' threshold for first sensation.

The randomized, double-blind, placebo-controlled, parallel group study involved 42 nonconstipated IBS patients from ages 19 to 63 years, including 20 females. Patients received 20 mg of octreotide daily. Each underwent a barostat study before and after the eight-week treatment to assess rectal sensitivity, using an intermittent, pressure-controlled, and a slow ramp volume-controlled distention protocol.

"The most important outcome of the study was the effects of the slow release of octreotide compared with an acute experience," Sjoerd Kuiken, MD, investigator of the study, told Medscape. "In its current form, it is not a safe drug. Patients have to be screened for gallstones every six months. It is only for treating severe and disabling cases of nonconstipated IBS now because of the adverse effects. Other data still have to be analyzed."

Octreotide has the additional benefits of slowing small bowel transit, inhibiting intraluminal secretion, and promoting absorption. The patients who received octreotide reported a 36% ± 2% effect on global relief, while those taking placebo reported a 27% ± 3% effect. Octreotide also improved stool consistency compared with placebo, with 49% ± 3% of patients having loose and watery stools vs 64% ± 2% in placebo (P < .01). However, abdominal pain and defecation frequency were not affected.

Novartis Pharma B.V. Arnhem provided grant and research support.

DDW 2005: Abstract 624. Presented May 17, 2005.

http://www.medscape.com/viewarticle/505360

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Non-steroidal anti-inflammatory drugs and gastrointestinal damage new
      #230162 - 12/08/05 12:51 PM
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Postgrad Med J 2001;77:82-88 ( February )
Review

Non-steroidal anti-inflammatory drugs and gastrointestinal damage - problems and solutions

R I Russell

University of Glasgow and Department of Gastroenterology, Royal Infirmary, Glasgow


Non-steroidal anti-inflammatory drugs (NSAIDs) have been used for many years for analgesic, anti-inflammatory, and more recently in the case of aspirin, antithrombotic purposes. The use of NSAIDs continues to increase; over 22 million prescriptions are written every year in the UK, and over 70 million in the US. These figures underestimate their full use as aspirin and other NSAIDs are widely available as "over-the-counter" preparations.

The use of these drugs can also be expected to increase in the years to come, partly because of the increasing age of the population and partly because of possible new and developing indications, particularly in vascular disease and cancer prevention. It is therefore of importance to assess the safety and side effects of NSAIDs, and to consider how their safety may be improved. It has long been known that NSAIDs may have a range of side effects, of which the commonest are gastrointestinal.

It is the purpose of this paper to examine the nature, range, and causation of the gastrointestinal side effects associated with the use of NSAIDs, and to consider how these may be reduced or modified. NSAIDs may also be associated with other adverse effects, although these are much rarer than gastrointestinal problems; these include nephropathies, skin rashes, and hepatitis. NSAIDs may also interact with other drugs such as antihyperglycaemic or antihypertensive agents.

NSAIDs may be associated with many gastrointestinal problems, ranging from mild to severe dyspeptic symptoms, the development of gastric or duodenal ulceration, haemorrhage or perforation, and other events which may lead to hospitalisation or death.

Endoscopic studies have shown a prevalence rate of 14%-25% of gastric and duodenal ulcers in NSAID users,1 although the difficulty of having accurate control groups makes exact figures difficult to obtain. Although endoscopic studies tend to show more gastric than duodenal ulcers associated with NSAID use, patients presenting with gastrointestinal bleeding on NSAIDs may have a similar frequency of gastric and duodenal ulceration. Dyspeptic symptoms occur in up to 60% of patients taking NSAIDs and there is a poor correlation between symptoms and endoscopically proved lesions; up to 50% of endoscopically confirmed ulcers associated with NSAIDs are asymptomatic.

It has been estimated that the individual risk of hospitalisation with gastrointestinal complications of NSAIDs is between 1/50 and 1/150 patient years.2 The risk of an upper gastrointestinal bleed is between 1/100 and 1/500 patient years; the risk of a gastrointestinal related death is between 1/1000 and 1/5000 patient years.

The risk of serious ulcer complications in patients on NSAIDs has been calculated in various studies, the relative risk (RR) for a serious gastrointestinal event overall being reported as 2.74 in a large meta-analysis, upper gastrointestinal bleeding RR 3.09, perforation RR 5.93, and ulcer related death RR 7.62.3

NSAIDs may have adverse effects in all parts of the gastrointestinal tract, not only the stomach or duodenum; the oesophagus, small intestine and colon may also be affected.

A recent necropsy study of 713 patients has been reported, of whom 244 had NSAIDs prescribed during the six months before death and 464 had not; death in all patients was unrelated to NSAID use. Ulcers of the stomach or duodenum were found in 21.7% of patients on NSAIDs and 12.3% of those not on NSAIDs (p<0.001), and small intestinal ulceration was found in 8.4% of NSAID users and 0.6% of patients not on NSAIDs (p<0.001).4 Damage to the small intestine in NSAID users has also been demonstrated at enteroscopy. Patients with small intestinal damage associated with chronic NSAID use may present with chronic iron deficiency anaemia or hypoalbuminaemia due to blood or protein loss, and may develop overt bleeding, perforation, or strictures.

In the oesophagus, chronic NSAID use may be associated, although rarely, with oesophagitis, ulceration, or stricture formation.5

In the large bowel, NSAID use may lead to the development of a non-specific colitis (with abdominal discomfort, bloody diarrhoea, and weight loss). NSAIDs may also cause an exacerbation of ulcerative colitis or Crohn's disease, if the associated arthropathy in inflammatory bowel disease is treated with NSAIDs.6 7

High risk factors for NSAID related gastrointestinal damage include older age group (especially over 70), previous history of peptic ulceration, and probably the first three months of NSAID treatment. Other high risk factors are smoking, underlying respiratory or cardiovascular disease, and concomitant drug use, particularly corticosteroids, aspirin, and anticoagulants (box 2).8 Perioperative use is also a risk factor. Individual NSAIDs incurring highest risk include azapropazone, ketoprofen and piroxicam, and those with least risk include ibuprofen, diclofenac, and etodolac. Higher doses are associated with increased risk and also the use of more than one NSAID. There is also an increased risk of gastrointestinal complications with relatively low dose prophylactic aspirin, which is widely used nowadays.9 There is debate on the possible interaction and increased risk of Helicobacter pylori causing ulceration with NSAIDs, and this will be discussed in a later section. The balance of physiological association and clinical evidence tends to support the possibility of some interaction occurring, especially in those patients at high risk and possibly in those who have bled. Well planned, prospective controlled studies are required to provide more information on this with respect to different types and doses of NSAIDs, different forms and strains of H pylori, and different types of erosions and ulcers.

NSAIDs interfere with the cyclo-oxygenase (COX) pathways which lead to the production of prostanoids (prostaglandins, prostacycline, and thromboxane). This interferes with mucosal protection by reducing the effectiveness of the mucus-bicarbonate barrier; gastric acid, and possibly also pepsin, are thus more likely to cause damage. The fact that most NSAIDs are also weak acids may also be a contributory factor.

It is now known that COX exists as two separate isoforms, COX-1 and COX-2, which differ markedly in their tissue expression and regulation.10-12 COX-1 is constitutively expressed in most tissues, including the stomach, duodenum, platelets, and kidneys; COX-1 plays a key part in the production of prostaglandins which regulate important physiological processes such as gastrointestinal cytoprotection (maintaining an effective mucus-bicarbonate barrier, submucosal blood flow, quicker and more effective mucosal adaptation to initial tissue damage, and more rapid recovery when such damage occurs). It is also involved in vascular homoeostasis and the maintenance of good renal function and in maintaining normal physiological functions in many other cells. This is an important "housekeeping" role. COX-2, on the other hand, is normally undetectable in most tissues, but it can be induced rapidly, and in large quantitiesto 200-300-foldby cytokines, growth factors, and hormones in the presence of inflammation and other pathological processes (box 3). Platelets appear to contain only COX-1.

Most conventional NSAIDs are non-selective in their COX inhibition, exerting their anti-inflammatory effects through the inhibition of COX-2, but having adverse effects (such as gastrointestinal mucosal damage and nephrotoxicity) primarily due to inhibition of COX-1. Some existing and longstanding NSAIDs, such as etodolac, a known safer NSAID with respect to gastrointestinal damage and which is known to have reduced adverse effects on mucosal prostaglandins, has been subsequently found to have a degree of COX-2 inhibition selectivity.

Currently, a range of new and specific COX-2 selective inhibitor NSAIDs have been, and are being further developed with the hope of reducing possible gastrointestinal side effects; the preliminary clinical results, as we shall see later, are encouraging. One of these, rofecoxib, is now available in this country.

HEALING OF NSAID RELATED ULCERS
There is evidence from both animal and human studies that NSAIDs retard the healing of gastric ulcers. Although it is frequently stated that a first step if gastrointestinal problems occur with NSAIDs is to withdraw NSAIDs or reduce the dose, in practical terms this is generally unrealistic, especially when there is a major inflammatory condition such as rheumatoid arthritis.

It may be possible to reduce the dose of NSAIDs in some individuals. It is also appropriate to try alternative conventional NSAIDs as there is a wide variability in responses to individual drugs. Some NSAIDs are more likely than others to cause gastrointestinal problems; those associated with greatest risk include azapropazone, ketoprofen, and piroxicam.

H2-receptor antagonists, especially in high doses, do heal NSAID related ulcers while NSAIDs are continued,13 but proton pump inhibitors may be expected to be more effective, and have now been shown to be so. Omeprazole has been shown to heal gastric ulcers faster than ranitidine.14 In two large studies comparing omeprazole (20 mg or 40 mg daily) with misoprostol (200 µg four times a day), the proton pump inhibitors healed significantly more gastric and duodenal ulcers than ranitidine or misoprostol.

No extra benefit was gained from using omeprazole at the higher dose.15 16

PREVENTION OF NSAID RELATED GASTROINTESTINAL PROBLEMS
The lowest dose of the safest NSAID which is effective in individual patients should be used if possible.

Avoidance or reduction of risk factors may be possible in some patients, such as smoking, use in patients with a past history of dyspeptic problems or peptic ulcer, perioperative use, or cotherapy with other drugs such as corticosteroids, anticoagulants, or aspirin. Advice should be given about "over-the-counter" preparations.

There will inevitably be patients in whom additional requirements will be necessary, such as those who continue to require high dose NSAIDs or in those with risk factors which cannot be modified.

In such patients there has been much interest in recent years in attempting to reduce risk by the coprescription with NSAIDs of drugs which may improve mucosal protection (the prostaglandin analogue misoprostol) or reduce gastric acid (H2-receptor antagonists or proton pump inhibitors). More recently, newer NSAIDsselective COX-2 inhibitorsoffer the prospect of greater gastrointestinal safety.

PROSTAGLANDINS
The prostaglandin analogue misoprostol has shown a reduction in ulceration compared with placebo ranging from 50% to 90% over 3-12 months; the dose used initially was 200 µg four times a day and subsequently 400-600 µg per day. Protection has been generally similar for both gastric and duodenal ulcers.17 18 A large blinded study of misoprostol compared with placebo (the "MUCOSA" study) reported a significant reduction of gastrointestinal bleeding and perforation with misoprostol at 800 µg daily.19 In this study, 27% of patients withdrew because of side effects, principally diarrhoea. Diarrhoea remains a problem for many patients with this preparation. Misoprostol has also been combined with a standard NSAID, diclofenac (arthrotec), and this has proved popular with a number of patients.

Theoretically, prostaglandin analogues have an advantage over acid suppressants in that they should provide mucosal protection throughout the gastrointestinal tract.

ACID SUPPRESSION
As gastric acid is a factor in causing gastroduodenal damage associated with NSAID use, reduction of gastric acid by the coprescription of acid suppressant drugs has been studied.

The use of H2-receptor antagonists in standard doses for the prevention of NSAID associated ulcers has shown some protection against duodenal ulcers.20 and the use of high dose famotidine (40 mg twice a day) has been shown to significantly reduce the cumulative incidence of both gastric and duodenal ulcers in patients with rheumatoid arthritis on long term NSAID therapy.21

Proton pump inhibitors cause more effective acid suppression than H2-receptor antagonists, and several randomised controlled trials lasting 3-6 months using omeprazole 20 mg daily have shown efficacy in preventing both gastric and duodenal ulcers while continuing long term NSAIDs, with about a 75%-80% reduction in ulcers compared with placebo.15 16 22

The proton pump inhibitors were shown in two of these studies to provide more effective protection than ranitidine (150 mg twice a day) or misoprostol (200 µg twice a day).

Omeprazole 20 mg daily has also been shown to protect against bleeding from ulcers in long term NSAID users.23

NEWER NSAIDS: COX-2 SPECIFIC INHIBITORS
The search for safer NSAIDs has recently focused on the development of preferential or selective COX-2 inhibitors. These compounds aim to exploit the belief that COX-1 is associated predominantly with the production of protective prostaglandins and has a "housekeeping" role, whereas COX-2 is induced in inflammation and associated with inflammatory processes. The development of these concepts has been recently reviewed.24

The definition of, and screening for, COX-2 selectivity has given rise to much debate, involving a variety of suggested systems that includes purified recombinant enzyme, transfected cells, and whole blood assays. The latter method may be the most appropriate at present, but all drugs suggested as COX-2 specific inhibitors require to be shown to have no significant inhibition of gastric mucosal prostaglandins, in addition to a good clinical safety profile and effectiveness.

Conventional longstanding NSAIDs have been found to vary with respect to their relative COX-1 to COX-2 inhibition capacity, but all have a significant effect on COX-1, thus interfering with gastric mucosal protection.

One NSAID, etodolac, which has been used widely for some years, has been shown in several studies to be clinically effective and have reduced gastrointestinal toxicity, demonstrated endoscopically and clinically; these studies also found no significant reduction of gastric mucosal prostaglandins compared with naproxen.25 26 Etodolac has since been found to have some degree of COX-2 selectivity.27

Other drugs with probable relative COX-2 selectivity include nabumetone, nimesulide, and meloxicam.24

Newer more specific COX-2 inhibitors currently under study include celecoxib and rofecoxib (the latter now being available in this country). Preliminary results of studies with these drugs indicate effectiveness and a good gastrointestinal safety profile. Celecoxib (25-400 mg twice a day) was associated with a significantly reduced incidence of adverse upper gastrointestinal problems including ulcers, gastrointestinal bleeding, and perforation in patients with osteoarthritis and rheumatoid arthritis compared with standard NSAIDs.28 Rofecoxib (12.5-25 mg a day) demonstrated a lower incidence of endoscopic ulcers compared with ibuprofen in patients with osteoarthritis in a multicentre study over 24 weeks.29 Rofecoxib has also shown reduced occurrence of ulcers, perforations, and gastrointestinal bleeding.

COX-2 specific inhibitors have little, if any, effect on platelet function, and may therefore be associated with a marked reduction of gastrointestinal bleeding associated with NSAID use.

These studies are promising and more data are awaited. The long term safety of these drugs remains to be established, particularly with respect to the kidney and in the possible, although less likely, impairment of healing of pre-existing peptic ulcers. It is also theoretically possible that COX-2 inhibitors may have a benefit in preventing colon cancer and possibly also in Alzheimer's disease. COX-2 inhibitors will not be effective in cardiovascular protection unlike aspirin, as the protective effects provided by aspirin are mediated through COX-1.

LOW DOSE ASPIRIN
Aspirin is widely used in low doses in patients with suspected or definite vascular disease. Aspirin is a major cause of upper gastrointestinal problems, and is a frequent cause of upper gastrointestinal bleeding. Even in low doses (75 mg daily), aspirin has effects on platelet levels of COX, which it acetylates and to which it binds irreversibly, thus impairing platelet function. This causes changes in the bleeding time, platelet aggregation, and the synthesis of thromboxane, which remain for the life of the platelet. The damage is worse with longer acting NSAIDs with long half lives and an extensive enterohepatic circulation, such as piroxicam.

With increasing use, aspirin is now a major cause of upper gastrointestinal problems, and in particular, upper gastrointestinal bleeding. One recent study reported an overall odds ratio of 3.2 (95% confidence interval (CI) 2.3 to 4.4) in gastrointestinal bleeding for daily aspirin use of at least one month, compared with 3.8 (95% CI 3.1 to 4.5) for non-aspirin NSAID use.9 This can be expected to increase with increasing use of low dose aspirin, especially common in older age groups.

Platelets contain only COX-1; thus only drugs such as aspirin and those NSAIDs which inhibit COX-1 will inhibit platelet function. COX-1 sparing NSAIDs such as etodolac, nabumetone, nimesulide, meloxicam, are likely to have little effect on platelet dysfunction. The highly specific COX-2 inhibitors (celecoxib, rofecoxib), have almost no effect on platelet function, and are likely, as mentioned previously, to lead to marked reductions in upper gastrointestinal bleeding. However, if used with low dose aspirin, there is likely to be a loss of benefit.

COX-2 specific inhibitors will not be helpful in vascular disease, and cannot be considered as a replacement in this respect for low dose aspirin.

A new antiplatelet agent, clopidrogel may be safer than aspirin, although more costly. Clopidrogel requires to be further assessed, but may be helpful in patients with peripheral artery disease, and in stroke or myocardial infarction in whom aspirin is contraindicated, or in whom aspirin fails to achieve the required therapeutic effect.

WHAT TO DO ABOUT H PYLORI?
H pylori and NSAIDs are the two most common causes of peptic ulceration.

The possible interactions of H pylori and NSAIDs have led to much discussion recently and no clear picture emerges that can apply to all situations. In many ways, NSAIDs and H pylori have similar adverse effects on mucosal protective mechanisms, and despite H pylori itself producing small amounts of prostaglandins, there remains the possibility of an additive damaging effect when both are present.30 Studies on mucosal adaptation and on neutrophils raise the possibility of some inter-relationship that may allow damage to occur more readily when NSAIDs are taken in the presence of H pylori.31

The development of an ulcer when NSAIDs are given to patients who are H pylori positive may depend on the interaction of a number of factors, including previous exposure to NSAIDs, past history, gastric acid output, and the use of acid suppression drugs such as proton pump inhibitors.

Aspirin may have different interactions with H pylori, particularly with respect to the risk of gastrointestinal haemorrhage.

Gastrointestinal haemorrhage from ulcers may be in a different category from non-bleeding ulcers, and really requires to be studied separately; other factors may be involved, such as the possible antiplatelet effects of many NSAIDs, which may be a further factor in bleeding.

Clinical studies in this area have given conflicting results, although one study in patients not previously given NSAIDs clearly demonstrated an advantage in eradicating H pylori before starting NSAIDs; significantly fewer lesions developed over two months in patients in whom H pylori had been eradicated before starting NSAIDs.32 In such patients, especially if risk factors are present (older age group, previous ulcer history), eradication of H pylori before starting NSAIDs may be indicated.

A large multicentre study has found that eradication of H pylori did not reduce the rate of ulcer relapse in existing long term NSAID users.33 In this study, it was also reported in a subgroup of 41 patients with gastric ulcers found at baseline endoscopy that eradication of H pylori was associated with delayed ulcer healing. However, in another prospective, randomised study of 195 patients with H pylori infection and NSAID associated bleeding ulcers, eradication of H pylori did not impair healing of gastric or duodenal ulcers.34 A prospective, randomised clinical outcome study compared H pylori eradication alone with long term omeprazole for the prevention of recurrent ulcer haemorrhage in high risk users of aspirin or non-aspirin NSAIDs.35 The results to date indicate that eradication of H pylori alone did not prevent recurrent ulcer bleeding associated with non-aspirin NSAIDs, but H pylori eradication alone was as effective as maintenance omeprazole in preventing recurrent haemorrhage associated with low dose aspirin. Perhaps the antiplatelet effects of NSAIDs are relevant there.

H pylori testing would probably not be indicated in patients who have already been on NSAIDs or aspirin for some time without any adverse effects. In patients with a past history of peptic ulcer or dyspepsia on NSAIDs, long term acid suppressive agents such as proton pump inhibitors are indicated even after eradication of H pylori.

More scientific and clinical data are required on these complex inter-relationships.


Conclusions:
The use of NSAIDs continues to increase, especially in the elderly.
NSAIDs may have adverse effects in any part of the gastrointestinal tract: oesophagus, stomach, duodenum, small intestine, or colon.
Risk factors for gastrointestinal damage due to NSAIDs include age, previous ulcer history, first three months of treatment, smoking, underlying cardiovascular or respiratory disease, concomitant drug use with corticosteroids and anticoagulants, high dose and multiple NSAIDs, and possibly in some cases H pylori.
Low dose prophylactic aspirin may also be associated with adverse gastrointestinal effects.
Healing of NSAID related ulcers can be achieved while NSAIDs are continued by the use of H2-receptor antagonists in high doses, or more effectively by proton pump inhibitors.
Prevention of NSAID related gastrointestinal problems may be achieved by identifying and if possible reducing risk factors, the coprescription of prostaglandin analogues or acid suppressive drugs (especially proton pump inhibitors), or by using the currently being developed and promising COX-2 specific inhibitors.
The development of COX-2 specific inhibitors offers the hope of real progress in producing much safer and effective NSAIDs.

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Zelnorm fails to win EU panel backing new
      #233095 - 12/21/05 11:25 AM
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Novartis bowel drug fails to win EU panel backing

By Ben Hirschler, European Pharmaceuticals Correspondent

LONDON (Reuters) - A panel of experts decided on Thursday not to recommend Novartis AG's Zelnorm drug for irritable bowel syndrome in the European Union, hitting the company's shares and prompting it to launch an appeal.


The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) adopted the negative opinion following a review which began in October last year.

Novartis said it would appeal the medical experts' decision, which blocks EU approval for the drug as a treatment for women with constipation related to irritable bowel syndrome.

Shares in Novartis fell 1.7 percent to 67.15 Swiss francs on the setback for a medicine that has taken longer to become a major seller than the Swiss drugs giant originally expected.

Novartis pointed out the drug was already on sale in the United States and many other countries, and said it remained committed to ensuring it became available to women in Europe.

"Although we are disappointed with the CHMP opinion, we are confident in the clinical profile and benefits of Zelnorm," James Shannon, head of global pharmaceuticals development at Novartis, said in a statement.

WARNING ADDED

Zelnorm -- which is also known as Zelmac in some countries -- was approved by the U.S. Food and Drug Administration in 2002 for use in women with constipation relating to IBS.

However, safety information was added to Zelnorm's packaging in the United States in 2004, warning of the effects of diarrhoea and alerting patients to a condition where blood flow to the intestines is reduced.

"It's had a bit of a chequered history," said Mike Ward, an analyst with stockbroker Code Securities. "I think ultimately it will do reasonably well but it has been a long, hard struggle for them to get there."

The drug is sold in more than 56 countries as a treatment of IBS-C, or constipation resulting from irritable bowel syndrome, and in more than 20 countries as a treatment for chronic constipation. Worldwide sales were $299 million last year.


Recommendations from the agency's committee are normally endorsed by the European Commission within 90 days.

(additional reporting by Tom Armitage in Zurich)


(c) Reuters 2005

http://business.scotsman.com/latest.cfm?id=2413602005

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Hearburn Drugs Cause Diarrhea new
      #236753 - 01/08/06 05:10 PM
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Commonly used heartburn drugs appear to be contributing to the rapid increase of community-acquired Clostridium difficile diarrheal infection.

Suppression of gastric acid with proton-pump inhibitors drugs like Prilosec (omeprazole) or Nexium (esomeprazole) is associated with a two- to threefold increase in the risk of community acquired Clostridium difficile, according to researchers here.


The finding supports the hypothesis that the mechanism of increased C. difficile risk is related to the degree of gastric acid suppression, Sandra Dial, M.D., M.Sc., of McGill University and colleagues reported in the Dec. 21 issue of the Journal of the American Medical Association.


Analysis of medical records from patients treated by general practitioners in England found that the incidence of C. difficile diagnosed by GPs jumped from less than 1 case per 100,000 population in 1994 to 22 cases per 100,000 in 2004.


That increase is mainly due to the increased use of gastric acid suppressors, wrote Dr. Dial and colleagues.


The adjusted relative risk for current proton pump inhibitor exposure was 2.9 and the adjusted relative risk for current H2 -receptor agonist exposure was 2.0. Current exposure to NSAIDs, but not aspirin, was also associated with a slight increase in risk of C. difficile. Proton pump inhibitors more effectively suppress gastric acid than H2 -receptor agonists.


Decreased gastric acidity, they wrote, is "a known risk factor for other infectious diarrheal illnesses such as travelers' diarrhea, salmonellosis, and cholera."


The concluded, "Acid-suppressive agents are among the most frequently prescribed medications in the United Kingdom and North America, and it is in this context that the contribution of these agents by potentially increasing the pool of susceptible hosts to the increasing rates of [C. difficile-associated disease] need to be considered and more completely characterized."


C. Difficile is usually considered a nosocomial infection, but in this analysis the researchers identified 1,233 cases among patients who had not been hospitalized in the year prior to diagnosis. Those 1,233 cases account for 74% of the 1627 cases of C. difficile identified in the General Practice Research Database.


The researchers compared cases with age-matched controls. Four hundred of the 1,233 cases were diagnosed by clinical symptoms and 833 were identified by positive toxin assay.


The mean age of patients with community-acquired C. difficile was 71 and most of the cases were women. Other factors associated with C. difficile were history of renal failure, inflammatory bowel disease, malignancy, and methicillin-resistant Staphylococcus aureus-positive.



Primary source: Journal of the American Medical Association
Source reference:
Dial, S et al. "Use of Gastric Acid-Suppressive Agents and the Risk of Community-Acquired Clostridium difficile-Associated Disease" JAMA 2005; 294:2989-2995.

http://www.medpagetoday.com/Gastroenterology/GERD/tb/2362

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Cilansetron: ; Solvay Pharmaceuticals suspends registration activites in the U.S., new
      #239579 - 01/18/06 04:15 PM
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CILANSETRON; Solvay Pharmaceuticals suspends registration activites in the U.S., while discussions in Europe continue

Embargo : November 29, 2005 at 8:00 AM (Brussels time)

Solvay Pharmaceuticals announced today it has suspended regulatory activities for cilansetron with the United States regulatory agency, the Food and Drug Administration. Given the amount of clinical work requested and in the framework of the estimated potential market there, Solvay prefers to give priority to the development of other compounds in its research and development pipeline.

However, in the United Kingdom, the reference member state for Europe-wide registration, discussions on cilansetron with the Medicines and Healthcare products Regulatory Agency continue. Solvay expects to announce its decision for Europe during 2006.

Cilansetron, is a novel 5-HT3 receptor antagonist which decreases gastrointestinal motility, secretion, and sensation. Efficacy and safety studies have included more than 4,000 patients worldwide, both men and women, with diarrhea predominance (D-IBS). Both men and women recorded symptom improvements and improved quality of life.

D-IBS
On average, IBS affects more than 11% of the EU population, with total annual direct costs estimates of some Ł45 million in the UK alone. The common symptoms of D-IBS are diarrhea, abdominal pain/discomfort, and fecal urgency. IBS has a significant, negative impact on the quality of life for the many men and women who suffer from this condition, causing lost days of work and interfering as well with home-based, social and leisure activities.

SOLVAY PHARMACEUTICALS is a research driven group of pharmaceutical companies in Solvay that seeks to fulfil carefully selected, unmet medical needs in the therapeutic areas of neuroscience, cardio-metabolic, influenza vaccines, pancreatic enzymes, gastroenterology and men's and women's health. Solvay Pharmaceuticals employs about 13,000 people worldwide after the acquisition of Fournier Pharma in July 2005.

SOLVAY is an international chemicals and pharmaceuticals group with headquarters in Brussels. It is present in more than 50 countries and employs some 33,000 people in its Chemicals, Plastics and Pharmaceuticals activities. Including Fournier Pharma, its 2004 sales amounted to EUR 8.5 billion. Solvay is listed on the Euronext 100 index of top European companies.

http://www.solvaypress.com/pressreleases/0,,36423-2-0,00.htm

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Takeda Laxative Wins U.S. Approval for Adults new
      #247116 - 02/18/06 01:36 PM
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Takeda Laxative Wins U.S. Approval for Adults

WASHINGTON (Reuters) Jan 31 - U.S. health officials said on Tuesday that they approved a new prescription drug, called Amitiza, to treat adults with chronic constipation.

The drug, made by Japan's Takeda Pharmaceutical Co. Ltd. and privately held Sucampo Pharmaceuticals Inc., helps relieve constipation, abdominal bloating and discomfort, the Food and Drug Administration said in a statement.

It is intended for patients who experience constipation over time with no known cause, the agency said.

The new capsules work by increasing fluids in the intestines and should be taken twice daily with food.

Side effects can include headache, nausea, diarrhea and abdominal pain, among others, the FDA said.

The drug should be taken twice daily with food to help increase fluids in the intestines, the Food and Drug Administration said in a statement.

http://www.medscape.com/viewarticle/522740?src=mp

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Antidepressants for IBS new
      #252526 - 03/16/06 12:31 PM
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Irritable Bowel Syndrome: New and Emerging Therapies


Antidepressants

The rationale behind using these medications in modulating pain and gut function is that studies have evaluated the efficacy of both tricyclic antidepressants (TCAs) and SSRIs in IBS. The rationale behind their use is based on three theories. First, functional patients often have psychological comorbidities, particularly anxiety, somatization and depression. Second, these medications may have a modulating effect either through a centrally mediated action or a local gut action that changes visceral sensitivity and motor activity or both. Lastly, both SSRIs and TCAs seem to have a central effect in modulating pain.

Tricylics are well known for their pain-modulating effects. A recent metaanalysis assessed the efficacy of TCAs in the treatment of a variety of functional gastrointestinal disorders and found that the average number needed to treat was three. Recent studies further support the use of these medications in IBS. Drossman et al. evaluated the efficacy of the TCA desipramine in a 12-week, placebo-controlled study of patients with moderate to severe functional bowel disorders, although most met criteria for IBS. This medication (starting dose was 50 mg at bedtime) showed a statistically significant benefit over placebo in the per-protocol analysis, in which only the patients that completed treatment were included (73% versus 49%), but not in the intention-to-treat analysis. In clinical practice, tricyclic agents are often started at lower doses (e.g. 10 mg at bedtime) and gradually increased to the lowest, most effective dose to minimize side effects and increase tolerance. TCAs have been shown to improve symptoms particularly in IBS-D patients, presumably due to their anticholinergic effects.

The literature on SSRIs is even more limited but two recent studies evaluated the efficacy of paroxetine in IBS. In the first study, paroxetine was compared with psychotherapy and treatment as usual and was found to reduce health care costs, abdominal pain and health-related quality of life 3 months and 1 year later. A second study compared high-fiber diet alone or in conjunction with paroxetine or placebo. Overall, well being, which was measured by the Beck Depression Index and the IBS Quality of Life questionnaires, improved more with paroxetine compared with placebo (63% versus 26%). Anxiety also improved in the paroxetine group but bloating, pain and social functioning did not show improvement with the drug.

Other agents affecting both single and mixed receptor sites (similar to that of TCAs) are also being considered for the treatment of IBS. Combined reuptake inhibitors of both serotonin and norepinephrine, for example venlaxafine, may reduce colonic sensation and alter colonic tone. A newer similar agent, duloxetine, which was recently approved for the management of diabetic neuropathic pain, is also being considered for use in other chronic pain syndromes such as fibromyalgia and IBS.


Lucinda A Harris,a Lin Chang,b

aMayo Clinic College of Medicine, Scottsdale, Arizona, USA
bCenter for Neurovisceral Sciences and Women's Health, Division of Digestive Diseases, David Geffen School of Medicine at UCLA and VA Greater Los Angeles Healthcare System, Los Angeles, California, USA

Curr Opin Gastroenterol. 2006;22(2):128-135. ©2006 Lippincott Williams & Wilkins

http://www.medscape.com/viewarticle/524223_3

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Zelnorm Rejected Again in Europe new
      #255819 - 04/02/06 03:25 PM
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The European Medicines Agency's (EMEA) review committee has recommended against the approval of Swiss drug major Novartis' Zelnorm (tegaserod) for the treatment of women suffering from irritable bowel syndrome with constipation.

This advice followed an appeal procedure undertaken by the firm in December 2005 after the first time that the EMEA's Committee for Medicinal Products for Human Use recommended that the European Commission not approve the serotonin-4 receptor blocker.

Tegaserod, the active ingredient in Zelnorm, is a receptor agonist. It activates receptors in the body, known as 5-hydroxytryptamine (5HT) type 4 receptors. When these receptors are activated in the bowels, peristalsis that moves food along the bowels is stimulated. They also potentially reduce the sensitivity of the bowel. These effects are expected to relieve the symptoms described.

Which documentation has been presented by the Company to support the application to the CHMP?

The effects of Zelnorm were first tested in experimental models before being studied in humans. The main study in humans was done in 2660 women aged 18 to 65 years, and with symptoms of irritable bowel syndrome with constipation. The study compared Zelnorm 6 mg to placebo (a dummy treatment). Treatments were double blinded (neither the patients nor the doctors knew which treatment had been given until the end of the study).

The study looked at the effectiveness of Zelnorm to relieve the overall symptoms of the disease and discomfort or pain in the stomach or abdomen.

Which were the major concerns, which lead to the refusal of the marketing authorisation by the CHMP?

The CHMP was concerned that the results of the study would not translate into real benefit to the patient treated to relieve the symptoms of this disorder in standard health care setting. The CHMP was of the opinion that Zelnorm's benefits are not greater than its risks. Hence, the CHMP recommended that Zelnorm be refused marketing authorisation.

Commenting on the CHMP's decision, James Shannon, head of global drug development at Novartis Pharma, said he was disappointed.

http://www.pharmalive.com/News/index.cfm?articleid=325535&categoryid=51


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Marijuana and the gastrointestinal tract new
      #268966 - 06/12/06 03:38 PM
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J Endocrinol Invest. 2006;29(3 Suppl):47-57. Related Articles, Links


Marijuana endocannabinoids and the gastrointestinal tract.

Massa F, Monory K.

Department of Physiological Chemistry, Johannes Gutenberg-University Mainz, 55099 Mainz, Germany. massa@uni-mainz.de

In the past centuries, different preparations of marijuana have been used for the treatment of gastrointestinal (GI) disorders, such as GI pain, gastroenteritis and diarrhea. Delta9-tetrahydrocannabinol (THC; the active component of marijuana), as well as endogenous and synthetic cannabinoids, exert their biological functions on the gastrointestinal tract by activating two types of cannabinoid receptors, cannabinoid type 1 receptor (CB1 receptor) and cannabinoid type 2 receptor (CB2 receptor). While CB1 receptors are located in the enteric nervous system and in sensory terminals of vagal and spinal neurons and regulate neurotransmitter release, CB2 receptors are mostly distributed in the immune system, with a role presently still difficult to establish. Under pathophysiological conditions, the endocannabinoid system conveys protection to the GI tract, eg from inflammation and abnormally high gastric and enteric secretion. For such protective activities, the endocannabinoid system may represent a new promising therapeutic target against different GI disorders, including frankly inflammatory bowel diseases (eg, Crohn's disease), functional bowel diseases (eg, irritable bowel syndrome), and secretion- and motility-related disorders.

PMID: 16751708 [PubMed - in process]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16751708&query_hl=1&itool=pubmed_docsum

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New IBS drug in development in Japan new
      #272682 - 07/05/06 05:13 PM
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TOKYO, July 3 (Reuters) - Astellas Pharma , Japan's third-biggest drug maker, said on Monday it would give highest development priority to three new medicines.

Newly appointed president Masafumi Nogimori told a news conference on the company's research and development that Astellas will aim for speedy development of YM060 to treat irritable bowel syndrome, YM150 to prevent thromboembolism and YM311 treatment of renal anaemia and anaemia of cancer.

YM060, which the company sees as more effective in diarrhoea and lower bowel symptoms than competitors' products, is being filed for approval in Japan and is in phase II trials in Europe.


http://today.reuters.com/stocks/QuoteCompanyNewsArticle.aspx?view=CN&storyID=2006-07-03T095411Z_01_T136312_RTRIDST_0_HEALTH-JAPAN-ASTELLAS.XML&rpc=66

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Doctors group launches war on drug ads new
      #274351 - 07/17/06 11:17 AM
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Doctors group launches war on drug ads

American Medical Association seeks waiting period for FDA approval before marketing new prescriptions, devices to public.

By BLYTHE BERNHARD
The Orange County Register


Dr. Melvyn Sterling, internist practicing in Orange
"The reason those ads are there is to sell the drug, not to educate the public."


If there's an ailment, there's an ad for a prescription drug aimed at fighting it – from toe fungus to impotence.

Prescription drug advertising has swelled to a $4.8 billion industry since the U.S. Food and Drug Administration relaxed its restrictions on the ads in 1997, allowing for descriptions of the drugs' purpose. Many doctors say the ads are coming so fast that they don't have time to learn about the benefits and risks of a new drug before patients start requesting prescriptions.

Last month, the American Medical Association asked the FDA to impose a waiting period before new drugs and devices can be marketed to consumers.

"Doctors just want to make sure they have a chance to get up to speed on new drugs before the patients are being urged to seek these medications because of heavy advertising," said Dr. Ron Davis, the association's president-elect.

The ads can disrupt the patient-doctor relationship and contribute to risinghealth-care costs when patients insist on receiving new, more expensive drugs, said Davis, who works in the Henry Ford Health System in Detroit.

The drug industry's lobby, Pharmaceutical Research and Manufacturers of America, is opposed to a mandatory waiting period for drug ads. The lobby has voluntary guidelines encouraging drug companies to educate doctors and submit ads to the FDA for approval.

In response to the medical association's ruling, the lobby released a statement that reads, in part:

"Direct-to-consumer advertising provides doctors and patients with accurate, educational information about disease and treatment options."

Davis acknowledged that drug advertising can raise awareness and encourage communication between doctors and patients, but added that tighter regulations are necessary.

"We hope that the FDA will step forward and show leadership in this area," Davis said. "If that doesn't happen then legislation may be needed to make it a requirement."

Dr. Melvyn Sterling, an internist who practices in Orange, attended the medical association meetings that led to the policy changes. He said people should consider the source when reading or watching drug ads.

"The reason those ads are there is to sell the drug, not to educate the public," Sterling said.

And the ads aren't just coming in magazines and television.

A local pharmaceutical company, Valeant, flies a yellow banner off its Costa Mesa building: "New Zelapar orally disintegrating tablets. Now FDA approved!" The banner doesn't mention what the drug is used for (Parkinson's disease).

Officials for Valeant did not respond to requests for comment for this story. Irvine pharmaceutical company Allergan, which markets wrinkle smoothers and dry eye treatments in magazines, also did not respond.

Drug safety is another reason doctors are hoping for an advertising moratorium. Clinical drug trials sometimes are conducted with too few subjects for serious side effects to show up.

One famous example – the heavily promoted arthritis pill Vioxx – was later recalled because of a serious risk of heart attacks and strokes.

Patients should be aware of safer, cheaper alternatives, doctors said.

"A patient with arthritis should typically be given a trial on regular aspirin," Davis said. "The ads sometimes are for very expensive drugs when there are much less expensive drugs available that the patient should try first … A lot of patients are looking for that magic pill. "

It's not just new drugs for old ailments that concern doctors. Drugs are marketed for conditions that a few years ago didn't have a name: irritable bowel syndrome, restless leg syndrome and female sexual dysfunction, among others. Depending on the marketing, "SAD" can mean seasonal affective disorder or social anxiety disorder.

"To market a drug, it's best to market a disease," said Dr. John Abramson, author of "Overdo$ed America" and a clinical instructor at Harvard Medical School. "Much of the advertising is convincing people that they need drugs when often they don't need drugs, or what's being treated is ordinary, regular life."

Abramson said a moratorium on new drug advertising is a good first step, but that it's getting harder for doctors to find objective information on drugs.

Drug companies sponsor most of the clinical trials that appear in the doctors' medical journals, often next to ads for the drugs.

"There's now much, so much commercial influence that doctors aren't able to get the unbiased, non-commercial scientific truth," he said.

http://www.ocregister.com/ocregister/money/homepage/article_1203782.php

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Marijuana eases chronic pain new
      #274356 - 07/17/06 11:49 AM
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Marijuana eases chronic pain, study finds

Cannabis extract from marijuana gives powerful relief for chronic pain, and should be studied for future clinical use, a medical researcher has told a conference in Glasgow.

Dr William Notcutt of the James Paget Hospital in Great Yarmouth, England, said the cannabis extract used in his study - applied as a spray under the tongue - was remarkably effective in easing chronic pain. He announced the findings at the annual meeting of the British Association for the Advancement of Science.

"The cannabis extracts can produce high-quality pain relief, symptom control, and improvement in the quality of life, without significant side effects," said Dr Notcutt.

He tested cannabis extracts collected from cloned plants, in 23 sufferers of chronic pain.

Subjects were mostly patients with multiple sclerosis or spinal injury. Nine had used marijuana regularly in the past, while the remainder were 'naďve': they had either not used it at all, or had tried it infrequently.

The cannabinoid extract was given over eight weeks, and participants' pain levels monitored. Asked to rate their improvement in pain relief on a scale from one to 10, the majority rated it at "between 9 and 10".

Without their knowledge, a placebo was introduced during the trial, and later replaced with cannabinoid. When the extract was removed, pain levels shot up 20 to 30 per cent, and subsequently dropped off once the extract was again provided.

Dr Notcutt said subjects reported improvements ranging from 'life-changing' to allowing them to get a good night's sleep. One subject had returned to work; others had started driving, gardening and caring for children again.

In all, 17 of the 23 subjects found the extract useful in reducing pain. Of the remainder, three said it had little or no effect, two disliked the euphoria produced, and one was withdrawn from the program due to 'protocol violations'.

Previous anecdotal reports from multiple sclerosis patients have suggested that smoking cannabis has a beneficial effect. Dr Notcutt said he was interested in establishing if this was true, whether there were any side effects and what appropriate dosages might be.

Although cannabis use is illegal in most countries, some multiple sclerosis and cancer patients have been lobbying to legalise its medicinal use, particularly in Britain and the United States.

Despite his positive results, however, Dr Notcutt said more research was needed before scientists could recommend cannabis as a treatment.

"I think it's too early - we need a lot more basic information on just on how to use the drug," he told reporters. He decried the fact that, because of its status as a prohibited substance, very little is known about its pain-relieving properties.

"What we're trying to do is study it in depth, get a lot of information. What is going on, what are the effects on individual patients?"

Notcutt did the study in his own time, with cannabis extract supplied by GW Pharmaceuticals, a company licensed by the British government to grow and supply cannabis for medical research.

He said the use of cannabis extracts for pain alleviation could pave the way for the drug to be used for other conditions, including rheumatoid arthritis, epilepsy and cancer.

Studies in Europe suggest that 18 per cent of people suffer chronic pain, defined as pain that lasts six months or more.

Wilson da Silva - ABC Science Online

http://www.abc.net.au/science/news/health/HealthRepublish_358716.htm

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Citalopram (Celexa) Improves Symptoms of Irritable Bowel Syndrome new
      #286472 - 10/14/06 12:57 PM
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Citalopram Improves Symptoms of Irritable Bowel Syndrome

News Author: Laurie Barclay, MD
CME Author: Charles Vega, MD, FAAFP


Citalopram improves the symptoms of irritable bowel syndrome (IBS), according to the results of a placebo-controlled crossover trial reported in the August issue of Gut.

"Selective serotonin reuptake inhibitors (SSRIs) are frequently used in the treatment of IBS, although evidence of their efficacy is scarce," write J. Tack, MD, from the University of Leuven in Belgium, and colleagues. "Recently, we demonstrated that administration of the SSRI citalopram in healthy subjects decreases the sensitivity of the colon to distension and inhibits the colonic response to feeding. These observations may provide a rationale for use of citalopram in the treatment of IBS."

At a tertiary care center, 23 patients without depression and with IBS were recruited from and included in this crossover trial comparing 6 weeks of treatment with the SSRI citalopram (20 mg daily for 3 weeks and 40 mg daily for 3 weeks) with placebo. The primary outcome measure was IBS symptom severity, and depression and anxiety scores were also recorded. As a hypothesized predictor of symptomatic response to the drug, the effect of acute administration of citalopram on colonic sensitivity and on colonic response to feeding was evaluated.

Compared with placebo, citalopram significantly improved abdominal pain, bloating, impact of symptoms on daily life, and overall well-being after 3 and 6 weeks of treatment. However, there was only a modest effect on stool pattern, and changes in depression or anxiety scores were not related to symptom improvement. The effect of acute administration of citalopram during a colonic barostat study did not predict clinical response to the drug. Analysis of the first treatment period as a double-blind, parallel-group study confirmed that citalopram was significantly more beneficial than placebo.

"The SSRI citalopram significantly improves IBS symptoms, including abdominal pain, compared with placebo," the authors write. "The therapeutic effect is independent of effects on anxiety, depression, and colonic sensorimotor function."

Study limitations include criticisms of the crossover design, selection of patients from a tertiary care center only, and inability to determine the mechanism underlying the beneficial effect of citalopram.

"Based on the present study, the SSRI citalopram is a potentially valuable addition to our therapeutic options in IBS," the authors conclude. "Citalopram provided symptomatic benefit of rapid onset, was well tolerated, and was not associated with the side effects of tricyclic antidepressants, such as drowsiness or constipation.... Larger scale studies will be required to study the efficacy of citalopram or other SSRIs in the IBS patient population seen in primary practice and in secondary care."


Gut. 2006;55:1095-1103.


http://www.medscape.com/viewarticle/541393

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Antibiotic Rifaximin Appears Safe and Effective for Irritable Bowel Syndrome new
      #288017 - 10/26/06 10:29 AM
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Rifaximin Appears Safe and Effective for Irritable Bowel Syndrome

NEW YORK (Reuters Health) Oct 16 - Treatment with the nonabsorbed oral antibiotic rifaximin for 10 days can improve the symptoms of irritable bowel syndrome (IBS) for up to 10 weeks, findings from a small study suggest.

Previous reports have suggested that alterations in gut flora, primarily bacterial overgrowth, may influence the pathogenesis of irritable bowel syndrome. Therefore, treatment with agents that modify this flora might have an effect on disease outcomes, Dr. Mark Pimentel, from the Cedars-Sinai Medical Center in Los Angeles, and colleagues note in the Annals of Internal Medicine for October 17.

Neomycin therapy has proven useful in reducing IBS symptoms, but the bacterial overgrowth elimination rate is just 25%. By contrast, rifaximin, which has broad-spectrum activity, has been shown to achieve rates as high as 70%.

The present study involved 87 patients with IBS who were randomized to receive rifaximin 400 mg or placebo three times daily for 10 days. In addition to completing IBS-related questionnaires before and 7 days after treatment, the subjects kept weekly symptom diaries for 10 weeks.

Patients treated with rifaximin experienced significantly greater improvements in IBS symptoms than did controls (p = 0.02). This primarily related to a drop in bloating as no major differences were noted between the groups in abdominal pain, diarrhea, or constipation.

Rifaximin was generally well tolerated and was associated with only rare, minor side effects that occurred with similar frequency in the control group.

"The clinical challenge is to identify the subset of patients with IBS who are most likely to have bacterial overgrowth that produces symptoms relative to the many other factors contributing to patients' clinical state," Dr. Douglas A. Drossman, from the University of North Carolina at Chapel Hill, comments in a related editorial.

"Pimentel and colleagues should be congratulated for their efforts to increase awareness of this important subgroup of patients with IBS symptoms who need to be identified and treated. However, until better evidence is available, decisions relating to diagnosis and treatment remain within the art of medicine," he adds.

Ann Intern Med 2006;145:557-563,626-628.


http://www.medscape.com/viewarticle/546127

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Rifaximin vs Placebo in Reducing Symptoms in Adults With IBS new
      #291305 - 11/26/06 02:39 PM
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Efficacy of Rifaximin vs Placebo in Reducing Symptoms in Adults With IBS


David A. Johnson, MD, FACG, FACP

The Effect of a Nonabsorbed Oral Antibiotic (Rifaximin) on the Symptoms of the Irritable Bowel Syndrome: A Randomized Trial
Pimentel M, Park S, Mirocha J, Kane SV, Kong Y

Ann Intern Med. 2006;145:557-563

Summary
Irritable bowel syndrome (IBS) is a prevalent condition that has been labeled as a "functional bowel disorder." By this delineation, its cause has been thought to be indefinable. The primary symptoms of this disorder include constipation, diarrhea, abdominal bloating, and cramping. Recent attention has focused on a potential infectious component of IBS.

In this study, Pimental and colleagues investigated the use of rifaximin in patients diagnosed with IBS as defined by the Rome I criteria. Rifaximin is a nonabsorbable, gut-selective antibiotic derived from the rifamycin family that may reduce bacterial overgrowth due to its broad-spectrum activity in vitro against gram-positive, gram-negative, aerobic, anaerobic, and microaerophilic bacteria.

This was a prospective, double-blind randomized controlled trial that involved 43 patients who received 400 mg of rifaximin 3-times daily and 44 who received placebo for 10 days. Patient symptom and stool diaries were completed prior to entry, during the study, and the week following treatment.

Global improvement was found to vary widely across weeks for most patients, and the data were reported as an averaging of the symptoms over all 10 weeks of the study. This percentage was significant as a function of group (P = .020), but not as a function of week (P = .78) or group-by-week (P = .96). The patients in the rifaximin group had a 36.4% improvement in global symptoms compared with 21.0% for the placebo group.

The rifaximin group also reported significantly less bloating on a visual analog scale compared with the placebo group (P = .010), a difference that persisted after controlling for differences between groups in baseline pain scores (P = .001). Besides bloating, none of the secondary endpoints improved with treatment compared with placebo on the visual analog scale: abdominal pain (P = .32), diarrhea (P = .67), and constipation (P = .069).

Viewpoint
Rifaximin is currently US Food and Drug Administration-approved for the treatment of traveler's diarrhea, although these study findings suggest a more expanded potential role for this antibiotic. However, before recommending widespread globalized use of this medication for all patients with IBS, healthcare providers should be aware of several limitations of this study. First, although this was a "multicenter study," there was a considerable imbalance between enrollment from the 2 study sites (83 participants vs 3 participants). Second, because the global measure includes pain, it is important to note that there was an imbalance in baseline pain scores between the 2 patient groups at entry. The imbalance (higher baseline pain scores in the rifaximin group) potentially favors the reduction in the global scores. Additionally, this primary outcome measure is unique in the spectrum of the recent treatment intervention evaluations for IBS trials, and therefore makes comparisons with other trials somewhat difficult. Third, the study authors relied solely on the use of the lactose breath test to define small bowel bacterial overgrowth. Future tests in this area should evaluate the use of other breath tests to define bacterial overgrowth in the small intestine. Fourth, the data suggest that rifaximin may be of more help in the subset of patients with bloating. In IBS, abdominal bloating is reported in more than 50% of patients, and a recent study suggests that changes in abdominal girth can reach 12 cm in more than 50% of patients.[1]

Clearly, this study highlights a new concept in the potential pathogenesis of IBS. An infectious cause may offer a tremendous opportunity to manage an otherwise somewhat frustrating disease -- both for patients and their treating physicians.

Abstract

References
Houghton LA, Lea R, Agrawal A, Reilly B, Whorwell PJ. Relationship of abdominal bloating to distention in irritable bowel syndrome and effect of bowel habit. Gastroenterology. 2006;131:1003-1010.


David A. Johnson, MD, FACG, FACP, Professor of Medicine, Chief of Gastroenterology, Eastern Virginia School of Medicine, Norfolk, Virginia


David A. Johnson, MD, FACG, FACP, has disclosed that he has received grants for clinical research from AstraZeneca, TAP, Wyeth, Novartis, and Abbott, and grants for educational activities from AstraZeneca and Novartis. Dr. Johnson has also disclosed that he has served as an advisor or consultant to AstraZeneca, TAP, and Novartis.


Medscape Gastroenterology. 2006;8(2) ©2006 Medscape

http://www.medscape.com/viewarticle/547055?src=mp

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Enteric Bacteria and IBS new
      #291306 - 11/26/06 02:51 PM
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Advances in Functional Gastrointestinal Disorders -- Enteric Bacteria and IBS


Brooks D. Cash, MD, FACP, FACG
Las Vegas, Nevada; Monday, October 23, 2006 --

The functional gastrointestinal disorders (FGIDs), chief among them the irritable bowel syndrome (IBS), are extremely common reasons for seeking healthcare and can be extremely frustrating to patients and clinicians because of the lack of a reliably identifiable pathophysiologic etiology and an even less reliable response to therapy. Considered by many as heterogeneous disorders with a variety of organic and psychological causes, the FGIDs have been the topic of a great deal of groundbreaking research and clinical developments over the last several years. In IBS, organic abnormalities such as abnormal serotonin signaling and homeostasis, altered densities of inflammatory cells and humoral inflammatory mediators, and disturbed visceral proprioception and central processing of pain have all been demonstrated in select groups of patients. More recently, significant attention has been directed toward clarifying the role of intestinal bacteria in the evolution of IBS symptoms. The recognition of postinfectious IBS as a common sequel of acute infectious gastroenteritis,[1] in addition to data demonstrating prevalence values of small intestinal bacterial overgrowth (SIBO) between 30% and 70% in patients with IBS, is driving forward research into the fields of probiotic therapy as well as antibiotic therapy to ease IBS symptoms.[2,3] This report highlights the research in this area, as presented on Monday, October 23, 2006, at the annual scientific meeting of the American College of Gastroenterology (ACG).

Diagnosing SIBO in IBS

The typical methods involved in diagnosing SIBO are breath-test measurements of expired gases after a sugar load (most commonly glucose or lactulose) or small bowel fluid aspiration and culture. The prevalence of SIBO diagnosed via breath testing rages from 10% to as high as 84% in the literature.[4,5] Breath testing can be difficult to perform because of the strict requirements for patient compliance and, in the case of glucose breath testing, variability in the absorption of glucose. Similarly, the gold standard, jejunal aspirate and culture, is limited by the invasiveness of the procedure and the anatomic extent of aspirating tube advancement, usually to the proximal 40-60 cm of the small intestine. Several investigators reported their experience with each of these diagnostic techniques during this year's ACG meeting. Bratten and colleagues[6] from Northwestern University in Chicago, Illinois, performed lactulose breath testing (for hydrogen [H+] and methane [CH4+]) in 175 patients with IBS and 23 non-IBS controls. They found that 21% (37/175) of the IBS patients produced CH4+ compared with 9% (2/23) of controls (P = .16). They also found that patients who had CH4+-positive breath tests were more than twice as likely as CH4+-negative IBS patients to have constipation as their predominant stool pattern (odds ratio [OR] = 2.61; 95% confidence interval [CI]: 1.24-5.54; P = .01) and were significantly less likely to have diarrhea (OR = 0.28; 95% CI: 0.13-0.63; P = .001). The observation that CH4+-positive breath tests correlate with constipation has been made by other investigators, but the mechanisms underlying the association between CH4+ and constipation remain poorly understood.[7]

Ruff and colleagues[8] from the Mayo Clinic College of Medicine in Rochester, Minnesota, reported the results of a retrospective analysis of clinical parameters and results of duodenal aspirate culture in 690 patients. Using the criteria of > 100,000 colony-forming units (cfu)/mL of aspirate for the diagnosis of SIBO, these investigators failed to detect an increased prevalence of SIBO in patients with diagnosed IBS or the symptom of bloating. These results contrast with previous reports using less restrictive cfu/mL criteria for the diagnosis of SIBO, and should be viewed cautiously. Potential pitfalls in this analysis include that many of the patients were taking narcotics, a systematic program of aspiration in patients with IBS was not undertaken, and the duodenal aspirates may not be adequate to rule out distal SIBO.

Bacterial Overgrowth -- Is it Hype or Hope?

During a clinical symposium convened during this year's ACG meeting, leading experts in the field addressed issues surrounding the diagnosis of SIBO and the use of antibiotics and probiotics.[9-11] Dr. Jack DiPalma[9] opened the symposium with a discussion of bacterial overgrowth. He highlighted some of the clinical conditions that predispose patients to bacterial overgrowth, such as postsurgical states, age extremes, and motility abnormalities, as well as the symptoms of overgrowth such as chronic diarrhea, malabsorption, and nutrient deficiencies. He touched on the various diagnostic tests for bacterial overgrowth and identified the best predictive factors among these tests: fasting elevations in H+ or CH4+, a positive 14C D-xylose test, or jejunal culture with > 105 cfu/mL. Dr. DiPalma also discussed the well-known limits of the so-called "gold standard" of small bowel fluid aspiration and culture, which include the invasive nature of the test, oral floral contamination, culture transport difficulties, limited access to the distal small bowel, and the unclear relevance of colonization in the elderly. He concluded by reviewing the ideal testing measures that should be present when testing for bacterial overgrowth. These include measuring both H+ and CH4+, using a standard dose of breath-test substrate, confirming the fasting state of patients undergoing testing when fasting elevations are found during fructose or glucose testing, and the need to test before a colon cleansing (or waiting for at least 30 days after a colon cleansing to test).

Dr. Lawrence Schiller[10] followed with a discussion of prebiotics and probiotics. It is interesting to note that there are more than 1015 bacteria in the human gut, of which 500 different species have been identified and one third have been cultured. In comparison, the average human body contains approximately 1014 cells. The bacteria have been selected, through the innate immune system (that part of the immune system that responds to immunogenic patterns rather than specific antigens), to coexist in the gut and provide for enterocyte nutrients, vitamin production, defense against pathogenic bacteria, and to modulate mucosal inflammation and permeability. Prebiotics are substances that can be ingested and which foster bacterial growth, and include fructo-oligosaccharides, inulin, and lactulose. Very few data exist regarding the role of prebiotics as therapies for IBS. The probiotics are live organisms that can be ingested for health benefits, but there is little theoretical basis for the selection of particular strains of probiotics, and the exact contributions of probiotics to intestinal health are unknown. Examples of probiotics include Lactobacillus and Bifidobacterium species and Escherichia coli Nissle 1917. Yeasts such as Saccharomyces species can also be used as probiotic therapy. Potential mechanisms of action for probiotics include displacement of pathogens, enhancement of bacterial function, and modification of signaling. Although complications of probiotic therapy are rare and some mixtures have been reported to improve IBS symptoms, many unanswered questions remain. These include whether live organisms need to be ingested, whether enteric colonization occurs, the ideal duration of therapy, and what biochemical signatures are most predictive of treatment success.

Dr. Mark Pimentel[11] concluded the symposium with a discussion of the rationale for the use of antibiotics in IBS. He eloquently presented the evidence for the role of enteric bacteria in the etiology of IBS symptoms and how intrinsic or extrinsic factors can produce alterations in the normal motility pattern of the gut, leading to abnormal levels of enteric bacteria which then induce inflammation and/or further alterations in gut function through the elaboration of H+ and/or CH4+. Dr. Pimentel then reviewed the evidence supporting the use of antibiotics, often in combination with promotility agents such as tegaserod, for the effective treatment of IBS. The promotility agents are used to promote more effective peristalsis and intestinal stripping waves and may have a role in preventing recurrence, although this concept has not been studied rigorously. When used for this purpose, tegaserod is usually administered at a lower dose (2 mg) and in a fasting state (every night at bedtime) rather than the standard regimen used in the settings of IBS with constipation and chronic constipation (6 mg twice daily) in order to minimize potential motility-related side effects such as diarrhea. Although it is clear that there is much that we do not know regarding the role and effects of modulation of the enteric flora in patients with IBS, this is a very exciting corner of the IBS world and additional data are eagerly awaited.

One of the overarching concerns surrounding the use of probiotics is their safety. In another abstract presented during this meeting, Adler and colleagues[12] reported results of a safety study evaluating the effects of the probiotic E coli strain M-17 in 138 healthy individuals. Subjects ingested 120 mL/day of E coli strain M-17 every day for 8 weeks, a dose that represents a 10-fold increase over standard dosing regimens. The M-17 was generally well tolerated, with associated adverse events seen in 6.5% of patients, most of which were mild. Multiple laboratory parameters were followed, and although there were some changes from baseline, all laboratory values remained within normal limits. Additional clinical data reflecting effects on symptoms in patients with IBS are eagerly awaited.

Concluding Remarks
The field of FGIDs continues to generate meaningful and important research. Emerging data surrounding the role of enteric bacteria in the origin of IBS symptoms are among the hottest topics in this field. During this year's ACG meeting, excellent overviews and original research were presented regarding the yield of diagnostic maneuvers for the detection of SIBO and the various treatment approaches to IBS involving the manipulation of the intestinal flora; such data will no doubt add to this controversial growing body of literature.

References
Halvorson H, Schlett CD, Riddle MS. Postinfectious irritable bowel syndrome--a meta-analysis Am J Gastroenterol. 2006;101:1-6.
Whorwell PJ, Altringer L, Morel J, et al. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol. 2006;101:1581-1590. Abstract
Pimentel M, Park S, Mirocha J, et al. The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med. 2006;145:557-563. Abstract
Harris LA, Crowell MD, DiBaise JK, et al. Is small intestinal bacterial overgrowth (SIBO) really prevalent in irritable bowel syndrome (IBS)? Am J Gastroenterol. 2005;100:S336.
Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. a double-blind, randomized, placebo-controlled study. Am J Gastroenterol. 2003;98:412-419. Abstract
Bratten J, Spanier J, Jones MP Lactulose hydrogen breath testing (LHBT) in patients with IBS and controls: differences in methane (CH4) but not hydrogen (H2). Am J Gastroenterol. 2006;101;S479. [Abstract 1236]
Pimental M, Lin H, Enayati P, et al. Methane, a gas produced by enteric bacteria, slows intestinal transit and augments small intestinal contractile activity. Am J Physiol Gastrointest Liver Physiol. 2006;290:G1089-G1095. Abstract
Ruff KC, Saio-Loftus YA, Locke GR, et al. Failure to detect association with irritable bowel syndrome (IBS) and small intestinal bacterial overgrowth (SIBO). Am J Gastroenterol. 2006;101;S486. [Abstract 1261]
DiPalma JA. Diagnosis and treatment of bacterial overgrowth. In: ACG Clinical Symposium: Bacterial Overgrowth: Hype or Hope. Program and abstracts of the American College of Gastroenterology 2006 Annual Scientific Meeting and Postgraduate Course; October 20-25, 2006; Las Vegas, Nevada.
Schiller LR. Prebiotics and probiotics. In: ACG Clinical Symposium: Bacterial Overgrowth: Hype or Hope. Program and abstracts of the American College of Gastroenterology 2006 Annual Scientific Meeting and Postgraduate Course; October 20-25, 2006; Las Vegas, Nevada.
Pimentel M. IBS: Is SBO really a factor? In: ACG Clinical Symposium: Bacterial Overgrowth: Hype or Hope. Program and abstracts of the American College of Gastroenterology 2006 Annual Scientific Meeting and Postgraduate Course; October 20-25, 2006; Las Vegas, Nevada.
Adler SN, Jacob H, Levine L. An open label, high dose prospective trial of the safety of the probiotic E. coli strain M-17 in healthy volunteers. Am J Gastroenterol. 2006;101:S134. [Abstract 273]




Copyright © 2006 Medscape.

http://www.medscape.com/viewarticle/546502

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Neuromuscular Dysfunction and IBS: Clinical Implications for Drug Use new
      #298897 - 02/04/07 04:30 PM
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Neuromuscular Dysfunction and IBS: Clinical Implications
Brooks D. Cash, MD, FACP, FACG

Conclusion
The heterogeneity in the pathogenesis of IBS creates unique challenges when designing and assessing the efficacy of novel therapies. As our knowledge continues to evolve regarding the various factors that may play a role in causing symptoms of IBS, so too will our approach to designing effective therapies. For the foreseeable future, it is unlikely that there will be a "magic bullet" for IBS sufferers. Given our current level of understanding, the practice of subgrouping IBS patients on the basis of predominant bowel pattern is a good first step, but clearly it is not the final answer to defining which drugs will be most effective for which patients. As the process of new drug discovery proceeds, emphasis should be placed not only on how often or how much a drug improves global and individual symptoms in IBS sufferers, but also on ways in which the clinician can identify the subset of patients most likely to benefit from a specific drug. This strategy will not only allow the clinician to more effectively treat his/her patients, but should allow scientists to add further pieces to the ever evolving puzzle of IBS.

http://www.medscape.com/viewarticle/548600_4

Medscape Gastroenterology. 2006;8(2) ©2006 Medscape

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Antidepressant Therapy (Imipramine and Citalopram) for Irritable Bowel Syndrome new
      #309446 - 06/20/07 01:56 PM
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Dig Dis Sci. 2007 May 15;

Antidepressant Therapy (Imipramine and Citalopram) for Irritable Bowel Syndrome: A Double-Blind, Randomized, Placebo-Controlled Trial.

Talley NJ, Kellow JE, Boyce P, Tennant C, Huskic S, Jones M.
Department of Medicine, Nepean Hospital, University of Sydney, Sydney, NSW, Australia.

BACKGROUND: The efficacy of antidepressants in irritable bowel syndrome (IBS) is controversial. No trials have directly compared a tricyclic with a selective serotonin reuptake inhibitor. Our aim was to determine whether imipramine and citalopram are efficacious in IBS.

METHODS: This was a randomized, double-blind, placebo-controlled, parallel group pilot trial with imipramine (50 mg) and citalopram (40 mg).

RESULTS: Of 51 IBS patients randomized, baseline characteristics were comparable among the treatment arms; the majority was diarrhea-predominant. Adequate relief of IBS symptoms (primary endpoint) was similar for each treatment arm. Improvements in bowel symptom severity rating for interference (P = 0.05) and distress (P = 0.02) were greater with imipramine versus placebo, but improvements in abdominal pain were not. There was a greater improvement in depression score (P = 0.08) and in the SF-36 Mental Component Score (P = 0.07), with imipramine. Citalopram was not superior to placebo. Approximately 20% of the variance in scores was explained by treatment differences for abdominal pain, bowel symptom severity disability, depression and the mental component of the SF-36.

CONCLUSION: Neither imipramine nor citalopram significantly improved global IBS endpoints over placebo.

PMID: 17503182 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17503182&ordinalpos=40&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

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FDA permits the restricted use of Zelnorm new
      #312922 - 08/09/07 11:41 AM
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Under an investigational new drug protocol program, restricted use of tegaserod maleate has been approved to benefit certain patients who have no other treatment options. Under the protocol, tegaserod may only be used to treat irritable bowel syndrome with constipation and chronic idiopathic constipation in women younger than 55 years who have had no satisfactory response to other available treatments or had satisfactory improvement of symptoms during prior tegaserod therapy.

Key exclusion criteria for tegaserod use include a history or current diagnosis of cardiovascular ischemic disease, symptoms suggestive of cardiovascular ischemic disease, the presence of any cardiovascular risk factors according to National Institutes for Health guidelines, and uncompensated depression or anxiety or suicidal ideation or behavior. Tegaserod will remain off the market for general use.

http://www.fda.gov/cder/drug/infopage/zelnorm/default.htm



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Role of Antibiotics vs Conventional Pharmacotherapy in Treating Symptoms of Irritable Bowel Syndrome new
      #321612 - 01/03/08 04:45 PM
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Review Article: The Role of Antibiotics vs Conventional Pharmacotherapy in Treating Symptoms of Irritable Bowel Syndrome

C. L. Frissora; B. D. Cash

Conclusion: Antibiotics are an emerging therapeutic option for IBS, and many questions surrounding the exact role of enteric bacteria in the diagnosis and management of IBS remain unanswered. Results to date suggest that appropriately targeted antibiotic therapy may offer important benefits as an alternative to, or in addition to, symptom-directed pharmacotherapies in the treatment of IBS. Clear demonstration of superiority of one treatment approach over another will require a suitably designed, randomized, placebo-controlled trial. Given the breadth of the IBS symptom spectrum and current limitations in symptom-directed therapies related to adverse effects and blinding, it is unlikely that such a trial will be conducted. More likely, continued reports of efficacy with directed antibiotic therapy in patients with symptoms consistent with IBS or other functional GI disorders will lead to the complementary use of these medications in a stepwise or combined fashion. The potential benefit of antibiotics in diminishing the need for chronic daily pharmacotherapy or reducing the frequency of repeated courses of therapy in IBS warrants additional exploration.

Aliment Pharmacol Ther. 2007;25(11):1271-1281. ©2007 Blackwell Publishing


http://www.medscape.com/viewarticle/557851_4

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Clinical trial: phase 2 trial of lubiprostone for irritable bowel syndrome with constipation. new
      #324814 - 02/15/08 11:20 AM
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Aliment Pharmacol Ther. 2008 Jan 28 [Epub ahead of print] Links
Clinical trial: phase 2 trial of lubiprostone for irritable bowel syndrome with constipation.Johanson JF, Drossman DA, Panas R, Wahle A, Ueno R.
University of Illinois College of Medicine, Rockford, Illinois, USA.

Background: Analyses of a trial in constipated patients indicated that lubiprostone may be an effective treatment for IBS-C. Aim: To assess efficacy and safety of 3 lubiprostone doses for IBS-C. Methods: 195 IBS-C patients received daily doses of 16 mcg (8 mcg twice daily [BID]), 32 mcg (16 mcg BID), or 48 mcg (24 mcg BID) lubiprostone or placebo BID for 3 months. Gastrointestinal parameters were recorded by patients in daily diaries. Results: After 1 month, lubiprostone showed significantly greater improvements in mean abdominal discomfort/pain scores vs. placebo (p=0.023). After 2 months, all lubiprostone groups showed significantly greater improvements in mean abdominal discomfort/pain scores (p</=0.039). After 3 months of treatment, the improvement in each lubiprostone arm was greater than placebo, but the test for trend was no longer significant. Treatment with lubiprostone showed significantly higher rates of gastrointestinal adverse events (AEs; p=0.020), especially diarrhea and nausea. Conclusion: Lubiprostone significantly improved gastrointestinal symptoms of IBS-C at all doses. Higher doses of lubiprostone, especially the 48 mcg/day group, were associated with more gastrointestinal AEs. From these data, the 16 mcg/day dose demonstrated the optimal combination of efficacy and safety. These results warrant further study of lubiprostone for treatment of IBS-C patients.

http://www.ncbi.nlm.nih.gov/pubmed/18248656?ordinalpos=19&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

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Zelnorm no longer available except for emergency use new
      #328130 - 04/11/08 12:05 PM
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Zelnorm (tegaserod maleate) Information


Novartis, the manufacturer of Zelnorm, has notified the FDA that they will no longer provide Zelnorm (tegaserod maleate) under a treatment investigational new drug application (T-IND) protocol to treat irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) in women younger than 55.

Novartis has agreed to continue to supply Zelnorm for use in emergency situations. Requests for Zelnorm for this purpose may be made to the FDA which in turn authorizes shipment of the drug by the manufacturer.

An emergency situation is defined as one that is immediately life-threatening or serious enough to qualify for hospitalization. FDA may deny authorization, even in life-threatening situations, if available evidence fails to provide a reasonable basis for concluding that Zelnorm may be effective for the intended use, or if exposure to Zelnorm would pose an unreasonable or a significant additional risk to patients. The following conditions are cause for denial of authorization:

prior history of heart attack or stroke
unstable angina
hypertension
hyperlipidemia
diabetes
age greater than 55 years
smoking
obesity
depression
anxiety
suicidal ideation
Physicians with patients who may qualify for treatment with Zelnorm for emergency use may contact FDA's Division for Drug Information about the emergency IND process at druginfo@fda.hhs.gov.

http://www.fda.gov/CDER/DRUG/infopage/zelnorm/default.htm

Zelnorm History and Information, Plus Safer Alternatives

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FDA Approves Amitiza for IBS-C new
      #330113 - 05/23/08 10:59 AM
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FDA Approves Amitiza for IBS-C

The U.S. Food and Drug Administration today approved Amitiza (lubiprostone) for the treatment of Irritable Bowel Syndrome with Constipation (IBS-C) in adult women aged 18 and over. There is currently no prescription drug therapy for IBS-C. With this approval, Amitiza becomes the only FDA-approved medical treatment for IBS-C available in the United States.

Irritable bowel syndrome is a disorder characterized by cramping, abdominal pain, bloating, constipation, and diarrhea. IBS causes a great deal of discomfort and distress to its sufferers. It affects at least twice as many women as men.

"For some people IBS can be quite disabling, making it difficult for them to fully participate in everyday activities," said Julie Beitz, M.D., director of the Office of Drug Evaluation III, Center for Drug Evaluation and Research, FDA. "This drug represents an important step in helping to provide medical relief from their symptoms."

The safety and efficacy of Amitiza was established in two major studies involving 1,154 patients diagnosed with IBS-C. The majority of the patients studied were women (approximately 8 percent were men). Patients enrolled in the studies were experiencing at least mild abdominal discomfort or pain that was associated with at least two of the following additional symptoms: 1) fewer than 3 spontaneous bowel movements per week (that did not result from laxative use); 2) hard stools; or 3) moderate or severe straining with bowel movements. In the studies some patients received Amitiza and others were given a placebo. More patients treated with Amitiza reported that their IBS symptoms were moderately or significantly relieved over a 12 week treatment period than patients who received placebo. The safety of long term treatment was assessed in a study in which all patients were treated with Amitiza for a duration that ranged 9 to 13 months.

The efficacy of Amitiza in men was not conclusively demonstrated for IBS-C.
Amitiza, like most prescription medications, is accompanied by some side effects. Common side effects of Amitiza include nausea, diarrhea, and abdominal pain. Other rare side effects include urinary tract infections, dry mouth, syncope (fainting), peripheral edema (swelling of the extremities), dyspnea (difficulty breathing), and heart palpitations.

Amitiza should be taken twice-a-day in 8 microgram doses with food and water. Patients and their health care professionals should periodically assess the need for continued therapy.

Amitiza is not approved for use in children and men. It is not to be administered to patients suffering from severe diarrhea or patients with known or suspected bowel obstructions. Its safety and efficacy has not been established in patients with renal or hepatic impairment, pregnant, or nursing mothers.

http://www.fda.gov/bbs/topics/NEWS/2008/NEW01828.html

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Survey: Marijuana Use In Patients With IBS new
      #354453 - 01/12/10 03:17 PM
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Take the survey here http://ibd-cannabis-survey.limequery.com/index.php?sid=63892&newtest=Y&lang=en

The University of Calgary, Canada has a research project about capturing cannabis use in patients with IBS and the attempt to identify patten of use, symptoms that subjectively benefit and side effects, in order to finally capture which patient group may be a target for future clinical trials in this.

As this internet questionnaire is a international approach it will additionally answer whether the presumed effects / pattern vary by regional or cultural factors.

Reports from patients suggest that use of cannabis/marijuana reduces symptoms associated with Irritable Bowel Syndrome (IBS).

We are conducting a study that is assessing the use, the benefits and the side effects of cannabis/marijuana for the self-treatment of irritable bowel syndrome . This questionnaire is directed to all patients with IBS that use cannabis/marijuana for their IBS.

We are asking you to complete the internet based questionnaire. Please make sure that you respond to all questions which may take you approximately 10 minutes.

This research study has been approved by the University of Calgary Conjoint Health Research Ethics Board. You are under no obligation to complete this questionnaire. Your responses to this questionnaire will be kept strictly anonymous.

Thank you for taking the time to read this material and fully respond to the questionnaire.

If you have any questions please contact us at: Cannabis_use_in_IBS@gmx.com


There are 31 questions in this survey.

A note on privacy:

This survey is anonymous.

The record kept of your survey responses does not contain any identifying information about you unless a specific question in the survey has asked for this. If you have responded to a survey that used an identifying token to allow you to access the survey, you can rest assured that the identifying token is not kept with your responses. It is managed in a separate database, and will only be updated to indicate that you have (or haven't) completed this survey. There is no way of matching identification tokens with survey responses in this survey.

Take the survey here http://ibd-cannabis-survey.limequery.com/index.php?sid=63892&newtest=Y&lang=en

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Children's Belly Aches Don't Disappear With Antidepressant new
      #356592 - 03/11/10 01:14 PM
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Children's Belly Aches Don't Disappear With Antidepressant

Elavil worked no better than placebo in study of kids with gastrointestinal disorders

THURSDAY, Oct. 1 (HealthDay News) -- Contradicting some previous research in adults, a new study suggests that the antidepressant amitriptyline (Elavil), is no better than a placebo at treating painful gastrointestinal disorders in children.

"The high placebo effect we identified in this study suggests that further studies of the use of certain antidepressants in children with functional bowel disorders are needed. While several trials have demonstrated a beneficial effect of antidepressants, including amitriptyline, for the treatment of irritable bowel syndrome in adults, more research is needed to determine how effective this drug is, if at all, in children," study author Dr. Miguel Saps of Children's Memorial Hospital in Chicago, said in a news release from the American Gastroenterological Association.

The drug is used to treat depression, but it is sometimes prescribed on an "off-label" basis to children who have certain painful gastrointestinal disorders. The drug is thought to reduce pain, the researchers noted.

"Off label" means that the drug is not federally approved for use to treat a condition. However, doctors can still prescribe it for that purpose.

In the study, 83 children with painful gastrointestinal disorders were randomly assigned to take the drug or a placebo. Of those who took the drug, 63 percent reported feeling better, while 5 percent felt worse. Among those taking the placebo, 57.5 reported feeling better and 2.5 percent felt worse, the study authors reported.

The study findings appear online in advance of publication in an upcoming print issue of the journal Gastroenterology.

"Many pharmaceutical products are prescribed for off-label use in children due to the lack of clinical trials testing the efficacy of the drugs in children and adolescents," Saps explained in the news release. "Therefore, the pediatric gastroenterologist frequently has to make treatment decisions without the evidence of how drugs work in children," he added.

More information

Learn more about abdominal pain in children from the American College of Gastroenterology.



-- Randy Dotinga



SOURCE: American Gastroenterological Association, news release, Oct. 1, 2009

http://healthday.com/Article.asp?AID=631484

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Adverse effects of drugs on small intestine and colon new
      #356744 - 03/16/10 11:23 AM
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Clinical Gastroenterology, Volume 24, Issue 2, Pages 133-141 (April 2010)
ABSTRACT

Adverse effects of drugs on small intestine and colon

Zeino Zeino, Guy Sisson, Ingvar Bjarnason

The small and large intestine are one of the most common sites for the adverse action of drugs, accounting for 20–40% of all drug side effects. The most important factor in the diagnosis of drug-induced intestinal side effect is awareness.

The mechanisms of damage are invariably complex, but may be due to topical effects, a known pharmacologic action of the drug on motility (for instance cholinergic/anti-cholinergic effect) and/or secretion, immune suppression and in the case of cytotoxic drug treatment a combination of many actions.

The diagnosis of damage may be simple and widely recognised (NSAID-induced enteropathy resulting in bleeding, protein loss and rarely perforation and diaphragm disease), or at other times ignored (tricyclic antidepressants increasing constipation) or life threatening (docetaxene).

Some associations require further research (statin and anti-retroviral associated irritable bowel symptoms). Diagnosis is traditionally made by symptom improvement on discontinuation of the drug. More lately capsule enteroscopy is used to aid diagnosis.

Department of Gastroenterology, King's College Hospital, Denmark Hill, London SE5 9RS, UK


PII: S1521-6918(10)00022-3

doi:10.1016/j.bpg.2010.02.008

© 2010 Elsevier Ltd. All rights reserved.

http://www.bpgastro.com/article/PIIS1521691810000223/abstract?rss=yes

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Benefit/risk ratio of Renzapride not sufficient to warrant further study in IBS-C new
      #357515 - 04/07/10 01:32 PM
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Clinical trial: renzapride treatment of women with irritable bowel syndrome and constipation – a double-blind, randomized, placebo-controlled, study

A. J. LEMBO*, F. CREMONINI*, N. MEYERS† & R. HICKLING†
*Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA, USA ; †Alizyme Therapeutics Ltd, Cambridge, UK


Correspondence to Dr A. J. Lembo, Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Rabb/Rose 1, Boston, MA 02215, USA.


Copyright Journal compilation © 2010 Blackwell Publishing Ltd

Aliment Pharmacol Ther 31, 979–990

ABSTRACT

Background

Renzapride, a 5-hydroxytryptamine type-4 (5-HT4) receptor agonist and 5-HT3 receptor antagonist, has been proposed as a new treatment of irritable bowel syndrome with constipation (IBS-C).

Aim

To assess the efficacy and safety of renzapride in women with IBS-C.

Methods

Women with IBS-C were randomized to renzapride 4 mg daily, 2 mg b.d. or placebo for 12 weeks. The primary outcome measure was global relief of IBS symptoms. A subset of patients were enrolled in a 12-month, open-label study of renzapride 4 mg daily.

Results

A total of 1798 patients were included in the efficacy analysis and 971 patients entered the long-term study. The mean (S.E.M.) number of months with relief of overall IBS symptoms was 0.55 (0.04), 0.60 (0.04) and 0.44 (0.04) in the renzapride 4 mg daily, 2 mg b.d. and placebo groups (P = 0.027 and P = 0.004 respectively). Small yet statistically significant differences in favour of renzapride were observed on stool consistency and frequency, and bloating/abdominal distension scores. Renzapride was generally well tolerated; however, three episodes of ischaemic colitis were reported in the long-term study.

Conclusion

Given the limited increase in efficacy over placebo and the incidence of ischaemic colitis observed, our data suggest that the benefit/risk ratio of renzapride is not sufficient to warrant further study in IBS-C.

Publication data Submitted 9 November 2009 First decision 30 November 2009 Resubmitted 8 February 2010 Accepted 10 February 2010 Epub Accepted Article 16 February 2010

http://www3.interscience.wiley.com/journal/123286564/abstract

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An over-the-counter drug for constipation offers superior symptom relief compared with a commonly used prescription agent new
      #359774 - 07/16/10 03:17 PM
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By Charles Bankhead, Staff Writer, MedPage Today

Published: July 08, 2010

Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Nonprescription treatment for chronic constipation, polyethylene glycol, appears superior to commonly used prescription drug lactulose.

An over-the-counter drug for constipation offers superior symptom relief compared with a commonly used prescription agent, results of a systematic review suggest.

Polyethylene glycol (brand name Miralax) led to greater improvement in stool frequency and form, relief of abdominal pain, and need for additional treatments as compared with lactulose (brand names Enulose, Generlac, Kristalose, Chronulac, Cephulac, Constilac, Cholac, Duphalac, Constulose, Evalose, Heptalac), according to combined data from 10 randomized clinical trials involving more than 850 adults and children.

With the exception of relief of abdominal pain, PEG demonstrated superiority in children and adults alike, authors of the review reported in the Cochrane Database of Systematic Reviews.

"We conclude that polyethylene glycol should be used in preference to lactulose in the treatment of chronic constipation," Heather Lee-Robichaud, MD, of Northern General Hospital in Sheffield, England, and co-authors wrote.

Chronic constipation affects a substantial proportion of adults and children. Owing to the subjective nature of symptoms and lack of consensus about a clinical definition, prevalence estimates range from 2% to 35%, the authors noted.

Numerous factors have been cited as possible causes of chronic constipation, but the etiology remains largely unknown, they continued. Treatment recommendations usually begin with hygienic measures, such as increased physical activity and hydration and dietary modification. If these steps fail to relieve symptoms, patients usually turn to suppositories, laxatives, enemas, and manual evacuation.

Pharmacologic therapy for chronic constipation spans a wide range of prescription and nonprescription agents, which generally have a modest impact on symptoms, owing to the poor understanding of the pathophysiology of chronic constipation, the authors wrote. A group of drugs known collectively as "laxatives" constitute the most common type of drug therapy.

The laxative class includes PEG and lactulose, both of which are osmotic laxatives that work by increasing the amount of water in the large bowel. More than a dozen randomized clinical trials have compared the two agents, but their relative efficacy and cost-effectiveness remain unclear. To address that uncertainty, Lee-Robichaud and co-authors performed a systematic review and meta-analysis of the clinical trials.

A literature search identified 16 randomized comparisons of PEG and lactulose, 10 of which the authors included in their analysis. The trials included children and adults who had chronic constipation by Rome III diagnostic criteria (Gastroenterology 2006; 130: 1480-1491) or fecal impaction. The primary outcome of the analysis was change in stool frequency. Secondary outcomes included need for additional therapies (such as enemas or other types of laxatives), global symptom improvement, and relief of abdominal pain.

The 10 trials included a total of 868 patients, 322 adults and 546 children.

Five trials involving 407 patients compared PEG and lactulose effects on stool frequency. All five studies favored PEG, resulting in a mean treatment effect of 0.65 (0.15 to 1.15) versus lactulose. Separate analyses of children and adults also showed a consistent advantage for PEG, with mean treatment effects of 1.57 for children and 0.28 for adults.

Two trials examined stool form, and both demonstrated superiority for PEG, resulting in a mean treatment effect of 0.89 (0.43 to 1.35). Results were similar for children and adults. The three trials that assessed relief of abdominal pain showed a mean treatment effect of 2.09 in favor of PEG (1.26 to 3.44). The three trials that assessed need for additional products yielded a mean treatment effect difference of 4.00 in favor of PEG (2.01 to 7.95).

Co-author Richard L. Nelson, MD, also of Northern General Hospital, cautioned that drug treatment should be reserved for patients with chronic constipation, not for those who have only occasional episodes. Moreover, the decision to use drug therapy is complicated by the subjective nature of patient symptoms and complaints.

"The border between normal variation and a symptom of disease can be very hazy," Nelson said in a statement.

The authors reported no disclosures.

Primary source: Chochrane Database of Systematic Reviews
Source reference:
Lee-Robichaud H, et al "Lactulose versus polyethylene glycol for chronic constipation" Cochrane Database Syst Rev 2010; DOI: 10.1002/14651858.CD007570.pub2.

http://www.medpagetoday.com/Gastroenterology/GeneralGastroenterology/21063

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Phase 3 clinical trials of linaclotide for IBS constipation new
      #361417 - 10/13/10 02:44 PM
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Ironwood And Forest Announce Positive Linaclotide Results From Phase 3 Trial In Patients With Irritable Bowel Syndrome With Constipation

Article Date: 14 Sep 2010 - 4:00 PDT

Ironwood Pharmaceuticals, Inc. (NASDAQ: IRWD) and Forest Laboratories, Inc. (NYSE: FRX) today announced positive top-line results from the first of two Phase 3 clinical trials assessing the efficacy and safety of the investigational drug, linaclotide, in patients with irritable bowel syndrome with constipation (IBS-C).

Analyses of the data indicate clinically meaningful and statistically significant improvement was achieved for linaclotide-treated patients compared to placebo-treated patients for all four primary efficacy endpoints, which included two composite responder endpoints encompassing abdominal pain and complete spontaneous bowel movements (CSBMs), as well as individual responder endpoints for abdominal pain and CSBMs.

Significant improvement was also achieved for linaclotide-treated patients compared to placebo-treated patients for all pre-specified secondary endpoints, which are measures of abdominal pain, abdominal discomfort, bloating, and bowel symptoms. The safety results were consistent with those observed in previous linaclotide trials, with diarrhea being the most common adverse event in linaclotide-treated patients. A second Phase 3 trial of linaclotide in IBS-C is ongoing with top-line results expected in Q4 2010.

"There are millions of patients suffering from IBS-C and limited treatment options to address both their abdominal pain and bowel symptoms, which were improved in this first clinical study"

"The results of this Phase 3 trial, combined with the previously reported positive IBS-C and chronic constipation trial results, further support our belief that linaclotide has the potential to improve abdominal pain and bowel symptoms, offering a promising treatment for more than 30 million individuals suffering from these chronic gastrointestinal disorders," said Peter Hecht, Chief Executive Officer of Ironwood.

"There are millions of patients suffering from IBS-C and limited treatment options to address both their abdominal pain and bowel symptoms, which were improved in this first clinical study," said Howard Solomon, Chairman and Chief Executive Officer of Forest Laboratories. "These results are very promising. We believe linaclotide will be a valuable treatment for these patients. We look forward to receiving the results of the second pivotal trial in Q4 2010."

This trial, LIN-MD-31, is part of Ironwood and Forest's Phase 3 program investigating the effect of linaclotide treatment on patients with IBS-C or chronic constipation (CC). Previously, Ironwood and Forest reported positive results of two Phase 3 trials in patients with CC. The companies expect to file a New Drug Application in mid-2011 in the United States. The IBS-C trials were designed to also support regulatory submission in Europe. Today, in a separate press release, Ironwood and its European partner, Almirall, announced top line results from LIN-MD-31 for the E.U. endpoints. Trial LIN-MD-31 Primary Efficacy Endpoint Results

http://www.medicalnewstoday.com/articles/200947.php?nfid=79339

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Proton Pump Inhibitor Drugs Tied to 80% Increase in Clostridium difficile Risk new
      #361986 - 11/10/10 11:29 AM
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PPI Use Tied to 80% Increase in Clostridium difficile Risk

By: HEIDI SPLETE, Internal Medicine News Digital Network

SAN ANTONIO – Proton pump inhibitor use was associated with an 80% increase in the risk of Clostridium difficile–associated diarrhea, based on data from a meta-analysis of 21 studies.

Proton pump inhibitors (such as Prilosec or Prevacid) are generally considered safe, resulting in some degree of indiscriminate use, said Dr. Sailajah Janarthanan of Wayne State University in Detroit. PPIs have faced scrutiny for a possible association with C. difficile–associated diarrhea (CDAD), but results from previous studies have yielded mixed results, Dr. Janarthanan said.
increase in the risk of Clostridium difficile–associated diarrhea, an analysis indicates.

"Given the millions of individuals on PPIs, even a slight increase in the risk of CDAD conferred by these drugs will have major public health implications," she emphasized.

To explore the relationship between PPIs and CDAD, Dr. Janarthanan and her colleagues looked at data from 21 peer-reviewed published studies. The 7 cohort studies and 14 case-control studies included 133,054 individuals.

Overall, there was a significant increase in the risk of CDAD in patients taking PPIs (risk estimate, 1.80). The risk estimate in the case-control studies was 1.55 and in the cohort studies 2.07. The CDAD risk was significantly higher for patients taking PPIs whether the types of studies were considered separately or as a whole.

C. difficile represents an escalating threat to public health, and CDAD cost the United States an estimated $3 billion in 2005, Dr. Janarthanan said at the annual meeting of the American College of Gastroenterology.

The results of the studies reviewed by Dr. Janarthanan and her associates were limited by the lack of randomized, controlled trials, she noted, and the impact of PPIs on CDAD remains controversial.

"Indiscriminate use of PPIs without proper indication should be discouraged," she said. "There is a real-time need for guidelines on the use of PPIs, especially in hospitals."

http://www.internalmedicinenews.com/news/gastroenterology/single-article/ppi-use-tied-to-80-increase-in-iclostridium-difficilei-risk/bdda11aa8b.html


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Antiobiotic Rifaximin (Xifaxan) for Patients with Irritable Bowel Syndrome without Constipation new
      #362811 - 01/07/11 02:59 PM
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Reged: 12/09/02
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Rifaximin Therapy for Patients with Irritable Bowel Syndrome without Constipation

Mark Pimentel, M.D., Anthony Lembo, M.D., William D. Chey, M.D., Salam Zakko, M.D., Yehuda Ringel, M.D., Jing Yu, Ph.D., Shadreck M. Mareya, Ph.D., Audrey L. Shaw, Ph.D., Enoch Bortey, Ph.D., and William P. Forbes, Pharm.D. for the TARGET Study Group

N Engl J Med 2011; 364:22-32January 6, 2011

Comments open until January 12, 2011

Abstract
Article
References
Citing Articles (1)
Comments
Background

Evidence suggests that gut flora may play an important role in the pathophysiology of the irritable bowel syndrome (IBS). We evaluated rifaximin, a minimally absorbed antibiotic, as treatment for IBS.

Full Text of Background...
Methods

In two identically designed, phase 3, double-blind, placebo-controlled trials (TARGET 1 and TARGET 2), patients who had IBS without constipation were randomly assigned to either rifaximin at a dose of 550 mg or placebo, three times daily for 2 weeks, and were followed for an additional 10 weeks. The primary end point, the proportion of patients who had adequate relief of global IBS symptoms, and the key secondary end point, the proportion of patients who had adequate relief of IBS-related bloating, were assessed weekly. Adequate relief was defined as self-reported relief of symptoms for at least 2 of the first 4 weeks after treatment. Other secondary end points included the percentage of patients who had a response to treatment as assessed by daily self-ratings of global IBS symptoms and individual symptoms of bloating, abdominal pain, and stool consistency during the 4 weeks after treatment and during the entire 3 months of the study.

Full Text of Methods...
Results

Significantly more patients in the rifaximin group than in the placebo group had adequate relief of global IBS symptoms during the first 4 weeks after treatment (40.8% vs. 31.2%, P=0.01, in TARGET 1; 40.6% vs. 32.2%, P=0.03, in TARGET 2; 40.7% vs. 31.7%, P<0.001, in the two studies combined). Similarly, more patients in the rifaximin group than in the placebo group had adequate relief of bloating (39.5% vs. 28.7%, P=0.005, in TARGET 1; 41.0% vs. 31.9%, P=0.02, in TARGET 2; 40.2% vs. 30.3%, P<0.001, in the two studies combined). In addition, significantly more patients in the rifaximin group had a response to treatment as assessed by daily ratings of IBS symptoms, bloating, abdominal pain, and stool consistency. The incidence of adverse events was similar in the two groups.

Full Text of Results...
Conclusions

Among patients who had IBS without constipation, treatment with rifaximin for 2 weeks provided significant relief of IBS symptoms, bloating, abdominal pain, and loose or watery stools. (Funded by Salix Pharmaceuticals; ClinicalTrials.gov numbers, NCT00731679 and NCT00724126.)

Full Text of Discussion...

Read the Full Article...
Source Information

From Cedars–Sinai Medical Center, Los Angeles (M.P.); Beth Israel Deaconess Medical Center and Harvard Medical School — both in Boston (A.L.); University of Michigan Health System, Ann Arbor (W.D.C.); Connecticut Gastroenterology Institute at Bristol Hospital, Bristol (S.Z.); University of North Carolina at Chapel Hill, Chapel Hill (Y.R.); and Salix Pharmaceuticals, Morrisville, NC (J.Y., S.M.M., A.L.S., E.B., W.P.F.).

Address reprint requests to Dr. Forbes at 1700 Perimeter Park Dr., Morrisville, NC 27560.

Members of the TARGET Study Group are listed in the Supplementary Appendix, available at NEJM.org.
Media in This Article
Figure 1Study Design.
Figure 2Enrollment, Randomization, and Follow-up in the TARGET 1 and TARGET 2 Studies.
Article Activity

1 article has cited this article

The irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by recurring symptoms of abdominal pain, bloating, and altered bowel function in the absence of structural, inflammatory, or biochemical abnormalities.1 IBS often does not respond to current treatment options, including dietary and lifestyle modifications, fiber supplementation, psychological therapy, and pharmacotherapy.2,3 Because no reliable biologic or structural markers have been identified, the effects of pharmacotherapy are typically assessed by asking patients to report whether they had adequate relief of IBS symptoms (with a binary response of yes or no).4 Given the limitations of available therapies, there is an unmet medical need for novel therapeutic approaches.

Patients with IBS may have alterations in the intestinal microbiota,5-7 thus leading investigators to consider targeting the intestinal microbiota for the treatment of this condition. Although some patients have had improvement with neomycin therapy, clinical trials have shown that it has marginal efficacy, and side effects limit the use of the drug.8 The use of systemic antibiotics has been reported with mixed results.9

Rifaximin (Xifaxan, Salix Pharmaceuticals) is an oral, nonsystemic, broad-spectrum antibiotic that targets the gut and is associated with a low risk of bacterial resistance.10-12– It has shown efficacy in small-scale studies of IBS. 13,14 We present the results of two large-scale, identically designed, multicenter trials — TARGET 1 and TARGET 2 — of 3 months' duration that examined the relief of IBS symptoms after a 2-week course of rifaximin.
Methods
Study Patients

Eligible patients were at least 18 years of age; had undergone a colonoscopic examination within the previous 2 years; had received a diagnosis of and had current symptoms of IBS (as assessed according to the Rome II diagnostic criteria for IBS15), in particular, symptoms of abdominal pain and discomfort; and did not have adequate relief of global IBS symptoms and of IBS-related bloating at both the time of screening and the time of randomization. Eligible patients rated the average daily amount of abdominal pain and of bloating as a score of 2 to 4.5 on a 7-point Likert scoring system (with 0 indicating not at all; 1, hardly; 2, somewhat; 3, moderately; 4, a good deal; 5, a great deal; and 6, a very great deal) and rated the average daily consistency of their stools as 3.5 or more on a 5-point scale for stool consistency (with 1 indicating very hard; 2, hard; 3, formed; 4, loose; and 5, watery) over the course of at least 7 days.

Exclusion criteria were constipation-predominant IBS (according to the definition in the Rome II criteria15), a history of inflammatory bowel disease, diabetes, unstable thyroid disease, previous abdominal surgery (other than cholecystectomy or appendectomy), human immunodeficiency virus infection, and renal or hepatic disease. Patients were excluded if they were currently taking alosetron, tegaserod, lubiprostone, warfarin, or antipsychotic, antispasmodic, antidiarrheal, probiotic, or narcotic drugs or if they had taken antibiotics within the previous 14 days or rifaximin within 60 days before signing the informed-consent form for the study. Patients were allowed to take antidepressant agents of the selective serotonin-reuptake inhibitor and tricyclic antidepressant classes, provided that they had been taking a stable dose for at least 6 weeks. All patients provided written informed consent before study-related procedures were initiated.
Study Design and Procedures

The protocols were approved by the institutional review board or independent ethics committee at each center, and the studies were conducted in accordance with applicable laws and regulations (see the Supplementary Appendix, available with the full text of this article at NEJM.org). After a screening phase of 7 to 13 days, eligible patients were randomly assigned with the use of an interactive voice-response system to either rifaximin or placebo, in a 1:1 ratio. The randomization code was computer-generated, and randomization was performed in blocks of four, stratified according to center. After completing the 14-day study-treatment period, patients were evaluated for 10 additional weeks. Study visits were conducted on days 1, 7, 14, 28, and 84, and patients were monitored by means of telephone calls on days 42, 56, and 70. Efficacy assessments were obtained daily by means of an interactive voice-response system over the course of the entire study (Figure 1Figure 1Study Design.).

The protocol was designed by Salix Pharmaceuticals in collaboration with the academic authors. Data were collected by investigators at each center (see the Supplementary Appendix) and were monitored by Quintiles (a contract research organization) under the supervision of Salix Pharmaceuticals. The data were analyzed by personnel at Salix Pharmaceuticals, in collaboration with the academic authors. All the authors participated in the interpretation of the data and in the writing of the manuscript. The first two authors wrote the first draft of the manuscript, and all the authors, in addition to an employee of Salix, assisted in the revision of subsequent drafts. All the authors made the decision to submit the manuscript for publication. The trial protocol, including the statistical analysis plan, is available at NEJM.org. All the authors vouch for the completeness and veracity of the data and analyses, as well as the fidelity of this report to the trial protocol.
Efficacy and Safety End Points

The primary end point was the proportion of patients who had adequate relief of global IBS symptoms for at least 2 of the 4 weeks during the primary evaluation period (weeks 3 through 6). This end point was determined from the response (yes or no) to the following question, which was asked weekly: "In regard to all your symptoms of IBS, as compared with the way you felt before you started the study medication, have you, in the past 7 days, had adequate relief of your IBS symptoms?" The threshold for clinical relevance — adequate relief during at least 2 weeks per month — was defined prospectively. In addition, the proportion of patients who reported that they had adequate relief during at least 2 weeks per month ("monthly response") during months 1, 2, and 3 was assessed to identify the onset and duration of the therapeutic effect. Patients who started to take antibiotics (other than the study medication) or who took more than two doses of a medication that was prohibited per the study protocol were considered not to have had a response to treatment starting from the time the medication was initiated, regardless of their response data.

The key secondary end point, the proportion of patients who had adequate relief of IBS-related bloating during the primary evaluation period, was determined from the response (yes or no) to the weekly question, "In regard to your symptoms of bloating, as compared with the way you felt before you started study medication, have you, in the past 7 days, had adequate relief of your IBS symptom of bloating?" The onset and duration of relief of bloating were also assessed in an analysis of monthly response, as described above for the primary end point.

For other secondary end points, the proportion of patients who had relief was determined from the patients' daily assessments of IBS symptoms, bloating, and abdominal pain and discomfort (as rated on a 7-point scale); relief was defined as a score of either 0 (not at all) or 1 (hardly) for at least 50% of the days in a given week or a score of 0 (not at all), 1 (hardly), or 2 (somewhat) for 100% of the days in a given week for at least 2 of the 4 weeks during a given month.

An exploratory end point, which was included at the request of the Food and Drug Administration (FDA), was the proportion of patients who had relief of the composite of abdominal pain and discomfort and loose or watery stools (as measured by improvement in stool consistency), on the basis of daily assessments. Relief was defined as a decrease of at least 30% from baseline in weekly mean ratings of IBS-related abdominal pain or discomfort and a weekly mean stool-consistency score of less than 4 (with 4 indicating loose stools and lower scores indicating more formed stools) for at least 2 of the 4 weeks during a given month. This exploratory end point is consistent with the recommended composite end point for IBS with diarrhea in a recently released draft of FDA guidelines.16 Safety assessments included the monitoring of adverse events, results of clinical laboratory testing, findings from physical examinations, and vital signs.
Statistical Analysis

We estimated the sample size for each study assuming that 40% of the patients in the placebo group and 55% in the rifaximin group would meet the criteria for the primary end point (i.e., would have adequate relief of global IBS symptoms, as assessed weekly) for at least 2 of the first 4 weeks after treatment. With these assumptions, a sample of 300 patients would be needed in each group for the studies to have 95% power to show the 15-percentage-point difference between the groups, at a significance level of 0.05.

All efficacy and safety analyses were performed on a modified intention-to-treat population, which included all patients who received at least one dose of the study drug. Missing data were imputed with the use of the last-observation-carried-forward method, whereby missing values were replaced with the last nonmissing value; baseline values were not carried forward. Two sensitivity analyses were conducted, one in which missing data were regarded as indicating that the patients who terminated the study prematurely had had no relief of symptoms, and the other in which missing data were imputed with the use of the multiple-imputation method.

Binary data (i.e., data on the proportion of patients who had or did not have adequate relief of symptoms) were analyzed with the use of logistic regression; fixed-effect terms included the study group and the analysis center. There were five analysis centers, which we formed prospectively by grouping the study centers according to geographic region in order to assess the effects of geographic location on the end points. For the analysis of ordinal data (i.e., data on the number of months in which patients had relief for at least 2 weeks per month), we used the proportional-odds model for the ordinal outcome. The number of consecutive months with relief during the first 3 months after treatment was summed for each patient, so that each patient received a score of 0, 1, 2, or 3.

We analyzed the changes from baseline in continuous outcomes (i.e., symptom scores) by fitting fixed-effects linear models to the data. An initial model with terms for treatment, analysis center, baseline ratings of the response variable, and interaction of baseline ratings with treatment was fitted. The interaction term was tested at the 0.05 level. A nonsignificant interaction was dropped from the model in subsequent analyses.

Spearman correlation analyses were applied to the mean change from baseline in daily assessments of adequate relief of IBS symptoms (yes or no) to determine whether the weekly assessments of adequate relief paralleled the pattern seen with the daily assessments. Safety data were summarized with the use of descriptive statistics.
Results
Study Patients

A total of 1260 patients who had IBS without constipation were enrolled in the studies (623 patients in TARGET 1 and 637 in TARGET 2) and underwent randomization at one of 179 investigative sites in the United States (1217 patients) and Canada (43 patients) (Figure 2Figure 2Enrollment, Randomization, and Follow-up in the TARGET 1 and TARGET 2 Studies.). The studies were conducted in parallel from June 2008 through August 2009. In TARGET 1, all the patients who underwent randomization took at least one dose of the study drug. In TARGET 2, two patients (one in each group) underwent randomization but did not receive a study drug. Thus, 1258 patients received at least one dose of the study drug and were included in the modified intention-to-treat population. More than 90% of the patients completed the entire 12-week study. The baseline characteristics of the patients were similar in the two studies and across treatment groups (Table 1Table 1Demographic and Baseline Characteristics of the Modified Intention-to-Treat Population in the Two Studies.). The rate of adherence to the study drug, defined as the use of at least 70% of the dispensed tablets, was at least 97% in both study groups in both studies.
Efficacy during the Primary Evaluation Period (Weeks 3 through 6)
Adequate Relief of Global IBS Symptoms

Significantly more patients in the rifaximin group than in the placebo group met the criteria for the primary end point of adequate relief of global IBS symptoms for at least 2 of the first 4 weeks after treatment (40.8% vs. 31.2%, P=0.01, in TARGET 1; 40.6% vs. 32.2%, P=0.03, in TARGET 2; 40.7% vs. 31.7%, P<0.001, in the two studies combined) (Figure 3AFigure 3Analyses of Primary, Key Secondary, and Other Secondary End Points.). The last-observation-carried-forward method was applied in the case of 5.8% of the patients in the rifaximin group and 5.7% of the patients in the placebo group in TARGET 1 and in the case of 5.4% in the rifaximin group and 8.4% in the placebo group in TARGET 2. Overall, sensitivity analyses that were performed to address the effect of missing values yielded results that were consistent with those of the primary efficacy analysis (see the Supplementary Appendix). On the basis of daily assessments of IBS symptoms, the proportion of patients with a response to treatment, as rated on a 7-point scale during the primary evaluation period, was significantly greater in the rifaximin group than in the placebo group (42.7% vs. 30.6%, P<0.001, in TARGET 1; 37.8% vs. 28.4%, P=0.007, in TARGET 2; 40.2% vs. 29.5%, P<0.001, in the two studies combined) (Figure 3A).
Adequate Relief of IBS-Related Bloating

Significantly more patients in the rifaximin group than in the placebo group met the criteria for the key secondary end point, adequate relief of IBS-related bloating for at least 2 of the first 4 weeks after treatment (39.5% vs. 28.7%, P=0.005, in TARGET 1; 41.0% vs. 31.9%, P=0.02, in TARGET 2; 40.2% vs. 30.3%, P<0.001, in the two studies combined) (Figure 3A). Sensitivity analyses that were performed to assess the effect of missing values yielded similar results (see the Supplementary Appendix). On the basis of daily assessments of IBS-related bloating as rated on a 7-point scale during the same primary evaluation period, a significantly greater proportion of patients in the rifaximin group than in the placebo group had relief (39.2% vs. 32.5%, P=0.05, in TARGET 1; 43.5% vs. 30.9%, P<0.001, in TARGET 2; 41.3% vs. 31.7%, P<0.001, in the two studies combined) (Figure 3A).
Relief of IBS-Related Abdominal Pain and Loose or Watery Stools

A significantly greater proportion of patients in the rifaximin group than in the placebo group had relief of IBS-related abdominal pain and discomfort during the primary evaluation period (44.3% vs. 36.3%, P=0.03, in TARGET 1; 42.9% vs. 34.4%, P=0.02, in TARGET 2) (Figure 3A). In an assessment of the composite end point of abdominal pain or discomfort and loose or watery stools, significantly more patients in the rifaximin group than in the placebo group had relief during the primary evaluation period (46.6% vs. 38.5%, P=0.04, in TARGET 1; 46.7% vs. 36.3%, P=0.008, in TARGET 2), and a significantly greater proportion of patients in the rifaximin group had relief with respect to the individual components of this end point (Figure 3A).
Efficacy during the Entire Study Period (Months 1 through 3)
Durability of Response on the Basis of Weekly Assessment

In analyses of the monthly response evaluated on the basis of weekly assessments, more patients in the rifaximin group than in the placebo group in both studies had adequate relief of global IBS symptoms within the first month, with continued relief during the first 2 months and during all 3 months in both studies (P=0.05 in TARGET 1, P=0.005 in TARGET 2, and P<0.001 in the two studies combined, for relief during all 3 months) (Figure 3B). With respect to IBS-related bloating, in TARGET 1, significantly more patients in the rifaximin group than in the placebo group had adequate relief in the first month, with continued relief during the first 2 months, but there were no significant between-group differences with respect to relief during all 3 months; in TARGET 2, significant benefits of rifaximin were seen with respect to IBS-related bloating for all 3 months (P=0.10 in TARGET 1, P=0.003 in TARGET 2, and P=0.001 in the two studies combined, for relief during all 3 months) (Figure 3B). The percentages of patients in each group with adequate relief of global IBS symptoms in TARGET 1 and TARGET 2 are provided in Figure 4Figure 4Percentage of Patients with Adequate Relief of Global IBS Symptoms in the TARGET 1 and TARGET 2 Studies Combined., and in Figure 1A and 1B in the Supplementary Appendix.
Durability of Response on the Basis of Daily Assessment

The analyses of monthly response evaluated on the basis of daily assessments also support a durable response to rifaximin in patients with IBS over the course of 3 months. Patients treated with rifaximin, as compared with patients who received placebo, had adequate relief of global IBS symptoms during the entire 3 months of the study (P=0.003 in TARGET 1, P=0.01 in TARGET 2, and P<0.001 in the two studies combined) and of IBS-related bloating (P=0.01 in TARGET 1, P<0.001 in TARGET 2, and P<0.001 in the two studies combined) (Figure 3B).

An analysis of the monthly response evaluated on the basis of daily assessments of IBS-related abdominal pain and discomfort showed that significantly more patients in the rifaximin group than in the placebo group had relief for the entire 3 months (P=0.05 in TARGET 1, P=0.04 in TARGET 2, and P=0.01 in the two studies combined) (Figure 3B). An analysis of the monthly response evaluated on the basis of the assessment of the composite end point of abdominal pain and stool consistency also showed a significant benefit with rifaximin as compared with placebo (P=0.04 in TARGET 1, P=0.01 in TARGET 2, and P=0.001 in the two studies combined) (Figure 3B).

The mean improvement from baseline in daily symptom scores (global IBS symptoms, IBS-related bloating, IBS-related abdominal pain or discomfort, stool consistency, and the percentage of days with stool urgency) was greater for the patients who received rifaximin than for the patients who received placebo (Figure 2 through 6 in the Supplementary Appendix).
Responsiveness and Construct Validity of Patient-Reported Outcomes

The response of patients with respect to adequate relief of global IBS symptoms and of IBS-related bloating was consistent with the response with respect to other IBS-related assessments. In addition, patients who had adequate relief of global IBS symptoms and of IBS-related bloating had greater improvements in daily symptom-severity scores than did patients who did not have adequate relief, regardless of study group, during each week in each study (P<0.001).

We tested the validity of using assessments of global IBS symptoms to measure changes in IBS symptoms by examining the correlation between these measures and changes in daily severity scores and bowel function; the results support the validity and usefulness of the primary end point of global IBS symptoms. Evidence for convergent validity (Spearman's correlation of 0.40 or higher) was observed between weekly adequate relief of global IBS symptoms and measures of daily symptom severity and bowel function.
Safety

The safety profile of rifaximin was similar to that of placebo (Table 2Table 2Adverse Events during the 12-Week Study.). Serious adverse events were recorded in 10 patients in the rifaximin group (1.6%) and 15 patients in the placebo group (2.4%). There were no cases of Clostridium difficile–associated diarrhea or ischemic colitis. No deaths were reported.
Discussion

Treating IBS is important because the symptoms cause substantial impairment in health-related quality of life, leading to increased use of health resources and reduced work productivity.17-20 These two phase 3 studies showed that a short course of rifaximin leads to sustained amelioration of the symptoms of IBS without constipation in a subgroup of affected patients.

The antibiotic effect of rifaximin is the presumed mechanism for its sustained beneficial effects in patients with IBS. A response to antibiotic therapy in patients with IBS has been shown to correlate with normalization of the results of lactulose hydrogen breath tests.8,13 However, there is debate about which antibiotic-related effect is most important. On the basis of existing data, there are three reasonable explanations: rifaximin affects gut bacteria and reduces bacterial products that negatively affect the host, the effect on gut flora reduces local mucosal engagement of bacteria such as the immune responses of the host, or the antibiotic alters both the bacteria and the host response. Whatever the final pathway, the durable effects suggest that rifaximin is affecting an underlying cause of IBS that is linked to an alteration in the intestinal microbiota.6,7,21,22 Some patients in both of our studies did not have a response to treatment, a finding that is consistent with the results of other placebo-controlled clinical trials involving patients with IBS23-25 and that may reflect differences in the underlying cause of the symptoms.

Similar percentages of patients in the rifaximin group and in the placebo group had adverse events. In this short-term study, the incidence of infections was similar in the two groups, and there were no cases of C. difficile–associated diarrhea or ischemic colitis.

In summary, the results of these two phase 3 studies showed that treatment with rifaximin at a dose of 550 mg three times daily for 14 days provides better relief of symptoms of IBS than does placebo for up to 10 weeks after completion of therapy.

Supported by Salix Pharmaceuticals.

Dr. Pimentel reports receiving grant support (to his institution) and consulting fees and honoraria from Salix Pharmaceuticals and reports that Cedars–Sinai Medical Center holds patents licensed by Salix Pharmaceuticals; Dr. Lembo reports receiving consulting fees from Salix Pharmaceuticals, Ironwood Pharmaceuticals, Prometheus, Ardelyx, Theravance, GlaxoSmithKline, and AstraZeneca, receiving payment for participation in several advisory-board meetings relating to the development of rifaximin for the treatment of IBS, and receiving payment as a member of the speakers' bureau of Salix Pharmaceuticals; Dr. Chey reports receiving consulting fees and honoraria from Procter & Gamble, Ortho-McNeil, Prometheus, and Salix Pharmaceuticals, payment for the development of educational presentations, and payment or reimbursement for travel and accommodations from Procter & Gamble, Prometheus, and Salix Pharmaceuticals; Dr. Zakko reports receiving grant support (to his institution), consulting fees, payment for the development of educational presentations, and payment or reimbursement for travel and accommodations from Salix Pharmaceuticals and holding stock in Salix Pharmaceuticals; Dr. Ringel reports receiving consulting fees from Salix Pharmaceuticals, Ironwood Pharmaceuticals, Procter & Gamble, Pfizer, and Danisco, participating in several advisory-board meetings related to the development of rifaximin for the treatment of IBS, receiving payment for the development of educational presentations and as a member of the speakers' bureau of Salix Pharmaceuticals, and receiving research grants from Danisco USA, General Mills, and SmartPill. Drs. Yu, Mareya, and Bortey report being employees of and holding stock in Salix Pharmaceuticals; Dr. Shaw reports being an employee of Salix Pharmaceuticals and reports that she holds stock in the company; and Dr. Forbes reports being an officer and employee of Salix Pharmaceuticals and holding stock in the company.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

No other potential conflict of interest relevant to this article was reported.
Source Information

From Cedars–Sinai Medical Center, Los Angeles (M.P.); Beth Israel Deaconess Medical Center and Harvard Medical School — both in Boston (A.L.); University of Michigan Health System, Ann Arbor (W.D.C.); Connecticut Gastroenterology Institute at Bristol Hospital, Bristol (S.Z.); University of North Carolina at Chapel Hill, Chapel Hill (Y.R.); and Salix Pharmaceuticals, Morrisville, NC (J.Y., S.M.M., A.L.S., E.B., W.P.F.).

http://www.nejm.org/doi/full/10.1056/NEJMoa1004409#t=article

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Heather is the Administrator of the IBS Message Boards. She is the author of Eating for IBS and The First Year: IBS, and the CEO of Heather's Tummy Care. Join her IBS Newsletter. Meet Heather on Facebook!

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Editorial - Antibiotic Rifaximin (Xifaxan) Therapy for the Irritable Bowel Syndrome new
      #362812 - 01/07/11 03:01 PM
HeatherAdministrator

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Editorial
Antibiotic Therapy for the Irritable Bowel Syndrome

Jan Tack, M.D., Ph.D.

N Engl J Med 2011; 364:81-82January 6, 2011

Article
References

The irritable bowel syndrome (IBS) is one of the most common conditions seen in clinical practice. The number of effective pharmacologic agents for IBS is limited, and therapeutic innovation is hampered by a lack of complete understanding of the pathophysiology of the syndrome, which is probably heterogeneous.1 Alterations in the bacterial flora are increasingly considered to be a relevant pathogenetic factor.2 Consequently, probiotics are being studied as treatment for IBS, but the magnitude of improvement in symptoms with probiotics is limited.2 Some studies have suggested that there are beneficial effects with poorly absorbed antibiotics, but the results of the studies have been questioned because of issues with patient selection, the choice of end point, and the statistical analysis, and, most of all, because lactulose breath test results were interpreted as indicative of small-intestine bacterial overgrowth.3-6

In this issue of the Journal, Pimentel et al. report the results of two identically designed, large, double-blind, placebo-controlled trials (TARGET 1 and TARGET 2) of rifaximin, a poorly absorbed antibiotic, in patients with IBS without constipation.7 A total of 1260 patients were randomly assigned to receive rifaximin, at a dose of 550 mg three times daily, or placebo for 2 weeks, followed by a 10-week posttreatment follow-up period. The primary end point was the proportion of patients who reported adequate relief of IBS symptoms, as assessed by responses (yes or no) to a question about relief of symptoms that was asked weekly during the first 4 weeks after treatment. The key secondary end point was the proportion of patients reporting adequate relief of bloating during the same period.

In both studies, patients consistently met the criteria for relief of global IBS symptoms and IBS-related bloating. In the rifaximin groups, as compared with the placebo groups, a significantly higher proportion of patients reported adequate relief of IBS symptoms (41% vs. 32% in the two trials combined, P<0.001) or bloating (40% vs. 30%, P<0.001) for at least 2 of the first 4 weeks. Similarly significant results were obtained in an analysis of relief of symptoms during the 10-week period after the end of the double-blind treatment phase.

These large, high-quality, multicenter studies confirm that, as a group, patients who have IBS without constipation have a significantly better response to rifaximin than to placebo. Rifaximin is a poorly absorbed antibiotic with broad-spectrum activity against gram-negative bacteria, gram-positive bacteria, and anaerobes, including Clostridium difficile. It has been extensively used in the treatment and prevention of travelers' diarrhea, for which it has shown a favorable side-effect and safety profile, with low risk for the development of resistance.8

The TARGET studies have some attractive findings. First, the sustained benefit over at least 10 weeks, after a short treatment course, is appealing. Second, the beneficial effects of rifaximin include its effects on bloating, which is one of the most challenging symptoms of IBS. Third, the similarity of the results in both studies confirms the reproducibility of the therapeutic effect. On the other hand, the therapeutic gain, with the rates of response to treatment (i.e., adequate relief) ranging between 9 and 12% more with rifaximin than with placebo, is in the lower spectrum of what is considered to be clinically relevant.9 Although it is clear that not all patients have a response with rifaximin, the available data suggest that a subgroup of patients may have a substantial response.5,7 It is unclear whether this group can be identified by demographic characteristics, symptoms, or results of lactulose breath testing. Most important, IBS is a chronic disorder, and although the therapeutic effect persists after the 2-week treatment period, the response over time suggests that there is some loss of efficacy, as compared with placebo, with respect to certain symptoms toward the end of the 10-week follow-up period. It is unknown whether patients would have a favorable response again with retreatment.

The mechanism underlying the beneficial effect of rifaximin with respect to symptoms of IBS is a matter of controversy. Initial studies of poorly absorbed antibiotics for the treatment of patients with IBS were based on the hypothesis that a large proportion of these patients had small-intestine bacterial overgrowth, a disorder characterized by the presence of abnormally high numbers of bacteria in the small intestine.7 Initial studies reported the presence of small-intestine bacterial overgrowth in up to 80% of patients, on the basis of a rapid rise in breath hydrogen during lactulose breath testing. However, this test is prone to false positive results, and several other investigators failed to reproduce these high incidences.10 When the standard method of jejunal aspiration and bacterial culturing was used, small-intestine bacterial overgrowth was found in only 4% of patients with IBS.10 More recently, it was suggested that the use of proton-pump inhibitors conferred a predisposition to enhanced bacterial colonization of the small intestine.10 Most studies assessing poorly absorbed antibiotics in the treatment of patients with IBS, including the present study, do not report or adjust for the concomitant use of proton-pump inhibitors, so this remains an area of controversy. The most likely mode of action of rifaximin is a reduction in overall bacterial load, especially in the large bowel.8 This may lead to decreased bacterial fermentation and less bloating, possibly in combination with decreased secretion of bacterial products or host responses to bacterial products that contribute to the generation of symptoms.

Neither rifaximin nor any other antibiotic has been approved for the treatment of IBS, and the Food and Drug Administration is currently reviewing the new-drug application for rifaximin for the treatment of patients who have IBS without constipation and IBS-related bloating. With three studies confirming the efficacy of the drug after a short-term regimen and a relatively short follow-up period,5,7 rifaximin has the potential to provide a welcome addition to the limited armamentarium of agents that are available to treat IBS. Moreover, rifaximin had a favorable safety profile in these studies, with no treatment-associated major adverse events and no cases of C. difficile colitis. At the current stage of knowledge, however, clinicians should proceed with caution. IBS is a chronic condition, and some regulatory authorities recommend that studies be conducted that will address the efficacy of rifaximin when it is used for continued or intermittent treatment of IBS (see www.tga.gov.au/docs/pdf/euguide/ewp/078597en.pdf), and this seems to be even more appropriate in the case of antibiotic therapy that may have a risk of inducing resistance over time. Furthermore, taking into account the high prevalence of IBS in the general population, the effect that larger-scale use of poorly absorbed antibiotics may have on antibiotic-resistance profiles should be taken into account.6 Studies aimed at better identifying the patients with IBS who may have a response to rifaximin and, especially, studies that will assess the longer-term effect of rifaximin treatment are eagerly awaited. Until this information becomes available, it seems prudent to restrict the use of nonabsorbable antibiotics to patients in whom small-intestine bacterial overgrowth has been confirmed, or to single-treatment cycles in patients who have IBS without constipation and who have not had a response to currently available symptom-directed therapies.1

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.
Source Information

From the Department of Pathophysiology, Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium.

http://www.nejm.org/doi/full/10.1056/NEJMe1011211

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Antacids increase risk of pneumonia new
      #362925 - 01/14/11 04:35 PM
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Use of acid-suppressive drugs and risk of pneumonia: systematic review and meta-analysis

Chun-Sick Eom, Christie Y. Jeon, Ju-Won Lim, Eun-Geol Cho, Sang Min Park and Kang-Sook Lee

From the Department of Family Medicine (Eom, Lim, Cho, Park), Seoul National University Hospital, Seoul, Republic of Korea; the Department of Epidemiology (Jeon), Harvard School of Public Health, Boston, USA; and the Department of Preventive Medicine (Lee), College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Dr. Sang Min Park, Department of Family Medicine, Seoul National University Hospital, 101 Daehangno, Jongno-gu, Seoul, 110-744, Republic of Korea. E-mail sangmin.park.snuh@gmail.com

Dr. Kang-Sook Lee, Department of Preventive Medicine, College of Medicine, Catholic University of Korea, 505 Banpo-Dong, Seocho-Gu, Seoul 137-701, Republic of Korea. E-mail leekangs@catholic.ac.kr

Background: Observational studies and randomized controlled trials have yielded inconsistent findings about the association between the use of acid-suppressive drugs and the risk of pneumonia. We performed a systematic review and meta-analysis to summarize this association.

Methods: We searched three electronic databases (MEDLIN E [PubMed], Embase and the Cochrane Library) from inception to Aug. 28, 2009. Two evaluators independently extracted data. Because of heterogeneity, we used randomeffects meta-analysis to obtain pooled estimates of effect.

Results: We identified 31 studies: five case–control studies, three cohort studies and 23 randomized controlled trials. A meta-analysis of the eight observational studies showed that the overall risk of pneumonia was higher among people using proton pump inhibitors (adjusted odds ratio [OR] 1.27, 95% confidence interval [CI] 1.11–1.46, I2 90.5%) and histamine2 receptor antagonists (adjusted OR 1.22, 95% CI 1.09–1.36, I2 0.0%). In the randomized controlled trials, use of histamine2 receptor antagonists was associated with an elevated risk of hospital-acquired pneumonia (relative risk 1.22, 95% CI 1.01–1.48, I2 30.6%).

Interpretation: Use of a proton pump inhibitor or histamine2 receptor antagonist may be associated with an increased risk of both community- and hospital-acquired pneumonia. Given these potential adverse effects, clinicians should use caution in prescribing acid-suppressive drugs for patients at risk.

http://www.cmaj.ca/cgi/content/abstract/cmaj.092129v1

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Rifaximin: a unique gastrointestinal-selective antibiotic for enteric diseases new
      #363409 - 02/10/11 10:23 AM
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Current Opinion in Gastroenterology:
January 2010 - Volume 26 - Issue 1 - p 17-25
doi: 10.1097/MOG.0b013e328333dc8d
Gastrointestinal infections: Edited by Mitchell Cohen

Rifaximin: a unique gastrointestinal-selective antibiotic for enteric diseases


Purpose of review: Rifaximin is gaining attention for its potential activity in a multitude of gastrointestinal diseases. We review the unique pharmaceutical properties of this antibiotic and the published evidence in the literature regarding the use of rifaximin for different gastrointestinal disorders.

Recent findings: Rifaximin is a gastrointestinal-selective antibiotic with a broad spectrum of antimicrobial activity, an excellent safety profile, minimal drug interactions, and negligible impact on the intestinal microbiome. Rifaximin is currently approved in the United States for the treatment of travelers' diarrhea caused by noninvasive diarrheagenic Escherichia coli and is approved in more than 30 other countries for a variety of gastrointestinal disorders. Considerable research with this medication has been conducted for the treatment and prevention of travelers' diarrhea, the treatment of portal systemic encephalopathy, Clostridium difficile infection, small bowel intestinal overgrowth, irritable bowel syndrome, inflammatory bowel disease, pouchitis, and colonic diverticular disease.

Summary: Rifaximin is effective for the treatment of travelers' diarrhea and can be considered as the treatment of choice for uncomplicated travelers' diarrhea. When invasive travelers' diarrhea pathogens are suspected, an alternative antibiotic should be administered. Rifaximin appears promising as a chemoprophylaxis for travelers' diarrhea and as a treatment of portal systemic encephalopathy. This antibiotic may be effective for other gastrointestinal diseases, but more well designed clinical studies are needed to confirm its efficacy for these off-label indications. Future studies will determine whether the development of significant bacterial resistance will limit rifaximin use.

http://journals.lww.com/co-gastroenterology/Abstract/2010/01000/Rifaximin__a_unique_gastrointestinal_selective.5.aspx

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Antibiotics that reduce gut bacteria linked to obesity new
      #364654 - 05/06/11 12:25 PM
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Antibiotics that reduce gut bacteria linked to obesity

By Steve Connor, Science Editor

Tuesday, 3 May 2011

Scientists believe that the widespread use of antibiotics may be playing a significant role in exacerbating the obesity epidemic.

Growing evidence suggests that oral antibiotic medicines may be affecting the growth of beneficial bacteria in the human intestine which is influencing whether some people put on weight when they overeat or take too little exercise, they said.

The latest study, which has yet to be published in a peer-reviewed scientific journal, centres on a technique for counting the bacterial genes in the human intestine. It found that lean people are likely to have a more diverse community of gut flora compared to obese individuals.

Previous work has already established a difference in the gut bacteria of lean and overweight people, but the latest work is being seen as lending support to the controversial idea that bacteria-killing antibiotics may be playing a role in predisposing some people to being fat.

"It is a very real possibility," said Stanislav Dusko Ehrlich, a microbiologist at the French National Institute for Agricultural Research in Jouy-en-Josas, who was part of the Meta-HIT consortium of pan-European scientists who carried out the work.

"What we have found is that bacterial communities in the gut appear to be different between lean and obese people. We can't be certain whether that perturbation is the cause, contribution or consequence of being overweight. But these bacteria are candidates for being a cause and that must be investigated," he said.

Previous studies on laboratory mice and farm animals have established a link between gut flora, the use of antibiotics and an increase in body fat, but scientists have been wary of extrapolating these findings to humans.

The study investigated the bacterial genes found in the gut flora of 177 Danish people, 55 of whom were lean, with the rest either overweight or obese. Scientists in the Meta-HIT consortium found that most people in the study carried in their intestines around 600,000 distinct bacterial genes. But about a third of the obese participants had only about 360,000 bacterial genes – about 30 or 40 per cent fewer – which suggests they possessed a distinctly poorer community of gut flora, which is typically composed of about 160 different species of microbial lifeforms.

Microbes that live inside us

* The healthy human gut contains 100 trillion microbial cells, 10 times as many as the human cells that comprise the body.

* About 1,000 species of microbe can live in the human gut, but at any one time a person typically has about 160.

* Members of the same family tend to have similar communities of gut bacteria.

* The two dominant groups of gutbacteria, the Bacteroidetes and the Firmicutes, help us to break down food.

http://www.independent.co.uk/news/science/antibiotics-that-reduce-gut-bacteria-linked-to-obesity-2278042.html

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Latest FDA watch list includes GI drugs new
      #367294 - 04/23/12 01:42 PM
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Latest FDA watch list includes GI drugs

The FDA put 16 drugs on its quarterly watch list, identified through the Adverse Event Reporting System. McNeil Consumer Healthcare's diarrhea treatment Imodium and over-the-counter proton pump inhibitors are among the products, for risks of pancreatitis and diarrhea linked to Clostridium difficile, respectively. However, a drug's presence on the list does not mean patients should stop taking the therapy. The FDA suggests that patients with questions speak with their physician.

http://www.medscape.com/viewarticle/762205

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3-month FDA delay for potential IBS drug linaclotide new
      #367295 - 04/23/12 01:45 PM
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Ironwood faces 3-month FDA delay for potential IBS drug linaclotide

Boston Business Journal by Julie M. Donnelly, Reporter

Date: Monday, April 23, 2012, 2:03pm EDT


Ironwood Pharmaceuticals and its partner Forest Laboratories Inc. have announced the U.S. Food and Drug Administration will delay its approval decision for the companies' potential drug for irritable bowel syndrome (IBS), called linaclotide.

The delay is due to the agency's request for an additional analysis of existing clinical data, the companies said. The FDA has not requested a new clinical trial.

The drug candidate was submitted to the FDA in August 2011 and a decision was expected in June. In February the company had received an encouraging sign that the approval process was on schedule, sending shares up 7 percent.

FDA action is now expected by September. Cambridge, Mass-based Ironwood and New York-based Forest continue to plan for a 2012 launch.

The efficacy and safety of linaclotide was studied in a clinical trial program of more than 2,800 patients for the treatment of irritable bowel syndrome with constipation and chronic constipation.

Ironwood and Forest plan to co-promote linaclotide in the U.S. Ironwood has out-licensed linaclotide to Almirall for European development and commercialization, and to Astellas Pharma Inc. for development and commercialization in Japan, Indonesia, Korea, the Philippines, Taiwan, and Thailand.

http://www.bizjournals.com/boston/news/2012/04/23/ironwood-faces-three-month-fda-delay.html

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FDA approves Linzess to treat certain cases of irritable bowel syndrome and constipation new
      #368133 - 08/31/12 11:25 AM
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FDA NEWS RELEASE

For Immediate Release: Aug. 30, 2012


FDA approves Linzess to treat certain cases of irritable bowel syndrome and constipation

The U.S. Food and Drug Administration today approved Linzess (linaclotide) to treat chronic idiopathic constipation and to treat irritable bowel syndrome with constipation (IBS-C) in adults.

According to the National Institutes of Health, an estimated 63 million people are affected by chronic constipation. Chronic idiopathic constipation is a diagnosis given to those who experience persistent constipation and do not respond to standard treatment. Additionally, an estimated 15.3 million people are affected by IBS. IBS-C is a subtype characterized mainly by abdominal pain and by hard or lumpy stools at least 25 percent of the time and loose or watery stools less than 25 percent of the time.

Linzess is a capsule taken once daily on an empty stomach, at least 30 minutes before the first meal of the day. Linzess helps relieve constipation by helping bowel movements occur more often. In IBS-C, it may also help ease abdominal pain.

"No one medication works for all patients suffering from these gastrointestinal disorders," said Victoria Kusiak, M.D., deputy director of the Office of Drug Evaluation III in FDA's Center for Drug Evaluation and Research. "With the availability of new therapies, patients and their doctors can select the most appropriate treatment for their condition."

The safety and effectiveness of Linzess for the management of IBS-C were established in two, double-blind studies. A total of 1,604 patients were randomly assigned to take 290 micrograms of Linzess or a placebo for at least 12 weeks. Results showed Linzess was more effective in reducing the amount of abdominal pain and increasing the number of complete spontaneous bowel movements compared with placebo.

The safety and effectiveness of Linzess for the management of chronic idiopathic constipation also were established in two, double-blind studies. A total of 1,272 patients were randomly assigned to take Linzess at doses of 145 mcg or 290 mcg or a placebo for 12 weeks. Results from these studies showed patients taking Linzess experienced more complete spontaneous bowel movements than those taking the placebo. The 290 mcg dose is not approved for chronic constipation because studies indicated it was no more effective than the 145 mcg dose.

Linzess is approved with a Boxed Warning to alert patients and health care professionals that the drug should not be used in patients 17 years of age and younger. The most common side effect reported in during the clinical studies was diarrhea.

Linzess is co-marketed by Ironwood Pharmaceuticals Inc., based in Cambridge, Mass., and Forest Pharmaceuticals Inc.,




http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm317505.htm

Safer Alternatives to Linzess

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Heartburn drugs, NSAID painkillers use linked to IBS symptoms new
      #369351 - 03/18/13 01:24 PM
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PPI, NSAID use linked to IBS symptoms

Keszthelyi D. BMC Gastroenterol. 2012;doi:10.1186/1471-230X-12-121.

October 9, 2012

Patients with IBS reported more use of proton pump inhibitors and nonsteroidal anti-inflammatory drugs before onset of their symptoms than controls in a recent study.


In a retrospective, observational study, researchers evaluated 287 patients with IBS who had been taking one or more proton pump inhibitors (PPIs), nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRI), diuretics or angiotensin-converting enzyme (ACE) inhibitors within 6 months of the onset of IBS symptoms. They were matched by age and sex with 287 controls.

Patients with IBS reported significantly more PPI and NSAID use than controls (21.2% vs. 5.2% for PPIs; 20.55% vs. 3.8% for NSAIDs), and the two medications were more frequently used in conjunction among those with IBS (7.6% of patients compared with 0%, P<.001). SSRI use was also more common among participants with IBS (10.84% vs. 2.1%). Diuretics and ACE inhibitors, included as control medications, were used similarly between groups.

Patients with IBS were significantly more likely to have comorbidities, including psychiatric comorbidities (40.4% compared with 3.5%; OR=16.6; 95% CI, 7.9-34.8) and GERD or functional dyspepsia (25.2% vs. 9.8%; OR=2.0; 95% CI, 1.1-3.5) than controls. Rheumatoid arthritis also was more common among IBS patients (6.1% vs. 0%).

After adjusting for comorbidities, investigators observed significant associations between IBS and PPI (OR=2.1, 1.1-4.1) and NSAID use (OR=5.2, 2.5-11.0), but not with SSRI (OR=0.9, 0.3-2.7). The associations with PPIs and NSAIDs remained significant after excluding patients with psychiatric comorbidities (OR=3.0, 1.3-7.0 for PPIs; OR=4.1, 1.7-9.6 for NSAIDs) and those with RA or arthritis (OR=3.1, 1.5-6.2 for PPIs; OR=5.7, 2.65-12.2 for NSAIDs) from analysis (95% CI for all).

"Prescribing PPIs for upper GI complaints or NSAIDs for pain relief may potentially trigger mechanisms resulting in symptom generation representative for IBS," the researchers wrote. "Further research should include prospective evaluation of PPI users and NSAID users monitoring the development of IBS symptoms in relation to drug exposure to ascertain whether this increased exposure to PPIs and NSAIDs should be considered as legitimate etiological factors in IBS."


http://www.healio.com/gastroenterology/irritable-bowel-syndrome/news/online/%7B48a99177-5185-4271-91f3-98429715516c%7D/ppi-nsaid-use-linked-to-ibs-symptoms

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On Anti-Depressants? Some Raise Risk of C. Diff Infection new
      #369518 - 05/13/13 05:51 PM
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Some Antidepressants May Raise Risk for Gastro Infection

Researchers aren't sure why these meds are linked to chances of contracting C. difficile

TUESDAY, May 7 (HealthDay News) -- People who take certain types of antidepressants may be at higher risk for potentially deadly Clostridium difficile infection, a new study suggests.

This type of infection is one of the most common caught by hospital patients and causes more than 7,000 deaths each year in the United States. Several medications are thought to increase the risk for this infection, including antidepressants.

In this study, University of Michigan researchers examined C. difficile infection in people with and without depression, and found that those with major depression had a 36 percent higher risk than those without depression. Older, widowed people were 54 percent more likely to catch C. difficile than older married people. People who lived alone had a 25 percent higher risk than those who lived with others.

The researchers then investigated if there was a link between antidepressants and C. difficile infection. They found that only two -- Remeron (mirtazapine) and Prozac (fluoxetine) -- increased the risk, and that each drug doubled the risk.

The findings, published May 6 in the journal BMC Medicine, should improve identification and early treatment of C. difficile infection in people taking these antidepressants, the researchers said.

The reason for the increased risk of infection in people taking the antidepressants is unknown, and people who have been prescribed the drugs need to keep taking them unless their doctor tells them otherwise, the researchers said. The research showed an association between antidepressant use and increased risk of contracting the infection, but it did not prove a cause-and-effect link.

"Depression is common worldwide," study leader Dr. Mary Rogers said in a university news release. "We have long known that depression is associated with changes in the gastrointestinal system."

"The interaction between the brain and the gut, called the 'brain-gut axis,' is fascinating and deserves more study," Rogers said. "Our finding of a link between depression and Clostridium difficile should help us better identify those at risk of infection and perhaps encourage exploration of the underlying brain-gut mechanisms involved."

More information

The American Academy of Family Physicians has more about C. difficile infection.

-- Robert Preidt

SOURCE: BMC Medicine, news release, May 6, 2013

Last Updated: May 07, 2013

Health News Copyright © 2013 HealthDay. All rights reserved.

http://consumer.healthday.com/Article.asp?AID=676154

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Older drugs are better than new ones new
      #369613 - 06/13/13 02:00 PM
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New drugs trail many old ones in effectiveness against disease


By Sharon Begley

NEW YORK ' Mon Jun 3, 2013 4:04pm EDT

(Reuters) - Despite the more than $50 billion that U.S. pharmaceutical companies have spent every year since the mid-2000s to discover new medications, drugmakers have barely improved on old standbys developed decades ago.

Research published on Monday showed that the effectiveness of new drugs, as measured by comparing the response of patients on those treatments to those taking a placebo, has plummeted since the 1970s.

While that is already unwelcome news to drug and biotech companies, the consequences for the pharmaceutical industry could get worse under President Barack Obama's healthcare law.

The law established an independent research institute to compare the effectiveness of different treatments for the same condition. That way, patients as well as private insurers and government programs such as Medicare can stop paying for less effective therapies. If the new analysis is correct, then "comparative effectiveness research" could conclude that older drugs, which are more likely to be generics, are better than pricey new brand names that deliver the most profits for drugmakers.

Fears of a crisis in drug innovation have grown over the years. When the healthcare journal Prescrire in 2011 ranked new drugs, only 17 of the 984 developed since 2001 were deemed "a real advance" or better. And a survey of 184 expert physicians in 15 specialties published last month in Nature Reviews Drug Discovery showed the doctors were more likely to rate drugs more than a decade old as "transformative."

To be sure, drugs that completely change outcomes for patients continue to emerge. Gleevec, from Novartis, greatly extends life for leukemia patients, for instance. New antivirals such as Incivek from Vertex Pharmaceuticals have doubled the cure rate in hepatitis C, and Eylea from Regeneron Pharmaceuticals is better than anything previously developed for macular degeneration.

Because of those and other examples, "we believe that a lot continues to be accomplished in terms of yielding very, very positive results for patients, so there seems to be a disconnect between that and this paper," said Randy Burkholder, deputy vice president of policy at the Pharmaceutical Research and Manufacturers of America (PhRMA) trade group.

CANCER TO MENTAL ILLNESS

The new study in the journal Health Affairs examined 315 clinical trials that compared a drug to a placebo and were published in four of the world's top medical journals (BMJ, Journal of the American Medical Association, Lancet and New England Journal of Medicine) from 1966 to 2010. The drugs targeted the full range of human ills, from cardiovascular disease and infections to cancer, mental disorders and respiratory illness.

In the early years, drugs easily beat the placebo: They were, on average, 4.5 times as effective, where effectiveness means how well they lowered blood pressure, vanquished tumors, lifted depression or did whatever else they were intended to.

But the trend line was inexorably downhill, found Dr Mark Olfson of Columbia University and statistician Steven Marcus of the University of Pennsylvania. By the 1980s drugs were less than four times better; by the 1990s, twice as good, and by the 2000s just 36 percent better than a placebo. Since older drugs were much superior to placebo and newer ones only slightly so, that means older drugs were generally more effective than newer ones.

"Their results are pretty compelling," said Dr Aaron Kesselheim of Harvard Medical School, who helped conduct the survey of physicians on "transformative" drugs but was not involved in this study. "It does appear that things are headed in the same direction, with newer drugs having relatively less efficacy."

Experts disagree on why that should be, but suspicions range from the U.S. regulatory process to basic biology.

"It may be that the drug discoveries based on low-hanging fruit were made long ago," said Olfson, as with discoveries based on the most basic or easily targeted causes of high blood pressure. In that case, older drugs based on those targets would pack a bigger punch than newer ones that target less-central causes of disease.

Or, it could be that the patients who volunteer for clinical trials have gotten harder to treat. In many cases, people volunteer because existing drugs are not helping their cancer, schizophrenia or other condition, Olfson said, "and may have forms of the disease where it's harder for a drug to demonstrate a benefit."

Another explanation could be that the scientific quality of clinical trials has improved over the decades, as the Health Affairs analysis found. Human studies in the 2000s were more likely than those in the 1960s to enroll hundreds of patients rather than dozens.

"It may be that the compounds aren't getting less effective but that they're getting looked at more carefully," said Dr Harold Sox of the Dartmouth Institute for Health Policy and Clinical Practice and former editor of the Annals of Internal Medicine.

'SOMETHING REAL IS GOING ON'

While experts agree that tougher trials and similar factors explain some of the decline in drugs' reported effectiveness, "something real is going on here," said Olfson. "Physicians keep saying that many of the new things just aren't working as well," and therefore prescribe antidepressant drugs called tricyclics (developed in the 1950s) instead of SSRIs (from the 1980s), or diuretics (invented in the 1920s) for high blood pressure instead of newer anti-hypertensives.

Whatever the reason for many new drugs packing less punch than old ones, that will not keep them from reaching patients.

"The way the drug regulatory system is set up, even if you have just a small advance, if you market it right it can be very profitable," said Kesselheim.

Critics of the high prices of drugs that are only marginally (if at all) more effective than older, cheaper, often generic medications hope that head-to-head studies will persuade more physicians to stop prescribing expensive but less effective drugs. The Affordable Care Act of 2010 - "Obamacare" - established the Patient Centered Outcomes Research Institute (PCORI) to conduct such comparative effectiveness research.

The drug industry says it isn't worried. "Our sector is not concerned about objective, high-quality patient-centered comparative effectiveness research," said PhRMA's Burkholder. "We believe the substantial value of our products will continue to be demonstrated."

(Reporting by Sharon Begley; Editing by Michele Gershberg and Douglas Royalty)

http://www.reuters.com/article/2013/06/03/us-drugs-effectiveness-idUSBRE95213D20130603

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Proton pump inhibitor (acid reflux drugs) may cause heart disease new
      #370282 - 09/23/13 03:22 PM
HeatherAdministrator

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Acid reflux drug may cause heart disease, study suggests

ScienceDaily, 07/11/2013

Drugs that help millions of people cope with acid reflux may also cause cardiovascular disease, report scientists from Houston Methodist Hospital and two other institutions in an upcoming issue of Circulation (now online). It is the first time researchers have shown how proton pump inhibitors, or PPIs, might cause cardiovascular problems. In human tissue and mouse models, the researchers found PPIs caused the constriction of blood vessels. If taken regularly, PPIs could lead to a variety of cardiovascular problems over time, including hypertension and a weakened heart. In the paper, the scientists call for a broad, large–scale study to determine whether PPIs are dangerous. "The surprising effect that PPIs may impair vascular health needs further investigation," said John Cooke, M.D., Ph.D., the study's principal investigator. "Our work is consistent with previous reports that PPIs may increase the risk of a second heart attack in people that have been hospitalized with an acute coronary syndrome. Patients taking PPIs may wish to speak to their doctors about switching to another drug to protect their stomachs, if they are at risk for a heart attack."


http://www.mdlinx.com/gastroenterology/newsl-article.cfm/4720792/ZZ956160859472514387259/?news_id=0&newsdt=092313&utm_source=monthly-top-articles&utm_medium=newsletter&utm_content=related-arts&utm_campaign=related-arts-section

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Antidepressants, psychological therapies effectively treated IBS new
      #371281 - 07/15/14 02:49 PM
HeatherAdministrator

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Antidepressants, psychological therapies effectively treated IBS

Ford AC. Am J Gastroenterol. 2014;doi:10.1038/ajg.2014.148.

July 9, 2014

Antidepressants and various psychological therapies effectively treated symptoms of irritable bowel syndrome in a recent study.

"IBS affects as many as one in ten people, and is difficult to treat,"Alexander C. Ford, MBChB, MD, FRCP, associate professor, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, told Healio.com/Gastroenterology. "Tricyclic antidepressants probably work in IBS, but more studies that are rigorously designed are required. Psychological therapies may also work, particularly hypnotherapy, but access to these is limited."

Armed with more current research, Ford and colleagues performed an updated systematic review and meta-analysis of randomized controlled trials (RCTs) collected from several databases up to December 2013. Studies that compared antidepressants or psychological therapies with placebo or controls in patients with IBS aged 16 years or older were included. Of the 46 studies analyzed, 10 psychological therapy trials and four antidepressant RCTs were published after the researchers' previous meta-analysis.
Alexander C. Ford, MD

Alexander C. Ford

Among the 17 included antidepressant RCTs evaluating 1,084 patients, 10 studied tricyclic antidepressants, six studied selective serotonin reuptake inhibitors and one studied both. A combined 43.9% of the antidepressant groups reported unimproved symptoms compared with 65% of the placebo groups. The relative risk for unimproved IBS symptoms after using antidepressants vs. placebo was 0.67 (95% CI, 0.58-0.77), with heterogeneity observed between studies (P=.06).

Cognitive behavioral therapy, relaxation therapy, hypnotherapy, multicomponent psychological therapy, dynamic psychotherapy, meditation therapy and stress management were among the 30 articles comparing psychological therapies with controls (n=2,189). Controls received symptom monitoring, "usual management" or supportive therapy. A pooled 51.9% of therapy groups reported unimproved symptoms compared with 76.1% of controls. The RR of symptoms that failed to improve with psychological therapy vs. controls was 0.68 (95% CI, 0.61-0.76); heterogeneity was observed between studies (P<.001).

"Despite the considerable number of studies published in the intervening 5 years since we last examined this issue, the overall summary estimates of treatment effect have remained almost identical," the researchers concluded. "The findings that antidepressants, as well as many of the psychological therapies we studied, are beneficial in IBS has implications for the management of a condition that clinicians often find challenging, and should encourage increased use of antidepressants by gastroenterologists and promote efforts to improve access for both patients and physicians to psychological therapies."

Learn more about hypnotherapy for all IBS symptoms





http://www.healio.com/gastroenterology/irritable-bowel-syndrome/news/online/%7B110d7145-1069-472f-8140-0dfba6d00c5a%7D/antidepressants-psychological-therapies-effectively-treated-ibs

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Antibiotics Early in Life May Boost Obesity Risk new
      #371358 - 08/18/14 03:13 PM
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Antibiotics Early in Life May Boost Obesity Risk

Published: Aug 17, 2014
By Salynn Boyles, Contributing Writer, MedPage Today
Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

Exposure to antibiotics early in life may permanently alter gut microbes in a way that could increase obesity risk years later, researchers reported.

In a study that compared outcomes in mice given low-dose penicillin versus those who were not, infancy was identified as a critical window of host-microbe metabolic interaction, suggesting that early-life antibiotic exposure can lead to lifelong metabolic changes, wrote Martin Blaser, MD, of NYU Langone Medical Center in New York City, and colleagues in the Aug. 14 issue of Cell.

This new finding expands on previous research by Blaser's group that tied antibiotic treatment from birth to accelerated growth in mice.

"We showed that the earlier we gave the antibiotic, the stronger the effect, and when we combined antibiotics with a high-fat diet the effect was potentiated and the mice got very fat," Blaser told MedPage Today. "We also showed that the metabolic effects remained when antibiotics were given for just 4 weeks in infancy, suggesting that early life exposure can have lifelong effects."

The Antibiotic-Obesity Link

Early life has been shown to be a critical period for metabolic development, and several epidemiological studies suggested a link between early antibiotic exposure to an increase in overweight status later in childhood, the researchers wrote.

Earlier this month, a study published in the International Journal of Obesity found exposure to antibiotics during the first year of life to be associated with a small increase in body mass index (BMI) in boys between the ages of 5 and 12, but not girls.

Blaser's team has studied the impact of antibiotic use on animal and human microbiome and how microbiome alteration impacts health for several years.

Microbes begin to colonize in the gut at birth, and Blaser and colleagues hypothesized that disruption of these communities with antibiotics early in life have long-term effects on weight and the risk for diseases associated with obesity, such as diabetes.

"For decades, farmers have been exposing livestock to low doses of antibiotics to promote growth; the earlier in life that exposure begins the more profound the effects," they wrote.

For the current study, they examined antibiotic exposure timing in an effort to determine if a critical window of exposure exists. They also addressed whether synergies exist between antibiotic exposure and dietary effects, and whether microbiota alterations are sufficient to impact metabolic phenotypes.

"Hypothesizing that early life was the critical period for programming host-microbe metabolic interactions, we sought to determine whether microbiota disruption limited to early life could induce metabolic effects," the researchers wrote. "In addition to long-term (28 week) low-dose penicillin (LDP) or none (control), groups of mice received 4 or 8 weeks of LDP, and to accelerate metabolic phenotypes, all were switched to high-fat diet (HFD) at 6 weeks of age."

Penicillin Altered Ileal Tissue

In female mice, all three low-dose penicillin groups developed elevated total, lean, and fat mass compared to controls, irrespective of low-dose penicillin duration. Compared to controls, following switch to high-fat diet, female low-dose penicillin mice had significantly elevated caloric intake and significantly faster total and fat mass accumulation rates from 6 to 20 weeks of age.

Later in life (weeks 20-28), all three low-dose penicillin groups showed significantly slower rates in lean mass growth compared to controls, indicating catch-up by the control mice.

Male mice on low-dose penicillin showed early elevations in total, lean, and fat mass but did not have increased food intake or feed efficiency from 6 to 8 weeks of age. The early-life changes in body composition were lost with age, which was consistent with an earlier reported increased early-life and gender-dependent sensitivity to high-fat diet that may override microbe-mediated effects, the researchers noted.

"By age 4 weeks, LDP induced substantial histopathologic effects in ileal tissues, notably shortened villi, which is consistent with changed ileal architecture in LDP-mediated livestock growth promotion," the researchers wrote. "Transcriptional profiling analysis of intestinal tissue by microarray and subsequent validation by Nanostring analysis revealed that the ileal atrophy from LDP was associated with a general decreased expression of genes involved in intestinal immune responses, with numerous consistencies across gender."

"Low-dose penicillin decreased expression of genes related to several biological functions, such as differentiation, activation, recruitment, and adhesion of immune cells, and functions specifically related to androgen-presenting cells, T cells, B cells and phagocytic cells," they explained.

High-Fat Diet Exacerbated Changes

Antibiotic exposure also induced numerous compositional changes in the microbiota, and introduction of the high-fat diet had further effects. After antibiotics were stopped in the mice given low-dose penicillin for both 4 and 8 weeks, the patterns associated with high-fat diet exposure of the control mice began to emerge, the group stated, but were never present in mice exposed to 28 weeks of low-dose penicillin.

"The persistent phenotypes after LDP cessation, despite microbiota normalization, provide evidence that the early-life microbiota influences adult body composition," the researchers wrote.

Low-dose penicillin suppressed early-life Lactobacillus, Allobaculum, Rikenellaceae, and Candidatus Arthromitus. This finding suggests a protective role for these organisms in the modulation of host metabolism.

"All microbiota members do not equally impact the host; prior studies indicate that these four organisms have either metabolic and/or immunologic interactions which may contribute to the observed protection from weight gain in the control animals," the researchers wrote.

Future Plans

Blaser's team is currently conducting research designed to determine if re-introducing these bacteria following antibiotic therapy will impact weight gain.

"Our findings imply that restoring good bacteria could prevent the long-term metabolic effects of early antibiotic exposure," stated co-author Laura M. Cox, PhD, in an accompanying statement.

Blaser said some combination of these bacteria or others that have not yet been identified could prove critical in early-life metabolic protection.

He added that the research team is also investigating the impact of early antibiotic use on diabetes risk.

In a prospective study reported earlier this summer, a different group of researchers showed that composition of gut bacteria in patients with type 2 diabetes differed from those of people without the disease.

Obese patients and those with diabetes had lower proportions of the bacteria Firmicutes, Bifidobacteria, and Clostridium Leptum, compared to healthy controls, Yalcin Basaran, MD, of Gulhane Military Medical Academy in Ankara, Turkey, and colleagues reported at the joint meeting of the Endocrine Society and the International Congress on Endocrinology in Chicago.

The analysis revealed that metabolic parameters such as weight (P<0.001), BMI (P<0.001), HbA1c (P=0.011), waist circumference (P<0.001), and fasting blood glucose (P=0.005) were significantly associated with reduced levels of these three types of bacteria in the gut.

Blaser said all of these studies point to an important developmental window early in life during which antibiotic exposure can have long-term effects on metabolism.

"We can't say what this window is, but the epidemiological studies have focused on the first year of life," he said. "Physicians need to know that antibiotics use could have long-term costs, and this needs to be factored into decisions about when to use them."

http://www.medpagetoday.com/Endocrinology/GeneralEndocrinology/47252?xid=nl_mpt_DHE_2014-08-18&utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=ST&eun=g379602d0r&userid=379602&email=heather%40helpforibs.com&mu_id=5372841&utm_term=Daily

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Medical Marijuana for Digestive Disorders: High Time to Prescribe? new
      #371473 - 09/17/14 02:08 PM
HeatherAdministrator

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Medical Marijuana for Digestive Disorders: High Time to Prescribe?


The American Journal of Gastroenterology , (9 September 2014) ' doi:10.1038/ajg.2014.245


Mark E Gerich, Robert W Isfort, Bryan Brimhall and Corey A Siegel

The use of recreational and medical marijuana is increasingly accepted by the general public in the United States. Along with growing interest in marijuana use has come an understanding of marijuana's effects on normal physiology and disease, primarily through elucidation of the human endocannabinoid system. Scientific inquiry into this system has indicated potential roles for marijuana in the modulation of gastrointestinal symptoms and disease. Some patients with gastrointestinal disorders already turn to marijuana for symptomatic relief, often without a clear understanding of the risks and benefits of marijuana for their condition. Unfortunately, that lack of understanding is shared by health-care providers. Marijuana's federal legal status as a Schedule I controlled substance has limited clinical investigation of its effects. There are also potential legal ramifications for physicians who provide recommendations for marijuana for their patients. Despite these constraints, as an increasing number of patients consider marijuana as a potential therapy for their digestive disorders, health-care providers will be asked to discuss the issues surrounding medical marijuana with their patients.

http://www.nature.com/ajg/journal/vaop/ncurrent/pdf/ajg2014245a.pdf

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Amitiza benefited patients with chronic idiopathic constipation new
      #371886 - 02/10/15 04:15 PM
HeatherAdministrator

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Amitiza benefited patients with chronic idiopathic constipation

Fukudo S, et al. Clin Gastroenterol Hepatol. 2015;doi:10.1016/j.cgh.2014.08.026.
February 4, 2015



Amitiza, a novel type 2 chloride channel activator, increased the frequency of spontaneous bowel movement and quality of life in patients with chronic idiopathic constipation, according to phase 3 trial data.
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Aiming to confirm the safety and efficacy of Amitiza (lubiprostone, Sucampo Pharmaceuticals) in Japanese patients with chronic idiopathic constipation, researchers performed a randomized, double blind, placebo-controlled trial involving 124 patients from 11 centers with chronic idiopathic constipation who received either 48 µg/day lubiprostone or placebo for 4 weeks. A second component of the study was a nonmasked long-term safety trial involving 209 patients with chronic idiopathic constipation at 17 centers who received 24 µg lubiprostone twice a day for 48 weeks. Patients completed a daily diary and questionnaires to report spontaneous bowel movement frequency and symptoms.

In the first part of the study, lubiprostone increased weekly average number of spontaneous bowel movements at week 1 (3.7 ± 2.8) compared with placebo (1.3 ± 1.8; P < .001), and patients reported greater changes from baseline in week 2 (P < .001), week 3 (P = .005) and week 4 (P = .042). The proportion of patients who reported first spontaneous bowel movement within 24 hours of taking lubiprostone was higher compared with placebo (P = .004), time to first spontaneous bowel movement was shorter (P = .027), and the proportion of patients who reported four or more spontaneous bowel movements during the first week was higher (75.4% vs. 29%; P < .001). Patients in the lubiprostone group also had better outcomes in constipation severity, treatment effectiveness and stool consistency.

In the second part of the study, frequency of spontaneous bowel movements increased compared with baseline in the lubiprostone group at all weeks throughout the study period (P < .0001). Irritable bowel syndrome quality of life (QOL) scores were increased at weeks 24 and 48 compared with baseline (both P < .0001) and significant increases in Short-Form health survey scores were also observed.

In the first part of the study, lubiprostone patients had more adverse drug reactions compared with placebo (41.9% vs. 16.1%; P = .003), but most were mild (diarrhea, P = .003; nausea, P = .017). In the second part of the study, 73.2% reported adverse drug reactions. No related severe adverse events were observed.

"In conclusion, lubiprostone 48 µg/d (24 µg twice daily) showed statistically significant and clinically meaningful improvements in constipation signs and symptoms in patients with [chronic idiopathic constipation], and was associated further with a favorable safety and tolerability profile in a Japanese population," the researchers wrote. "Results from these studies also suggest that lubiprostone improves health-related QOL in patients with [chronic idiopathic constipation] with long-term use." – by Adam Leitenberger

Disclosure: This trial was funded by Sucampo Pharma. Fukudo and other researchers report being paid consultants for Sucampo Pharma, and another researcher reports being a former director of Sucampo AG, a former employee of Sucampo Pharma Americas and a current shareholder of Sucampo Pharmaceuticals.


http://www.healio.com/gastroenterology/motility/news/online/%7Bafecda4e-8a96-41c8-9933-0cac1c9c0b01%7D/amitiza-benefited-patients-with-chronic-idiopathic-constipation

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Low-dose naltreoxone for the treatment of irritable bowel syndrome new
      #372675 - 01/26/16 01:20 PM
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Dig Dis Sci. 2006 Dec;51(12):2128-33. Epub 2006 Nov 1.

Low-dose naltreoxone for the treatment of irritable bowel syndrome: a pilot study.

Kariv R1, Tiomny E, Grenshpon R, Dekel R, Waisman G, Ringel Y, Halpern Z.

Preclinical studies have shown that a very low dose of naltreoxone hydrochloride (NTX), an opiate antagonist, can block excitatory opioid receptors without affecting inhibitory opioid receptors, resulting in analgesic potency without side effects. The present study assessed the efficacy and safety of PTI-901 (low-dose NTX) treatment in Irritable bowel syndrome (IBS) patients.

Forty-two IBS patients participated in an open-label study. Participants received 0.5 mg PTI-901/day for 4 weeks and were evaluated during baseline, during treatment, and at 4-week follow-up. Patients recorded degree of abdominal pain, stool urgency, consistency, and frequency. Primary outcomes were number of pain-free days and overall symptom relief, evaluated by a global assessment score.

Data were analyzed per protocol. Global assessment improved in 76% of 42 patients. During treatment, the mean weekly number of pain-free days increased from 0.5+/-1 to 1.25+/-2.14 (P=0.011). There were no significant adverse reactions. PTI-901 improves pain and overall feeling, and is well tolerated by IBS patients. A large, randomized, double-blind, placebo-controlled study is justified.

PMID:
17080248
[PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/17080248

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Mixed Opioid Agent Adds to Growing List of Therapies for IBS-D new
      #372676 - 01/27/16 02:48 PM
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Medscape Medical News

Mixed Opioid Agent Adds to Growing List of Therapies for IBS-D

Pam Harrison
January 27, 2016

Eluxadoline (Viberzi, Allergan), a new oral agent with mixed opioid effects, has met fairly stringent criteria for treatment response in men and women with irritable bowel syndrome (IBS) with predominant diarrhea, according to two phase 3 clinical trials published in the January 21 issue of the New England Journal of Medicine.

"Our primary outcome measure required simultaneous improvement in the daily scores for the worst abdominal pain and stool consistency on the same day for at least 50% of the days assessed; this end point is currently one of those recommended by the regulatory agencies in the United States and Europe to show treatment effect in trials involving patients with IBS and diarrhea," Anthony Lembo, MD, from Harvard Medical School, Boston, Massachusetts, and colleagues write.

"Patients who received eluxadoline reported a decrease in stool frequency and in urgency, which are two of the most bothersome symptoms of IBS with diarrhea."

The investigators randomly assigned 2427 adults with IBS and diarrhea to eluxadoline at a dose of 75 or 100 mg or placebo, twice a day, for 26 weeks (the IBS-3002 trial), or to the same three treatment groups for 52 weeks (IBS-3001 trial). Safety data were collected for 26 weeks in the IBS-3002 trial and for 52 weeks in the IBS-3001 trial. Loperamide was allowed as needed during the double-blind study interval, but patients were told they could take no more than four doses over the course of 24 hours.

From weeks 1 through 12, the proportion of patients receiving either dose of eluxadoline in the IBS-3001 trial who achieved a US Food and Drug Administration (FDA) end-point response was significantly greater, at 23.9% among those receiving the 75-mg dose and 25.1% for those receiving the 100-mg dose, compared with 17.1% of placebo controls (P = .01 and P = .004, respectively).

From weeks 1 through 26, the proportion of patients in the IBS-3001 trial receiving active treatment who reached the European Medicines Agency end-point response was higher in both dosing groups, at 23.4% in the 75-mg group and 29.3% for the 100-mg group compared with 19.0% for control patients receiving placebo (P = .11 and P < .0001, respectively).

In the IBS-3002 trial, 30.4% of those in the 75-mg group and 32.7% in the 100-mg group similarly reached a European Medicines Agency end-point response compared with 20.2% of placebo controls (P = .001 and P < .001, respectively).

"In addition, both doses of eluxadoline were significantly superior to placebo with respect to stool consistency, frequency, and urgency, although no significant reduction in episodes of incontinence was noted," the investigators observe.

The superior response to eluxadoline over placebo was seen within the first week of treatment, they add.

Continue Reading

http://www.medscape.com/viewarticle/857809


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FDA approves new drug for chronic constipation new
      #373523 - 01/26/17 03:05 PM
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FDA approves new treatment for chronic constipation

January 20, 2017

Trulance received FDA approval for the treatment of chronic idiopathic constipation, according to press releases from the manufacturer and the FDA.

"The impact of chronic constipation on the lives of affected patients is often underestimated," William D. Chey, MD, co-director of the Michigan Bowel Control Program at the University of Michigan and Healio Gastroenterology Peer Perspective Board member, said in a press release. "Trulance presents an exciting new treatment option for patients with chronic constipation. Its efficacy and safety profile, plus its negligible systemic absorption, are attractive attributes that make it a welcome addition to our treatment options."

The FDA approved Trulance (plecanatide, Synergy Pharmaceuticals) at a 3-mg dose, taken orally once a day with or without food. The drug works in the upper GI tract to mimic uroguanylin and improve regular bowel function.

Approval came after two randomized, double blind, placebo-controlled clinical trials in which efficacy was studied in more than 2,600 patients and safety in more than 2,700. Patients were diagnosed with chronic idiopathic constipation (CIC) due to producing less than three spontaneous bowel movements (SBM) per week in the previous 3 months.

The efficacy responder rate — defined as at least three complete SBM in a given week and at least one CSBM over baseline in the same week for at least 9 weeks — was greater in both studies compared with placebo (21% vs. 10% and 21% vs. 13%; both P < .005). Those treated with plecanatide showed improvement in stool frequency, stool consistency and straining.

The FDA and manufacturer noted diarrhea as the most common adverse reaction (5% vs. 1% in placebo). Due to the risk for dehydration and lack of safety and efficacy data, the FDA said plecanatide should not be used in pediatric patients aged younger than 6 years and avoided from age 6 to age 18.

"No one medication works for all patients suffering from chronic gastrointestinal disorders," Julie Beitz, MD, director of the Office of Drug Evaluation III in the FDA's Center for Drug Evaluation and Research, said in the FDA press release. "With the availability of new therapies, patients and their doctors can select the most appropriate treatment for their condition."

Synergy Pharmaceuticals said the medication will be available for CIC patients in the U.S. this quarter. It is also being studied in IBS-C, according to the company. – by Katrina Altersitz

Disclosures: Beitz is an employee of the FDA. Chey reports he is a consultant for Albreio, Allergan, Ardelyx, IM Health, Ironwood, Nestle, Prometheus, QOL Medical, Salix, Syn Biologic and Takeda, and has received grant or research support from Ironwood, Nestle, Perrigo and Prometheus.


http://www.healio.com/gastroenterology/motility/news/online/%7B7113d768-8a31-4238-b2bd-8b0a8af012cf%7D/fda-approves-new-treatment-for-chronic-constipation?utm_source=maestro&utm_medium=email&utm_campaign=gastroenterology%20news

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Heather is the Administrator of the IBS Message Boards. She is the author of Eating for IBS and The First Year: IBS, and the CEO of Heather's Tummy Care. Join her IBS Newsletter. Meet Heather on Facebook!

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Long-term cannabis use increases risk for IBS new
      #373628 - 10/19/17 04:04 PM
HeatherAdministrator

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Long-term cannabis use increases risk for IBS
October 18, 2017

ORLANDO — Cannabis use increased the risk for irritable bowel syndrome in the general population, according to a poster presented at the World Congress of Gastroenterology at ACG 2017. Additionally, the effects may be worse among men, Caucasians and Hispanics.

To determine the association between long-term cannabis use and the endogenous cannabinoid system, researchers analyzed 4,709,043 patients from the 2014 Nationwide Inpatient Survey. They found 0.03% had a primary admission for IBS and 1.32% for cannabis use disorder.

Cannabis use disorder was correlated with an increased risk for IBS (OR = 2.03; 95% CI, 1.53-2.71). The risk increased for men (OR = 3.48; 95% CI, 1.98-6.12) compared with women (OR = 1.48; 95% CI, 0.88-2.5) and among Caucasians (OR = 5.28; 95% CI, 1.77-15.76) and Hispanics (OR = 1.8; 95% CI, 1.02-3.18) compared with African-Americans (OR = 1.8; 95% CI, 0.65-5.03).

Following propensity matched analysis, the researchers found that cannabis use disorder was correlated with an 80% increased risk for IBS (OR = 1.82; 95% CI, 1.27-2.6).

Recently, Healio.com/Hepatology reported that chronic use of cannabinoid derivatives was also correlated with increased cannabinoid hyperemesis syndrome, which is categorized by episodes of severe nausea and cyclical vomiting. Symptoms improved with cannabis cessation. – by Talitha Bennett

Reference: Adejumo A, et al. P1150. Presented at: World Congress of Gastroenterology at American College of Gastroenterology Annual Scientific Meeting; Oct. 13-18, 2017; Orlando, FL.

Disclosure: Adejumo reports no relevant financial disclosures.


https://www.healio.com/gastroenterology/irritable-bowel-syndrome/news/online/%7Bfd43c6f4-62df-4d90-9c3a-d120678a2cdd%7D/long-term-cannabis-use-increases-risk-for-ibs

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Heather is the Administrator of the IBS Message Boards. She is the author of Eating for IBS and The First Year: IBS, and the CEO of Heather's Tummy Care. Join her IBS Newsletter. Meet Heather on Facebook!

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FDA OKs Reintroduction of Tegaserod (Zelnorm) for IBS-C in Women Under 65 new
      #373839 - 04/04/19 02:45 PM
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Bedminster, NJ, July 8, 2019 - https://www.alfasigmausa.com/zelnorm/

Alfasigma USA Acquires ZELNORMTM (tegaserod) for Reintroduction to the US Market

Alfasigma USA has acquired the brand ZELNORM (tegaserod), a treatment for IBS-C, from Sloan Pharma

In March 2019, ZELNORM was approved for reintroduction by the FDA for the treatment of adult women less than 65 years of age with IBS-C.

Alfasigma USA plans to relaunch the brand in the United States, making ZELNORM available by prescription in the coming weeks.

Megan Brooks - April 02, 2019

The US Food and Drug Administration (FDA) has approved the reintroduction of tegaserod oral tablets (Zelnorm, Sloan Pharma) for irritable bowel syndrome with constipation (IBS-C) in women younger than age 65, US WorldMeds Holdings has announced.

"We are excited about what the reintroduction of Zelnorm means for patients suffering from irritable bowel syndrome with constipation. We have continually heard from patients and clinicians alike that the IBS-C community is eager to have Zelnorm return to the US a s an available treatment option," P. Breckinridge Jones, CEO of US WorldMeds, said in the news release.

"The re-approval of Zelnorm is very good news for patients. We believe it will provide renewed access to a treatment option where other new medications have been insufficient for meeting patients' needs," added Jeffery Roberts, patient advocate and founder of the IBS Patient Group.
Checkered Past

Tegaserod for IBS-C has had a checkered past. The drug was first approved by the FDA in 2002 for the short-term treatment of women with IBS-C. It was suspended from the US market in March 2007 due to potential cardiovascular (CV) safety concerns.

In July 2007, the FDA announced that it would allow restricted use of the drug for IBS-C and chronic idiopathic constipation in women younger than 55 years with no history of heart problems.

Last October, following a safety review, the FDA's Gastrointestinal Drugs Advisory Committee (GIDAC) recommended overwhelmingly (11 yes, 1 no) to recommend reintroducing tegaserod for IBS-C in women without a history of CV ischemic disease and who have no more than one risk factor for CV disease.

The committee reviewed clinical data from 29 placebo-controlled trials and newly-available sources of treatment outcome data.

Pooled data from the clinical trials showed a statistically nonsignificant trend toward increased angina among those who took the drug in the clinical trial on which the drug's approval was based in 2002; however, a recent analysis of 18,000 participants in the entire clinical database found adverse CV events in 13 of 11,614 patients (0.11%) taking tegaserod, compared with only one patient (0.01%) out of 7031 in the placebo group, a difference that was statistically significant, according to information in an FDA briefing document for the committee.

"While an imbalance in CV safety events associated with tegaserod was noted, the strength of the signal was difficult to interpret due to limitations of the meta-analysis â€" for example, the trials were not designed to specifically evaluate CV safety, were of short duration, included a low CV-risk population, and involved retrospective assessment of CV information. In addition, the etiology of [CV ischemic] events related to the use of tegaserod is not well understood," the FDA explained in the briefing document.

Tegaserod is the only selective serotonin-4 (5-HT4) receptor agonist approved to treat IBS-C, US WorldMeds notes in the release.

In clinical trials, patients taking tegaserod experienced improvement in some of the most bothersome IBS-C symptoms; in the first 4 weeks, significantly more tegaserod-treated patients than placebo-treated patients reported an improvement in abdominal pain/discomfort and bloating. The frequency of bowel movements also increased from a median number of 3.8 per week at baseline to 6.3 per week at month 1, the company said.

Zelnorm will be available by prescription for patients in the coming months, according to the company.

See Safer Alternatives to Zelnorm


https://www.medscape.com/viewarticle/911237





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Heather is the Administrator of the IBS Message Boards. She is the author of Eating for IBS and The First Year: IBS, and the CEO of Heather's Tummy Care. Join her IBS Newsletter. Meet Heather on Facebook!

Edited by Heather (08/20/19 03:31 PM)

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Cannabis could help a person defecate new
      #373944 - 04/14/20 12:17 PM
HeatherAdministrator

Reged: 12/09/02
Posts: 7793
Loc: Seattle, WA

Does cannabis make you poo?
Meg Hartley
April 13, 2020

Between cannabis calming our nerves, its effect on the gut’s microbiome, and the endocannabinoid system being involved in the activity in this department, it looks like weed can, indeed, make us poo.

I spoke with medical cannabis expert and integrative medicine physician Dustin Sulak, D.O. “Endocannabinoids absolutely do affect motility, both directly and indirectly. The most powerful way in which cannabis could help a person defecate is by helping them to relax and get into a more parasympathetic state,” said Sulak.

Another way to think of a parasympathetic state is “rest and digest,” with defecation being part of the digest aspect. This is opposed to the sympathetic nervous system, which prepares the body to act quickly. There is an evolutionary reason for not being able to poo while in a fight-or-flight state enacted by the sympathetic nervous system: “If we’re escaping from a bear attacking us, we don’t want to have to defecate,” said Sulak.

He continued, “Conversely, when it’s time to relax and empty our bowels, we don’t want to feel threatened. That has to happen in a place where we feel comfortable. But, unfortunately, a lot of people are taking their stressors around with them, even into the bathroom, with their phones or just in their minds, remaining stressed out, feeling threatened in some way.”

But cannabis, and endocannabinoids that our bodies produce, can help. “Our inner pharmacy’s version of cannabis, the endocannabinoids, and herbal cannabis, have the ability to suppress this excessive sympathetic activity. So if the fight-or-flight response is turned on too strongly, the right dose of cannabis can suppress it. This is obvious to people who use cannabis to help them relax and find relief from anxiety. The same mechanism would allow someone to shift into rest and digest, or parasympathetic dominance, and get the job done,” he said.

The Goldilocks zone

Endocannabinoids help keep the body in balance. One of those endocannabinoids, 2-AG, is an important physiologic regulator of gastrointestinal motilityâ€"i.e., poopingâ€"and behaves like THC. “That’s one of our body’s signaling molecules that mimics THC, or THC mimics it. 2-AG is active in regulating the sympathetic and parasympathetic influence on the gut, and in the gut itself, where it suppresses excessive activity and brings the system into balance,” said Sulak.

So in this way, cannabis could lead to a deuce by helping keep our nervous system and our gut in the “Goldilocks zone,” or the healthy range of activity.

Cannabis can also help someone get into the needed relaxed state by relieving pain. “When people are in chronic pain, even if it has nothing to do with the rectumâ€"if it’s their foot or their leg or their headâ€"that still creates a kind of threatening internal state. So it can be hard when in pain or feeling anxiety to relax enough to use the bathroom. Cannabis can be very useful for that,” said Sulak.

Dr. Sulak concluded with a word of caution: “For people with constipation not related to stress or pain, cannabis could potentially worsen the issue because it can suppress muscular contractions and secretion in the colon, the same ways in which it can help with diarrhea.”

The endocannabinoid system (ECS) is also integral to the brain-gut axis, which modulates activity in this realm, including helping people poop. This 2016 study says that the ECS is “An important physiologic regulator of gastrointestinal motility,” meaning bowel movements.

Foremost psychopharmacology researcher Ethan Russo, M.D., also told us, “A lot of people note easier bowel movements after cannabis. This can alleviate both constipation or diarrhea associated with irritable bowel syndrome, a presumptive clinical endocannabinoid deficiency syndrome. THC also positively alters the gut microbiome and this effect should not be discredited.”

Additionally, a 2019 study found that cannabis consumption was associated with a 30% decrease in constipation.

https://www.leafly.com/news/health/does-marijuana-make-you-poo


--------------------
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For IBS Patients, Cannabis Linked to Fewer Rehospitalizations new
      #373947 - 05/05/20 02:14 PM
HeatherAdministrator

Reged: 12/09/02
Posts: 7793
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For IBS Patients, Cannabis Linked to Fewer Rehospitalizations, Shorter Stays
30-day readmission rate and overall costs were lower in cannabis users

by Diana Swift, Contributing Writer May 5, 2020

Cannabis use may help ease symptoms of irritable bowel syndrome (IBS) that are strong enough to send patients to the hospital, an analysis of the Agency for Healthcare Research and Quality's 2016 Nationwide Readmissions Database suggested.

In their cohort study of hospitalized IBS sufferers, Catherine Choi, MD, of Rutgers New Jersey Medical School in Newark, New Jersey, and colleagues found that all-cause 30-day readmission rates were 12.7% in non-cannabis users and 8.1% in cannabis users. After adjustment for age, sex, median income by zip code, insurance status, Charlson Comorbidity Index, hospital bed size, teaching status, and location, the adjusted odds ratio in cannabis users was 0.53 (95% CI 0.28-0.99).

The study was presented in an online press program organized by Digestive Disease Week, which was to have started on May 2 but was cancelled because of the COVID-19 pandemic.

In addition, cannabis use appeared to correlate with shorter hospital stays, for an adjusted mean difference of -0.44 days (95% CI -0.85 to -0.03, P=0.036), as well as with lower total hospitalization charges, for an adjusted mean difference of -$3,473 (95% CI -$46,773 to -$174, P=0.04). Cannabis use was also associated with a slightly higher survival rate compared with non-use.

The researchers identified 6,798 adult patients with IBS of whom 357 were cannabis users. The inclusion criterion was a principal diagnosis of IBS using ICD-10 CM codes, the exposure of interest was cannabis, and the primary outcome was 30-day readmission to hospital. For patients with and without cannabis use, the mean age differed substantially at 36.7 (range 34.5-38.9) years and 53.3 (52.6-54.1) years, respectively. Women accounted for 62% and 81% of the two groups, respectively.

The most common three reasons for readmission in non-users were enterocolitis due to Clostridium difficile, IBS without diarrhea, and sepsis. In users, the indications for rehospitalization were cyclical vomiting, IBS-diarrhea, and endometriosis. Among non-users, independent factors predicting readmission were mean age (0.99, 95% CI 0.98-1.33, P=0.04), having private insurance (0.56, 95% CI 0.41-0.77, P<0.01), and home healthcare (1.98, 95% CI 1.40-2.82, P<0.01). None of the factors analyzed predicted readmission in cannabis users, the researchers noted.

Adding medical marijuana to standard analgesics is under discussion for easing pain or increasing pain tolerance in such conditions as fibromyalgia-related back pain.

Asked for his perspective, Anthony J. Lembo, MD, of Beth Israel Deaconess Medical Center in Boston, who was not involved with the research, noted that to date no studies have evaluated the effect of cannabis on IBS symptoms. "While the authors hypothesize that cannabis use is associated with better control of irritable IBS compared to no cannabis use, the current study does not provide information to support or disprove this hypothesis," he told MedPage Today.

Lembo pointed out that cannabis users in the study who were hospitalized with a principal diagnosis of IBS were significantly different from those who did not use cannabis: "Specifically, they differed in age and sex, both of which are likely to contribute to reasons for readmissions," he said. "And cyclic vomiting was one of the most common reasons for readmission in the cannabis group, which is a known complication of cannabis use."

He said that such intergroup differences and the small number of cannabis users in the study preclude drawing conclusions about factors affecting survival, adding: "And it's worth noting that use of ICD-10 codes likely under-represents the true number of patients with these disorders. I don't think there is more you can interpret from these data."

Disclosures

One study co-author reported relationships with Allergan, Bayer, BeiGene, Bristol-Myers Squibb, Confirm, Conatus, Intercept, Mallinckrodt, Novartis, Resusix, Saro, Valeant, Gilead, Exelixis, Hologic, Shire, Genfit, and Prometheus outside of the submitted work. All other authors reported no conflicts of interest.

Lembo reported having no conflicts of interest in regard to his comments.

Primary Source

Digestive Disease Week

Source Reference: Choi CJ, et al "Cannabis use is associated with reduced 30-day readmission among hospitalized patients with irritable bowel syndrome: a nationwide analysis" DDW 2020; Abstract #Mo1560.


https://www.medpagetoday.com/meetingcoverage/ddw/86306

--------------------
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Heartburn drugs that are proton pump inhibitors could trigger IBS and SIBO new
      #373965 - 12/07/20 01:28 PM
HeatherAdministrator

Reged: 12/09/02
Posts: 7793
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Growing evidence suggests popping too many heartburn pills is actually CAUSING tummy troubles

Proton pump inhibitors could trigger debilitating gut symptoms, experts claim
Over-reliance on the drugs could even explain a recent surge in IBS diagnoses
Heartburn is caused when vital stomach acid travels up towards the throat

By Eve Simmons For The Mail On Sunday

Published: 17:01 EST, 5 December 2020 ' Updated: 17:01 EST, 5 December 2020

Tis the season for indigestion, with the festivities leaving many reaching for heartburn tablets.

The pills, which stop the burn caused by stomach acid travelling up into the back of the throat after a meal, are among the top ten most frequently prescribed in the world, with two million Britons relying on them almost daily.

But a growing body of evidence suggests that the most popular type of heartburn medication, known as proton pump inhibitors (PPIs), could in fact trigger a whole host of debilitating gut symptoms.

In fact, experts warn that the over-reliance on PPI drugs such as omeprazole and lansoprazole could even explain a recent surge in diagnoses of irritable bowel syndrome (IBS).

'It's a Catch-22 situation because these drugs work well to control the initial symptoms, but the long-term effects can be detrimental,' says Dr Rehan Haidry, consultant gastroenterologist at University College Hospital, London.

'Two in three patients I see with heartburn have been taking these for years and go on to develop flatulence, bloating and bowel problems. It's no coincidence.'

Heartburn, or indigestion, is caused when stomach acid, which is vital for breaking down food, travels up towards the throat.

The most common trigger is overeating, which puts extra pressure on the muscular barrier between the stomach and food pipe, making it prone to leaks.

Diets high in acidic foods and drinks â€" caffeine, red wine and chocolate, for example â€" exacerbate the problem, which is also termed acid reflux.

Drugs, available both from the GP and over the counter, combat this by limiting the amount of acid produced in the stomach cells by blocking chemicals involved in its production â€" and are highly effective.

But a recent study involving 300,000 patients found that taking PPIs for months on end was linked with a 65 per cent increased risk of developing embarrassing tummy upsets â€" most commonly, diarrhoea.

The research adds to a growing body of evidence pointing in the same direction. The problem lies with the reduction of acid in the stomach and bowel. 'We need some acid in the small bowel to kill off bacteria,' says Dr Haidry.

'Prolonged PPI use means less acid, but also makes the small bowel more welcoming to bacteria, allowing it to grow rather than move through the digestive system.'

While gut bacteria are beneficial, too much causes problems.

'Bacteria feed on sugars in foods we eat, causing a fermentation process. This results in the release of hydrogen and methane gas, causing bloating and cramps and other symptoms,' adds Dr Haidry.


The condition, called small intestinal bacterial overgrowth, or SIBO, is up to seven times more common in frequent PPI takers, according to a 2013 analysis by Harvard Medical School. Most frustratingly, it is known to make acid reflux far worse.

There is a breath test that measures the amount of hydrogen gas produced shortly after eating, but it is not widely available on the NHS and studies show it can miss the problem in up to a third of patients.

Many are instead given a diagnosis of irritable bowel syndrome â€" a catch-all term which, according to Dr Haidry, denies targeted, effective treatment.

'Really we need a combination of hydrogen breath test and a sample of bacteria taken from the small bowel for diagnosis,' he adds. 'But often the diagnosis is clear when patients tell me their history of PPI use and the onset of symptoms.



'We can give antibiotics to destroy bacteria in the small bowel, while avoiding foods high in fermentable sugars, such as beans, fruit and root vegetables, can cut the amount of gas produced.'

Despite the growing body of evidence supporting the link between PPIs and gut issues, it remains controversial â€" not all doctors support Dr Haidry's theory. But it's certainly the case that patients are not getting timely treatment.

Alex Rainer, a 29-year-old logistics manager from Hertfordshire, is one such case. She has been taking a PPI daily for nine years â€" a mixture of prescription and over-the-counter tablets â€" to treat heartburn. But at the beginning of the year she noticed a strange sensation in her abdomen.

Now, every few weeks she'll spend the best part of 48 hours rushing back and forth to the toilet. 'I get a weird 'watery' feeling, like something is bubbling in there,' she says.

'It's very painful and grumbly. Sometimes I'll feel a big grumble, then have to run to the loo. But 85 per cent of the time the drug stops my reflux, so I just put up with it.'

With such effective drugs, many like Alex are reluctant to give them up, and what's the alternative?

'It is very important to stop the flow of acid, as prolonged reflux can increase the risk of throat and gullet cancers,' says Dr Haidry.

'But this can be done through some short-term PPI treatment and lifestyle interventions, like not eating too late, reducing smoking and cutting down on trigger foods.'

Other over-the-counter medications, such as Gaviscon, that work to neutralise acid rather than stop its production, can also help, as can simply going for a short walk after meals. Surgery to 'tighten' the opening between stomach and gullet may sometimes help too.

'But it's essential that the root cause of the problem is identified first â€" often it's nothing to do with acid,' Dr Haidry adds.

'To send people off with pills for ever is simply not good enough.'

https://www.dailymail.co.uk/health/article-9021285/Growing-evidence-suggests-popping-heartburn-pills-actually-CAUSING-tummy-troubles.html

--------------------
Heather is the Administrator of the IBS Message Boards. She is the author of Eating for IBS and The First Year: IBS, and the CEO of Heather's Tummy Care. Join her IBS Newsletter. Meet Heather on Facebook!

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