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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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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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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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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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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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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., 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 £45 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
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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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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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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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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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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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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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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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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