An Asia-Pacific, double blind, placebo controlled, randomised study to evaluate the efficacy, safety, and tolerability of tegaserod in patients with irritable bowel syndrome.

BACKGROUND: Tegaserod has been shown to be an effective therapy for the multiple symptoms of irritable bowel syndrome (IBS) in Western populations. However, little information is available regarding the use of tegaserod in the Asia-Pacific population. AIMS: To evaluate the efficacy, safety, and tolerability of tegaserod versus placebo in patients with IBS from the Asia-Pacific region. PATIENTS: A total of 520 patients from the Asia-Pacific region with IBS, excluding those with diarrhoea predominant IBS. METHODS: Patients were randomised to receive either tegaserod 6 mg twice daily (n=259) or placebo (n=261) for a 12 week treatment period. The primary efficacy variable (over weeks 1-4) was the response to the question: "Over the past week do you consider that you have had satisfactory relief from your IBS symptoms?" Secondary efficacy variables assessed overall satisfactory relief over 12 weeks and individual symptoms of IBS. RESULTS: The mean proportion of patients with overall satisfactory relief was greater in the tegaserod group than in the placebo group over weeks 1-4 (56% v 35%, respectively; p<0.0001) and weeks 1-12 (62% v 44%, respectively; p<0.0001). A clinically relevant effect was observed as early as week 1 and was maintained throughout the treatment period. Reductions in the number of days with at least moderate abdominal pain/discomfort, bloating, no bowel movements, and hard/lumpy stools were greater in the tegaserod group compared with the placebo group. Headache was the most commonly reported adverse event (12.0% tegaserod v 11.1% placebo). Diarrhoea led to discontinuation in 2.3% of tegaserod patients. Serious adverse events were infrequent (1.5% tegaserod v 3.4% placebo). CONCLUSIONS: Tegaserod 6 mg twice daily is an effective, safe, and well tolerated treatment for patients in the Asia-Pacific region suffering from IBS and whose main bowel symptom is not diarrhoea.

Helicobacter pylori related functional dyspepsia in a defined malaysian population.

The objective of the study was to determine the prevalence of H. pylori in functional dyspepsia among the three main races in Malaysia. Gastric antral biopsies from 233 (98 males, 135 females; age range: 17-75 years, mean age 39.5 years) patients attending the Universiti Kebangsaan Malaysia (UKM) gastroenterology clinic were assessed for the presence of H. pylori by culture and histology. About a third of the cases (79 of 233 (34%); 34 males, 45 females; mean age 42.6 yrs) were positive for H. pylori. The presence of H. pylori was always associated with antral gastritis. Malay patients were least likely to be positive for H. pylori (10 of 88 (11.4%); 5 males, 5 females; mean age 35.7 yrs) compared to the Chinese (43 of 95 (45%); 19 males; 24 females; mean age 40.2 yrs) and Indian patients (23 of 41 (56%); 10 males, 13 females; mean age 48.1 yrs). We found that H. pylori were most common among Chinese followed by Indians. However, the relative risk for the Indians was 8.58 and 6.29 for the Chinese compared to Malays. We conclude that the prevalence of H. pylori in patients with functional dyspepsia differs considerably with respect to ethnic groups.

Optimal treatment for duodenal ulcer disease: a cost-decision analysis in Malaysian patients.

The aim of the present study was to determine the cost-efficiency of different duodenal ulcer disease treatment practices in Malaysia. Six Malaysian gastroenterologists met to discuss the direct costs related to Helicobacter pylori (HP) eradication treatment. Five treatment strategies were compared: (i) histamine H2 receptor antagonists (H2RA), acid suppression therapy for 6 weeks followed by maintenance therapy as needed; (ii) bismuth triple + proton pump inhibitor (PPI), bismuth (120 mg, q.i.d.), metronidazole (400 mg; t.i.d.), tetracycline (500 mg, q.i.d.) for 7 days and PPI, b.i.d., for 7 days; (iii) OAC, omeprazole (20 mg, b.i.d.), amoxycillin (1000 mg, b.i.d.) and clarithromycin (500 mg, b.i.d.) for 7 days; (iv) OMC, omeprazole (20mg, b.i.d.), metronidazole (400mg, b.i.d.) and clarithromycin (500 mg, b.i.d.) for 7 days; and (v) OAM, omeprazole (20 mg, b.i.d.), amoxycillin (1000 mg, b.i.d.) and metronidazole (400 mg, b.i.d.) for 7 days. A decision tree model was created to determine which therapy would be the most cost-effective. The model considered eradication rates, resistance to anti-microbial agents, compliance and cost implications of treatment regimens, physician visits and ulcer recurrences during a 1 year time period assumption. The H2RA maintenance therapy was the most expensive treatment at Malaysian Ringgit (MR) 2335, followed by bismuth triple therapy (MR 1839), OMC (MR 1786), OAM (MR 1775) and OAC, being the most cost-effective therapy, at MR 1679. In conclusion, HP eradication therapy is superior to H2RA maintenance therapy in the treatment of duodenal ulcer disease. Of the HP eradication regimens, OAC is the most cost-effective.

Interrelations between interleukin-6, interleukin-1 beta, plasma C-reactive protein values, and in vitro C-reactive protein generation in patients with inflammatory bowel disease.

Acute phase proteins are released from the liver in response to cytokines, and measurement of serum concentrations offers a valuable means of assessing inflammatory bowel disease. C-reactive protein (CRP) is a participating prominent component of the acute phase response in active Crohn's disease. This study aimed at determining the comparative role of the cytokines interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6), in driving CRP production in inflammatory bowel disease, and to test the hypothesis that there is a difference in the profile of cytokines generated in these two conditions. Serum CRP, the release of the cytokines IL-1 beta and IL-6 from monocytes, and the ability of monocyte conditioned medium to stimulate CRP synthesis by hepatocytes in an in vitro system was measured in patients with ulcerative colitis and Crohn's disease. Monocytes from patients with Crohn's disease produced more 1L beta-1 than monocytes from patients with ulcerative colitis or normal controls. There was no increased tendency for monocytes from Crohn's disease patients to produce more 1L-6, so the greater circulating values of IL-6 reported by a number of authors in Crohn's disease may reflect the participation of a larger number of cells of the monocyte-macrophage series, or production of IL-6 by other cell types. Correlation of cytokine production by monocytes with in vitro CRP release from cultured hepatocytes in response to monocyte conditioned medium showed that, in that system, IL-1 beta was the stronger stimulus to CRP production. Some of the differences in the inflammatory processes of ulcerative colitis and Crohn's disease may reflect differences in the amount of IL-1beta and IL-6 generated from macrophages and monocytes.

Evaluation of therapies in the treatment of Helicobacter pylori associated non-ulcer dyspepsia.

This randomised double blind placebo controlled study evaluated the effectiveness of colloidal bismuth subcitrate (CBS), ampicillin and their combination in the treatment of Helicobacter Pylori in non-ulcer dyspepsia (NUD) and assessed if elimination of this organism is associated with improvement of gastritis and the symptoms. Forty-eight NUD patients with H. pylori and histologic gastritis were randomly allocated to one of the three regimens for 28 days. Symptoms were assessed before and after treatment. Forty-three patients completed the trial. Repeat endoscopy within 48 hours of completing treatment showed suppression of H. pylori in 6 of 7 patients (85.7%) on combined therapy and one of 8 patients (12.5%) on CBS therapy (p = 0.0205). There was no suppression of the bacteria in patients treated with ampicillin. Repeat endoscopy performed 2 weeks after completing treatment showed suppression of H. pylori in 3 of 7 patients (42.9%) on combined therapy and none in the other two groups. Patients on combined therapy who had suppression of H. pylori, 48 hours or 2 weeks after completing treatment were noted to have historical improvement of their gastritis (p = 0.0001 and p = 0.05 respectively). This was also associated with improvement of symptoms in these patients.

Peripheral blood monocyte cytokine production and acute phase response in inflammatory bowel disease.

Cytokines released from activated mononuclear leukocytes are involved in triggering the acute phase response and many of the inflammatory manifestations of ulcerative colitis and Crohn's disease. The ability of circulating monocytes from patients with ulcerative colitis and Crohn's disease to generate the cytokines interleukin 1 beta (IL 1 beta) and tumour necrosis factor alpha (TNF alpha), both spontaneously and in response to stimulation by lipopolysaccharide, was compared. IL 1 beta generation in response to lipopolysaccharide was significantly higher in Crohn's disease than in ulcerative colitis and normal controls, with a dramatic increase in patients with active disease. There was a significant reduction in lipopolysaccharide stimulated TNF alpha generation in ulcerative colitis patients compared with Crohn's disease and normal control subjects. IL 1 beta and TNF alpha release correlated significantly with serum C reactive protein and serum alpha 1 acid glycoprotein in Crohn's disease. The ability of conditioned medium from monocytes in Crohn's disease to enhance release of alpha 1 acid glycoprotein from the liver cell line HepG2 in culture was assessed. There was a significant positive correlation between TNF alpha and IL 1 beta presence in the supernatant and alpha 1 acid glycoprotein production. The differences in the cytokine profile in patients with Crohn's disease compared with ulcerative colitis suggest an intrinsic difference in the ability to produce cytokines in patients with these two forms of inflammatory bowel disease, and may explain features such as the enhanced ability to generate a brisk C reactive protein response in Crohn's disease.

Review article: assessment of drug therapy in inflammatory bowel disease.

This review article surveys the clinical and laboratory parameters used to assess and quantitate inflammation in ulcerative colitis and Crohn's disease, with particular reference to their usage in controlled trials of drugs in inflammatory bowel disease.