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Infliximab is a chimeric monoclonal antibody to tumour necrosis factor alpha (TNFα) with efficacy in inducing and maintaining remission of inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis and psoriasis. Infliximab is generally administered over 2h with a further 1-h postinfusion observation. This time interval has substantial impact on healthcare resources and is costly in terms of patient's time away from work.To examine the safety and tolerability of a 1-h, relative to a 2-h maintenance of infusion of infliximab, and to determine the effect of corticosteroid premedication and concurrent immunosuppressor use on infusion reaction rates.A prospective cohort study with variable follow-up duration of 2165 consecutive infliximab infusions in 415 patients during 2009 was conducted. Diagnosis, infusion episode number, infusion rate, premedication, concurrent immunosuppressor therapy, the nature and the outcome of infusion reactions were examined.The majority of infusions (74%) were for management of inflammatory bowel disease. Infusion reactions clustered within the first eight infusions with subsequent sporadic reactions. The infusion reaction incidence rate per 1000 person days in 274 1-h infusions from 54 patients and 1356 2-h infusions from 256 patients were 0.08 and 0.28 respectively (P=0.07). Poisson regression model confirmed that the concurrent use of immunosuppressor therapy was associated with a lower infusion reaction rate, whereas corticosteroid premedication was not.During maintenance therapy, infliximab infusion can be safely administered over 1h in patients with no past history of significant infliximab infusion reaction. Corticosteroid premedication had no impact on the infusion reaction rates.

Tumour necrosis factor-blockade with infliximab has advanced the treatment of Crohn's disease. While infliximab is efficacious, it remains to be determined whether patients who enter clinical remission with an anti-tumour necrosis factor therapy can have their treatment stopped and retain the state of remission.To assess in patients with Crohn's disease who obtained infliximab-induced remission, the proportion who relapsed after infliximab discontinuation.This longitudinal cohort study examined patients from a University-based IBD referral centre. Forty eight patients with Crohn's disease in full clinical remission and who then discontinued infliximab were followed up for up to 7 years. Crohn's disease relapse was defined as an intervention with Crohn's disease medication or surgery.Kaplan-Meier analysis of the proportion of patients with sustained clinical benefit demonstrated that 50% relapsed within 477 days after infliximab discontinuance. In contrast, 35% of patients remained well, and without clinical relapse, up to the end of the nearly 7-year follow-up.In patients with Crohn's disease with an infliximab-induced remission, stopping infliximab results in a predictable relapse in a majority of patients. Nevertheless, a small percentage of patients sustain a long-term remission.

Aliment Pharmacol Ther 2010; 32: 522-528 Summary Background Randomized, controlled trials have demonstrated that anti-TNF agents are efficacious in inducing remission in cases of Crohn's disease and ulcerative colitis. However, response rates for anti-TNF agents in 'real life' clinical practice are less well-defined. Aims To examine the response rates and long-term outcomes of infliximab and adalimumab treatment for out-patients with ulcerative colitis and to study the variables associated with response rates. Methods In a prospective study, a single-centre out-patient cohort was treated and followed up according to a structured protocol of clinical care. Response to treatment was assessed using a physician's global assessment that focused on normalization of bowel frequency, absence of blood with defecation and tapering of corticosteroids to zero. Results Fifty-three ulcerative colitis patients were included in the study. Responses to induction therapy were 96.4% (27/28) for infliximab and 80% (20/25) for adalimumab (P = 0.0889). Responses to maintenance therapy were similar: infliximab 77.8% (14/18) and adalimumab 70.0% (14/20) (P = 0.7190). Multivariate analyses of the induction and maintenance responses did not reveal confounding elements. No new safety signals were identified. Conclusions This long-term follow-up of a single-centre cohort of ulcerative colitis patients demonstrates that 'real-life' out-patient treatment with infliximab and adalimumab is effective in induction and maintenance of response.

Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract. From the perspective of the patient, symptoms of the disease significantly impair quality of life and interfere with activities of daily living. Conventional medical treatment of Crohn's disease includes the use of nonspecific anti-inflammatory drugs, immunosuppressives and antibiotics. These therapies are characterized by a delayed onset of action, incomplete response rates and a substantial risk of adverse effects. Although surgery is frequently used to treat complications, postoperative recurrence is an important problem. Infliximab, a chimeric monoclonal antibody directed toward tumour necrosis factor alpha, is highly effective for the treatment of active Crohn's disease. In randomized, placebo-controlled clinical trials, 82% of patients who received 5 mg/kg of infliximab had a clinically significant response, compared with 17% of those given placebo (P0.001). Moreover, infliximab is the only medical therapy that has been shown to be effective for the treatment of fistulizing Crohn's disease. Infusion reactions are the most common adverse effect. Whether treatment with infliximab is associated with an increased risk of neoplasia, infection or autoimmune disease is unknown. Therefore, further long term safety studies are required. Despite the relatively high cost of drug acquisition, preliminary pharmacoeconomic analysis indicates that infliximab is cost effective compared with existing treatments. Infliximab is recommended for the treatment of active Crohn's disease refractory to conventional drugs, and is the treatment of choice for fistulizing Crohn's disease.

Interleukin (IL)-10 is a cytokine with potent anti-inflammatory properties. We investigated the safety and efficacy of different doses of human recombinant (rhu)IL-10 in patients with Crohn's disease (CD).A prospective, multicenter, double-blind, placebo-controlled study was conducted in 329 therapy-refractory patients with CD. Clinical improvement was defined by a reduction of the Crohn's Disease Activity Index (CDAI) by 100 points or more and clinical remission by a decrease of the CDAI to150 points. At selected centers, patients underwent ileocolonoscopies and activation of the nuclear factor-kappa B (NF-kappa B) system was assessed in biopsy specimens.Subcutaneous treatment with rhuIL-10 over 28 days induced a fully reversible, dose-dependent decrease in hemoglobin and thrombocyte counts but no clinically significant side effects. No differences in the induction of remission were observed between rhuIL-10 groups (1 microg, 18% [9.6-29.2]; 4 microg, 20% [11.3-32.2]; 8 microg, 20% [11.1-31.8]; 20 microg, 28% [18-40.7]; and placebo, 18% [9.6-29.6]). Clinical improvement was observed in 46% (33.7-59) in the 8-microg/kg rhuIL-10 group in comparison with 27% (17-39.6) in patients taking placebo. Responders to rhuIL-10 showed inhibition of NF-kappaB p65 activation in contrast to nonresponders.Up to 8 microg/kg of rhuIL-10 was well tolerated. A tendency toward clinical improvement but not remission was observed in the 8-microg/kg dose group. Further studies should delineate which subgroups of patients with CD benefit from rhuIL-10 therapy.

Patients with Crohn's disease often have relapses. Better treatments are needed for the maintenance of remission. Although methotrexate is an effective short-term treatment for Crohn's disease, its role in maintaining remissions is not known.We conducted a double-blind, placebo-controlled, multicenter study of patients with chronically active Crohn's disease who had entered remission after 16 to 24 weeks of treatment with 25 mg of methotrexate given intramuscularly once weekly. Patients were randomly assigned to receive either methotrexate at a dose of 15 mg intramuscularly once weekly or placebo for 40 weeks. No other treatments for Crohn's disease were permitted. We compared the efficacy of treatment by analyzing the proportion of patients who remained in remission at week 40. Remission was defined as a score of 150 or less on the Crohn's Disease Activity Index.Forty patients received methotrexate, and 36 received placebo. At week 40, 26 patients (65 percent) were in remission in the methotrexate group, as compared with 14 (39 percent) in the placebo group (P=0.04; absolute reduction in the risk of relapse, 26.1 percent; 95 percent confidence interval, 4.4 percent to 47.8 percent). Fewer patients in the methotrexate group than in the placebo group required prednisone for relapse (11 of 40 [28 percent] vs. 21 of 36 [58 percent], P=0.01). None of the patients who received methotrexate had a severe adverse event; one patient in this group withdrew because of nausea.In patients with Crohn's disease who enter remission after treatment with methotrexate, a low dose of methotrexate maintains remission.

Despite a decreased incidence of ulcer disease and improvements in the management of acute upper gastrointestinal (GI) bleeding, mortality remains at about 6-7%. Although endoscopic haemostatic therapy has been demonstrated to be the mainstay of management, the search continues for less invasive medical modalities that might also improve patient outcome. In vitro data have indicated the important role of acid in impairing haemostasis and causing clot digestion. Therefore, theoretically, maintenance of a high intragastric pH (above 6.0) during management of upper GI bleeding is warranted. Until recently, available agents did not permit such a sustained elevation in gastric pH. Early studies with H2-receptor antagonists have not demonstrated significant improvements in important patient outcomes, such as rebleeding, surgery or mortality. With the availability of intravenous formulations of proton pump inhibitors, it is now possible to aim at maintaining gastric pH above 6.0 for 24 h per day. Recent clinical trial data would appear to support the use of proton pump inhibitors to decrease the rate of rebleeding and the need for surgery. This paper provides a review of non-variceal acute GI bleeding, with special reference to the role of proton pump inhibitors in this clinical setting.

Azathioprine is effective for Crohn's disease but acts slowly. A loading dose may decrease the time to response.A placebo-controlled study was conducted in patients with active Crohn's disease despite prednisone treatment. Patients were randomized to a 36-hour infusion of azathioprine, 40 mg/kg (51 patients), or placebo (45 patients) followed by oral azathioprine, 2 mg/kg, for 16 weeks. Prednisone was tapered over 5 weeks. The primary outcome measure was complete remission at week 8, defined by discontinuation of prednisone and a Crohn's Disease Activity Index of/=150 points. Erythrocyte concentrations of the azathioprine active metabolite, 6-thioguanine nucleotide, were measured.At week 8, 13 patients (25%) were in complete remission in the azathioprine-loaded group compared with 11 patients (24%) in the placebo group. The frequency of complete remission did not increase after 8 weeks in either group. Both groups achieved steady state of 6-thioguanine nucleotide by week 2, and no differences were found in mean concentrations between the groups. There were no significant differences in the frequency of adverse events between the groups.A loading dose does not decrease the time to response in patients with steroid-treated Crohn's disease beginning azathioprine therapy. Steady state of erythrocyte 6-thioguanine nucleotide and complete response occurred earlier than previously reported.

Ulcerative colitis and Crohn's colitis are chronic intestinal diseases usually treated with various nonsteroidal antiinflammatory agents to maintain remission. Corticosteroids, while useful in acute treatment of these diseases, present side-effects generally too serious to allow maintenance therapy. Colon-specific drug delivery may permit use of corticosteroids for maintenance therapy if doses can be reduced while maintaining efficacy. In this study, two prodrugs (dexamethasone-beta-D-glucuronide (DXglrd) and budesonide-beta-D-glucuronide (BUDglrd)) were administered by intragastric (i.g.) infusion to conventional and colitic rats. In addition, dexamethasone (DX) and budesonide (BUD) were administered either i.g. or subcutaneously (s.c.) to healthy and colitic rats. Colon-specific delivery was assessed using the drug delivery index (DDI). In conventinal rats, DDIs for DXglrd ranged from about five to as high as 11 in the luminal contents relative to DX administered sc or i.g. DDI values were also elevated in the mucosa of both healthy and colitic rats following i.g. administration of DXglrd. BUD was delivered somewhat less effectively from BUDglrd to the rat large intestine than was DX from DXglrd. The data are consistent with efficacy studies and support the conclusion that local delivery of corticosteroids to the large intestine is due, at least in part, to higher levels of drug delivery into the mucosal tissues.

Patients with chronic ulcerative colitis may develop colitis-related dysplasia and/or sporadic adenomata. Differentiating between these two processes is important because they may dictate different therapeutic approaches. Although distinguishing features of sporadic adenomata versus colitis-related dysplasia have been suggested previously on an a priori basis, they have never been verified by follow-up analysis. We have identified six chronic ulcerative colitis patients whose discrete adenomata were managed conservatively, with subsequent continuation in their surveillance programs.Mean patient age was 69 yr with a mean 21.3 yr of ulcerative colitis. Surveillance endoscopy of 63 patient-yr duration yielded 24 adenomata. A mean follow-up after the initial adenoma diagnosis was 7.2 yr with no carcinoma identified (including the examination of one prophylactic colectomy specimen). One patient, with a 34-yr history of ulcerative colitis and a single sporadic adenoma subsequently developed dysplasia of flat mucosa 14 months later.Our findings concur with previous reports and indicate that small, discrete adenomata with morphology identical to those seen in the general population occur in patients with ulcerative colitis. Such lesions in patients older than 45 yr, with tubular or tubulovillous architecture and low-grade dysplasia, are effectively treated by polypectomy only and are not necessarily an indication for colectomy. However, sporadic adenomata and colitis-related dysplasia can develop metachronously. It is suggested that subsequent to a diagnosis of sporadic adenoma in a patient with chronic ulcerative colitis, surveillance should increase to colonoscopic examination every 6 to 12 months.

The present study provides an overview of the current state of health economics studies of gastroesophageal reflux disease (GERD). It indicates the strengths and weaknesses of individual studies, and the state of health economics analysis in general as they apply to GERD. Specifically, this study adopts a pharmacoeconomic perspective, which is a subsection of health economics analytical methods, to provide a comparative analysis of alternative courses of action based on cost and consequence. The pharmacoeconomic outlook is most effective when it considers a comprehensive societal perspective, with special consideration given to other relevant viewpoints, such as the payer, the primary provider and, most important, the patient. Pharmacoeconomics provides several specific analytical techniques for GERD-related health economics analysis. The Canadian Association of Gastroenterology consensus conference on GERD in 1996 thought that a cost effective analysis was the most appropriate technique to assess the pharmacoeconomics of GERD. Six previous studies on GERD health economics have been performed comparing omeprazole with H2 receptor antagonists. These studies vary in cost data collected and in analytical techniques. In general, the existing outcome measurements of these previous health economics studies are not ideal. Namely, they combine various GERD grades, use randomized controls, are endoscopically based, assess pharmaceutical therapy only and are short term. More appropriate health economic trials in GERD, which focus on GERD management strategies and therapeutic treatment of GERD, need to be designed and conducted. These economic assessments, however, should not replace detailed thinking, careful observation, good judgement and common sense.

The effect of insulin on intestinal sodium-dependent glucose transport and brush border membrane surface area was examined in male Sprague-Dawley rats following a 30-day period of nontreated streptozocin-induced diabetes. Nontreated diabetic rats were hyperglycemic and demonstrated increased jejunal and ileal Na-dependent glucose transport Jmax (maximal transport capacity) and Na-K ATPase activity compared with controls. Daily administration of insulin resulted in a steady decline in blood glucose levels over a period of 6 days. Jejunal Jmax was normalized after 2 days of insulin therapy, while ileal Jmax was normalized 12 h following a single insulin injection. The normalization of Na-K ATPase activity lagged behind Na-dependent glucose transport regulation by 24 h in both jejunum and ileum. Brush border surface area was increased in the ileum of diabetic rats as a result of an increase in microvillus height. Insulin treatment resulted in a decrease in ileal microvillus height to control values by 12 h, which correlated directly with the decrease in Na-dependent glucose transport. Insulin had no effect on jejunal brush border surface area. In conclusion, these findings indicate that the jejunum and ileum respond differentially to experimentally induced diabetes, and these regions also utilize different adaptive mechanisms to regulate Na-dependent glucose transport.

Tacrolimus (FK506) is at present the mainstay of immunosuppression for small intestinal transplantation. This study investigates the effects of chronic treatment with varying dosages of tacrolimus on animal well-being, weight gain, intestinal permeability, and the active transport of nutrients as measured by in vitro studies quantifying glucose flux. The effect of acute treatment with high-dose tacrolimus on glucose flux was also investigated. In the chronic studies, juvenile male Lewis rats were given tacrolimus in a dosage of 0.1 mg/kg, 0.5 mg/kg, and 2 mg/kg q. second day by subcutaneous injection for five weeks. In the acute studies, animals were treated with 2 mg/kg given q. 24 hr [mult] 48 hr, 24 hr and 12 hr prior to sacrifice. In the acute treatment groups, tacrolimus caused no change in glucose flux. In the chronically treated animals, FK506 levels were within the clinically relevant range. Chronic treatment with 0.5 and 2 mg/kg caused a significant reduction in weight gain. These same groups of animals had a significant increase in intestinal permeability as measured by absorption of 99Te-DTPA. Glucose flux was affected in all chronically treated groups, with net flux increasing in the jejunum and decreasing in the ileum. These findings show that chronic treatment with low-dose tacrolimus is well tolerated, but in higher doses there are significant effects in intestinal permeability and nutrient uptake, and animal weight gain. We suggest that these changes are due to alterations in intestinal permeability that do not appear to be mediated by an acute drug effect and more likely represent chronic changes, possibly from alterations in gene expression. These findings suggest that further studies regarding the effects of tacrolimus on nutrient transport, intestinal permeability, and the known immunologically related functions of tacrolimus should be done.

Quality of life (QOL), a subjective index of health perception and function, embraces physical, social, and emotional performance but has not had a prominent role in clinical trials of inflammatory bowel disease (IBD). To test the robustness of the Inflammatory Bowel Disease Questionnaire (IBDQ), a disease-specific QOL index, this study assessed its validity, reliability, and responsiveness during a multicenter trial.Three hundred five patients with stable Crohn's disease received cyclosporin or placebo for 18 months. IBDQ and dimensional scores (bowel, social, systemic, and emotional) were correlated with disease activity (Crohn's disease activity index [CDAI] and Harvey-Bradshaw index). Concordance of IBDQ scores was tested in 280 stable subjects. Linear regression evaluated change in IBDQ scores over time.IBDQ scores correlated highly with CDAI (r = -0.67; P0.0001). The reliability coefficient for IBDQ score was 0.70 vs. 0.66 for CDAI and 0.55 for Harvey-Bradshaw index. Regression line slopes of IBDQ scores were significantly different in patients who deteriorated from those who remained stable ([b]0.15; P0.0001). QOL scores were lower in patients who required surgery.The IBDQ is a valid reliable assessment tool that reflects important changes in the health status of patients with IBD. The IBDQ is a robust measure of therapeutic efficacy and should be used in future clinical trials in IBD.

In inflammatory bowel disease, prostaglandins are mucosal protective whereas leukotrienes are proinflammatory. Recent evidence suggests that the formation and action of leukotrienes are calcium-dependent, whereas the formation and action of prostaglandins are not. To examine the possibility that, because of differential regulation of arachidonic acid metabolism, calcium channel blockade might alter mucosal eicosanoid synthesis and accelerate healing during inflammatory bowel disease, we treated a 4% acetic acid-induced colitis model with verapamil and/or misoprostol and determined the effects on colonic macroscopic injury, mucosal inflammation as measured by myeloperoxidase activity, in vivo intestinal fluid absorption, and mucosal prostaglandin E2 and leukotriene B4 (LTB4) levels as measured by in vivo rectal dialysis. In colitic animals, verapamil treatment significantly improved colonic fluid absorption and macroscopic ulceration. This mucosal-protective effect of verapamil occurred in the presence of a twofold reduction in mucosal LTB4 synthesis. In noncolitic animals, verapamil alone had no effect on in vivo fluid absorption, macroscopic ulceration, or myeloperoxidase activity but did induce a threefold reduction in LTB4 synthesis in addition to shifting arachidonic acid metabolism towards a sixfold stimulation of prostaglandin E2 synthesis. Our results show that, when administered before the experimental induction of colitis, the calcium channel blocker, verapamil, has a mucosal-protective effect that occurs as a consequence of reduced mucosal leukotriene synthesis and increased prostaglandin synthesis. This differential regulation of arachidonic acid metabolism may play an important role in the development of novel therapeutic agents for inflammatory bowel disease.

The intestinal absorption of nutrients is increased in diabetic rats fed chow, yet short-term (two week) studies have demonstrated reduced and near-normal intestinal nutrient absorption in diabetic rats fed a diet high in polyunsaturated fatty acids. In this study we undertook to establish the effect of 10 weeks' feeding of isocaloric semisynthetic diets with high or low ratios of saturated (S)-to-omega-3 polyunsaturated (P) fatty acids ("fish oil") when given to streptozotocin diabetic rats. The fasting plasma glucose concentration was approximately 10% lower in diabetic rats fed P as compared with S, although the oral and intravenous glucose tolerance tests and the time-course of the oral and intravenous glucose-stimulated immunoreactive insulin levels were similar in P and S, as also were the levels of the hemoglobin A1C. The fasting plasma triglyceride concentrations were similar in P and S, but the fasting plasma cholesterol concentrations were approximately 20% lower in diabetic rats fed P as compared with S. Feeding P to diabetic animals was associated with a heavier intestine, which was comprised of a greater proportion of mucosal than submucosal tissue. The enhanced jejunal uptake of fatty acids 18:0 (stearic) and 18:2 (linoleic) as well as cholesterol observed in diabetic as compared with non-diabetic animals fed S was not observed in those fed P. The enhanced uptake of glucose in diabetic rats was also influenced by diet, with a lower rate for jejunal and ileal uptake of glucose in diabetic rats fed P than in those fed S.(ABSTRACT TRUNCATED AT 250 WORDS)

Diarrhea in streptozocin-induced chronically diabetic rats is caused by an impaired adrenergic regulation of intestinal fluid and electrolyte transport. Stimulation of alpha 2-adrenergic receptors on enterocytes normally promotes NaCl absorption and inhibits HCO3 secretion. The purpose of this study was to determine if adrenergic denervation of intestinal mucosa in chronically diabetic rats alters postsynaptic receptor response, and if the alpha 2-adrenergic agonist clonidine could correct observed fluid malabsorption. Mucosal norepinephrine stores, a measure of adrenergic tone, were markedly reduced in diabetic rats compared with nondiabetic littermates. In vitro, short-circuit current changes to exogenously added l-epinephrine were significantly greater in diabetics, suggesting that denervation hypersensitivity was due to increased numbers of postsynaptic alpha 2-adrenergic receptors. In vivo loop studies demonstrated net fluid secretion in the ileum and colon of diabetics. In diabetics, clonidine reversed the secretion to absorption, but it had no effect on fluid absorption in controls. We conclude that diabetic diarrhea in streptozocin-induced chronically diabetic rats is due to impaired adrenergic regulation of mucosal ion transport, accompanied by a postsynaptic denervation hypersensitivity that can be reversed by clonidine, and accompanied by net intestinal fluid secretion that can be effectively reversed with clonidine.