Faculty Bibliography

BACKGROUND: The tablet formulation of sodium phosphate (NaP) is a prescription osmotic purgative that has been marketed since 2001. The use of NaP tablets in patients with constipation has not been studied previously. OBJECTIVE: This study assessed the tolerability and efficacy of 28 days of therapy with NaP tablets (1.5 g NaP/tablet) in patients with chronic constipation. METHODS: Adults with functional constipation or constipation-predominant irritable bowel syndrome and Z-3 spontaneous bowel movements (BMs) during the 7-day screening/baseline period were eligible for this open-label, dose-ranging study. Patients were randomized to receive starting doses of 4 NaP tablets (group A) or 8 NaP tablets (group B) each morning for 28 days. After a minimum of 48 hours, the NaP dose could be titrated upward (in the case of no BM or no relief of symptoms) or downward (in the case of a predefined excess laxative response) by 2 tablets/d to a minimum of 2 tablets/d or a maximum of 12 tablets/d. Patients kept a diary of their BMs and gastrointestinal symptoms. A serum chemistry panel was obtained weekly. The primary end points were the constipation response (based on the change from baseline in weekly number of BMs) and the global sense response (based on daily scores for the patient's overall sense of change in their bowel problems). RESULTS: At randomization, there were 18 patients in group A and 25 in group B. Of these, 40 patients (16 group A, 24 group B) had > or 7 days of diary information while taking study treatment and were evaluable for efficacy. The constipation response rate was 100% in group A and 95.8% in group B, and the respective global sense response rates were 68.8% and 79.2%. Four patients in group B withdrew due to adverse events, none of which were serious. Five patients had occasional hypokalemia that required no treatment. Changes from baseline in serum concentrations of calcium, inorganic phosphorus, and potassium were not clinically significant and did not require treatment. CONCLUSIONS: In this small study, NaP tablets taken daily were generally well tolerated (particularly in the low-dose group) and produced prompt relief of constipation--generally within the first week of treatment--that was sustained over the 28-day treatment period. A reasonable starting dose appears to be 2 to 4 tablets (3-6 g NaP) daily

BACKGROUND: Repifermin (keratinocyte growth factor-2) has been shown to reduce inflammation in animal models of colitis. AIM: To evaluate repifermin for the treatment of active ulcerative colitis. METHODS: Eighty-eight patients with active ulcerative colitis were enrolled in a 6-week, double-blind trial. Patients were randomized to receive treatment for five consecutive days with intravenous repifermin at a dose of 1, 5, 10, 25 or 50 microg/kg, or placebo. The primary objective of the study was to evaluate the safety of repifermin. The primary efficacy outcome was clinical remission at week 4, defined as a score of zero on the endoscopic appearance and stool blood components of the Mayo score and a score of zero or unity on the stool frequency and physician's global assessment components. RESULTS: At week 4, the rates of clinical remission in the 1, 5, 10, 25 and 50 microg/kg repifermin groups were 19%, 9%, 0%, 0% and 0%, respectively, and 11% for the placebo group (P = 0.32 for repifermin vs. placebo). The frequencies of commonly occurring adverse events and severe adverse events were similar in both groups. CONCLUSIONS: Intravenous repifermin at a dose of 1-50 microg/kg was very well tolerated, but there was no evidence that repifermin was effective for the treatment of active ulcerative colitis at these doses. An additional study to determine the efficacy of repifermin at doses of > 50 microg/kg or for a longer treatment duration may be warranted, as the maximally tolerated dose was not reached in the present study.

Extraintestinal manifestations of both Crohn's disease and ulcerative colitis (UC) have been well described, although pulmonary findings are often overlooked. We summarize the experience of more than 400 cases of pulmonary manifestations of inflammatory bowel disease (IBD). These manifestations will be categorized by disease mechanism into drug-induced disease, anatomic disease, over-lap syndromes, autoimmune disease, physiologic consequences of IBD, pulmonary function test abnormalities, and nonspecific lung disease. We intend to provide the clinician with a practical working update on the spectrum of pulmonary dysfunction associated with IBD

Small bowel diverticulosis (SBD) is a rare entity. Most cases of diverticulosis are asymptomatic. SBD is often discovered incidentally during contrast studies and endoscopy. When patients report chronic gastrointestinal symptoms such as abdominal pain, bloating, flatulence, and anemia, SBD is often an overlooked diagnosis. Patients requiring treatment for SBD are those with complications such as malabsorption, hemorrhage, obstruction, and acute inflammation with abscess or rarely perforation. Malabsorption can be managed with broad-spectrum antibiotics and vitamin supplementation. Hemorrhage is treated conservatively with resuscitation efforts, but recurrent bleeding requires surgery. Enteroliths causing obstruction in the duodenum can be relieved by endoscopy, that is, by manipulation, but jejunoileal obstruction requires a resection. Pseudo- obstruction may be managed with prokinetics such as metoclopramide, erythromycin, and the 5-hydroxytryptamine 4 agonist tegaserod. Uncomplicated cases of SBD are treated with bowel rest and antibiotics. However, perforation or abscess formation not amenable to percutaneous drainage mandates surgical resection. Any patient with a triad of anemia, abdominal pain, and an abdominal radiograph with dilated loops of small bowel merits SBD in the differential diagnosis

OBJECTIVE: Recent reports indicate that allelic variants in NOD2/CARD15 are associated with Crohn's disease (CD) susceptibility, and that homozygosity or compound heterozygosity at this locus for any of three recently defined sequence variants confers a greatly increased risk of CD. These sequence changes include two missense mutations, R702W and G908R, and a frameshift insertion, 1007insC. The aim of this study was to determine the frequency of these NOD2/CARD15 variants in familial and sporadic CD patients in the Ashkenazi population and to determine their effects on disease susceptibility and age of disease onset (AOO). METHODS: Allele and genotype frequencies of these three variants were determined in 481 CD patients of Jewish descent and 110 Jewish controls; 169 patients had a family history of CD, and 312 were 'sporadic' cases. Variants were detected by polymerase chain reaction using allele-specific primers labeled with fluorescent dye. RESULTS: Familial cases had a significantly higher frequency of the G908R variant than sporadic cases (0.127 vs 0.059, p = 0.0003) and correspondingly, a significantly higher proportion of homozygotes and compound heterozygotes (11.8% vs 4.5%, p = 0.0027). Homozygotes and compound heterozygotes had an OR for CD of 14.6 for familial cases and 5.1 for sporadic cases. There was no increased risk of CD for simple heterozygotes. The AOO was significantly lower for CD patients who were homozygotes and compound heterozygotes for NOD2/CARD15 (17.5 vs 22.4 yr, p = 0.04), but only for familial cases. CONCLUSIONS: NOD2/CARD15 contributes more to CD susceptibility in familial cases than in sporadic cases, and to an earlier AOO. There is no increased risk of CD for individuals carrying only a single copy of these NOD2/ CARD15 variants, whereas individuals carrying two copies have a 5-15-fold increased risk. The penetrance of the NOD2/CARD15 mutations was estimated at less than 1%

OBJECTIVES: Budesonide controlled ileal release (CIR) capsules deliver budesonide, a glucocorticosteroid with high topical and low systemic activity, to the distal ileum and the proximal colon. In four previous controlled trials in Crohn's disease, remission rates ranged from 51% to 69%. We sought to evaluate the efficacy and safety of this drug in a population of patients in the United States with Crohn's disease. METHODS: In this multicenter, double blind, randomized trial, 200 patients in the United States with mild to moderate Crohn's disease (Crohn's Disease Activity Index [CDAI] between 200 and 450) involving the distal ileum and/or ascending colon received 9 mg of budesonide CIR once daily, 4.5 mg b.i.d., or placebos for 8 wk. The primary outcome was remission defined by a CDAI of 150 or less. RESULTS: Remission was achieved in 48%, 53%, and 33% with 9 mg once daily, 4.5 mg b.i.d., and placebos, respectively, after 8 wk of treatment. Differences between the groups were not significant. The differences in mean change from baseline CDAI between the combined budesonide and placebo groups was significant (p < 0.05). There was no difference in observed adverse events between treatment groups, although a modest decrease in plasma cortisol levels was observed relative to the placebo (p < 0.01). CONCLUSIONS: Treatment of symptomatic Crohn's disease with budesonide CIR capsules (9 mg daily) was safe, and remission rates were similar to those achieved in previous trials. Although the remission rate did not significantly differ from the placebo response in this study, there was a significant change in the mean CDAI from baseline in the combined treatment groups relative to the placebo

The bewildering array of medications in the therapy of inflammatory bowel disease (IBD) often confounds the clinician in the choice of specific agents regarding the balance between safety and efficacy. This review surveys and evaluates currently available IBD therapies as well as those used in clinical trials of ulcerative colitis. The primary purpose is to provide the busy clinician with a practical guide to the use of established and newly emerging medical therapies of IBD

BACKGROUND & AIMS: We evaluated etanercept, a human soluble tumor necrosis factor receptor: Fc fusion protein, for the treatment of active Crohn's disease. METHODS: Forty-three patients with moderate to severe Crohn's disease were enrolled in an 8-week placebo-controlled trial. Patients were randomized to subcutaneous etanercept 25 mg or placebo twice weekly. The primary outcome measure was clinical response at week 4, defined as a decrease in the baseline Crohn's Disease Activity Index score > or =70 points or a Crohn's Disease Activity Index score <150 points. RESULTS: At week 4, 39% of etanercept-treated patients had clinical response as compared with 45% of placebo-treated patients (P = 0.763). The frequency of common adverse events including headache, new injection site reaction, asthenia, abdominal pain, Crohn's disease-related anemia, and skin disorders was similar in both groups. Likewise, the frequency of severe or serious adverse events was similar in both groups. CONCLUSIONS: Subcutaneous etanercept at a dose of 25 mg twice weekly is safe, but not effective, for the treatment of patients with moderate to severe Crohn's disease. The dose of etanercept administered in this study is that approved for rheumatoid arthritis. Higher doses or more frequent dosing may be required to attain a response in patients with active Crohn's disease.