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Biomedical subjects

Richard N Fedorak

Publications and source records attributed to Richard N Fedorak.

At least 19 recordsLinked to original sources
PubMed2006

Onercept for moderate-to-severe Crohn's disease: a randomized, double-blind, placebo-controlled trial.

BACKGROUND AND AIMS: Onercept is a recombinant, soluble human p55 receptor to tumor necrosis factor-alpha. METHODS: A randomized, double-blind, placebo-controlled, dose-ranging trial was performed to evaluate the efficacy of onercept induction therapy in patients with Crohn's disease (CD). Patients (n = 207) with moderate-to-severe acute or chronic active CD were randomized to receive subcutaneous onercept (10, 25, 35, or 50 mg) or placebo 3 times weekly for 8 weeks. Primary analysis was induction of remission (defined as a CD activity index score < or = 150) at week 8. RESULTS: A total of 104 patients had acute active CD. Remission rates at week 8 were 23.5% for placebo (n = 17), and 34.8%, 20.0%, 26.1%, and 28.6% for onercept 10 mg (n = 23), 25 mg (n = 20), 35 mg (n = 23), and 50 mg (n = 21), respectively (P = .98). A total of 103 patients had chronic active CD. Remission rates at week 8 were 23.8% for placebo (n = 21), and 23.8%, 9.1%, 35.3%, and 13.6% for onercept 10 mg (n = 21), 25 mg (n = 22), 35 mg (n = 17), and 50 mg (n = 22), respectively (P = .66). There were no differences between treatment groups in the incidence of adverse events. However, mild-to-moderate injection-site reactions occurred in up to 12% of onercept-treated patients. CONCLUSIONS: Onercept was well tolerated but was not effective at the doses studied in patients with active CD.

Adult↗
PubMed2006

The role of antibiotic and probiotic therapies in current and future management of inflammatory bowel disease.

Abundant evidence indicates that the intestinal microflora have a role in the pathogenesis of inflammatory bowel disease (IBD). The composition of the gut microflora is altered in IBD patients with increased "pathogenic" bacteria and decreased bifidobacteria and lactobacilli. In light of this dysbiosis, various methods have been examined to alter the composition of the intestinal microflora, including the administration of antibiotics and introduction of probiotic species. This article summarizes studies evaluating the efficacy of antibiotics and probiotics in the induction and maintenance of remission of ulcerative colitis, Crohn's disease, and pouchitis.

Anti-Bacterial Agents↗
PubMed2006

Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial.

BACKGROUND & AIMS: Tumor necrosis factor blockade has been shown to be an effective treatment strategy in Crohn's disease (CD). Adalimumab is a human immunoglobulin G1 (IgG(1)) monoclonal antibody targeting tumor necrosis factor (TNF). A randomized, double-blind, placebo-controlled, dose-ranging trial was performed to evaluate the efficacy of adalimumab induction therapy in patients with CD. METHODS: A total of 299 patients with moderate to severe CD naive to anti-TNF therapy were randomized to receive subcutaneous injections at weeks 0 and 2 with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg or placebo. The primary endpoint was demonstration of a significant difference in the rates of remission at week 4 (defined as a Crohn's Disease Activity Index score <150 points) among the 80 mg/40 mg, 160 mg/80 mg, and placebo groups. RESULTS: The rates of remission at week 4 in the adalimumab 40 mg/20 mg, 80 mg/40 mg, and 160 mg/80 mg groups were 18% (P = .36), 24% (P = .06), and 36% (P = .001), respectively, and 12% in the placebo group. Adverse events occurred at similar frequencies in all 4 treatment groups except injection site reactions, which were more common in adalimumab-treated patients. CONCLUSIONS: Adalimumab was superior to placebo for induction of remission in patients with moderate to severe Crohn's disease naive to anti-TNF therapy. The optimal induction dosing regimen for adalimumab in this study was 160 mg at week 0 followed by 80 mg at week 2. Adalimumab was well tolerated.

Adalimumab↗
PubMed2006

Probiotics in the treatment of inflammatory bowel disease.

The demonstration that immune and epithelial cells can discriminate between different microbial species has extended our understanding of the actions of probiotics beyond simple antimicrobial concepts. Several probiotic mechanisms of action, relative to inflammatory bowel disease, have been elucidated: (1) competitive exclusion, whereby probiotics compete with microbial pathogens; (2) immunomodulation and/or stimulation of an immune response; (3) antimicrobial activity and suppression of pathogen growth; (4) enhancement of barrier activity; and (5) induction of T cell apoptosis. The unraveling of these mechanisms of action has led to new support for the use of probiotics in the management of clinical inflammatory bowel disease. While level 1 evidence now supports the therapeutic use of some probiotics in the maintenance treatment of pouchitis, only level 2 and 3 evidence are currently available in support of the use of probiotics in the treatment of ulcerative colitis and Crohn's disease. Nevertheless, one significant and consistent finding has emerged over the course of research in the past year: not all probiotic bacteria have similar therapeutic effects. Rigorously designed, controlled clinical trials, to investigate the unresolved issues related to efficacy, dose, duration of use, single or multistrain formulation, and the concomitant use of prebiotics, synbiotics or antibiotics, are vital.

Colitis, Ulcerative↗
PubMed2006

Recommendations for probiotic use.

Probiotics are live microbial organisms that are administrated as supplements or in foods to benefit the host. It is the recommendation that they may be helpful in the prevention and treatment of acute diarrhea in adults and children, the prevention of antibiotic-associated diarrhea in adults and children, and the maintenance of remission and prevention of pouchitis. Although early results indicate that probiotics may also be useful in immunologic modulation to prevent atopy, treatment of radiation intestinal disease, vaginosis, ulcerative colitis, and the irritable bowel syndrome, the studies available are not sufficient to say they are definitely helpful. Even fewer data are available to recommend probiotics for the treatment of H pylori and Crohn disease and for the prevention of cardiovascular risk factors or other degenerative diseases. Clearly, larger and better-designed studies of probiotics are necessary, including comparative and dose-ranging trials.

Cardiovascular Diseases↗
PubMed2006

Bacterial antigens alone can influence intestinal barrier integrity, but live bacteria are required for initiation of intestinal inflammation and injury.

Intestinal flora plays a critical role in the initiation and perpetuation of inflammatory bowel disease. This study examined whether live fecal bacteria were necessary for the initiation of this inflammatory response or whether sterile fecal material would provoke a similar response. Three preparations of fecal material were prepared: (1) a slurry of live fecal bacteria, (2) a sterile lysate of bacterial antigens, and (3) a sterile filtrate of fecal water. Each preparation was introduced via gastric gavage into the intestines of axenic interleukin-10 gene-deficient mice genetically predisposed to develop inflammatory bowel disease. Intestinal barrier integrity and degrees of mucosal and systemic inflammations were determined for each preparation group. Intestinal barrier integrity, as determined by mannitol transmural flux, was altered by both live fecal bacterial and sterile lysates of bacterial antigens, although it was not altered by sterile filtrates of fecal water. However, only live fecal bacteria initiated mucosal inflammation and injury and a systemic immune response. Fecal bacterial antigens in the presence of live bacteria and sterile fecal bacterial antigens have different effects on the initiation and perpetuation of intestinal inflammation.

Animals↗
PubMed2006

A defect in epithelial barrier integrity is not required for a systemic response to bacterial antigens or intestinal injury in T cell receptor-alpha gene-deficient mice.

BACKGROUND AND AIMS: Genetically induced disruption of the intestinal epithelial barrier leads to development of intestinal inflammation. In the interleukin-10 gene-deficient inflammatory bowel disease (IBD) mouse model, for instance, a primary defect in intestinal epithelial integrity occurs before the development of enterocolitis. In humans, a causal role for epithelial barrier disruption is still controversial. Although studies with first-degree relatives of IBD patients suggests an underlying role of impaired barrier function, a primary epithelial barrier defect in IBD patients has not been confirmed. The purpose of this article is to examine whether a primary epithelial barrier disruption is a prerequisite for the development of intestinal inflammation or whether intestinal inflammation can develop in the absence of epithelial disruption. We examined the intestinal epithelial integrity of the T cell receptor (TCR)-alpha gene-deficient mouse model of IBD. MATERIALS AND METHODS: In vivo colonic permeability, determined by mannitol transmural flux, was assessed in 6-week-, 12-week-, and 25-week-old TCR-alpha gene-deficient and wild-type control mice using a single-pass perfusion technique. Mice were scored for intestinal histological injury and intestinal cytokine levels measured in organ cultures. Systemic responses to bacterial antigens were determined through 48-h spleen cell cultures stimulated with sonicate derived from endogenous bacterial strains. RESULTS: In contrast with previous findings in the interleukin-10 gene-deficient IBD model, TCR-alpha gene-deficient mice did not demonstrate evidence of primary intestinal epithelial barrier disruption at any age, despite developing a moderate to severe colitis within 12 weeks. A rise in intestinal interferon (IFN)-gamma levels preceded the onset of mucosal inflammation and then correlated closely with the degree of intestinal inflammation and injury. Spleen cells from TCR-alpha gene-deficient mice released IFN-gamma in response to stimulation with endogenous luminal bacterial antigens, a finding that suggests that the systemic response to bacterial antigens occurred independently of epithelial barrier disruption. CONCLUSIONS: Intestinal inflammation and a systemic response to bacterial antigens can develop in the absence of a measurable disruption of intestinal permeability.

Age Factors↗
PubMed2006

The bacteriology of biopsies differs between newly diagnosed, untreated, Crohn's disease and ulcerative colitis patients.

The bacterial community (microbiota) that inhabits the gut of humans appears to be an important source of antigens that drive the chronic immunological processes characteristic of Crohn's disease (CD) and ulcerative colitis (UC). Most of the members of the microbiota have not yet been cultured, but nucleic-acid-based methods of detection and enumeration can provide information about the community. This investigation used these methods to obtain information about the bacteria associated with mucosal surfaces in the gut of 20 CD and 15 UC patients. Biopsies were collected from inflamed and non-inflamed sites in the intestines of newly diagnosed, untreated patients. Biopsies were also collected from several intestinal sites of 14 healthy subjects. The bacterial collections associated with the biopsies were analysed by generating PCR/denaturing gradient gel electrophoresis (DGGE) profiles, the preparation of 16S rRNA gene clone libraries, and qualitative PCR to detect specific groups of bacteria. The total numbers of bacteria associated with the biopsies were determined by real-time quantitative PCR. DGGE profiles generated from the terminal ileum and various colonic regions were characteristic of each individual but differed between subjects. DGGE profiles and 16S rRNA gene libraries showed that the bacteria associated with inflamed and non-inflamed tissues did not differ. UC patients had more bacteria associated with biopsies than did CD patients (P<0.01). Statistical analysis of the composition of 16S rRNA gene libraries showed that the bacterial collections in UC and CD patients differed (P<0.05). Unclassified members of the phylum Bacteroidetes were more prevalent in CD than in UC patients. Therefore, the types and numbers of bacteria associated with biopsy samples were distinctly different for UC and CD patients. The observations made in this study should permit targeting of specific bacteriological abnormalities in investigations of the pathogenesis of inflammatory bowel diseases and provide targets for medical interventions.

Adolescent↗
PubMed2005

Probiotics and nutraceuticals: non-medicinal treatments of gastrointestinal diseases.

The demonstration that immune and epithelial cells can discriminate between different microbial and bioactive plant species has extended the known mechanism(s) of action of nutraceuticals and probiotics beyond simple nutrition and/or antimicrobial effects. The progressive unravelling of these plant and bacterial effects on systemic immune and intestinal epithelial cell function has led to new credence for the use of probiotics and nutraceuticals in clinical medicine. Level I evidence now exists for the therapeutic use of probiotics in infectious diarrhea in children, recurrent Clostridium difficile-induced infections and post-operative pouchitis. Additional evidence is being acquired for the use of probiotics in other gastrointestinal infections, irritable bowel syndrome and inflammatory bowel disease. Not all individual probiotic strains have the same efficacy, and future clinical trials may focus on multistrain preparations agents with known efficacy. The use of nutraceuticals and probiotics as therapeutic agents for gastrointestinal disorders is rapidly moving into clinical usage. Scientific studies are providing mechanisms of action to explain the therapeutic effects, and randomized controlled trials are providing the necessary evidence for their incorporation into the therapeutic armamentarium.

Colorectal Neoplasms↗
PubMed2005

Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin.

BACKGROUND: Selective blockade of interactions between leukocytes and vascular endothelium in the gut is a promising strategy for the treatment of inflammatory bowel diseases. METHODS: We conducted a multicenter, double-blind, placebo-controlled trial of MLN02, a humanized antibody to the alpha4beta7 integrin, in patients with active ulcerative colitis. We randomly assigned 181 patients to receive 0.5 mg of MLN02 per kilogram of body weight, 2.0 mg per kilogram, or an identical-appearing placebo intravenously on day 1 and day 29. Eligible patients also received concomitant mesalamine or no other treatment for colitis. Ulcerative colitis clinical scores and sigmoidoscopic assessments were evaluated six weeks after randomization. RESULTS: Clinical remission rates at week 6 were 33 percent, 32 percent, and 14 percent for the group receiving 0.5 mg of MLN02 per kilogram, the group receiving 2.0 mg per kilogram, and the placebo group, respectively (P=0.03). The corresponding proportions of patients who improved by at least 3 points on the ulcerative colitis clinical score were 66 percent, 53 percent, and 33 percent (P=0.002). Twenty-eight percent of patients receiving 0.5 mg per kilogram and 12 percent of those receiving 2.0 mg per kilogram had endoscopically evident remission, as compared with 8 percent of those receiving placebo (P=0.007). For the minority of patients in whom an MLN02 antibody titer greater than 1:125 developed, incomplete saturation of the alpha4beta7 receptor on circulating lymphocytes was observed and no benefit of treatment was identifiable. CONCLUSIONS: In this short-term study, MLN02 was more effective than placebo for the induction of clinical and endoscopic remission in patients with active ulcerative colitis.

Adult↗
PubMed2005

Targeted delivery, safety, and efficacy of oral enteric-coated formulations of budesonide.

Budesonide is a potent corticosteroid with a high first-pass metabolism rate. Two commercially available enteric-coated pH-dependent release formulations (Entocort EC and Budenofalk) deliver budesonide to the ileum and proximal colon, regions most commonly affected in Crohn's disease. The drug's effectiveness in this disease has been proven in multiple, placebo-controlled trials, where it has been shown to be superior to mesalamine and placebo, and equivalent to prednisolone for the control of mild to moderately active right-sided Crohn's disease. This beneficial therapeutic effect comes with less adrenal suppression and a small improvement in the clinical adverse effect profile, as compared to prednisolone. However, budesonide provides no benefit over conventional therapy for left-sided colonic disease, and it is less effective for treatment of more severe disease activity and more distal colonic disease. Continuous budesonide does not prolong remission and is, therefore, best used in an intermittent fashion to treat acute exacerbations.

Administration, Oral↗
PubMed2005

Association with selected bacteria does not cause enterocolitis in IL-10 gene-deficient mice despite a systemic immune response.

Resident bacteria have been implicated to play a major role in the development of inflammatory bowel disease. While luminally sterile IL-10 gene-deficient mice remain disease-free, their conventionally raised littermates develop enterocolitis associated with increased numbers of luminal and mucosal adherent bacteria. To investigate the role of defined bacteria on the initiation and development of this enterocolitis, we associated luminally sterile IL-10 gene-deficient mice with pure strains of resident bacteria. Axenic, luminally sterile mice were either monoassociated with viridans group Streptococcus or Clostridium sordellii or co-associated with Bacteroides vulgatus and Clostridium sordellii. Seven to 22 weeks later the mice were analyzed for intestinal histologic injury, epithelial permeability, and an inflammatory immune response to bacterial antigens. Despite optimal colonization none of the tested bacteria caused intestinal inflammation, release of inflammatory cytokines from the epithelia, or disruption of the epithelial barrier integrity. However, in the case of association with Bacteroides vulgatus and Clostridium sordellii, a systemic immune response to bacterial-derived antigens was measured, with a magnitude similar to that seen in conventional sick Il-10 gene-deficient mice. This response was not detected in mice associated with viridans group Streptococcus. We conclude that colonization of the intestinal lumen with individual bacterial species may not be sufficient to alter epithelial barrier integrity, increase intestinal cytokine release, or cause intestinal inflammation in susceptible IL-10 gene-deficient mice, despite the ability of these same bacteria to stimulate a systemic response.

Animals↗
PubMed2005

Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn's disease.

BACKGROUND & AIMS: Crohn's disease causes an increase in osteopenia and osteoporosis. This study assessed the efficacy of adding etidronate to calcium and vitamin D supplementation for treatment of low bone mineral density in Crohn's disease. METHODS: One hundred fifty-four patients with Crohn's disease with decreased bone mineral density, determined by using dual-energy x-ray absorptiometry, were randomly assigned to receive etidronate (400 mg orally) or not for 14 days; both groups were then given daily calcium (500 mg) and vitamin D (400 IU) supplementation for 76 days. This cycle was repeated 8 times during a period of 24 months. Biochemical characteristics and bone mineral densities were assessed at 6, 12, and 24 months. RESULTS: After 24 months bone mineral density significantly increased from baseline in both the etidronate- and the non-etidronate-treated groups (both groups receiving calcium and vitamin D supplementation) at the lumbar spine (P < .001), ultradistal radius (P < .001), and trochanter (P = .004) sites, but not at the total hip. The increase in bone mineral density was similar in each treatment group. No bone mineral density differences were found when groups were analyzed according to gender, corticosteroid use, bone mineral density at baseline, or age. CONCLUSIONS: Low bone mineral density is frequently associated with Crohn's disease. Supplementation with daily calcium and vitamin D is associated with increases in bone mineral density. The addition of oral etidronate does not further enhance bone mineral density.

Absorptiometry, Photon↗
PubMed2005

A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease.

BACKGROUND & AIMS: To investigate the efficacy and safety of certolizumab pegol (a polyethylene-glycolated Fab' fragment of anti-tumor necrosis factor, CDP870) in Crohn's disease. METHODS: In a placebo-controlled, phase II study, 292 patients with moderate to severe Crohn's disease received subcutaneous certolizumab 100, 200, or 400 mg or placebo at weeks 0, 4, and 8. The primary end point was the percentage of patients with a clinical response at week 12 (a Crohn's Disease Activity Index decrease of > or = 100 points or remission [Crohn's Disease Activity Index < or = 150 points]) in the intent-to-treat population. RESULTS: All certolizumab doses produced significant clinical benefit over placebo at week 2 (placebo, 15.1%; certolizumab 100 mg, 29.7% [P = .033]; 200 mg, 30.6% [P = .026]; 400 mg, 33.3% [P = .010]). At all time points, the clinical response rates were highest for certolizumab 400 mg, greatest at week 10 (certolizumab 400 mg, 52.8%; placebo, 30.1%; P = .006) but not significant at week 12 (certolizumab 400 mg, 44.4%; placebo, 35.6%; P = .278). Patients with baseline C-reactive protein levels of 10 mg/L or greater (n = 119) showed clearer separation between active treatment and placebo (week 12 clinical response: certolizumab 400 mg, 53.1%; placebo, 17.9%; P = .005; post hoc analysis) owing to a lower placebo response rate than patients with C-reactive protein levels of less than 10 mg/L. Adverse events were similar among groups. CONCLUSIONS: Certolizumab 400 mg may be effective and is well tolerated in patients with active Crohn's disease. High placebo response rates in the large patient subgroup with low C-reactive protein levels may have obscured statistical separation between certolizumab and placebo. Ongoing phase III trials are necessary to establish the clinical efficacy of certolizumab.

Adult↗
PubMed2005

Postoperative Crohn's disease.

More than three quarters of patients with Crohn's disease (CD) will require surgery. After resection, disease recurs postoperatively with a median time to second resection of about 10 years. Despite its importance, the postoperative period remains one of the most poorly understood clinical settings in the field. Postoperatively, CD may exhibit unique pathophysiologic features, but the current state of knowledge does not allow for identification of patients at risk for relapse, and leaves clinicians without guidance on optimal maintenance treatment. Therapies used as maintenance for CD in other settings may have different efficacies when used after surgery, and clinical research in patients requiring surgery is limited by the subset of patients available for study. Despite the many limitations in current knowledge of postoperative CD, it is an exciting field because new developments have improved patient care, and ongoing research has the potential for further gains.

Anti-Bacterial Agents↗
PubMed2005

VSL#3 probiotic-mixture induces remission in patients with active ulcerative colitis.

BACKGROUND AND AIMS: Intestinal bacteria have been implicated in the initiation and perpetuation of IBD; in contrast, "probiotic bacteria" have properties possibly effective in treating and preventing relapse of IBD. We evaluated the safety and efficacy of VSL#3 and the components, and the composition of the biopsy-associated microbiota in patients with active mild to moderate ulcerative colitis (UC). METHODS: Thirty-four ambulatory patients with active UC received open label VSL#3, 3,600 billion bacteria daily in two divided doses for 6 wk. The presence of biopsy-associated bacteria was detected using a nucleic acid-based method and the presence of VSL#3 species confirmed by DNA sequencing of 16S rRNA. RESULTS: Thirty-two patients completed 6 wk of VSL#3 treatment and 2 patients did not have the final endoscopic assessment. Intent to treat analysis demonstrated remission (UCDAI < or = 2) in 53% (n = 18); response (decrease in UCDAI > or = 3, but final score > or =3) in 24% (n = 8); no response in 9% (n = 3); worsening in 9% (n = 3); and failure to complete the final sigmoidoscopy assessment in 5% (n = 2). There were no biochemical or clinical adverse events related to VSL#3. Two of the components of VSL#3 were detected by PCR/DGGE in biopsies collected from 3 patients in remission. CONCLUSION: Treatment of patients with mild to moderate UC, not responding to conventional therapy, with VSL#3 resulted in a combined induction of remission/response rate of 77% with no adverse events. At least some of the bacterial species incorporated in the probiotic product reached the target site in amounts that could be detected.

Adult↗