Julius J. Deren

An open-label trial of the PPARγ ligand rosiglitazone for active ulcerative colitis

OBJECTIVES:Previous research has demonstrated that ligands for the γ subtype of peroxisome proliferator-activated receptors (PPARs) reduce inflammation in two different murine models of colitis. This study was designed to examine the potential efficacy of rosiglitazone, a ligand for the γ subtype of PPARs, as a therapy for active ulcerative colitis.METHODS:Fifteen patients with mild to moderately active ulcerative colitis despite therapy with 5-aminosalicylic acid compounds were enrolled in an open-label study of rosiglitazone (4 mg b.i.d. p.o.) for 12 wk. Thirteen of 15 patients were receiving concomitant therapy with corticosteroids and/or immunomodulator medications. Disease activity was measured with the Disease Activity Index.RESULTS:After 12 wk of therapy, four patients (27%) had achieved clinical remission, of whom three (20%) also had an endoscopic remission. Four additional patients (27%) had a clinical response without achieving remission. Two patients were hospitalized with worsened disease activity, and one patient was withdrawn for nephrotic syndrome.CONCLUSIONS:These data suggest that ligands for the γ subtype of PPARs may represent a novel therapy for ulcerative colitis. A double blind, placebo-controlled, randomized trial is warranted.

Rosiglitazone for Active Ulcerative Colitis: A Randomized Placebo-Controlled Trial

BACKGROUND & AIMS Thiazolidinedione ligands for the gamma subtype of peroxisome proliferator-activated receptors (PPARgamma), widely used to treat type 2 diabetes mellitus, have been proposed as novel therapies for ulcerative colitis (UC). METHODS This multicenter, randomized, double-blind, placebo-controlled clinical trial compared the efficacy of rosiglitazone (Avandia; GlaxoSmithKline, Philadelphia, PA) 4 mg orally twice daily vs placebo twice daily for 12 weeks in 105 patients with mild to moderately active UC. Disease activity was measured with the Mayo score. The primary end point was clinical response (>/=2-point reduction) at week 12. Clinical remission (Mayo score </=2), endoscopic remission, and quality of life were secondary outcomes. RESULTS After 12 weeks of therapy, 23 patients (44%) treated with rosiglitazone and 12 patients (23%) treated with placebo achieved clinical response (P = .04). Remission was achieved in 9 patients (17%) treated with rosiglitazone and 1 patient (2%) treated with placebo (P = .01). Endoscopic remission was uncommon in either treatment arm (8% rosiglitazone vs 2% placebo; P = .34). Clinical improvement was evident as early as 4 weeks after beginning treatment (P = .049). Quality of life was improved significantly at week 8 (P = .01), but not at week 4 (P = .48) or week 12 (P = .14). Serious adverse events were rare. CONCLUSIONS Rosiglitazone was efficacious in the treatment of mild to moderately active UC.

Efficacy of anti-tumor necrosis factor therapy in patients with ulcerative colitis

OBJECTIVES:Tumor necrosis factor-α (TNF-α) is an important cytokine involved in the pathogenesis of inflammatory bowel disease. The monoclonal antibody to TNF-α, infliximab, is effective in treating Crohns disease. Preclinical studies suggest the importance of TNF-α in treating ulcerative colitis (UC). We report the effectiveness of infliximab for UC and examine factors predictive of response to medication.METHODS:Data from all UC patients receiving infliximab at four institutions were analyzed. Disease activity was determined by the Disease Activity Index.RESULTS:A total of 27 patients with active UC received inpatient (37%) and outpatient (63%) infliximab as single (52%) or multiple (two to 15) infusions (48%). Twelve patients (44%) achieved remission and six patients (22%) had partial response. Nine patients had no response; five subsequently underwent total colectomy. The median time to achieve response and remission was 4 days and the median duration 8 wk. Nine of the 18 patients who responded experienced 19 relapses; 18 of these relapses (95%) were successfully treated with repeat infusions. Steroid-refractory patients were less likely to respond to infliximab therapy than were steroid-responsive patients (33% vs 83%; p = 0.026). No other factors were predictive of response to infliximab. Two patients developed serious adverse events, including death in one case.CONCLUSIONS:Preliminary evidence suggest effectiveness of infliximab in the treatment of UC, including medically refractory severe disease. Individuals who are refractory to corticosteroids, however, may be unlikely to respond to infliximab. A randomized controlled trial is necessary to further investigate the efficacy of infliximab in patients with UC.

CANCER RISK IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Patients with inflammatory bowel disease (IBD) are at increased risk for developing cancer of the gastrointestinal tract, particularly colorectal cancer. Because of the relative rarity of IBD in the general population, it has been difficult to quantify this risk. Efforts to reduce the risk have included both prophylactic surgery and endoscopic screening programs. Because of the potential impact on quality of life and life expectancy, the optimal strategy for reducing this risk has not been defined. This article reviews the current literature relating to the risk of cancer for patients with IBD and methods to reduce this risk.

Direct and Indirect Effects of Dextrose and Amino Acids on Gut Mass

Oral intake of an elemental diet maintains small intestinal mucosal mass compared to the atrophy seen after intravenous infusion of the same diet. The greatest difference in intestinal mass occurs in the proximal bowel and is thought to occur because of rapid absorption in the proximal small bowel. This study was designed to determine the effects of the individual components of the elemental diet and their site of administration within the small bowel on small intestinal mass. Rats were maintained on intravenous alimentation and the proximal gut (by intragastric infusion) or the ileum was continuously infused with equal volumes of 30% dextrose, 5% dextrose, 5% amino acids, saline, or 30% mannitol. After 1 week of combined intravenous alimentation and gut infusion, the rats were killed and parameters of small intestinal epithelial mass were determined sequentially for the entire bowel. Although saline- and mannitol-infused controls did not differ from uninfused intravenously fed rats, proximal infusion of 30% dextrose reproduced the effects of a complete elemental diet. Proximal infusion of amino acids but not 5% dextrose had a limited effect on the duodenum and jejunum. Ileal infusion of 30% dextrose led to local hyperplasia of the site of infusion and in addition produced hyperplasia of the proximal gut. Ileal amino acid infusion, but not 5% dextrose infusion, led to local ileal hyperplasia. We conclude that: (1) intraluminal dextrose and amino acids have direct effects in maintaining gut mass (2) the gut is more responsive to amino acids compared to 5% dextrose, and (3) ileal 30% dextrose infusion leads to remote effects in the proximal gut, perhaps mediated by hormonal or neurovascular factors.

Distinction between dysplasia-associated lesion or mass (DALM) and adenoma in patients with ulcerative colitis

Polyps with epithelial dysplasia in ulcerative colitis (UC) represent either dysplasia-associated lesions or masses (DALMs) or sporadic adenomas. DALMs are frequently associated with associated carcinoma and are an indication for colectomy. Removal of the polyp is treatment of choice for sporadic adenomas. Differentiating between these 2 lesions is not always easy. The goal of this study was to distinguish DALMs from adenomas in patients with UC on a genetic basis. We evaluated genetic alterations in DALMs and compared them with a previously published set of dysplastic polyps in patients with UC that were considered adenomas for the following reasons: (1) polyps were located outside of current active disease; (2) polyps had histological features of sporadic adenomas; and (3) patients displayed a uneventful follow-up after polypectomy (UC-adenomas). In addition, adenomas not associated with UC were studied. Genetic alterations on chromosome 3p were assessed for the markers D3S1766, D3S2409, and D3S2387. LOH with or without microsatellite instability was found in 70%, 37%, and 57% of cases of DALM, respectively. In contrast, UC-adenomas lesions exhibited genetic alterations in 8.3%, 11.7%, and 15.3% for the respective markers. Spontaneous adenomas exhibited genetic alterations in 10.5%, 7.1%, and 0% of cases, which were not significantly different from the UC-adenoma results. These results indicate that UC-adenomas are genetically and biologically similar to sporadic adenomas and that UC-adenomas may biologically represent sporadic adenomas, supporting on a genetic basis the criteria chosen to diagnose adenomas in UC. Genetic markers on chromosome 3p may be useful in the differential diagnosis between DALM and UC-adenomas.

Trypsin-Like Nature of the Pancreatic Factor That Corrects Vitamin B12 Malabsorption Associated with Pancreatic Dysfunction

Hog pancreas was subfractionated and assessed for its ability to correct vitamin B(12) malabsorption in patients with pancreatic dysfunction and in rats with partial pancreatic extirpation. The constituent obtained from the pancreas that increased vitamin B(12) absorption in both humans and rats was soluble at 50,000 g, heat labile, acid stable, and approximately 20,000-25,0000 in molecular weight. The active subfractions contained tryptic and chymotryptic but no amylase or lipase activity. Thrice-crystallized trypsin corrected the vitamin B(12) malabsorption in both patients with pancreatic insufficiency and in rats with subtotal pancreatectomy. These data indicate that pancreatic proteolytic enzymes-in particular, trypsin-are necessary for optimal vitamin B(12) absorption.

The Role of the Pancreas in Vitamin B12 Absorption: Studies of Vitamin B12 Absorption in Partially Pancreatectomized Rats

The effect of partial pancreatectomy (80-90%) on vitamin B(12) absorption was studied in the rat. The absorption of 5 ng of (57)Co-labeled vitamin B(12) was significantly reduced from 70 +/-2.5% (mean +/-SE) in control and sham-operated rats to 32 +/-2.6% in partially pancreatectomized rats. Hog pancreatic extract (0.17 g/kg) improved vitamin B(12) absorption from 30.0 to 61.0% in partially pancreatectomized rats but did not alter vitamin B(12) absorption in control rats. Chloramphenicol did not enhance vitamin B(12) absorption in partially pancreatectomized rats with pancreatic extract-improved vitamin B(12) malabsorption. The partially pancreatectomized rats with pancreatic extract-improved vitamin B(12) malabsorption were sacrificed and the stomach and small bowel studied in vitro to further define the pathogenesis of the vitamin B(12) malabsorption. Rat gastric intrinsic factor stimulated vitamin B(12) uptake by intestinal sacs prepared from partially pancreatectomized rats 3.1-fold. Gastric intrinsic factor prepared from partially pancreatectomized rats was as effective in promoting vitamin B(12) uptake by rat intestinal sacs as intrinsic factor prepared from control rats. These data indicate that partially pancreatectomized rats develop an abnormality in the absorption of labeled vitamin B(12) which can be corrected by pancreatic extract. The vitamin B(12) malabsorption is due to neither an alteration in gastric intrinsic factor activity nor an impairment of the intrinsic factor-vitamin B(12) receptor in the intestine. It is suggested that in the partially pancreatectomized rats the intrinsic factor-vitamin B(12) complex exists in a form which is not available for absorption.

Selective Inhibition of Vitamin B12 Absorption by Para-Aminosalicylic Acid

A patient is described in whom vitamin B12 malabsorption was induced by the daily oral administration of 8 g of para-aminosalicylic acid. Para-aminosalicylic acid did not alter intestinal morphology, intestinal maltase, or sucrase activities, xylose excretion, or lead to steatorrhea. Thus, para-aminosalicylic acid should be added to the list of pharmacological agents that may induce a reversible malabsorption of vitamin B12.

Studies of Glycerol Transport Across the Rabbit Brush Border

The unidirectional movement of glycerol across rabbit brush border was studied in vitro. The permeability coefficient for glycerol across the ileal brush border decreased from 3.41 x 10-4 cm · sec-1 at 0.05 mm to 0.65 at 5 mm, and remained constant at this level from 5 to 50 mm. Glucose and phlorizin did not inhibit glycerol movement. N-ethyl-maleimide inhibited glycerol by more than 55% from a 0.05 mm solution, but did not affect glycerol uptake from a 50 mm solution. Glycerol movement across the ileal brush border measured from a 0.05 mm solution was 2 times greater than the movement across proximal intestine. By contrast, glycerol movement across proximal and distal intestine was similar when measured from a 50 mm solution. It is concluded that glycerol movement occurs both by diffusion via the aqueous regions of the membrane and by a saturable carrier-mediated mechanism.