Charles A. Sninsky

Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease ☆ ☆☆ ★

BACKGROUND & AIMS Azathioprine is effective for Crohns disease but acts slowly. A loading dose may decrease the time to response. METHODS A placebo-controlled study was conducted in patients with active Crohns 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 Crohns Disease Activity Index of </=150 points. Erythrocyte concentrations of the azathioprine active metabolite, 6-thioguanine nucleotide, were measured. RESULTS 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. CONCLUSIONS A loading dose does not decrease the time to response in patients with steroid-treated Crohns disease beginning azathioprine therapy. Steady state of erythrocyte 6-thioguanine nucleotide and complete response occurred earlier than previously reported.

Nausea, Vomiting, and Abdominal Pain After Roux-en-Y Anastomosis: Motility of the Jejunal Limb++++++

The Roux-en-Y anastomosis is a surgical procedure performed to divert the pancreaticobiliary juices from the gastric pouch in patients who have alkaline reflux gastritis or esophagitis, or both, that develop after vagotomy and Billroth I or II operations. After the Roux-en-Y procedure the inflammation subsides but is often replaced by a characteristic group of symptoms--chronic abdominal pain, nausea, and vomiting worsened by eating. Using a semiconductor recording probe, we investigated the Roux limb in 7 subjects who were fasted and then fed (liquid and solid meals). In the fasted state the migrating motor complex was either completely absent or grossly disrupted. Only 1 subject converted to a fed-state motility pattern in the Roux limb after a liquid meal (Osmolite), and all 7 subjects failed to convert to a fed state after a solid meal. These studies suggest that the Roux-en-Y syndrome of pain, nausea, and vomiting is secondary to a defect in motor function and that the Roux limb is acting as an area of functional obstruction.

Preliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn's disease

BACKGROUND & AIMS Recombinant human interleukin 11 (rhIL-11) is a cytokine with thrombocytopoietic activity and anti-inflammatory and mucosal protective effects. The objectives of this study were to investigate the safety and tolerability of rhIL-11 in patients with Crohns disease and to explore the effects of dose and schedule on platelet count and Crohns disease activity. METHODS A multicenter, double-masked, placebo-controlled, dose-escalation study of 76 patients with active Crohns disease was performed. Patients were randomized to receive subcutaneous placebo or rhIL-11 at doses of 5, 16, or 40 microgram. kg-1. wk-1 given 2 or 5 times weekly for 3 weeks. Clinical and laboratory safety data were recorded, and disease activity was measured at each visit. RESULTS Subcutaneous injection of rhIL-11 generally was well tolerated. Significantly greater increases in platelet counts were found among patients receiving rhIL-11 40 microgram. kg-1. wk-1 as 2 or 5 weekly doses and 16 microgram. kg-1. week-1 as 5 weekly doses compared with patients receiving placebo (P < 0.05). Patients receiving 16 microgram. kg-1. wk-1 had the highest clinical response rates, with a response seen in 42% of patients (5/12) receiving 5 weekly doses and 33% of patients (4/12) receiving 2 weekly doses, compared with 7% of patients (1/15) receiving placebo. CONCLUSIONS Short-term treatment with rhIL-11 is well tolerated in patients with active Crohns disease. The thrombocytopoietic effect of rhIL-11 seems to be both dose and schedule dependent and may be minimized with retained clinical benefit in Crohns disease at 16 microgram. kg-1. wk-1 given in 2 equal doses.

Effect of octreotide and erythromycin on idiopathic and scleroderma-associated intestinal pseudoobstruction

Treatment of chronic intestinal pseudoobstruction with prokinetic agents has been disappointing. Our study was designed to determine if octreotide and erythromycin would provide sustained relief from nausea, abdominal pain, and bloating in pseudoobstruction. Using gastrointestinal manometry, quantitative parameters of the activity front of the migrating motor complex at baseline and after prokinetic therapy with erythromycin and octreotide were determined in 14 patients with intestinal pseudoobstruction who had nausea, abdominal pain, and bloating. Patients were treated with erythromycin and octreotide for 20–33 weeks. Octreotide increased the frequency, duration, and motility index of activity fronts (AFs) from 1.2±0.3 AFs/4hr, 2.7±0.7 min, and 85±23 min mm Hg to 4.1±0.8 AFs/4 hr, 5.5±0.7 min, and 152±24 min mm Hg, respectively (P<0.05). Antral activity was decreased from 63±14 to 23±8% by octreotide (P<0.05). Erythromycin induced antral activity; however, small intestinal motor activity was suppressed. While on erythromycin and octreotide, five patients had long-term improvement of nausea and abdominal pain. All responders had at least 5 AFs/4 hr induced by octreotide. We conclude that octreotide and erythromycin relieve abdominal pain and nausea in pseudoobstruction. Patients who have at least 5 AFs/4 hr after octreotide administration are most likely to clinically respond.

DIABETES AND THE GASTROINTESTINAL TRACT

Gastrointestinal motility disorders are common in patients with diabetes. The entire gastrointestinal tract may be involved from the esophagus to the anal sphincter. Before instituting therapy, people with diabetes first require a careful diagnostic evaluation. Treatment includes tight glucose control and the use of antiemetics and prokinetic agents.

Human gastric myoelectric activity and gastric emptying following gastric surgery and with pacing

Postoperative gastric myoelectric activity, gastric emptying, and clinical course were correlated in 17 patients at high risk of developing gastroparesis after gastric surgery. In addition, an attempt was made to pace the stomach with an electrical stimulus and determine the effect of pacing on early postoperative gastric emptying. Gastric dysrhythmias (bradygastria, slow wave frequency < 2 cycles/min; tachygastria, slow wave frequency > 4 cycles/min) persisted beyond the first postoperative day in 6 patients (35%). Delayed gastric emptying was identified by a radionuclide meal in 15 patients (88%), but symptoms of gastroparesis developed in only 6 of 15 (40%). Patients with postoperative gastroparesis had more frequent dysrhythmias than asymptomatic patients (67% vs. 18%), but these differences were not significant, although we cannot exclude a type II statistical error. Gastric rhythm was entrained in 10 of 16 patients (63%). Pacing increased the gastric slow wave frequency (3.1 vs. 4.1 cycles/min; P < 0.01) but did not improve gastric emptying (gastric retention at 60 minutes, 86% +/- 6% for control and 90% +/- 2% for paced). In conclusion, gastric dysrhythmias do not appear to play a major role in the development of postsurgical gastroparesis. Although gastric rhythm could be entrained in the majority of patients, pacing did not improve gastric emptying overall.

Prevention and treatment of osteoporosis in patients with inflammatory bowel disease

Osteopenia or osteoporosis is common in patients with inflammatory bowel disease. The use of corticosteroids contributes to the decline in bone loss; however, osteoporosis may develop in patients with inflammatory bowel disease independent of corticosteroid use. Risk factors for the development of low bone mass in patients with inflammatory bowel disease include the general risk factors for osteoporosis as well as additional factors such as the presence of chronic inflammation, use of corticosteroids and other pharmaceuticals, and nutritional deficiencies as the result of small bowel disease or small bowel resections. Despite the high prevalence, few patients are entered into prophylactic regimens to prevent corticosteroid-induced bone loss. The American College of Rheumatology has recently published recommendations for the prevention and treatment of corticosteroid-induced osteoporosis. In this article, we highlight the special risks for osteoporosis in patients with IBD and adapt the recommendations for prevention and treatment of osteoporosis to this clinical setting.

Once-Daily Dosing of Delayed-Release Oral Mesalamine (400-mg Tablet) Is as Effective as Twice-Daily Dosing for Maintenance of Remission of Ulcerative Colitis

BACKGROUND & AIMS The practice of dosing mesalamines in divided doses for the treatment of ulcerative colitis (UC) began with sulfasalazine and was driven by sulfapyridine toxicity. This convention and the assumption that dosing multiple times a day is necessary to treat UC had not been challenged until recently. This study was conducted to determine the efficacy and safety of once-daily dosing of delayed-release mesalamine (Asacol 400-mg tablets) compared with twice-daily dosing for maintaining remission in UC patients. METHODS A multicenter, randomized, investigator-blinded, 12-month, active-control trial was conducted to assess the noninferiority of delayed-release mesalamine 1.6-2.4 g/day administered once daily compared with twice daily in patients with mild-to-moderate UC currently in clinical remission. The primary end point was maintenance of clinical remission at month 6. RESULTS A total of 1023 patients were randomized and dosed. The primary objective of noninferiority was met. At month 6, 90.5% of patients receiving once-daily dosing had maintained clinical remission, compared with 91.8% of patients receiving twice-daily dosing (95% confidence interval for twice daily - once daily, -2.3 to 4.9). At month 12, 85.4% of patients receiving once-daily dosing had maintained clinical remission, compared with 85.4% of patients receiving twice-daily dosing (95% confidence interval for twice daily - once daily, -4.6 to 4.7). Both regimens had low rates of withdrawals as a result of adverse events and serious adverse events. CONCLUSIONS Once-daily dosing of delayed-release mesalamine at doses of 1.6-2.4 g/day was shown to be as effective as twice-daily dosing for maintenance of clinical remission in patients with UC.

Disruption in neuropeptide Y and leptin signaling in obese ventromedial hypothalamic-lesioned rats

Electrolytic lesions placed in the ventromedial hypothalamus (VMH) of rats induce instant hyperphagia and excessive weight gain. Since neuropeptide Y (NPY) is a potent hypothalamic orexigenic signal, and leptin secreted by adipocytes regulates NPY output, we tested the hypothesis that altered NPYergic-leptin signaling may underlie hyperphagia in VMH-lesioned rats. VMH-lesioned rats exhibiting hyperphagia and excessive weight gain in a time-related fashion were sacrificed on days 2, 7, and 21 post-surgery. Quite unexpectedly, NPY concentrations in the hypothalamic paraventricular nucleus (PVN), a major site of NPY release for stimulation of feeding, and in other sites, such as the dorsomedial nucleus, lateral hypothalamic area and median eminence-arcuate nucleus decreased, with the earliest diminution occurring on day 2 in the PVN only. In vitro basal and K+-evoked NPY release from the PVN of VMH-lesioned rats was significantly lower than that of controls. Analysis of hypothalamic NPY gene expression showed that although the daily decrease in NPY mRNA from 0800 to 2200 h occurred as in control rats, NPY mRNA concentrations were markedly reduced at these times in the hypothalami of VMH-lesioned rats. Leptin synthesis in adipocytes as indicated by leptin mRNA levels was also profoundly altered in VMH-lesioned rats. The daily pattern of increase in adipocyte leptin mRNA at 2200 h from 0800 h seen in controls was abolished, higher levels of leptin gene expression at 2200 h were maintained at 0800 h. The pattern of increase in serum leptin and insulin levels diverged in VMH-lesioned rats. Serum insulin concentration increased to maximal on day 2 and remained at that level on day 21-post-lesion; serum leptin levels on the other hand, increased slowly in a time-related fashion during this period. These results demonstrate that hyperphagia and excessive weight gain in VMH-lesioned rats are associated with an overall decrease in hypothalamic NPY and augmented leptin signaling to the hypothalamus. The divergent time course of increases in serum leptin and insulin levels suggest independent mechanisms responsible for their augmented secretion, and neither these hormones nor VMH lesions altered the daily rhythm in NPY gene expression. These observations underscore the existence of an independent mechanism controlling the daily rhythm in hypothalamic NPY gene expression and suggest that leptin feedback action requires an intact VMH.

Ketorolac prevents postoperative small intestinal ileus in rats

The effect of ketorolac, a parenterally administered, nonsteroidal anti-inflammatory drug, was examined in a rat model of postoperative ileus. Small intestinal transit was measured by calculating the geometric center (GC) of distribution of 51CrO4. Laparotomy significantly delayed transit (GC: 2.2 +/- 0.2 after laparotomy versus 5.6 +/- 0.5 for unoperated controls, p < 0.01). The administration of ketorolac (1 mg/kg) improved the GC to 5.2 +/- 0.2 (p < 0.01), indicating normal intestinal transit after surgery in ketorolac-treated animals. Small intestinal myoelectric activity was recorded in rats with implanted electrodes. Animals treated with saline 2 hours postoperatively did not show return of the migrating myoelectric complex (MMC) in 183 +/- 25 minutes. In contrast, rats receiving ketorolac postoperatively had return of MMC activity in 59 +/- 18 minutes (p < 0.01). Preoperative ketorolac treatment reduced the duration of MMC inhibition after surgery from 197 +/- 55 minutes to 13 +/- 5 minutes (p < 0.05) when compared with saline. In summary, ketorolac hastens the return of MMC activity when given postoperatively. When ketorolac is administered preoperatively, it completely prevents the delay in intestinal transit and the inhibition of myoelectric activity seen in postoperative ileus. We concluded that ketorolac may be of benefit in the prevention and treatment of postoperative ileus.