Robin D. Rothstein

A double-blind multicenter comparison of domperidone and metoclopramide in the treatment of diabetic patients with symptoms of gastroparesis

Objective:A double-blind, multicenter, randomized trial was conducted to compare the side effects and efficacy of domperidone and metoclopramide in symptomatic diabetic gastroparesis.Methods:Ninety-three insulin-dependent diabetes patients with a ≥ 3-month history of gastroparesis symptoms were recruited; 48 received domperidone 2 × 10-mg tablets 4 times daily, and 45 received metoclopramide 1 × 10-mg tablet + 1 placebo tablet 4 times daily. Nausea, vomiting, bloating/distension, and early satiety were evaluated for severity after 2 and 4 wk. Adverse central nervous system (CNS) effects of somnolence, akathisia, asthenia, anxiety, depression, and reduced mental acuity were elicited and graded for severity at 2 and 4 wk.Results:Domperidone and metoclopramide were equally effective in alleviating symptoms of diabetic gastroparesis. Elicited adverse CNS effects were more severe and more common with metoclopramide. Somnolence was acknowledged by 49% of patients (mean severity score, 1.03) after 4 wk of metoclopramide compared with 29% of patients (mean severity score, 0.49) after 4 wk of domperidone (incidence, p= 0.02; severity; p= 0.03). A reduction in mental acuity was acknowledged by 33% of patients (mean severity score, 0.62) after 4 wk of metoclopramide, compared with 20% of patients (mean severity score, 0.27) after 4 wk of domperidone (incidence, p= 0.04; severity, p= 0.04). Akathisia, asthenia, anxiety, and depression were also acknowledged less often, and at a lower severity, after 4 wk of domperidone, although these differences were not statistically significant.Conclusions:Domperidone and metoclopramide effectively reduce the symptoms of diabetic gastroparesis; CNS side effects are more pronounced with metoclopramide.

Effect of Leuprolide Acetate in Treatment of Abdominal Pain and Nausea in Premenopausal Women with Functional Bowel Disease: A Double-Blind, Placebo-Controlled, Randomized Study

We have previously reported impressive results in using a gonadotropin-releasing hormone analog, leuprolide acetate (Lupron), in the treatment of moderate to severe symptoms (especially abdominal pain and nausea) in patients with functional bowel disease (FBD). Pain is the hallmark of patients with FBD, and there is no consistent therapy for the treatment of these patients. The purpose of the present study was to expand the investigation to study similar patients (menstruating females) in a multicenter, double-blind, placebo-controlled, randomized study using Lupron Depot (which delivers a continuous dose of drug for one month), 3.75 mg (N = 32) or 7.5 mg (N = 33), or placebo (N = 35) given intramuscularly every four weeks for 16 weeks. Symptoms were assessed using daily diary cards to record abdominal pain, nausea, vomiting, early satiety, anorexia, bloating, and altered bowel habits. Additional assessment tools were quality of life questionnaires, psychological profile, oralto-cecal transit using the hydrogen breath test, antroduodenal manometry, reproductive hormone levels, and global evaluations by both patient and investigator. Patients in both Lupron Depot-treated groups showed consistent improvement in symptoms; however, only the Lupron Depot 7.5 mg group showed a significant improvement for abdominal pain and nausea compared to placebo (P < 0.001). Patient quality of life assessments and global evaluations completed by both patient and investigators were highly significant compared to placebo (P < 0.001). All reproductive hormone levels significantly decreased for both Lupron Depot-treated groups by week 4 and were significantly different compared to placebo at week 16 (P < 0.001). This study shows that leuprolide acetate is effective in controlling the debilitating symptoms of abdominal pain and nausea in patients with FBD.

Distribution and density of substance P receptors in the feline gastrointestinal tract using autoradiography

Autoradiography was used to localize and quantify substance P receptors in the feline gastrointestinal tract. The specific binding of 125I-Bolton Hunter substance P was determined in the esophagus, lower esophageal sphincter, antrum, pylorus, duodenum, jejunum, ileum, ileocecal sphincter, and colon. Competitive binding studies indicated that substance P binding sites or NK-1 receptor sites were demonstrated. The concentration of NK-1 receptors was greatest in the distal half of the gastrointestinal tract, with the highest concentrations in the proximal colon. The circular muscle layer contained the greatest amount of substance P binding. The location and density of binding sites for substance P may be important in understanding the relative importance of both the pharmacological responses to this neuropeptide and the immunohistochemical evidence of the peptide at different sites in the intestine.

Mechanism of action of neurotensin at the ileocecal sphincter region

UNLABELLED Neurotensin, a neuropeptide identified in the distal small intestine, plays an unclear role in ileocecal sphincter regional function. The purpose of this study was to determine the effect and mechanism of action of neurotensin on the feline ileocecal sphincter (ICS), proximal colon, and distal ileum. Intraluminal pressures were recorded at these sites in anesthetized cats after superior mesenteric artery injection of neurotensin. Dose dependent tonic and phasic contractions were seen at all sites. Peak pressure responses were seen at the maximal dose used and were greater for the ICS than the distal ileum and the proximal colon. The threshold dose for peak pressures for neurotensin was 0.05 microgram/kg for all sites with the maximal peak pressures occurring at the maximal dose used (100 micrograms/kg). The motility index (MI [number of contractions x mean amplitude of contractions]) was determined for three minutes before and after neurotensin injection. The change in the motility index after neurotensin increased at doses above 0.05 micrograms/kg for the ileum and the ICS and 0.25 microgram/kg for the colon. Maximal responses for the motility index were seen at 1 microgram/kg for the distal ileum, and 10 micrograms/kg for the ICS and the proximal colon, with the greatest response seen at the ICS. Neurotensin-induced ICS relaxation was seen at 1 microgram/kg (50 +/- 10%, p less than 0.01) in 33% of cats. The contractile responses of the distal ileum and the proximal colon were not inhibited by naloxone, trimethaphan, tetrodotoxin, or atropine. The ICS contractile response was decreased by tetrodotoxin by 53%, p less than 0.05. The alpha 2 antagonist, yohimbine reduced the neurotensin induced ICS contraction from 31.6 +/- 3.4 to 21.9 +/- 3.3 mm Hg, p less than 0.05. Prazosin had no effect on neurotensin-induced contractions. In the presence of cimetidine and diphenhydramine, trimethaphan did not affect the neurotensin-induced contractile response at all three sites. However, neurotensin inhibited contractions induced by trimethaphan alone at all three sites. CONCLUSIONS 1. Neurotensin causes a dose-dependent contractile response at the distal ileum, ICS, and proximal colon. 2. Neurotensin has an inhibitory effect at all three sites. 3. The contractile response at the distal ileum and the proximal colon is mediated via smooth muscle receptors. 4. The contractile response of neurotensin at the ICS is mediated partly via alpha 2 receptors and partly via smooth muscle receptors.

NUTRIENT PHARMACOTHERAPY FOR GUT MUCOSAL DISEASES

The use of nutrients for pharmacotherapy is a recent advance in the treatment of gastrointestinal disorders or alterations of gut function and structure. Nutrients may have a direct effect on the gut, or may enhance the response to medications. Alternatively, pharmacologic agents may improve the absorption of nutrients. Potentially, pharmacotherapy may be an adjunct to the traditional approach used in the treatment of compromised patients.

Linaclotide: a novel compound for the treatment of irritable bowel syndrome with constipation

Introduction: Irritable Bowel Syndrome with constipation (IBS-C) is associated with abdominal pain and infrequent spontaneous bowel movements. Patients with Chronic Idiopathic Constipation do not have abdominal pain as a predominant symptom. Linaclotide represents a new class of medication approved in the USA for both of these common conditions. Linaclotide is approved for IBS-C only in the EU. The only other medication approved at this time for IBS-C is lubiprostone. Areas covered: This review will cover the mechanism of action of linaclotide, and review the pivotal pre-clinical and clinical trials leading to its approval in 2012. The indications, common side effects, and black box warnings listed for linaclotide are reviewed. Expert opinion: Linaclotide is superior to placebo for the treatment of both IBS-C and Chronic Idiopathic Constipation. The drug has minimal systemic bioavailability and a favorable safety profile. For IBS-C, it is appropriate as a first-line prescription treatment. For Chronic Idiopathic Constipation, osmotic or stimulant laxatives should be tried prior to using linaclotide due to their considerable lower cost.

Perforated villous adenoma of the cecum : Report of a case

Villous adenomas are common neoplasms of the colon, often causing anemia or hemoccult positive stools. Less typically, these lesions may result in abdominal pain, melena, obstruction, or change in bowel habits. Intussusception may occur, but this complication is unusual in adults. Spontaneous bowel perforation attributable to colonic polyps has not been previously reported. We present here the first reported case of an adenomatous polyp with bowel perforation and bladder involvement.

Measurement of Fractional Exhaled Nitric Oxide as a Marker of Disease Activity in Inflammatory Bowel Disease.

BACKGROUND AND AIMS Definitive diagnosis of IBD requires endoscopic and pathologic confirmation. These tools are also used to classify disease activity. Our aim was to determine if the fractional exhaled nitric oxide (FeNO) could be utilized to screen for IBD and assess for disease activity. METHODS We matched weighted IBD cases and controls from the 2009-2010 NHANES dataset. All subjects underwent measurement of FeNO using standardized techniques. We assessed for potential confounders for FeNO measurement including age, height, and asthma. For IBD subjects, we used the presence of diarrhea, fatigue, and weight loss as a proxy for IBD activity. Laboratory parameters examined to estimate disease activity included anemia (≤ 10 g/dl), iron deficiency (ferritin ≤ 20 ng/ml), hypoalbuminemia (≤ 3.2 g/dl), and CRP (≥ 1.1 mg/dl). RESULTS The weighted sample represented 199,414,901 subjects. The weighted prevalence of IBD was 2,084,895 (1.0%). IBD subjects had nearly the same FeNO level as those without IBD (17.0 ± 16.2 vs. 16.7 ± 14.5 ppb). The odds of a FeNO > 25 ppb was half (OR=0.501; 95% CI 0.497-0.504) for subjects with IBD compared to those without IBD after controlling for confounders. The AUROC curve for FeNO was 0.47 (0.35-0.59). FeNO levels were not higher in patients with laboratory values suggestive of active disease. FeNO levels were higher in IBD patients with diarrhea, rectal urgency, and fatigue but were lower in those with unintentional weight loss. CONCLUSION Measurement of FeNO does not appear to be useful to screen for IBD or assess disease activity.

Use of positron emission tomography and cortical evoked potentials in the evaluation of visceral sensation from the gastrointestinal tract

USE OF POSITRON EMISSION TOMOGRAPHY AND CORTICAL EVOKED POTENTIALS IN THE EVALUATION OF VISCERAL SENSATION FROM THE GASTROINTESTINAL TRACT. RD Rotbstein, M Stecker, A Ouyang. Departments of Medicine, University of Pennsylvania, Philadelphia, PA and The Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, PA. The central representation of visceral sensations have not been well defined in humans. ‘l’he use of positron emission tomography (PET) and cortical evoked potentials (EP) allows for anatomical localization of perceived sensation from the gastrointestinal tract. Aim: To determine the regions of the brain involved in sensing rectal sensation by measurement of cerebral blood flow (CBF) by PET and localization by EP. Methods: Standard lo-20 electrodes were placed in 5 normal subjects. A balloon catheter was inserted 15 cm into the rectum and connected to a rapid balloon inflation device which was triggered by a Viking 11 EP machine. Balloon volumes of 0.5, 10, and 20 cc were used and subject sensation was graded 0 to 10. PET scans were performed with 1 5 O-H20 using the equilibrium method during rectal balloon distension and were compared to the subject’s MRI image. Changes in cerebral blood flow (CBF) and amplitude of the waveforms by EPs were measured. Results: No subjective sensation, EPs or change in CBF was seen at 0 cc. A significant change in CBF occurred at a balloon volume of 10 cc in the orbital gyrus (p=O.O24), thalamus (p=O.O49), and pre-and post central gyrus (p=O.OSO). Trends toward significant increases in CBF were noted in the insula, putamen, cerebellem, medial frontal gyrus and cuneus. For EP, two peaks were noted (Nl, N2). There was a linear relationship between the amplitude of Nl and balloon volume (p=.O4) and between the amplitude of N2 and balloon volume (p= 0.001). There was no further increase in CBF and the amplitude of Nl and N2 at 20 cc. The subjective score was highly variable between subjects and there was not a linear relationship between sensation and balloon volume. EP or CBF. Conclusion: There is a plateau in CBF and EP, but not subjective sensation, to balloon distension over 10 cc. These findings suggest the probability of more than one pathway involved in the perception of visceral sensation. PET and EP are useful tools in mapping the cerebral representation for visceral sensation.