Gastroesophageal reflux disease-related symptom recurrence in patients discontinuing proton pump inhibitors for Bravo® wireless esophageal pH monitoring study. / Recurrencia sintomática relacionada con la enfermedad por reflujo gastroesofágico en pacientes que descontinúan los inhibidores de la bomba de protones durante el estudio inalámbrico de monitorización de pH esofágico Bravo®.

BACKGROUND: Patients with gastroesophageal reflux disease (GERD) are treated with proton pump inhibitors (PPIs). Those that do not achieve symptom relief, or non-responders, usually undergo esophageal pH monitoring off PPIs in order to confirm the presence of GERD. AIMS: To assess the efficacy of the reverse-PPI trial in evaluating the presence of GERD or its recurrence rates, as well as to identify a correlation between the symptom recurrence rates and GERD severity determined by 48-hour Bravo® esophageal pH-monitor testing. METHODS: A final total of 205 patients that underwent the 48-hour Bravo® esophageal pH-monitoring study were retrospectively included. Patients discontinued PPI usage for at least 7 days prior to testing, and completed symptom questionnaires during the 2-day test. The Bravo® test was considered positive if the percentage of time with esophageal pH <4 was >4.4%. RESULTS: A total of 363 patients underwent 48-hour Bravo® testing and of those patients, 205 were eligible for the study. Ninety-two patients reported symptoms as being «same/better¼ and 113 as being «worse¼ after stopping PPIs. Of the 92 patients with improved symptoms, 44 (48%) had documented acid reflux during the Bravo® study, compared with 65 of 113 (58%) patients with worsening symptoms that also complained of acid reflux. Of the 109 patients found to have confirmed GERD upon pH monitoring, 65 (59.6%) reported a worsening of symptoms, compared with 48 of 96 (50.0%) patients without GERD (p=0.043). Main symptoms stated to be worse included heartburn, chest pain, regurgitation, nausea, and belching (p<0.05). Of the 205 patients, 103 were off PPIs for 7 days. Seventy-two of them (68.9%) reported a worsening of symptoms, compared with 40 of the 102 (41.2%) patients that were off PPIs for>7 days (p=0.042) CONCLUSION: Symptom exacerbation following PPI cessation for at least 7 days correlated with acid reflux severity assessed by Bravo® testing. Patients off PPIs for 7 days had a higher likelihood of experiencing worsening symptoms, compared with those off PPIs for more than 7 days. These findings suggest that when PPIs are held for 7 days or less prior to Bravo® testing, acute worsening of upper GI symptoms due to the abrupt discontinuation of therapy may influence the Bravo® results. The etiology of this may be related to rebound acid hypersecretion and needs to be further elucidated in future studies.

Symptoms and esophageal motility based on phenotypic findings of scleroderma.

Scleroderma esophagus is characterized by ineffective peristalsis and reduced esophageal sphincter pressure. Esophageal disease in scleroderma can precede cutaneous manifestations and has been associated with Raynaud's phenomenon (RP) and pulmonary fibrosis (PF). The objective of the study is to evaluate the impact of cutaneous findings, RP, and PF on demographics, symptoms, and esophageal motility in patients with scleroderma. Scleroderma patients with esophageal involvement were included after review of esophageal manometries and charts over a 6-year period. High-resolution esophageal manometry was performed. Patients completed a symptom questionnaire. The study enrolled 28 patients (22 females; mean age 50.3 ± 12.8 years) with scleroderma esophagus. Patients without skin involvement (n= 12) reported more severe heartburn (P= 0.02), while those with cutaneous findings (n= 16) had more frequent dysphagia with solids (P= 0.02). Patients with RP (n= 22) had lower amplitude of distal esophageal contractions (P= 0.01) than those without RP (n= 6). Patients with PF (n= 11) reported more severe coughing and wheezing (both P= 0.03) than those without lung disease (n= 17). This study highlights subgroups of patients with scleroderma esophagus according to phenotypic findings of dermatologic changes, RP, and PF. Heartburn and dysphagia are important symptoms that may be associated with different stages of disease progression based on skin changes in scleroderma. RP was associated with greater esophageal dysmotility. Coughing and wheezing were more severe in patients with PF.

Use of the Montreal global definition as an assessment of quality of life in reflux disease.

According to the Montreal Consensus Group's classification, gastroesophageal reflux disease develops when the reflux of stomach contents causes troublesome symptoms and/or complications such as esophagitis. The characteristic gastroesophageal reflux disease symptoms included in this statement are retrosternal burning and regurgitation. Troublesome is meant to imply that these symptoms impact on the well-being of affected individuals; in essence, quality of life (QOL). Whether heartburn and regurgitation symptoms would be characterized as more troublesome in those with confirmed pathologic acid reflux was determined. A second purpose was to assess how well troublesome scores correlated with the results of a validated, disease-specific QOL instrument. Subjects who underwent esophagogastroduodenoscopy (EGD) with 48-hour wireless esophageal pH testing off proton pump inhibitor therapy were interviewed. Esophagitis on EGD or pH < 4.0 for ≥4.5% of time over the 2-day period was considered positive for acid reflux. Assessment of how troublesome their symptoms of heartburn and regurgitation were made using separate 0-100 visual analog scales (VAS). Subjects were then asked to complete the Quality of Life in Reflux and Dyspepsia (QOLRAD) 25-item questionnaire. Sixty-seven patients (21 males, 46 females) with mean age 47.8 ± 15.6 years were identified. Forty (59.7%) had an EGD or pH study positive for acid reflux. Overall 35/40 (87.5%) complained of either heartburn or regurgitation. There was no difference (P= 0.80) in heartburn VAS troublesome ratings for those with (54.0 ± 43.9) and without (56.7 ± 37.6) confirmed acid reflux. The same was true for regurgitation VAS troublesome ratings (P= 0.62). Likewise, mean QOLRAD scores did not differ between those with and without confirmed acid reflux by pH or EGD (4.5 ± 1.7 vs. 4.3 ± 1.7; P= 0.61). There was a moderately strong inverse correlation between patient self-rated VAS troublesome scores for both heartburn and regurgitation with each dimension (emotional distress, sleep disturbance, eating problems, physical/social functioning, and vitality) of the QOLRAD (P < 0.05 for all comparisons). In regression analysis, both heartburn and regurgitation troublesome ratings were associated with the overall QOLRAD score independent of pH data, frequency of reflux episodes, age, and gender. Use of the term troublesome in the Montreal Consensus Group classification is supported by our findings. It correlates well with the results of a validated disease-specific QOL instrument. Use of heartburn and regurgitation VAS may serve as accurate measures of the burden of reflux disease on patients. It is likely that these scales will not have sufficient discriminate value to identify individuals with pathologic acid reflux from those with negative studies.

Metabolic interactions between prokinetic agents domperidone and erythromycin: an in vitro analysis.

This study examined in vitro interaction between domperidone and erythromycin. Both are prescribed for refractory gastroparesis. Domperidone is metabolized via human cytochrome P4503A4. Erythromycin is a CYP3A4 inhibitor. Incubations evaluated domperidone metabolite formation in human liver microsomes and recombinant CYP3A4. Concentration- and time-dependent inhibition of 500 microM domperidone was studied with 2.5-200 microM erythromycin over 10-40 min. Domperidone metabolite (5-hydroxy domperidone, M3) formation was inhibited by erythromycin in a concentration- and time-dependent manner. The K(I) estimate was 18.4 microM in human liver microsomes and 4.1 microM in CYP3A4. Using a model incorporating CYP3A4 hepatic and gut inhibition, in vitro estimates from human liver microsomes and CYP3A4 were used to predict in vivo AUCi/AUC ratios of 2.54 and 4.95, respectively. Significant inhibition of domperidone metabolism by erythromycin occurs. This predicts greater domperidone drug exposure when used with erythromycin. This important drug-drug interaction will be evaluated in future human studies.

Lack of interaction between metoclopramide and morphine in vitro and in mice.

1. This study examined interactions via common metabolism or via common pharmacodynamic pathways between frequently co-prescribed metoclopramide (a prokinetic) and morphine (an opioid analgesic). 2. In human liver microsomes, morphine 3-glucuronide and morphine 6-glucuronide formation had V(max) estimates of 6.2 +/- 0.07 and 0.75 +/- 0.01 (nmole min(-1) mg(-1) protein) and K(m) estimates of 1080 +/- 37 and 665 +/- 55 (microM), respectively. The in vitro K(i) for morphine 3-glucuronide formation in the presence of metoclopramide in human liver microsomes or recombinant uridine diphosphoglucuronosyltransferase 2B7 predicted a lack of in vivo interaction. 3. Morphine (2 mg kg(-1) subcutaneously) delayed gastrointestinal meal transit in mice, metoclopramide (10 mg kg(-1) subcutaneously) had no effect on meal transit, and metoclopramide did not alter this effect of morphine. 4. Morphine (2 or 5 mg kg(-1) subcutaneously) was antinociceptive in mice (hot plate test) and metoclopramide (10 mg kg(-1) subcutaneously) did not alter the antinociceptive effects of morphine. 5. Together, the data suggest a lack of interaction between morphine and metoclopramide.

Therapeutic response to domperidone in gastroparesis: A prospective study using the GCSI-daily diary.

Common symptoms of gastroparesis include nausea, vomiting, early satiety, postprandial fullness, and upper abdominal pain. Domperidone is used for treatment of gastroparesis. Daily symptom scoring may help document efficacy. AIM: To determine the effectiveness of domperidone for gastroparesis symptoms using the gastroparesis cardinal symptom index-daily diary (GCSI-DD) and to determine which symptoms improve and when with domperidone treatment. METHODS: Symptomatic patients with diabetic or idiopathic gastroparesis were enrolled. Gastric emptying was performed using 4 hour scintigraphy. GCSI-DD recorded symptoms at baseline and during six weeks of treatment with domperidone 10 mg TID. GCSI-DD records severity of nausea, early satiety, postprandial fullness, upper abdominal pain, overall gastroparesis symptoms on a scale of 0 (no symptom) to 4 (very severe) and records the number of vomiting episodes per day. RESULTS: Thirty-four patients with gastroparesis (5 diabetic, 29 idiopathic) participated in this open label study. Treatment duration averaged 36.9 ± 7.6 days. Improvement in overall gastroparesis symptoms occurred on day 3 of treatment and maintained during the treatment. Early satiety, postprandial fullness, and overall symptom severity significantly improved from baseline to the final week of treatment (P < .05 for all), whereas nausea had borderline improvement (P = .055). Side effects included palpitations (5 patients), headache (5), breast tenderness (2), menstrual bleeding (2), dizziness (1), drowsiness (1), chest pain (1), swelling (1), constipation (1). CONCLUSIONS: Domperidone improves symptoms of gastroparesis, reducing overall gastroparesis symptom severity and decreasing early satiety, postprandial fullness, and nausea. GCSI-DD is useful to document efficacy of therapy for gastroparesis.

Pyloric sphincter characteristics using EndoFLIP® in gastroparesis. / Características del esfínter pilórico utilizando EndoFLIP® en gastroparesia.

INTRODUCTION AND AIMS: Pyloric sphincter abnormalities may be detected in gastroparesis. Botulinum toxin A (BoNT/A) injection into the pylorus has been used to treat gastroparesis with varying results. The aim of the present article was to assess whether pyloric sphincter characteristics using the endoscopic functional lumen imaging probe (EndoFLIP®) with impedance planimetry in patients with gastroparesis correlated with symptoms, gastric emptying, and therapeutic response to pyloric sphincter BoNT/A injection. METHODS: EndoFLIP® study was performed on patients undergoing gastroparesis treatment with BoNT/A. The gastroparesis cardinal symptom index (GCSI) was applied prior to treatment and at post-treatment weeks 2, 4, 8, and 12. RESULTS: Forty-four patients were enrolled (30 with idiopathic gastroparesis, 14 with diabetic gastroparesis). Smaller pyloric diameter, cross-sectional area (CSA), and distensibility correlated with worse vomiting and retching severity at baseline. Greater gastric retention tended to correlate with decreased CSA and pyloric distensibility. BoNT/A treatment resulted in a significant decrease in the GCSI score at 2 and 4 weeks after treatment, but not at post-treatment weeks 8 or 12. Nausea, early satiety, postprandial fullness, and upper abdominal pain improved up to 12 weeks, whereas loss of appetite, stomach fullness, and stomach visibly larger improved only up to 4 weeks. Retching and vomiting failed to improve. Greater pyloric compliance at baseline correlated with greater improvement in early satiety and náusea at 8 weeks and greater pyloric distensibility correlated with improvement in upper abdominal pain. CONCLUSIONS: EndoFLIP® characteristics of the pylorus provided important pathophysiologic information in patients with gastroparesis, in relation to symptoms, gastric emptying, and predicting the response to treatment directed at the pylorus.

Relating gastric scintigraphy and symptoms to motility capsule transit and pressure findings in suspected gastroparesis.

BACKGROUND: Wireless motility capsule (WMC) findings are incompletely defined in suspected gastroparesis. We aimed to characterize regional WMC transit and contractility in relation to scintigraphy, etiology, and symptoms in patients undergoing gastric emptying testing. METHODS: A total of 209 patients with gastroparesis symptoms at NIDDK Gastroparesis Consortium centers underwent gastric scintigraphy and WMCs on separate days to measure regional transit and contractility. Validated questionnaires quantified symptoms. KEY RESULTS: Solid scintigraphy and liquid scintigraphy were delayed in 68.8% and 34.8% of patients; WMC gastric emptying times (GET) were delayed in 40.3% and showed 52.8% agreement with scintigraphy; 15.5% and 33.5% had delayed small bowel (SBTT) and colon transit (CTT) times. Transit was delayed in ≥2 regions in 23.3%. Rapid transit was rarely observed. Diabetics had slower GET but more rapid SBTT versus idiopathics (P ≤ .02). GET delays related to greater scintigraphic retention, slower SBTT, and fewer gastric contractions (P ≤ .04). Overall gastroparesis symptoms and nausea/vomiting, early satiety/fullness, bloating/distention, and upper abdominal pain subscores showed no relation to WMC transit. Upper and lower abdominal pain scores (P ≤ .03) were greater with increased colon contractions. Constipation correlated with slower CTT and higher colon contractions (P = .03). Diarrhea scores were higher with delayed SBTT and CTT (P ≤ .04). CONCLUSIONS & INFERENCES: Wireless motility capsules define gastric emptying delays similar but not identical to scintigraphy that are more severe in diabetics and relate to reduced gastric contractility. Extragastric transit delays occur in >40% with suspected gastroparesis. Gastroparesis symptoms show little association with WMC profiles, although lower symptoms relate to small bowel or colon abnormalities.

High-resolution solid-state manometry of the antropyloroduodenal region.

Manometric recording from the pyloric channel is challenging and is usually performed with a sleeve device. Recently, a solid-state manometry system was developed, which incorporates 36 circumferential pressure sensors spaced at 1-cm intervals. Our aim was to use this system to determine whether it provided useful manometric measurements of the pyloric region. We recruited 10 healthy subjects (7 males:3 females). The catheter (ManoScan(360)) was introduced transnasally and, in the final position, 15-20 sensors were in the stomach and the remainder distributed across the pylorus and duodenum. Patients were recorded fasting and then given a meal and recorded postprandially. Using pressure data and isocontour plots, the pylorus was identified in all subjects. Mean pyloric width was 2.1 +/- 0.1 cm (95% CI: 1.40-2.40). Basal pyloric pressure during phase I was 9.4 +/- 1.1 mmHg, while basal antral pressure was significantly lower (P = 0.003; 95% CI: 2.4-8.4). Pyloric pressure was always elevated relative to antral pressure in phase I. For phases II and III, pyloric pressure was 7.7 +/- 2.3 mmHg and 9.4 +/- 1.1 mmHg, respectively. Pyloric pressure increased similarly after both the liquid and solid meal. In addition, isolated pressure events and waves, which involve the pylorus, were readily identified.

Gastric neuromuscular histology in patients with refractory gastroparesis: Relationships to etiology, gastric emptying, and response to gastric electric stimulation.

BACKGROUND: The aims of this study were to describe the histology in gastroparesis, specifically to relate histopathology to etiology of gastroparesis (idiopathic and diabetic gastroparesis), gastric emptying, and clinical response to gastric electric stimulation. METHODS: Full thickness gastric body sections obtained during insertion of gastric stimulator in gastroparetics were stained with Hematoxylin & Eosin, Masson Trichrome and immunohistochemical stains for Neuron-Specific Enolase and c-Kit. KEY RESULTS: In all, 145 gastroparetics (71 diabetics, 71 idiopathic, 2 post-surgical, and 1 chronic intestinal pseudo-obstruction) had full thickness gastric body biopsies. A lymphocytic infiltrate was seen in the intermyenteric plexus in 22 diabetic and 23 idiopathic gastroparesis patients. Fibrosis was present in the inner circular layer in 13 diabetic and 15 idiopathics and in the outer longitudinal layer in 46 diabetic and 51 idiopathics. Diabetic gastroparesis had less ganglion cells (3.27±1.82 vs 4.81±2.81/hpf; P<.01) and less ganglia (0.90±0.44 vs 1.10±0.50/hpf; P=.01) than idiopathic gastroparesis. Interstitial cells of Cajal (ICC) count was slightly lower in the inner circular layer in diabetic than idiopathics (2.77±1.47 vs 3.18±1.34/hpf; P=.08). Delayed gastric emptying was associated with reduced ICCs in the myenteric plexus. Global therapeutic response to gastric electric stimulation was inversely related to ganglia/hpf (R=-.22; P=.008). In diabetics, improvements in nausea, vomiting, and abdominal pain were inversely related to fibrosis. CONCLUSION AND INFERENCES: Histologic assessment of full thickness gastric biopsy specimens allows correlation of histopathology to the gastroparesis disease process, its etiology, gastric emptying, and response to gastric electric stimulation treatment.

Early satiety and postprandial fullness in gastroparesis correlate with gastroparesis severity, gastric emptying, and water load testing.

BACKGROUND: Early satiety (ES) and postprandial fullness (PPF) are often present in gastroparesis, but the importance of these symptoms in gastroparesis has not been well-described. The aims were: (i) Characterize ES and PPF in patients with gastroparesis. (ii) Assess relationships of ES and PPF with etiology of gastroparesis, quality of life, body weight, gastric emptying, and water load testing. METHODS: Gastroparetic patients filled out questionnaires assessing symptoms (PAGI-SYM) and quality of life (PAGI-QOL, SF-36v2). Patients underwent gastric emptying scintigraphy and water load testing. KEY RESULTS: 198 patients with gastroparesis (134 IG, 64 DG) were evaluated. Early satiety was severe or very severe in 50% of patients. Postprandial fullness was severe or very severe in 60% of patients. Severity scores for ES and PPF were similar between idiopathic and diabetic gastroparesis. Increasing severity of ES and PPF were associated with other gastroparesis symptoms including nausea/vomiting, satiety/early fullness, bloating, and upper abdominal pain and GERD subscores. Increasing severity of ES and PPF were associated with increasing gastroparesis severity, decreased BMI, decreased quality of life from PAGI-QOL and SF-36 physical health. Increasing severity of ES and PPF were associated with increasing gastric retention of a solid meal and decreased volume during water load test. CONCLUSIONS & INFERENCES: Early satiety and PPF are commonly severe symptoms in both diabetic and idiopathic gastroparesis. Early satiety and PPF severity are associated with other gastroparesis symptom severities, body weight, quality of life, gastric emptying, and water load testing. Thus, ES and PPF are important symptoms characterizing gastroparesis. ClinicalTrials.gov number: NCT NCT01696747.

Diabetic and idiopathic gastroparesis is associated with loss of CD206-positive macrophages in the gastric antrum.

BACKGROUND: Animal studies have increasingly highlighted the role of macrophages in the development of delayed gastric emptying. However, their role in the pathophysiology of human gastroparesis is unclear. Our aim was to determine changes in macrophages and other cell types in the gastric antrum muscularis propria of patients with diabetic and idiopathic gastroparesis. METHODS: Full thickness gastric antrum biopsies were obtained from patients enrolled in the Gastroparesis Clinical Research Consortium (11 diabetic, 6 idiopathic) and 5 controls. Immunolabeling and quantitative assessment was done for interstitial cells of Cajal (ICC) (Kit), enteric nerves protein gene product 9.5, neuronal nitric oxide synthase, vasoactive intestinal peptide, substance P, tyrosine hydroxylase), overall immune cells (CD45) and anti-inflammatory macrophages (CD206). Gastric emptying was assessed using nuclear medicine scintigraphy and symptom severity using the Gastroparesis Cardinal Symptom Index. RESULTS: Both diabetic and idiopathic gastroparesis patients showed loss of ICC as compared to controls (Mean [standard error of mean]/hpf: diabetic, 2.28 [0.16]; idiopathic, 2.53 [0.47]; controls, 6.05 [0.62]; P=.004). Overall immune cell population (CD45) was unchanged but there was a loss of anti-inflammatory macrophages (CD206) in circular muscle (diabetic, 3.87 [0.32]; idiopathic, 4.16 [0.52]; controls, 6.59 [1.09]; P=.04) and myenteric plexus (diabetic, 3.83 [0.27]; idiopathic, 3.59 [0.68]; controls, 7.46 [0.51]; P=.004). There was correlation between the number of ICC and CD206-positive cells (r=.55, P=.008). Enteric nerves (PGP9.5) were unchanged: diabetic, 33.64 (3.45); idiopathic, 41.26 (6.40); controls, 46.80 (6.04). CONCLUSION: Loss of antral CD206-positive anti-inflammatory macrophages is a key feature in human gastroparesis and it is associates with ICC loss.

Regional gastric emptying abnormalities in functional dyspepsia and gastro-oesophageal reflux disease.

To characterize proximal and distal stomach emptying in functional dyspepsia (FD) and gastro-oesophageal reflux disease (GORD). Eighty-three patients underwent gastric emptying (GE) scintigraphy and symptom scoring for the evaluation of upper gastrointestinal symptoms and were divided into three groups: FD (n = 25), GORD (n = 20) and FD + GORD (n = 38). Total, proximal and distal gastric retention were determined scintigraphically and compared with normal controls. Delayed total GE was observed in each subgroup: FD (56%), GORD (45%) and FD + GORD (55%). Greater proximal gastric retention was observed after meal ingestion in GORD compared to FD. Greater distal gastric retention was observed in FD and FD + GORD but it was only mild in GORD. Nausea, vomiting, early satiety, distention and regurgitation were associated with proximal gastric retention whereas there was no symptom associated with distal gastric retention. Multiple regression demonstrated total gastric retention at 30 min and 1 h was positively correlated with regurgitation whereas early proximal gastric retention was positively correlated with regurgitation and negatively correlated with nausea. Selective abnormalities of proximal and distal stomach emptying were demonstrated in GORD and FD. GORD and FD symptoms were associated with proximal gastric retention suggesting that proximal stomach motor function may be important in the pathogenesis of symptoms associated with these disorders.

Treatment of gastroparesis: a multidisciplinary clinical review.

This clinical review on the treatment of patients with gastroparesis is a consensus document developed by the American Motility Society Task Force on Gastroparesis. It is a multidisciplinary effort with input from gastroenterologists and other specialists who are involved in the care of patients with gastroparesis. To provide practical guidelines for treatment, this document covers results of published research studies in the literature and areas developed by consensus agreement where clinical research trials remain lacking in the field of gastroparesis.

Nausea and vomiting in gastroparesis: similarities and differences in idiopathic and diabetic gastroparesis.

BACKGROUND: Nausea and vomiting are classic symptoms of gastroparesis. It remains unclear if characteristics of nausea and vomiting are similar in different etiologies of gastroparesis. The aims of this article were as follows: to describe characteristics of nausea and vomiting in patients with gastroparesis and to determine if there are differences in nausea and vomiting in diabetic (DG) and idiopathic gastroparesis (IG). METHODS: Gastroparetic patients enrolling in the NIDDK Gastroparesis Registry underwent assessment with history and questionnaires assessing symptoms, quality of life, and a questionnaire characterizing nausea and vomiting. KEY RESULTS: Of 159 gastroparesis patients (107 IG, 52 DG), 96% experienced nausea, whereas 65% experienced vomiting. Nausea was predominant symptom in 28% and vomiting was predominant in 4%. Nausea was severe or very severe in 41%. PAGI-SYM nausea/vomiting subscore was greater with increased vomiting severity, but not nausea severity in DG than IG. Nausea was related to meals in 71%; lasting most of the day in 41%. Increasing nausea severity was related to decreased quality of life. Nausea often preceded vomiting in 82% of patients and vomiting often relieved nausea in 30%. Vomiting was more common in DG (81%) compared to IG (57%; p = 0.004). Diabetic patients more often had vomiting in the morning before eating, during the night, and when not eating. CONCLUSIONS & INFERENCES: Nausea is present in essentially all patients with gastroparesis irrespective of cause and associated with decreased quality of life. In contrast, vomiting was more prevalent, more severe, and occurred more often in DG than IG. Thus, characteristics of vomiting differ in IG vs DG.

Baseline features and differences in 48 week clinical outcomes in patients with gastroparesis and type 1 vs type 2 diabetes.

BACKGROUND: In studies of diabetic gastroparesis, patients with type 1 and type 2 diabetes mellitus (T1DM, T2DM) are often combined for analyses. We compared gastroparesis severity, healthcare utilization, psychological function, and quality of life in T1DM vs T2DM gastroparesis patients. METHODS: Questionnaire, laboratory, and scintigraphy data from patients with gastroparesis and T1DM and T2DM from seven centers of the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium Registry were compared at enrollment and after 48 weeks. Multiple regression models assessed baseline and follow-up differences between diabetes subtypes. KEY RESULTS: At baseline, T1DM patients (N = 78) had slower gastric emptying, more hospitalizations, more gastric stimulator implantations, higher hemoglobin A1c (HbA1c), and more anxiety vs T2DM patients (N = 59). Independent discriminators of patients with T1DM vs T2DM included worse gastroesophageal reflux disease, less bloating, more peripheral neuropathy, and fewer comorbidities (p ≤ 0.05). On follow-up, gastrointestinal (GI) symptom scores decreased only in T2DM (p < 0.05), but not in T1DM patients who reported greater prokinetic, proton pump inhibitor, anxiolytic, and gastric stimulator usage over 48 weeks (p ≤ 0.03). Gastrointestinal symptoms at baseline and 48 weeks with both subtypes were not associated with HbA1c, peripheral neuropathy, psychological factors, or quality of life. CONCLUSIONS & INFERENCES: Baseline symptoms were similar in T1DM and T2DM patients, even though T1DM patients had worse gastric emptying delays and higher HbA1c suggesting other factors mediate symptom severity. Symptom scores at 48 weeks decreased in T2DM, but not T1DM patients, despite increased medical and surgical treatment utilization by T1DM patients. Defining causes of different outcomes in diabetic gastroparesis warrants further investigation.

The effect of rabeprazole on regional gastric acidity and the postprandial cardia/gastro-oesophageal junction acid layer in normal subjects: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Postprandial intragastric acidity is not uniform. Postprandial proximal gastric acid pockets have been described in the present study. AIM: To determine the effects of rabeprazole on regional intragastric acidity and proximal acid pockets. METHODS: Ten normal subjects underwent two 8-day oral dosing regimens with placebo or rabeprazole 20 mg each morning in a randomized, double-blind protocol. Oesophago-gastric pH monitoring was performed on days 1 and 8. RESULTS: Rabeprazole increased fasting and postprandial gastric pH to above 4 in each area of the stomach on days 1 and 8. With placebo, acid pockets were identified at the cardia/gastro-oesophageal junction in 62 and 50 of 150 pull-throughs on days 1 and 8, respectively. Acid pockets were detected postprandially 3.1 +/- 0.2-5.8 +/- 0.1 cm below the proximal border of the lower oesophageal sphincter with a mean pH drop from 4.6 +/- 0.1 to 1.5 +/- 0.1. Rabeprazole decreased the number of acid pockets to 30 and 27 on days 1 and 8, respectively. Rabeprazole also decreased their length and magnitude of the pH drop. CONCLUSIONS: Rabeprazole increased intragastric pH on day 1 and 8 and maintained an elevated pH during and after meals. Postprandial acid pockets, identified in the region of the cardia/gastro-oesophageal junction area postprandially, were decreased in number, length and magnitude by rabeprazole.

Bile duct ligation induced acute inflammation up-regulates cyclooxygenase-2 content and PGE2 release in guinea pig gallbladder smooth muscle cell cultures.

INTRODUCTION: This study examines hypotheses that BDL induces increased guinea pig gallbladder smooth muscle PGE2 release by up-regulation of COX-2. METHODS: BDL, Sham and Control Hartley guinea pig gallbladders were placed in cell culture, grown to confluence and underwent Western Blot analysis for smooth muscle cell content of COX-1, COX-2, Prostacylin Synthase, actin, caldesmon, vinculin, meta-vinculin and tropomyosin and were assayed for basal release of 6-keto-PGF(1alpha), PGE2 and TxB2 by EIA. RESULTS: BDL did not alter content of smooth muscle cytoskeletal proteins. BDL for 48 h increased smooth muscle cell release of PGE2 and 6-keto-PGF(1alpha) by 3-fold or more when compared to the Control and Sham groups. Western Blot analysis showed increased content of COX-2 in the BDL group. CONCLUSIONS: BDL for 48 h markedly increased endogenous guinea pig smooth muscle cell PG release, which was due to increased COX-2 synthesis.

Effects of the selective serotonin reuptake inhibitor, fluoxetine, on regional gastric contractility.

UNLABELLED: Selective serotonin reuptake inhibitors (SSRIs) are increasingly used to treat a variety of disorders but have gastrointestinal side-effects. AIM: To determine the effects of the SSRI, fluoxetine, on gastric smooth muscle contractility. METHODS: Fundic, antral, and pyloric circular muscle contractility of guinea pig muscle strips were measured in vitro. Fluoxetine was added in concentrations from 0.1 nmol L(-1) to 100 mumol L(-1). Receptor antagonists were used to determine the neural pathways involved. RESULTS: Fluoxetine caused concentration dependent contractions, which were greatest in fundus compared with the antrum or pylorus. The contractile effects of fluoxetine in the antrum were reduced by tetrodotoxin, atropine, phentolamine, and the 5-HT(4) receptor antagonist GR 113808. The contractile effects of fluoxetine in the fundus were reduced by atropine, phentolamine, and GR 113808. CONCLUSIONS: Fluoxetine affects gastric contractility with regional variability - contracting the fundus more than the antrum or pylorus. The fluoxetine contractile effect is reduced by tetrodotoxin, atropine, phentolamine, and a 5-HT(4) receptor antagonist. These results suggest fluoxetine interacts with muscarinic, alpha-adrenergic, and serotoninergic receptors and/or ongoing reuptake/release of serotonin in the stomach.

Differential effects of sham feeding and meal ingestion on ghrelin and pancreatic polypeptide levels: evidence for vagal efferent stimulation mediating ghrelin release.

UNLABELLED: Ghrelin has been suggested to function as an appetite-stimulating signal from the gastrointestinal tract to the brain acting through a vagal afferent pathway. Ghrelin levels rise before meals and fall after meal ingestion. The purpose of this study was to investigate factors which regulate ghrelin release into the circulation by determining changes in systemic ghrelin concentrations after sham feeding and meal ingestion. METHODS: Fifteen normal subjects underwent sham feeding of a bacon and cheese toasted sandwich. Serial blood samples were obtained before and every 5 min for another 30 min during sham feeding and for 30 min after actual meal ingestion. Radioimmunoassay was used to measure plasma ghrelin and pancreatic polypeptide concentrations. RESULTS: During sham feeding, plasma ghrelin concentration increased from 1730+/-237 to 1917+/-269 pg/mL (P<0.05) and plasma pancreatic polypeptide increased from 417+/-50 to 841+/-97 pg/mL (P<0.01). Subsequent meal ingestion was characterized by an increase in pancreatic polypeptide from 782+/-88 to 1710+/-119 pg/mL (P<0.01), but no significant change in ghrelin levels. CONCLUSIONS: Plasma ghrelin and pancreatic polypeptide concentrations increase with sham feeding. This suggests a vagal efferent pathway mediating ghrelin release. In contrast to pancreatic polypeptide which rises with actual meal ingestion, ghrelin levels did not change.