Effect of metoclopramide on gastric liquid emptying in patients with diabetic gastroparesis

Metoclopramide tablets have been approved for use in the acute and chronic management of diabetic gastroparesis. Its efficacy as an antiemetic has been well documented. We measured the acute and chronic effects of oral metoclopramide on gastric liquid emptying in 12 diabetic patients with symptoms of stasis using scintiscanning techniques. We found that liquid emptying in these subjects was abnormal, as determined by residue area determination when compared to normal volunteers (P<0.01). Metoclopramide 10 mg orally acutely enhanced emptying, restoring it to control values (P<0.01). In contrast, when gastric emptying was evaluated following one month of chronic liquid metoclopramide use, 10 mg before each meal, the acute effect of the drug on emptying could no longer be demonstrated and residue areas returned to baseline values, suggesting that chronic oral administration of metoclopramide may result in a loss of the gastrokinetic properties of this drug.This work was supported in part by the Wechsler Research Foundation, No. 538475 and the Hunt Foundation. Dr. Van Thiel is the recipient of a Career Development Award from the National Institutes of Mental Health, No. AA00016.     

Comparison between gastric emptying of digestible and indigestible solids in diabetic patients

Summary We measured simultaneously gastric emptying of digestible and indigestible solids in 10 normal subjects and in 14 insulin-requiring diabetic patients. Our results demonstrate that in both diabetics and in controls the gastric emptying of digestible and indigestible solids occurs during the same phase of gastric motor activity, i.e. during the post-prandial period. However, gastric emptying of both digestible and indigestible solids is delayed in diabetic patients compared to controls.     

Effect of motilin on gastric emptying in patients with diabetic gastroparesis.

Erythromycin markedly accelerates gastric emptying, possibly because it acts as a motilin agonist. In the present study, the effect of an equipotent dose of motilin was tested. In six patients with severe diabetic gastroparesis, gastric emptying of liquids and solids was examined scintigraphically after motilin or placebo in a double-blind crossover study. Motilin (10 pmol.kg-1.min-1) or saline was infused over a 90-minute period starting 5 minutes before breakfast. Motilin markedly accelerated emptying. For liquids, the half-emptying time was reduced from 51 +/- 6 to 22 +/- 11 minutes (P less than 0.01) and for solids from 111 +/- 4 to 51 +/- 12 minutes (P less than 0.01). The mean increase in plasma motilin levels was 1315 +/- 342 pg/mL, corresponding to an effective infusion rate of about 4 pmol.kg-1.min-1. In the control experiments, basal motilin levels (173 +/- 17 pg/mL) were within the normal range but increased steadily postprandially, reaching 321 +/- 25 pg/mL at the end of the study period, probably reflecting gastric distension. The postprandial increase in pancreatic polypeptide level was blunted compared with accepted normal values but was more pronounced during motilin infusion, i.e., 650 +/- 217 vs. 279 +/- 66 pg/mL (P less than 0.01), probably because of the improved emptying. Our data show that motilin accelerates gastric emptying in diabetic gastroparesis and support the hypothesis that erythromycin's effect is mediated through motilin receptors.     

Effect of cisapride on gastric emptying in dyspeptic patients

The effect of the new gastrokinetic agent cisapride on gastric emptying was evaluated in 17 dyspeptic patients using the dual radionuclide technique. Eight patients with idiopathic dyspepsia and nine postsurgical dyspeptic patients were studied and compared to a control group. Gastric emptying of solids and liquids was determined after ingestion of a standardized meal using^99mTc-sulfur colloid scrambled eggs as the solid phase and [¹¹¹In]DTPA-labeled water as the liquid phase. Following a basal study and on a separate occasion, each patient received an intravenous bolus of 10 mg of cisapride after ingestion of the test meal; 10 of the patients were restudied after a two-week period of chronic oral administration of the drug (10 mg four times a day). Baseline gastric emptying of solids was significantly delayed in idiopathic and postsurgical patients; liquid emptying was only delayed in the postsurgical group. Intravenous and oral administration of cisapride significantly shortened gastric emptying in both groups. In all but one patient, the clinical improvement was confirmed by the test. Cisapride appears to be a good alternative to metoclopramide and domperiodone in the treatment of dyspeptic patients. The dual radionuclide technique appears to be a useful physiologic tool for evaluating and predicting the efficacy of a gastric prokinetic therapy in man.     

Effect of chronic administration of cisapride on gastric emptying of a solid meal and on dyspeptic symptoms in patients with idiopathic gastroparesis.

In a double blind crossover comparison with placebo, the effects of cisapride (10 mg tid for two weeks), a non-antidopaminergic gastrointestinal prokinetic drug, on gastric emptying times and on symptoms were evaluated in 12 patients with chronic idiopathic dyspepsia and gastroparesis. Gastric emptying was studied by a radioisotopic gamma camera technique. The test meal was labelled in the solid component (99mTc-sulphur colloid infiltrated chicken liver). Nine symptoms (nausea, belching, regurgitations, vomiting, postprandial drowsiness, early satiety, epigastric pain or burning, heartburn) were graded weekly on a questionnaire. Cisapride was significantly more effective than placebo in shortening the t1/2 of gastric emptying (p2 = 0.04), but no significant difference was observed between the two treatments with regard to the improvement of total symptom score (p2 = 0.09). No side effects were reported during the study.     

Simultaneous measurement of gastric emptying of digestible and indigestible solids in healthy humans.

Gastric emptying of digestible and indigestible solids has been simultaneously evaluated in healthy humans. Gastric emptying of indigestible solids occurs simultaneously during the emptying of digestible solids. The knowledge of the mechanism responsible for gastric emptying of both digestible and indigestible solids may contribute to improve physiologic insight in this field and to develop further clinical applications.     

Diabetic gastroparesis: an abnormality of gastric emptying of solids

Gastric emptying is delayed in subjects with gastroparesis diabeticorum. To ascertain whether solid or fluid gastric emptying is affected by visceral autonomic neuropathy, ten severe diabetics with gastroparesis and ten nondiabetic disease matched controls were studied. Subjects were screened to identify the presence or absence of autonomic neuropathy. The gastric emptying of fluids and solids was assessed by standard methodology utilizing a simultaneous dual radionuclide technique. If delayed gastric emptying was present on the initial study, metoclopramide (10mg IV bolus) was administered in a repeat study on a separate day. Screening modalities for autonomic neuropathy were markedly positive for the diabetic group, and were negative in the control group. The gastric emptying rate of fluids was normal in both groups and was not statistically different from previous standards developed using the same methodology (p = 0.53, analysis of covariance). The gastric emptying of solids was markedly delayed in the diabetic group in relation to the control group (p = .0035, analysis of covariance). Metoclopramide normalized delayed solid emptying rates without affecting fluid emptying rates.     

Relationship between the effects of cisapride on gastric emptying and plasma glucose concentrations in diabetic gastroparesis

BACKGROUND/AIMS: The effect of erythromycin on gastric emptying is attenuated during hyperglycaemia. The aim of this study was to determine in patients with diabetic gastroparesis whether the effect of cisapride on gastric emptying of solids and liquids is influenced by the plasma glucose concentration. METHODS: Nineteen patients with type 1 diabetes mellitus, who had delayed gastric emptying of solids and/or liquids, were studied. On 2 separate days, each patient received cisapride (20 mg) or placebo orally 60 min before scintigraphic measurement of gastric emptying of a mixed solid (ground beef) and liquid (dextrose) meal. The plasma glucose concentrations were measured at -5, 30, 60, 90, and 120 min during each gastric emptying measurement. RESULTS: Cisapride accelerated both solid (retention at 100 min 43 +/- 4 vs. 69 +/- 4%, p < 0.001) and liquid (T50 27 +/- 2 vs. 39 +/- 2 min, p < 0.001) gastric emptying. The mean plasma glucose level was not significantly different after placebo when compared with cisapride (19.5 +/- 1.1 vs. 18.2 +/- 1.0 mmol/l). The change in the 50% emptying time (T50) for liquid, but not solid, emptying was related (r = 0.55, p = 0.01) to the change in the plasma glucose AUC from 0 to 30 min between the placebo and cisapride tests, i.e., the acceleration was greater if the plasma glucose concentration was relatively less during the gastric emptying test performed on cisapride. CONCLUSION: The effect of cisapride on gastric emptying, at least that of liquids, in patients with diabetic gastroparesis appears to be dependent on the plasma glucose concentration.     

Effect of cisapride on delayed gastric emptying in gastro-oesophageal reflux disease.

Some patients with gastro-oesophageal reflux disease have delayed gastric emptying. This study investigates the effect of cisapride on gastric emptying in 34 patients with proved reflux and delayed gastric emptying of solids. They were enrolled in a double blind controlled crossover study. Placebo or cisapride (10 mg) tablets were given three times a day for three days followed by further assessment of gastric emptying. The protocol was repeated with the crossover tablet. Gastric emptying was assessed by a dual radionuclide technique. The percentage of a solid meal remaining in the stomach at 100 minutes (% R100 minutes) and the time taken for 50% of the liquid to empty (T50 minutes) were calculated and analysed by the Wilcoxon matched pairs signed ranks test and expressed as medians (ranges). For gastric emptying of solids the initial % R100 minutes (70 (60-100)%) was not significantly different from placebo (71 (35-100)%). After cisapride treatment a significant acceleration (p less than 0.001) in gastric emptying occurred (% R100 minutes, 50.5 (28-93)%). Similarly with gastric emptying of liquids, the initial T50 minute value was 26.5 (12-82) minutes, after placebo the value was 28 (11-81) minutes, but this was significantly accelerated with cisapride (p less than 0.03) to 22.5 (6-61) minutes. The acceleration in gastric emptying occurred in the proximal portion of the stomach for gastric emptying of both solids and liquids suggesting that this is the principal site of action of cisapride. We conclude that cisapride significantly accelerates gastric emptying of both solids and liquids in patients with gastro-oesophageal reflux disease and delayed gastric emptying.     

Effect of metoclopramide on normal and delayed gastric emptying in gastroesophageal reflux patients

Gastric emptying has an important role in the pathophysiology of gastroesophageal reflux disease. We investigated the effect of metoclopramide, a gastric prokinetic agent, in gastroesophageal reflux patients with normal as well as delayed emptying. Twenty-six patients with subjective and objective evidence of gastroesophageal reflux ingested an egg salad sandwich meal labeled with 99mtechnetium-DTPA for a baseline study, and then again on a separate day after receiving oral metoclopramide, 10 mg, 30 min prior to the test meal. The mean percent isotope remaining in the stomach after 90 min improved significantly (P less than 0.001) from 70.3 +/- 3.9% (SEM) to 55.2 +/- 4.2% after metoclopramide. Fourteen (54%) had a basal emptying in the normal range of 34-69% retention of isotope at 90 min, (means +/- 2 SD), while it was slow in 12 (46%). For those with delayed basal gastric emptying, the mean retention of 88.9 +/- 2.9% at 90 min was significantly (P less than 0.005) decreased by metoclopramide to 68.6 +/- 6.1%. In those patients with a normal basal gastric emptying and a mean retention of 54.4 +/- 2.3% at 90 min, there was also significant improvement (P less than 0.025) to 43.6 +/- 3.6% after metoclopramide. These data indicate that metoclopramide increased gastric emptying in gastroesophageal reflux patients with normal as well as delayed gastric emptying. Therefore on a patient management level a trial of metoclopramide is warranted in patients with gastroesophageal reflux disease and is not limited by the gastric emptying status of the patient.     

Evaluation of gastric emptying and motility in diabetic gastroparesis with magnetic resonance imaging: effects of cisapride

OBJECTIVE: The motor mechanisms that underlie both slow gastric emptying in diabetic gastroparesis and its acceleration by cisapride are poorly understood. We have recently shown that magnetic resonance imaging (MRI) allows concurrent evaluation of both gastric emptying and regional gastric motility. METHODS: Emptying and motility were measured in eight diabetic patients with previously demonstrated delayed gastric emptying using a rapid MRI technique during oral administration of cisapride and placebo. Studies were performed in a double blind fashion and each patient acted as his own control. Subjects were studied supine for 120 min in a 1.5 Tesla MRI scanner after ingestion of 500 ml of 10% Intralipid. Gastric emptying corrected for the volume of secretions was determined every 15 min using transaxial scans. Each transaxial scan was followed by 120 coronal scans at 1 s intervals. Coronal scans were angled to provide simultaneous imaging of the proximal and distal stomach. MRI studies were also performed in seven diabetic patients with normal emptying who served as disease controls. RESULTS: Emptying was slower in the gastroparetic patients (t(1/2): 124 +/- 10 min) compared to patients with normal emptying (81 +/- 9 min, p < 0.05). Cisapride accelerated gastric emptying (74 +/- 5 vs 124 +/- 10 min) in patients with gastroparesis. The contraction amplitudes in the proximal stomach of gastroparetic patients were increased during cisapride treatment (17.2% +/- 1.8% vs 13.2% +/- 0.6%; p < 0.02), whereas antral contraction frequency, amplitude, and velocity were unchanged. CONCLUSIONS: We conclude that cisapride-induced acceleration of liquid gastric emptying in diabetic gastroparesis does not appear to result from changes in antral contractility, but may be related to changes in proximal gastric tone or gastric outlet resistance.     

Effect of cisapride on gastric and esophageal emptying in insulin-dependent diabetes mellitus

The effects of cisapride on gastric emptying, esophageal emptying, gastrointestinal symptoms, and glycemic control were evaluated in 20 insulin-dependent diabetics who had delayed gastric emptying of the solid or liquid component of a meal, or both. A double-isotope technique was used to measure gastric emptying, and esophageal emptying was measured as the time for a bolus of the solid meal to enter the stomach. On 2 days each patient received cisapride (20 mg) or placebo orally, 60 min before an esophageal and gastric emptying test. A third gastric and esophageal emptying test was performed after each patient had orally taken 10 mg of cisapride or placebo q.i.d. for 4 wk. Single-dose cisapride increased esophageal emptying (p less than 0.01) and both solid and liquid gastric emptying (p less than 0.001). The response to cisapride was most marked in patients with the greatest delay in esophageal and gastric emptying (p less than 0.05). After administration of cisapride for 4 wk, gastric emptying of solid and liquid were faster (p less than 0.001), but esophageal emptying was not significantly different from the placebo test. Upper gastrointestinal symptoms were less after cisapride (p less than 0.05), whereas there was no change on placebo (p greater than 0.2). Plasma glucose and glycosylated hemoglobin concentrations were not different after cisapride compared with placebo. These results indicate that single-dose cisapride increases esophageal emptying in insulin-dependent diabetics and that chronic administration of cisapride is effective in the treatment of diabetic gastroparesis.     

Erythromycin enhances gastric emptying in patients with gastroparesis after vagotomy and antrectomy

We studied the effect of erythromycin on gastric emptying in nine patients with gastroparesis following truncal vagotomy and antrectomy, and assessed their clinical response to chronic oral erythromycin. Gastric emptying was evaluated using a solid-phase radio-labeled meal. Patients were studied after erythromycin 200 mg intravenously (N=9) and after an oral suspension of erythromycin 200 mg (N=7) each given 15 min after ingestion of the meal. Three parameters of gastric emptying were analyzed: half-emptying time (T1/2), area under the curve, and percent gastric residual at 2 hr. Nine patients were subsequently placed on oral suspension erythromycin 150 mg three times a day before meals (range 125–250 mg three times a day) and symptoms of nausea, vomiting, postprandial fullness, and abdominal pain were assessed before and after erythromycin. Intravenous erythromycin markedly accelerated the gastric emptying (all three parameters studied) of solids (P<0.01) in seven of nine patients with postsurgical gastroparesis [baselineT1/2 154±15 min; after intravenous erythromycin,T1/2 56±17 min (mean ±sem)]. Oral erythromycin enhanced (P<0.05) the gastric emptying rate (T1/2, area under the curve) in five of seven patients (baselineT1/2 146±16 min; after oral erythromycin,T1/2 87±20 min). Of the nine patients who were placed on oral maintenance erythromycin, three showed clinical improvement after two weeks. In summary, erythromycin significantly enhances gastric emptying in many patients with vagotomy and antrectomy-induced gastroparesis; however, only a small subset of patients respond clinically to chronic oral erythromycin.Dr. Belinda Ramirez is in private practice in San Antonio, Texas.     

Influence of cisapride on gastric emptying of solids and liquids monitored by13C breath tests

[¹³C]Acetate and [¹³C]octanoate breath tests were used to analyze the gastric emptying of liquids and solids in healthy controls and patients with functional dyspepsia both with and without cisapride. A standard test meal was labeled with either 150 mg [¹³C]acetate (liquid phase labeled in the water) or with 100 mg [¹³C]octanoate (solid phase labeled in the egg yolk). Six patients with dyspepsia and six healthy controls underwent a 4-hr breath test four times, ie, both the [¹³C]acetate and [¹³C]octanoate test with and without cisapride. Duplicate [¹³C]acetate or [¹³C]octanoate breath tests were performed in another 12 healthy controls in order to assess day-to-day variability of gastric emptying for liquids and solids. The mass spectrometric data were fitted to a power exponential function allowing mathematical analysis of half-emptying times and lag times. In patients with dyspepsia, gastric half emptying times of solids were significantly delayed as compared to the emptying of solids in the controls (203±41 vs 148±35 min;P<0.05). With cisapride, gastric emptying of solids was significantly accelerated (P<0.05) both in the patients (166±58 min) and in the controls (117±27 min). The gastric emptying of liquids did not differ in patients and controls, and cisapride had no effect on the emptying of liquids within the normal range. In the healthy controls, half emptying times both for liquids and solids were reproducible on the two different days (CV_intra: 5.58% for liquis, 20.01% for solids). We conclude that as an entirely noninvasive and nonradioactive tool¹³C-labeled breath tests are well reproducible and allow assessment of the effect of cisapride on the characteristics of gastric emptying.     

Abnormal gastric myoelectrical activity and delayed gastric emptying in patients with symptoms suggestive of gastroparesis

Gastric myoelectrical activity modulates gastric motor activity. Abnormalities in gastric myoelectrical activity may be associated with gastric motility disorders. The aim of this study was to investigate the correlation of gastric myoelectrical activity with gastric emptying in symptomatic patients with and without gastroparesis. Ninety-seven patients with symptoms suggestive of gastroparesis participated in the study. Gastric myoelectrical activity was recorded using surface electrogastrography. The electrogastrogram (EGG) was recorded for 30 min in the fasting state and for 120 min after a solid test meal. Gastric emptying of the solid meal was simultaneously monitored for 120 min. Patients with delayed gastric emptying showed a significantly lower percentage of normal gastric slow waves (P<0.03) and a significantly reduced increase of the dominant power in the postprandial EGG (P<0.02). Postprandial EGG parameters were found to be able to predict delayed emptying of the stomach. Postprandial gastric dysrhythmia predicts delayed gastric emptying with an accuracy of 78%, while the abnormality in postprandial EGG power predicts delayed gastric emptying with an accuracy of 75%. All patients with abnormalities in both the rhythmicity and the power had delayed gastric emptying. Patients with delayed gastric emptying have a lower percentage of normal gastric slow waves in the EGG and a lower postprandial increase in the dominant power. Abnormalities in the postprandial EGG seem to be able to predict delayed emptying of the stomach. However, a normal EGG does not seem to guarantee normal emptying of the stomach.     

Postprandial antropyloroduodenal motility and gastric emptying in gastroparesis--effects of cisapride.

There is little information about the organisation of antroduodenal contractions or pyloric motility in patients with gastroparesis. The mechanisms responsible for the acceleration of gastric emptying by cisapride in patients with gastroparesis are also poorly understood. Simultaneous manometric and scintigraphic recordings were performed in 12 patients with gastroparesis and nine healthy volunteers before and after cisapride administration. Antropyloroduodenal pressures were recorded with a sleeve/side hole manometric assembly and gastric emptying with a scintigraphic method. Thirty minutes after the solid component of the test meal had begun to empty from the stomach all subjects received 5 mg cisapride intravenously over 10 minutes and recordings continued for a further 60 minutes. In the 30 minutes before cisapride there was no significant difference in the number of antral pressure waves (median 20 v 33, NS), basal pyloric pressure, or the number of isolated pyloric pressure waves between patients and volunteers, but the number of antral waves of extent > or = 6 cm (median 1 v 5, p < 0.05) was less in the patients, as was gastric emptying (8% v 20%, p < 0.05). In the patients, there was no change in the number of antral waves after cisapride, but there was an increase in the number of antral waves > or = 6 cm in extent (median 7 v 1, p < 0.05) and in the rate of gastric emptying (26% v 8%, p < 0.01). In the healthy subjects, cisapride increased gastric emptying (31% v 20%, p < 0.05), but reduced the number of antral waves (10 v 33, p < 0.05). Cisapride had no significant effect on the number of antral waves of extent more than or equal to 6 cm (11 v 5, NS). The number of isolated pyloric pressure waves decreased after cisapride (4 v 11, p < 0.05). There was a relationship between gastric emptying and the number of antral pressure waves of extent more than or equal to 6 cm in both the patients (r=0.38, p<0.05) and healthy subjects (r=0.05, p<0.01). There was no significant relationship between gastric emptying and the number of antral waves. It is concluded that disturbance of the relationship between antral, pyloric, and duodenal pressure waves is a major abnormality of postprandial gastric motor function in patients with gastroparesis. The stimulation of antral pressure waves of extent more than or equal to 6 cm may contribute to the acceleration of gastric emptying produced by cisapride in patients with gastroparesis and in normal subjects.     

Effect of metoclopramide in diabetic gastroparesis

The aims of our study were to: determine the effect of metoclopramide parenterally and orally on delayed gastric emptying of a radionuclide test meal in symptomatic patients with diabetic gastroparesis not explained by ulceration or other mechanical problems; and evaluate in a double-blind crossover fashion the efficacy of metoclopramide in relieving the symptoms of diabetic gastroparesis. Thirteen patients with subjective evidence of gastric stasis had delayed gastric emptying of an isotope-labeled semisolid meal which was significantly accelerated (p less than 0.05) after 10 mg of metoclopramide parenterally. Patients then received metoclopramide 10 mg and placebo before meals and prior to retiring for 3 weeks in a randomized double-blind crossover design. During metoclopramide therapy nausea, vomiting, anorexia, fullness, and bloating were significantly (p less than 0.05) ameliorated compared to placebo with an overall mean symptom reduction of 52.6%. Gastric emptying studies after completion of the trial is seven patients, subjectively improved and receiving open-labeled metoclopramide, showed significantly less gastric retention. Individual improvements in gastric emptying after parenteral or oral metoclopramide, however, could not be correlated with symptom change during the treatment trial. We conclude that metoclopramide is an important therapeutic adjunct in the management of diabetic gastroparesis and its therapeutic effects are mediated through its prokinetic properties as well as centrally mediated antiemetic actions.