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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

Background:

Alosetron reduces symptoms of dyspepsia, but the physiological basis for the symptomatic benefit is unclear.

Aim:

To assess 5-HT3 antagonism on postprandial gastric volume and symptoms after ingestion of maximum tolerable volume of a liquid meal.

Methods:

In 36 healthy volunteers, we assessed effects of placebo, 0.5 and 1 mg b.d. alosetron on fasting and postprandial gastric volumes (using single photon emission computed tomography) and symptoms based on 100 mm VAS, 30 min after maximum volume ingested.

Results:

The 5-HT3 antagonist reduced postprandial symptoms (aggregate score: P < 0.05), nausea (P < 0.001), and tended to reduce bloating (P=0.08). Both 0.5 and 1 mg alosetron reduced nausea (P < 0.025); 1 mg alosetron reduced aggregate symptoms (P < 0.05) and bloating (P < 0.05). Effects on pain (P=0.19) and fullness (P=0.14) were not statistically significant. There were no significant effects of the 5-HT3 antagonist on volume of meal tolerated or on SPECT-measured fasting or postprandial gastric volumes.

Conclusion:

5-HT3 antagonism reduces aggregate symptoms, nausea and bloating after a liquid meal without increase in gastric volumes, suggesting a role for 5-HT3 in afferent functions in healthy humans during the postprandial period.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

The accommodation response to meal ingestion is a robust, vagally mediated reflex in health. It results in a reduction in gastric tone and an increase in compliance, thereby facilitating the ingestion of large volumes of solids or liquids without inducing postprandial symptoms such as pain or bloating or the vomiting reflex. In health, the mechanisms involved in development of postprandial symptoms are incompletely understood. In several conditions,1–4 a reduced accommodation response appears to contribute to postprandial symptoms such as early satiety, distention and weight loss.4, 5 One mechanism proposed is that increased wall tension6 results in food/air stimulation of visceral afferents or alteration of cerebral perception and development of gastric hypersensitivity postprandially. These findings suggest that measurement of gastric accommodation or the change in gastric volume after a meal may facilitate our understanding of the mechanical factors that may result in upper gastrointestinal symptoms in the postprandial period. Symptoms in these patients may reflect either a lack of accommodation, visceral (mechanical or chemical) hypersensitivity, or a change in the gastric emptying rate. Correction of impaired accommodation might reduce postprandial symptoms in dyspepsia.7–9

Serotonergic type 3 receptors modulate intrinsic cholinergic neurones in the gut myenteric plexus.10 5-HT3 receptors have been located on vagal afferent neurones, dorsal root ganglion cells11 and in the vomiting centre in the brainstem.

Recently, alosetron was reported to reduce dyspepsia symptoms,12 an effect that was independent of gastric emptying. However, the physiological basis for this reduction in dyspepsia is unclear, and may reflect either gastric relaxation or reduced visceral sensitivity due to mechanical or chemical stimulation of visceral afferents. The gold standard to measure accommodation involved the placement of a polyethylene balloon into the proximal stomach and measurement of intragastric volumes in the fasting and postprandial periods under barostatic conditions.1 More recently, three-dimensional imaging with ultrasound, MRI and SPECT has been introduced13–15 to measure gastric volume noninvasively.

Previous studies had shown the feasibility of pertechnetate imaging of the gastric mucosa, identifying gastric wall motion under dynamic scintigraphy,16 and measuring gastric volume15, 17 by a three-dimensional (tomographic acquisition) single photon emission computed tomography (SPECT)-AnalyseAVW system.15

In parallel with these novel imaging studies to measure gastric volume, standardized meal tests4, 18 and questionnaires quantify postprandial symptoms in health, disease states and in response to pharmacological agents. These tests appear to partially assess the sensory and motor functions of the proximal stomach.19

In this study, the noninvasive methods were used to assess the physiological basis of the reduction in dyspepsia in response to the 5-HT3 antagonist, alosetron. Our hypothesis was that the measured postprandial change in gastric volume and the volume of liquid nutrient required to induce maximum tolerated symptoms would be dose-dependently increased by antagonism of 5-HT3 receptors in healthy humans. Our aims were to compare the effects of two doses of the 5-HT3 antagonist, alosetron, and placebo on fasting and postprandial gastric volumes and symptoms induced by ingestion of a liquid nutrient drink to the point of maximum tolerance in healthy volunteers.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

Study design

The study was a double-blind, two-dose, placebo-controlled assessment of the effects of alosetron, 0.5 and 1 mg b.d. for 7 days, on fasting and postprandial gastric volume and postprandial symptoms in healthy human volunteers. Following an initial screening, subjects underwent, on separate days, assessments of gastric volume using the novel SPECT technique and of the maximum tolerable volume of a liquid nutrient drink, which has been referred to as the ‘satiety test’ in the published literature.4

Study participants

Thirty-seven healthy volunteers were recruited from the local community by public advertisement. They were screened by means of an abridged bowel disease questionnaire to ensure they had no gastrointestinal symptoms or previous chronic gastrointestinal illness. Participants were randomized to one of three groups: placebo, 0.5 mg or 1 mg b.d. alosetron.

Exclusion criteria were:

• abdominal surgery other than appendectomy or tubal ligation;

• positive symptoms on an abridged bowel disease questionnaire, which served to screen for functional or organic gastrointestinal diseases;

• use of medications that may alter gastrointestinal motility;

• over-the-counter medications (except multivitamins) within 7 days of study.

Experimental protocol

After a screening interview and consent, subjects received study medication b.d. (fasting and after evening meal) for 1 week according to the randomization schedule.

On day 6, subjects presented to the testing facility in the General Clinical Research Center at Mayo Clinic after an 8-h fast. Intravenous access was obtained, subjects were placed in a supine position on the SPECT table, and 20 mCi 99mTc-pertechnetate was given intravenously. SPECT image acquisition was started 10 min after the 99mTc-pertechnetate injection. Imaging was performed with three orbits, each lasting 10 min (one during fasting and two postprandially).

On day 7, subjects presented fasting to the testing facility for the nutrient drink test.

Measurement of fasting and postprandial gastric volume using SPECT AnalyseAVW

The gastric mucosa [both parietal (oxyntic) cells and nonparietal (mucous) cells] is able to take up and excrete technetium 99mTc-pertechnetate from the circulating blood pool.20 This property is now widely used to identify ectopic gastric mucosa in patients with suspected Meckel’s diverticulum and retained antral mucosa using radionuclide imaging.20 Uptake of 99mTc-pertechnetate is found in all parts of the stomach, although there could be regional differences in radionuclide incorporation due to variations in thickness or surface area of the gastric mucosa.21 In a previous study, Prather and colleagues administered 5.0 mCi 99mTc-pertechnetate intravenously and noted sufficient uptake to allow the entire stomach to be visualized.15 To ensure sufficient visualization and quantification of volumes on tomographic images, higher dosages of 99mTc-pertechnetate was administered intravenously in the Kuiken et al. study.22 Radiation exposure is within permissible ranges for research and clinical studies.

Tomographic studies were acquired on a large field of view dual-head gamma camera system (Helix SPECT System, Elscint Ltd., Haifa, Israel) equipped with low-energy, high-resolution collimators. Subjects were positioned supine on the imaging table with the detectors over the upper and mid abdomen to insure imaging of the stomach and small bowel. Ten minutes after the intravenous injection of 20 mCi 99mTc sodium pertechnetate, dynamic tomographic acquisition was performed using the multiorbit mode of the system.22 Briefly, in this mode, the system performs three 360° orbits, each lasting 10 min. For each orbit, images were acquired into a 128 × 128 matrix, every 6° at 3 s per image. After completion of the acquisition, images from the orbit were reconstructed using filtered back-projection (Ramp-Butterworth filter, order 10, cut-off 0.45 Nyquist) to produce transaxial images of the stomach. Imaging was performed fasting and for 20 min (two 10-min orbits) after ingestion of a 300-mL ENSURE Plus drink (Ross Products, Division of Abbott Laboratories, Columbus, OH) through a straw while lying under the SPECT camera.

SPECT data analysis

For estimation of gastric volume, the transaxial images were transferred via Interfile to a dedicated Unix workstation. Stomach volume measurements were performed using the AnalyseAVW PC 2.5 (Biomedical Imaging Resource, Mayo Foundation, Rochester, MN) software system,23 which has been used previously in gastric volumetric imaging studies.22 To measure the volume of the stomach, it is necessary to identify the stomach in the transaxial SPECT images and to separate it from the background noise. This was accomplished using a semiautomated segmentation algorithm (Object Extractor, AnalyseAVW PC 2.5), which requires the user to identify an appropriate seed point and grey scale threshold. Because 99mTc-pertechnetate is taken up by the gastric mucosa, the ‘fill interior holes’ option was used to produce a solid stomach volume as opposed to a hollow shell. Three-dimensional renderings of the stomach were produced, and the same user (D.B.) manually removed any extraneous structures, such as the upper duodenum or a kidney in close proximity to the stomach, which had not been removed in the segmentation algorithm. The SPECT method has been validated by simultaneous measurements of the postprandial to fasting volume ratio by means of a barostatically controlled balloon and SPECT.24

Nutrient drink test to induce postprandial symptoms

An adaptation of the method of Tack et al. was used.4 Briefly, subjects were asked to ingest a nutrient drink (ENSURE) from a glass as it was filled by a perfusion pump at a constant rate of 30 mL per minute. The subjects were instructed to maintain intake at the filling rate. At 5-min intervals, they scored their sense of fullness or satiety using a graphic rating scale that combined verbal descriptors on a scale graded of 0–5 (1, threshold; 5, maximum satiety). Participants were told to stop meal intake when a score of 5, or maximum satiety, was reached. The total calorie intake at satiety score equal to 5 was estimated. In accordance with the method of Tosetti et al.,18 30 min after completing the test, participants were requested to score their symptoms (bloating, fullness, nausea and pain) using a visual analogue scale with 100 mm lines anchored with the words ‘none’ and ‘worst ever’ at the left and right ends of the lines.

Symptom data analysis

Each symptom was scored on the visual analogue scale 30 min after reaching the maximum tolerable volume of ENSURE; the aggregate symptom score was calculated as the numerical sum of individual symptom scores.

Study endpoints

The primary study endpoints for the SPECT study were total gastric volume in the postprandial period measured as the absolute volume and as the ratio of postprandial over fasting volume. The secondary end-point was the fasting gastric volume.

For the nutrient drink test, the maximum tolerable volume and the aggregate score of symptoms 30 min after nutrient drink ingestion were the primary endpoints. Each individual symptom was assessed as a secondary end-point.

The data obtained from gastric volume (SPECT) analysis during fasting and postprandially were compared across treatment groups using analysis of variance (ANOVA or ANOVA on ranks) when necessary. Similarly, ANOVA was used to assess the symptom endpoints after the nutrient drink, that is, the maximum tolerable volume, the aggregate symptom score 30 min after meal ingestion and the individual symptoms. When there was a P-value of 0.05 or less on ANOVA, Dunnett’s comparison was performed using the placebo group as control. For other comparisons, Mann–Whitney rank sum test was used to assess individual symptoms in each of the alosetron groups compared to placebo. The nonparametric test was needed because symptom scores, particularly pain scores, were not normally distributed.

Statistical analysis

A multiple linear regression analysis was performed to assess the influence on the postprandial gastric volume response of age, body mass index, fasting gastric volume and maximum ENSURE volume tolerated during the nutrient drink test.

Statistical analyses were performed on Sigma Stat.25

Sample size estimation

Previous data22 indicated that the coefficient of variation (CV%) in SPECT volume estimates of stomach volumes was 15–25%. The sample size proposed (12 subjects per treatment group) was selected to provide > 80% power to detect differences in means of 25–33% between the groups if the standard deviation was 0.15 or 0.2, respectively. These estimates had been based on ANOVA using a two-sided alpha-level of 0.05 and n=12 subjects per each of three groups.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

Participant demographics, conduct of study and adverse effects

The study involved 37 participants. In the 0.5 mg group we recruited an additional participant to the intended 12 per treatment group while strictly maintaining the study blind, because it turned out that one participant did not take the study medication on the day of the SPECT study. The data of this participant are included in accordance with intention-to-treat principles.

One subject, who was eventually found to be randomized to placebo, did not fast on the day of the study, and the estimated fasting volume of the stomach was > 800 mL, which is greater than the average postprandial gastric volume of ∼750 mL noted in the remaining participants of this study. This participant later admitted she had ingested breakfast prior to the study, and her data were excluded from the entire analysis. Hence data from 36 of the 37 participants enrolled were included in the analysis.

Participant demographics are shown in Table 1. There were no significant differences in the age and body mass indices of the three groups; the gender distribution turned out to be different when the randomization schedule was revealed, with significantly more females in the placebo group than the 1 mg alosetron group (P=0.03) by Fisher’s exact test, but not the 0.5 mg alosetron group. As predicted from the pharmacological effects of alosetron, six participants experienced constipation, which was classified as pebbly stools (n=1), harder stool consistency (n=2), and moderate (n=2) or severe (n=1) constipation. The former three subjects required no treatment; two subjects had received 1 mg b.d. and one subject 0.5 mg b.d. alosetron. The three participants with moderate or severe constipation (all of whom were receiving 0.5 mg b.d. alosetron) self administered a fibre supplement (Konsyl) as permitted by the protocol as ‘rescue’. Two participants took Konsyl on day 3, and one took it on day 7 after all of the tests were completed. In all six participants, constipation was no longer experienced from 2 days after stopping the study medication. One of the placebo-treated subjects experienced headaches repeatedly 1 h after dosing. Headaches were treated with acetaminophen and resolved after the last dose of study medication.

Table 1.   Demographics of participants Thumbnail image of

Gastric volumes measured by SPECT-AnalyseAVW

There were no significant effects of alosetron on fasting or postprandial gastric volumes (Figure 1). The postprandial to fasting volume ratios for the entire and for the proximal segment of the stomach were also not significantly different (Figure 2). There was no significant correlation between body mass index (BMI) and fasting or postprandial gastric volumes. Multiple linear regression analysis exploring the relationship between accommodation response, BMI, age, fasting gastric volume and maximum tolerable drink volume showed a significant effect only for fasting gastric volume (t=– 4.74, P < 0.001).

image

Figure 1.  Gastric images during fasting and postprandially from three healthy volunteers treated with placebo (left panel) or alosetron (0.5 mg, middle panel; 1 mg, right panel). Note the similarity in volumes.

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image

Figure 2.  Effect of alosetron and placebo on fasting and postprandial gastric volumes and the ratio of postprandial/fasting volume. Note there are no differences between alosetron and placebo.

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The regression equation was:

inline image

Maximum tolerated volume during drink test and postprandial symptoms

The total volume of Ensure ingested and the time taken to reach the maximum tolerable volume were not significantly different between placebo and the two doses of alosetron (Figure 3). Alosetron significantly reduced overall postprandial symptoms (aggregate score: P < 0.05 by ANOVA, Figure 4) as well as nausea (P < 0.001 by ANOVA, Figure 5) and tended to reduce bloating (P=0.08 by ANOVA, Figure 5). Both 0.5 and 1 mg alosetron significantly reduced nausea scores (P < 0.025) relative to placebo. The 1 mg dose of alosetron reduced overall postprandial symptom score (P < 0.05), reduced bloating (P=0.049) but had no statistically demonstrable effect on pain scores (P=0.19). The 0.5 mg alosetron dose did not influence overall symptom score or pain or bloating scores (Figure 5). Neither of the doses of alosetron significantly altered the symptom of postprandial fullness (P=0.14 for comparison of 1 mg alosetron vs. placebo).

image

Figure 3.  Volume of nutrient drink ingested at the report of full satiation. Note the total volume ingested is similar for the three groups.

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Figure 4.  Effect of alosetron and placebo on aggregate symptom score 30 min after completion of the nutrient drink test. Note that ANOVA identifies a significant effect of alosetron, which is due to the significant difference in scores with the 1.0 mg b.d. alosetron treatment group.

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image

Figure 5.  Effect of alosetron on individual symptoms of nausea, bloating, pain and fullness. Apart from the significant effect on nausea, there are trends indicating marked effects on bloating (P=0.08), which are significant with the 1 mg alosetron dose. Both 0.5 and 1 mg doses of alosetron result in reduced pain scores. The 1 mg dose of alosetron decreased bloating scores (P=0.049).

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

Our study has shown that a 5-HT3 antagonist, alosetron, reduces aggregate symptoms after a meal intended to induce maximum tolerable symptoms in healthy human subjects. The effect of alosetron is unrelated to any change in the volume of nutrient drink tolerated or the measured fasting or postprandial gastric volume. Although the precise mechanism of the effect of alosetron on symptoms is not completely elucidated, these data suggest a role for 5-HT3 mechanisms in visceral afferent sensation and provide the potential rationale for further study of 5-HT3 antagonists in patients with dyspepsia. The potential benefit of alosetron in dyspepsia was demonstrated in a recently published phase II clinical trial.12

Postprandial symptoms may arise from mechanical stimulation of afferents by the meal or from a change in sensitivity of afferents by chemical stimulation in the stomach or proximal small intestine. Our study also suggests that gastric relaxation is not always necessary for reduction of postprandial symptoms, because we observed a reduction in symptom scores without a significant increase in the postprandial relaxation of the stomach. The observed reduction in symptom scores may more likely be related to effects of the drug on chemosensitive afferents, as previously suggested by Feinle and Read.26

The lack of effect of alosetron on gastric volumes with reduced postprandial symptoms is consistent with a preliminary report which showed that another 5-HT3 antagonist, ondansetron,27 reduced symptoms in response to distension without altering tone, accommodation or compliance. In the latter study, the gastric volumes were measured with an intraluminal barostatically controlled balloon. Zerbib et al.28 and Bjornsson et al.29 also reported that two different 5-HT3 antagonists (alosetron and granisetron, respectively) did not alter fasting tone or compliance when tested with an intraluminal barostatically controlled balloon. The beneficial effects of the 5-HT3 antagonist may be mediated at the level of extrinsic afferents or centrally. There are central effects of alosetron in the dog,30 however human studies suggest that it has no significant anxiolytic activity.31 These data suggest that any central effects of the drug are more likely to be directed at centres such as the vomiting centre, rather than the limbic system.

We considered the possibility that the lack of effect of alosetron on gastric accommodation measured by SPECT may have been a technical failure. Thus, in contrast to the barostat, which imposes a continuous distending drive, it is conceivable that the already appropriate accommodation in healthy subjects could not be enhanced without the isobaric pressure load in the presence of alosetron. We cannot completely exclude this possibility and, hence, it is still possible that the drug may enhance accommodation in dyspeptics with reduced relaxation responses. However, reduced gastric volume postprandially has been observed in dyspeptics using the SPECT technique,32 and our data with alosetron confirm those of other investigators who studied the effects of 5-HT3 antagonists with the barostat device.27–29

An alternative hypothesis for the genesis of dyspeptic symptoms is the ‘chemical’ sensitivity of the small intestinal mucosa, which is abnormal in response to acid perfusion33 in dyspeptics. This mechanism of dyspepsia may be influenced by alosetron. Further studies are needed to specifically address the effect of 5-HT3 antagonists on duodenal sensitivity to chemical stimulation with acid or nutrients in health and disease.

Alosetron did not affect ‘satiety’ sensations during the actual ingestion of the nutrient drink or the symptom of fullness 30 min postprandially. Satiety is defined as the ‘condition of being full or gratified beyond the point of satisfaction’; we believe that the participants may equate the symptoms of ‘satiety’ and fullness. Our observation of nonsignificant differences in ‘fullness’ scores, maximum tolerable volumes and postprandial accommodation volumes are therefore internally consistent. We note that Tosetti et al. also reported virtually identical mean satiety and fullness scores 30 min after a volume load test in their preliminary report on dyspeptic patients.18 Because of the overlap in definition of symptoms of fullness and satiety, we elected to exclude the less familiar term ‘satiety’ when assessing the symptoms 30 min postprandially.

In view of the known location of 5-HT3 receptors at the vomiting centre, it was expected that alosetron would reduce the sensation of nausea. This was observed with both doses of alosetron, however it is important to note that bloating was significantly improved by the 1 mg dose. These data are consistent with the known location of 5-HT3 receptors on vagal10, 34 and visceral11, 35 afferents and that they may be blocked by the drug, thereby reducing meal-induced nausea and bloating.

Despite double-blinded and random allocation to treatment, the groups were unbalanced for gender, with significantly more females in the placebo group than the alosetron group. Previous studies suggest that alosetron is less effective in symptom relief among males with irritable bowel syndrome,36 therefore our study would have biased against finding a beneficial effect on symptoms in the 1 mg alosetron group.

In conclusion, our data suggest that alosetron reduces postprandial symptoms in health through effects on visceral afferents rather than by increasing postprandial gastric volume. These studies support the need for further clinical appraisal of 5-HT3 mechanisms in the development of postprandial symptoms. Antagonists to the 5-HT3 receptors show promise in the treatment of patients with functional dyspepsia. The lack of any significant inhibition of gastric emptying by 5-HT3 antagonists37 would suggest that this approach may also be beneficial among the dyspeptics with mild to moderate delay in gastric emptying of solids. Formal studies are required in dyspeptic patients to prove efficacy of 5-HT3 antagonism. The combination of noninvasive SPECT imaging to measure gastric volume and the nutrient drink test to assess postprandial symptoms appears to be an effective experimental medicine approach to evaluate the therapeutic potential of such medications in the future.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

This study was supported in part by grants RO1–DK54681 and K24–DK02638 (Dr M. Camilleri) and by General Clinical Research Center grant (#RR00585) from the National Institutes of Health, and by Glaxo Wellcome Pharmaceuticals. Dr Kuo who is a Fellow in the Division of Gastroenterology at Massachusetts General Hospital was supported by grant T32-DK07191-26 and by a grant from the American Academy of Pharmaceutical Medicine. The authors thank Mr Tim Hardyman for excellent technical support and Mrs Cindy Stanislav for secretarial assistance.

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  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References
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