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Keywords:

  • GERD ;
  • Pharmacodynamic study;
  • Pumosetrag

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. Author Contribution
  11. References

Background

Low basal lower esophageal sphincter (LES) pressure and transient LES relaxations are major causes of gastroesophageal reflux disease (GERD). Pumosetrag, a novel selective partial 5HT3 receptor agonist, showed a promising effect on reducing reflux events in health. We aimed to evaluate the effect of pumosetrag on changes in reflux episodes, lower esophageal sphincter pressure (LESP), and specific symptoms in patients with GERD receiving a refluxogenic meal.

Methods

Patients with GERD, who developed heartburn and/or regurgitation after ingestion of a refluxogenic meal, were randomized to 1 of 3 dose levels of pumosetrag (0.2, 0.5, or 0.8 mg) or placebo. Before and after 7 days of treatment, patients underwent manometry, intraesophageal multichannel, intraluminal impedance and pH after a standard refluxogenic meal.

Key Results

A total of 223 patients with GERD [125 (56%) women, mean (SD) age = 36 (12) years] were enrolled. No overall treatment effects were detected for the total number of reflux episodes (acidic and weakly acidic) (p > 0.5); however, significant treatment effects (p < 0.05) on the number of acid reflux episodes were observed with lower values on pumosetrag 0.2 mg (10.8 ± 1.1), 0.5 mg (9.5 ± 1.1), and 0.8 mg (9.9 ± 1.1) compared with placebo (13.3 ± 1.1). Significant treatment effects (p < 0.05) were also observed for the percentage of time pH was <4, with less time for pumosetrag at 0.5 mg (10%) and 0.8 mg (10%) compared with placebo (16%).

Conclusions & Inferences

In GERD, the partial 5HT3 agonist pumosetrag significantly reduced the rate of acid reflux events but did not result in a significant change in LESP or symptomatic improvement over a 1-week treatment period.

Key Messages
  • Gastroesophageal reflux disease (GERD) is a common chronic condition but 15% to 20% of patients with GERD experience persistent symptoms despite taking proton pump inhibitors.
  • Pumosetrag is a novel selective partial 5HT3 receptor agonist and has shown promise increasing lower esophageal sphincter pressure (LESP) in animal models.
  • We aimed to evaluate the effect of pumosetrag on changes in reflux episodes, LESP and specific symptoms in patients with GERD after a refluxogenic meal. We postulated the drug would reduce reflux episodes in patients on or off acid suppression.
  • In 223 patients with GERD who were randomized to 1 of 3 dose levels of pumosetrag (0.2 mg, 0.5 mg or 0.8 mg) or placebo, pumosetrag significantly reduced the rate of acid reflux events, although no benefit was demonstrated on the total rate of reflux events.
  • Pumosetrag did not significantly change LESP or symptoms over a one-week treatment period.
  • 5HT3 agonists appear unlikely to be of benefit for breakthrough GERD symptoms on acid suppression.

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. Author Contribution
  11. References

Gastroesophageal reflux disease (GERD) is a very common chronic condition in the community; 15–20% of the adult population have heartburn at least weekly.[1, 2] According to the American College of Gastroenterology guidelines,[3] acid suppression is the mainstay of therapy for GERD and proton pump inhibitors (PPIs) are the first choice. However, 15–20% of patients with GERD experience persistent symptoms while taking PPIs.[4, 5] Unfortunately, complete resolution of reflux symptoms does not guarantee normalization of intraesophageal and intragastric pH; up to 50% of GERD patients without Barrett's esophagus continue to show pathologic GERD and a low intragastric pH despite PPI therapy that achieves complete control of reflux symptoms.[6]

Defective esophagogastric motility is considered to be a major mechanism leading to GERD.[3] Most notably,[6-10] transient relaxations of the lower esophageal sphincter (LES) are considered a key pathophysiologic abnormalities in the majority of patients with GERD. Modulation of esophageal motor dysfunction by increasing lower esophageal sphincter pressure (LESP) represents a new approach for patients with PPI refractory GERD.[11]

Pumosetrag is a selective partial agonist at 5HT3 receptors in the enteric nervous system.[12, 13] In experiments examining the upper gastrointestinal (GI) tract in cats,[14] intragastric administration of pumosetrag (1 and 10 mg/kg) increased LESP and tended to decrease the duration of exposure of the lower esophagus to acidic gastric contents suggesting utility in the treatment for GERD.[14] Several animal and human studies[14-16] have demonstrated poor oral absorption rate of pumosetrag, suggesting that systemic effects of pumosetrag might be limited. Coleman et al.[16] evaluated the effects of pumosetrag on upper GI motility in healthy volunteers and showed that pumosetrag delays gastric emptying in association with relaxation of the proximal stomach. Moreover, in a recent human study, this 5HT3 partial agonist was shown to reduce the rate of reflux episodes after a refluxogenic meal in healthy subjects.[17] However, there is no study of the effects of pumosetrag on esophageal parameters in GERD subjects, including subjects with PPI refractory GERD.

We therefore aimed to evaluate the effects of three doses of pumosetrag versus placebo on esophageal function, including reflux episodes and LESP and specific symptoms (heartburn, acid regurgitation, and weakly acidic regurgitation) in patients with GERD receiving a refluxogenic meal. We also aimed to assess the safety and tolerability of pumosetrag.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. Author Contribution
  11. References

Design

We conducted a randomized, double-blind, placebo-controlled multicenter study to evaluate the physiologic esophageal effects of pumosetrag or placebo, as well as safety and tolerability of pumosetrag in patients with GERD.

Study subjects

Subjects with clinical GERD, between 18 and 60 years of age, were recruited by advertisement at the five study sites (Mayo Clinic, Rochester, MN; Mayo Clinic, Scottsdale, AZ; Mayo Clinic, Jacksonville, FL; Advanced Clinical Research Institute, Anaheim, CA; Lynn Health Science Institute, Oklahoma City, OK). Patients with at least a 3-month history of symptoms of GERD (heartburn, regurgitation) who developed at least moderate heartburn and/or regurgitation (at least a 4 on a 0-10 categorical scale) within 2 h following ingestion of the refluxogenic meal while in the supine position[17] were enrolled. Only subjects on PPI were enrolled if they took a stable PPI regimen for the duration of the study; subjects did not undergo a baseline endoscopy.

We excluded patients with the following characteristics: (i) previous or planned GI tract surgical procedures, except cholecystectomy or appendectomy, (ii) any significant esophageal diseases, such as presence or known history of reflux esophagitis, endoscopic Barrett's esophagus, dysplastic changes in the esophagus, or primary esophageal motility disorders, or (iii) any significant systemic disease. Subjects were only allowed to be on birth control, hormone replacement therapy, and stable thyroid replacement. During the study period, prokinetics including metoclopramide and domperidone and anticholinergic were prohibited. Fig. 1 provides a flow diagram of study participant enrollment. The study was approved by the Mayo Foundation's Institutional Review Board.

image

Figure 1. Flowchart of the subjects for this study.

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Randomization, concealed allocation, and study medications

Each subject was assigned a unique patient number to ensure blinded allocation of both treatment group and sequence. Patients with GERD were randomized to oral pumosetrag (0.2, 0.5 or 0.8 mg) or identical placebo. These doses were chosen on the basis of the previous phase I study in volunteer.[17]

Study procedures

The study consisted of three study visits during three study periods, a 10-day screening period, a 1-week treatment period, and a 1-day end of study period. Patients were randomized after completion of the screening procedures during visit 2. The end of study period consisted of one study visit when patients returned for the final efficacy evaluation and for the final safety evaluations after completing study medication. A follow-up phone call was made to patients the following day to collect any safety information from the previous day's procedures. The duration of study participation after randomization was approximately 8 days. The total duration of dosing with study medication was 1 week.

Informed consent was obtained during the screening period. Subjects who met the inclusion and exclusion criteria were randomized to oral pumosetrag (0.2, 0.5, or 0.8 mg) or identical placebo. Fig. 2 shows the study protocol. On day 1, study participants underwent the esophageal high-resolution manometry (HRM; Sandhill Scientific, Highlands Ranch, CO, USA) to measure LESP as well as intraesophageal impedance and pH after eating a refluxogenic meal, before study medication was given. After esophageal physiology tests, study participants took the study medication (placebo or pumosetrag 0.2, 0.5, or 0.8 mg, t.i.d.) for 1 week. On day 8 (Fig. 2), study participants underwent the esophageal HRM (Sandhill Scientific) to measure LESP as well as intraesophageal impedance and pH after eating a refluxogenic meal, after the last dose of test drug. Heartburn and regurgitation symptoms were also collected every 15 min throughout the entire 2-h procedure using a 0-10 categorical scale. Heartburn and regurgitation symptoms were also collected every 15 min throughout the entire 2-h procedure using a 0-10 categorical scale. Severity of symptoms was also rated on a 0-10 categorical scale (0 = no symptoms, 1–3 = mild, 4–6 = moderate, 7–9 = severe, 10 = very severe). Heartburn was defined as ‘burning pain behind the breastbone’. Regurgitation was defined as ‘sensation of food coming back into my throat’. Adverse events were recorded during the study period.

image

Figure 2. Study protocol.

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High-resolution manometry

A solid-state HRM assembly with multiple solid-state sensors spaced at 1-cm intervals was used[18, 19] (Sandhill Scientific). The catheter had circumferential pressure sensors. Prior to intubation, the catheter was calibrated between 0 and 300 mmHg and zeroed to atmospheric pressure. Studies were performed in a semi-supine position after an overnight fast. The HRM catheter was passed transnasally and positioned to record from the hypopharynx to the stomach with three intragastric sensors. The catheter was fixed in place by taping it to the nose. The manometric protocol included a 5-min period to acclimatize to the catheter and to assess basal sphincter pressure, followed by the administration of ten 5-mL water swallows. Subsequently, the data were analyzed using the analysis software. The resting LESP was quantified as the end-expiratory pressure over at least five respiratory cycles.

Multichannel intraluminal impedance and pH

The detailed method of the multichannel intraluminal impedance and pH (MII-pH) assessment used in this study was written in the previous study.[17] Briefly, study participants underwent the multichannel intraluminal impedance and pH (MII-pH) assessment (Sandhill Scientific) after eating a standard refluxogenic meal.[17, 20] Subjects were placed in the right lateral decubitus position and esophageal intraluminal impedance, and pH was recorded for 2 h to identify the total number of reflux episodes, including acid and weakly acidic reflux events.

Statistical analysis

All continuous data are summarized as means or least squares adjusted for covariates, mean values (±SEM). The primary efficacy analysis examined the total number of reflux events (acid, separately, weakly acid, and total) at the last dose of testing using ancova models with the corresponding baseline number as a covariate. A specific contrast for overall drug (pumosetrag) versus placebo and a contrast for a (linear) dose trend were also assessed. For these endpoints, a square root transformation was used to stabilize variances across the treatment groups. The secondary endpoints included the proportion of time that pH was <4 during a provocative procedure as measured by MII-pH (an arcsine square root transformation was first applied), mean LESP (mmHg), and symptom severity scores for acid taste, heartburn, and regurgitation. For each of these endpoints, the corresponding baseline values were also included as a covariate in the ancova models. In addition, esophageal acid clearance time (ACT) was estimated by: (tracing duration [per protocol] of 120 min) * (proportion of time with pH <4)/(number of acid reflux events). Additional models were also examined including use (yes vs no) of acid-reducing medications (antacid, H2 blockers, low dose (≤35 mg/day) or high dose (>35 mg/day) PPI as a covariate in the models). These models also included an ‘interaction’ term (cross-product of acid-reducing medication use by treatment group). All the analyses followed the intention to treat paradigm (including all randomized subjects in the analyses) by imputing the missing values in dropouts using the corresponding overall mean in subjects with non-missing data. A compensatory downward adjustment to the error degrees of freedom in the ancova model (subtracting one degree of freedom for each missing value imputed) was used. The incidence, severity, and type of adverse events were recorded, and clinically significant changes or abnormalities in the subject's physical examination, vital signs, clinical laboratory tests, and ECG results were assessed for safety evaluations.

Sample size assessment

Differences between treatment groups of 20–30% in the number of reflux events (total, acid, weakly acidic) could have been detected with 80–90% power (using a two-sided alpha level of 0.05), assuming N = 56 subjects per group based on the variation in reflux events observed during baseline study.[17] The observed baseline data for the primary endpoints were similar to that observed for the corresponding variation observed post-treatment (pooled over treatment groups). The ancova models would have provided similar power to detect somewhat smaller differences by incorporating the baseline values as covariates and making the specified transformations (to stabilize variances across treatment groups).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. Author Contribution
  11. References

A total of 223 patients with GERD [125 (56%) women, mean (SD) age = 36 (12) years] were enrolled in this study. Among the patients with GERD, 55 subjects were randomized to pumosetrag 0.2 mg, 56 subjects to pumosetrag 0.5 mg, 56 subjects to pumosetrag 0.8 mg, and 56 subjects to placebo (Fig. 1). Overall, 21% (47/223) were on PPI during the study period including 20% (11/56) randomized to placebo (Table 1).

Table 1. The mean LESP, proportion (%) time with pH <4, and symptom scores at the last dose of test drug [mean (adjusted for baseline values) ± SEM, unless otherwise noted]
 Placebo (n = 56)Pumosetrag 0.2 mg (n = 55)Pumosetrag 0.5 mg (n = 56)Pumosetrag 0.8 mg (n = 56)p-valuea
  1. NA, not applicable for treatment effects; BMI, body mass index; PPIs, proton pump inhibitors; LESP, lower esophageal sphincter pressure.

  2. a

    From ancova model for corresponding transformed response variable.

  3. b

    Symptom scores recorded on a scale of 0-10.

Age (years) baseline mean (SD)37.1 ± 13.534.9 ± 11.933.5 ± 11.138.5 ± 13.1NA
Female gender, n (%)27 (48)28 (51)39 (70)31 (55)NA
BMI baseline mean (SD)29.3 ± 6.228.8 ± 6.628.7 ± 6.229.9 ± 6.7NA
On PPI, n (%)11 (20)12 (22)10 (18)14 (24)0.81
Proportion (%) time with pH <416.1 ± 2.015.9 ± 2.010.2 ± 2.010.4 ± 2.00.02
Mean LESP (mmHg)20.5 ± 1.619.6 ± 1.619.8 ± 1.618.2 ± 1.60.76
Mean velocity of esophageal contraction3.9 ± 0.33.8 ± 0.34.0 ± 0.34.0 ± 0.30.96
Acid tasteb1.2 ± 0.21.7 ± 0.21.4 ± 0.21.6 ± 0.20.45
Heartburnb2.0 ± 0.22.3 ± 0.22.5 ± 0.22.4 ± 0.20.61
Regurgitationb1.9 ± 0.22.0 ± 0.22.4 ± 0.22.2 ± 0.20.52

Esophageal reflux events on day 8

The mean (adjusted for baseline) number of acid/weakly acidic reflux events after 7-day treatment period on placebo and each pumosetrag dose is shown in Table 2 and Fig. 3. While pumosetrag did not significantly reduce the total number of reflux episodes after a refluxogenic meal, significant (p = 0.029) overall treatment effects for the number of acid reflux event were observed. In particular, a dose–response was noted with pumosetrag 0.2, 0.5, and 0.8 mg, significantly reducing the number of acid reflux episodes after a refluxogenic meal (p = 0.005 for linear trend, Fig. 3).

Table 2. Summary of reflux events by use of acid-reducing medications and treatment group
 Placebo (n = 56)Pumosetrag 0.2 mg (n = 55)Pumosetrag 0.5 mg (n = 56)Pumosetrag 0.8 mg (n = 56)
ARM statusARM+ (n = 27)ARM− (n = 29)ARM+ (n = 27)ARM− (n = 29)ARM+ (n = 26)ARM− (n = 30)ARM+ (n = 30)ARM− (n = 26)
  1. SE, standard error; ARM, acid-reducing medication [antacids, H2 blockers, PPIs (proton pump inhibitors)].

Total reflux events (mean ± SE)25 ± 2.318 ± 2.220 ± 2.318 ± 2.223 ± 2.317 ± 2.223 ± 2.218 ± 2.3
Acid reflux events (mean ± SE)17 ± 1.610 ± 1.511 ± 1.610 ± 1.511 ± 8.89 ± 1.511 ± 1.59 ± 1.6
Weakly acidic reflux events (mean ± SE)9 ± 1.78 ± 1.610 ± 1.78 ± 1.613 ± 1.79 ± 1.612 ± 1.610 ± 1.7
image

Figure 3. Number of reflux episodes during impedance pH study over 2 h on pumosetrag 0.2, 0.5, 0.8 mg, or placebo in gastroesophageal reflux disease. p = 0.029 for overall treatment effects.

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Table 1 provides the mean (SEM) symptom score for each reflux symptom after the 7-day treatment period on placebo and each pumosetrag dose. The symptom scores for heartburn and acid regurgitation were not significantly different between placebo and each pumosetrag dose (p > 0.4, Table 1).

Proportion (%) of time that pH <4 at the last dose of test drug

The proportion (%) time with pH <4 at the last dose of test drug on placebo and pumosetrag is shown in Table 1. Overall treatment effects were observed (p = 0.02) with pumosetrag 0.5 and 0.8 mg reducing the proportion of time that pH was <4 to 10.4% and 10.2%, respectively, compared with placebo (16.1%), while little reduction in the proportion of time that pH was <4 was observed for pumosetrag 0.2 mg. In addition, we estimated esophageal ACT, which was not significantly different across the treatment arms; in an ancova model (including age, gender, BMI, baseline ACT, and treatment group), the p-value for overall treatment effects was 0.42.

Lower esophageal sphincter pressure and distal esophageal contraction

There were no significant effects on the LESP during manometry at all dose levels of pumosetrag (Table 1). In particular, the fasting overall LESP for pumosetrag 0.2, 0.5, and 0.8 mg (19.6 ± 1.6 mmHg, 19.8 ± 1.6 mmHg, or 18.2 ± 1.6 mmHg, respectively) was similar to placebo (20.5 ± 1.6 mmHg). There were no significant differences on the esophageal peristalsis during manometry at all dose levels of pumosetrag or placebo (Table 1).

Acid suppression therapy and response

In a secondary analysis, treatment effects were significant for acid events in those subjects on acid-reducing drugs (p = 0.02), but not in those subjects not taking acid-reducing drugs (p > 0.5; Table 2). No treatment effects on the total number of reflux events nor weakly acidic events in either subgroup according to acid-reducing medication status were detected.

Safety

No serious adverse events were reported as shown in Table 3. Diarrhea was not more common on the drug, and only one subject experienced pruritus. Abnormalities of blood pressure or ECG were not observed. Abnormalities of blood biochemical tests including bilirubin, γ-glutamyltranspeptidase, and alanine aminotransferase did not occur during treatment with pumosetrag.

Table 3. The number of patients with GERD experiencing adverse events on pumosetrag or placeboa
 Placebo (n = 56)Pumosetrag 0.2 mg (n = 55)Pumosetrag 0.5 mg (n = 56)Pumosetrag 0.8 mg (n = 56)
  1. a

    No other adverse events such as bloating/gas, flushing, rash, stiff neck, elevated liver function test, or sleep disturbances were observed.

  2. GERD, gastroesophageal reflux disease.

Abdominal pain01 (1.8%)1 (1.8%)2 (3.6%)
Nausea5 (8.9%)2 (3.6%)6 (10.7%)5 (8.9%)
Vomiting1 (1.8%)1 (1.8%)4 (7.1%)1 (1.8%)
Diarrhea4 (7.1%)2 (3.6%)2 (3.6%)2 (3.6%)
Constipation0001 (1.8%)
Pruritus, generalized001 (1.8%)0
Headache1 (1.8%)2 (3.6%)3 (5.4%)1 (1.8%)
Stiff neck0000

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. Author Contribution
  11. References

This is the first randomized placebo-controlled study to evaluate the effects of pumosetrag on gastroesophageal reflux episodes and LESPs in patients with documented symptomatic GERD. Pumosetrag significantly reduced the rate of acid reflux events, although no benefit was demonstrated on the total rate of reflux events. In addition, pumosetrag at doses of 0.5 and 0.8 mg significantly reduced the proportion of time that pH was <4 during the impedance study. No significant changes were observed in LESP or on distal esophageal contractions after 1 week of treatment.

The smooth muscle LES and crural diaphragm are two key components that prevent gastroesophageal junction valve incompetence but gastric and upper small intestinal emptying is also important in reducing reflux events.[21] A number of animal studies have demonstrated that pumosetrag, a 5HT3 receptor partial agonist, has upper GI prokinetic activity.[12-14] Moreover, Venkova et al.[14] studied the effect of pumosetrag on LESP in anesthetized cats, and they showed that pumosetrag (0.1–10 mg/kg) dose dependently increased the LESP in cats. The present study has shown that pumosetrag reduced the rate of acid reflux events by about 30% in patients with GERD vs placebo group. Notably, a dose–response curve was possibly noted with pumosetrag 0.2 and 0.5 mg, reducing the number of acid reflux episodes after a refluxogenic meal (p = 0.005 for linear trend, Fig. 3); however, relatively similar data were shown on reducing the number of acid reflux episodes between pumosetrag 0.5 and 0.8 mg. The fact that pumosetrag reduced the rate of acid reflux events suggests that it may have an effect on reducing the transient LES relaxation, but we did not evaluate transient LESPs in this study. Our study was not designed to determine the effect of pumosetrag on weakly acidic reflux events, and while the relevance of weakly acidic reflux continues to be debated, this deserves investigation.[22] Further studies are also required to test the drug effect on the LES. Recently, in a randomized, double-blind, placebo-controlled crossover study by Choung et al.,[17] the pharmacodynamic effects of pumosetrag (0.5, 0.8 and 1.4 mg) were assessed in healthy volunteers. In this study, pumosetrag 0.5 mg significantly reduced the rate of reflux episodes after a refluxogenic meal from 10 (±2.2) on placebo to 6 (±1.2) on drug over the 2-h period following ingestion of the meal. We also evaluated the esophageal physiology after a 7-day pumosetrag or placebo treatment in patients with GERD, but these findings were not confirmed in the present study with symptomatic GERD patients in contrast to healthy volunteers.

Notably, we found that pumosetrag 0.5 and 0.8 mg reduced the proportion of time that pH was <4 during the impedance study compared with placebo. The fact that pumosetrag reduced the proportion of time that pH was <4 during the impedance study suggests that it may have an effect on gastric function reducing the amount of gastric acid reaching the esophagus. Interestingly, about 50% of subjects in each group were on acid suppression therapy (antacids, H2 blockers, or PPIs) during the study and patients on acid suppression therapy were more likely to have fewer acid reflux events on treatment vs placebo. More work is warranted to determine the effect of pumosetrag on acid reflux events in patients on acid suppression therapy.

The current study was adequately powered as noted in the statistical analysis section, and we consider that a type II error is unlikely to explain the negative reflux episode findings. However, this study had some limitations. Notably, the study subjects were a selected population who had reflux symptoms for at least 3 months and who developed symptoms after a screening refluxogenic meal test. Recently, Weijenborg et al.[23] reported that patients with proven GERD have a better response to antireflux medication than uninvestigated patients with reflux symptoms and we do not know whether selecting an uninvestigated GERD population in the current study reduced the opportunity to detect a true therapeutic effect. Moreover, the present study only evaluated the 2-h observation period after refluxogenic meal in the pH impedance study. Because the half-life of pumosetrag is relatively short,[14, 17] the desirable drug effect could have been shown beyond 2 h. Thus, the lack of effect in 2-h impedance study does not exclude the possibility of pumosetrag benefitting symptoms, when assessed in the usual way over days, in esophageal function testing even though we considered the 2-h observation period to be sufficient as a proof of principal (pumosetrag mean half-life ranging from 1.73 to 5.2 h after oral administration).

Pumosetrag was well-tolerated in our study. Upper GI symptoms (including nausea or vomiting) were reported in about 3–10% of subjects following 0.2, 0.5, and 0.8 mg, but this was not different from placebo. We only observed that one patient on pumosetrag 0.5 mg had skin symptoms. In contrast, earlier studies including Coleman et al.[16] observed more frequent flushing and pruritus on high doses of pumosetrag; how this might occur despite its poor absorption is unclear but presumably reflects activation of 5HT3 receptors. We did not observe increased diarrhea on pumosetrag, but this was seen by Fujita et al.,[15] where pumosetrag significantly increased colonic motility in subjects with constipation. We observed no significant cardiovascular events, ECG changes, or liver enzyme abnormalities but our study was relatively short (1 week of therapy).

In conclusion, in subjects with symptomatic GERD, the novel partial 5HT3 agonist pumosetrag significantly reduced the rate of acid reflux events but did not result in a significant change in LESP and improvement in symptoms' score over a 1-week treatment period. Although safe and despite promising animal work, this 5HT3 agonist does not appear to represent a potential approach for the management of GERD.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. Author Contribution
  11. References

The authors wish to thank Lori M. Anderson for her assistance in the preparation of the manuscript.

Author Contribution

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. Author Contribution
  11. References

RSC, GRL, DDF, DK, MDC, KDV, ARZ, and NJT involved in design, analysis, writing, and revising of this article; RSC, GRL, PJW, WCO, MDC, and KDV recruited participants; ARZ and WSH contributed to statistical analysis.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. Author Contribution
  11. References