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Abstract

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

Aim:

To investigate the effect of cisapride, a selective 5-hydroxytryptamine-4 receptor agonist, on the frequency of nocturnal transient lower oesophageal sphincter relaxations and oesophageal acid exposure in patients with gastro-oesophageal reflux disease.

Methods:

In a double-blind, placebo-controlled study, 10 patients with gastro-oesophageal reflux disease (six male and four female; mean age, 54 ± 10.4 years) were randomly assigned to 5-day treatments with cisapride, 10 mg q.d.s., or placebo, separated by a 2-day washout period before the treatment crossover. Sleep stages, lower oesophageal sphincter tone and oesophageal pH were monitored overnight at the end of each treatment regimen. Gastric emptying was assessed before treatment.

Results:

Cisapride decreased the frequency of transient lower oesophageal sphincter relaxations during sleep (1.2 ± 0.2/h vs. 2.7 ± 0.5/h with placebo; P=0.004) and oesophageal acid exposure (17.2 ± 9.9% with placebo vs. 7.2 ± 4.2% with cisapride; P=0.4). Cisapride increased lower oesophageal sphincter tone from 12.7 ± 2.8 mmHg with placebo to 16.9 ± 3.9 mmHg (P=0.03), and decreased heartburn episodes and antacid consumption. All patients had normal gastric retention data over 4 h.

Conclusions:

In patients with gastro-oesophageal reflux disease, cisapride significantly decreased the frequency of transient lower oesophageal sphincter relaxations during sleep and increased lower oesophageal sphincter pressure without changing gastric emptying. We hypothesize, therefore, that 5-hydroxytryptamine-4 mechanisms are important in the control of transient lower oesophageal sphincter relaxations in humans.


INTRODUCTION

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

Cisapride is a prokinetic drug that facilitates the release of acetylcholine at the level of the myenteric plexus. It is a selective antagonist of the 5-hydroxytryptamine-4 (5-HT4) receptor and, to a lesser degree, of the 5-HT3 receptor. Cisapride enhances the amplitude of oesophageal peristaltic contractions and increases baseline lower oesophageal sphincter (LOS) pressure.1–3 It also relieves heartburn and related symptoms in mild to moderate gastro-oesophageal reflux disease.4 Cisapride was approved in the USA for the treatment of nocturnal heartburn.5 For this indication, it may exert its positive effects by increasing oesophageal motility, accelerating gastric emptying or enhancing salivation and submucosal gland secretion in the oesophagus.1–3, 6, 7 It is not known if cisapride's effects could be mediated by decreasing the rate of nocturnal transient lower oesophageal sphincter relaxations (TLOSRs). Our goal was to investigate the effect of cisapride on the frequency of nocturnal TLOSRs and oesophageal acid exposure in patients with gastro-oesophageal reflux disease.

MATERIALS AND METHODS

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

Patients

Ten patients (six males and four females; mean age, 54 ± 10.4 years) with endoscopic erosive oesophagitis at the time of inclusion (Los Angeles classification scale B–D) were recruited from gastroenterology clinics and/or the endoscopy unit at the University of Kansas Medical Center. In accordance with federal and pharmaceutical regulations, before entering the study patients were scrutinized for heart disease and QT intervals of > 450 ms on their electrocardiogram tracings, as well as abnormal blood levels of potassium, calcium, magnesium and creatinine. Medications and foods known to interact with cisapride were excluded. The protocol was approved by the Human Investigation Committee of the University of Kansas Medical Center. All subjects signed an informed consent.

Manometric technique

A pH-probe (Medtronic Functional Diagnostics Zinectics, Inc., Salt Lake City, UT, USA) was attached to a water-perfused motility catheter with seven ports 5 cm apart, and a reverse Dent-sleeve (Dent-sleeve Pty, Ltd, Parkside, Australia), so that the oesophageal acidity was monitored 5 cm above the LOS simultaneously with the LOS pressure and motor function in the body of the oesophagus.

Protocol

Gastro-oesophageal reflux disease therapy was discontinued 72 h prior to participation in the study. Patients were randomly allocated to one of two groups according to the initial medication: cisapride or placebo, 10 mg q.d.s. for 5 days, followed by a 2-day washout period. Half of the patients started the study with cisapride and the other half with placebo. A crossover of the medications for another 5 days followed. Antacids were the only medications allowed to control gastro-oesophageal reflux disease symptoms during the study. The patients kept records of the frequency of heartburn symptoms and the quantity of antacids used as rescue medication during the study. At the end of each 5-day treatment regimen, the patients spent a night in the sleep laboratory at the Kansas University Medical Center for overnight monitoring of the sleep stages by electroencephalography, continuous measurement of LOS tone, oesophageal pressure and pH. Additionally, swallowing was recorded using a microphone (Medtronic Functional Diagnostics Zinectics, Inc., Salt Lake City, UT, USA) attached to the laryngeal area of the neck. Patients were admitted to the sleep laboratory at 18.00 h after fasting for 8 h, and stayed overnight to 06.00 h the next morning.

After topical anaesthesia, the catheter assembly was introduced transnasally in the oesophagus and positioned so that the Dent-sleeve straddled the LOS. An accommodation time of 10–15 min was allowed, and then 10 wet swallows were performed to assess the oesophageal motility function, followed by 45–60 min of recording in the recumbent position. A standardized dinner containing 900 kcal was served at 19.30 h. Electroencephalography electrodes were attached to the patients' heads after dinner. The subjects remained in a recumbent position watching television until 23.30 h when the lights were switched off and the patients went to sleep. Evening doses of cisapride were administered 30 min before dinner and at 22.00 h. Electroencephalography and motility tracings were synchronized so that the pressure events could be related to the stage of sleep. Smoking, antacids and sleeping pills were not allowed during the overnight study.

Gastric emptying for solids was assessed by gastric scintigraphy before the patients started the study drug regimen. After an 8-h overnight fast, subjects ingested a standardized meal (scrambled eggs, two slices of whole-wheat toast with grape jelly and 4 oz of water) radiolabelled with 1 mCi 99mTc sulphur colloid. The radioactivity was measured using a gamma camera on pairs of images, front and back, in the upright position of the body every hour for 4 h. Normal gastric emptying was defined as less than 10% retention of the isotope in the stomach at the fourth hour.8

Data analysis

Motility and pH tracings were reviewed blindly by one investigator (N.P.) for TLOSRs, motility function of the oesophagus and acid gastro-oesophageal reflux episodes. Baseline LOS was estimated as the visual mean of the end-expiratory pressure points during the pull-through procedure and the initial 10 min of recording. TLOSRs were defined according to the standard criteria:9–11 (i) relaxation rate, > 1 mmHg/s; (ii) time to reach maximal relaxation, < 5 s; (iii) nadir pressure ≤ 2 mmHg from the intragastric pressure; (iv) duration of the relaxation, > 10 s; (v) absence of swallowing for 4 s before to 2 s after the onset of relaxation; (vi) oesophageal contractions at the onset of TLOSRs and at LOS closure were considered as optional.

A gastro-oesophageal reflux episode was defined as an abrupt pH drop below pH 4 for > 5 s, which ended when the pH rose above 4 for > 18 s.

Sleep assessment

Polysomnography was performed with the SensorMedics Inc. Model 4100 Data Acquisition and Analysis System. Electroencephalography tracings were analysed (R.W.) independently from the motility recordings. Data were collected using a standard montage for assessing sleep in sleep disorders, and comprised two channels of the electroencephalogram, two channels of the electro-oculogram (left and right) and one channel (bipolar) of the submental electromylogram. Each patient's record was manually scored in 30-s epochs using the scoring criteria of Rechtschaffen and Kales.12 Transient arousals were scored using the criteria set forth by a task force of the American Sleep Disorders Association.13

Statistics

Data are presented as the mean and standard error, unless otherwise stated. A paired t-test was applied to compare the number of nocturnal heartburn episodes, number of antacids, baseline LOS pressure, number of TLOSRs and acid oesophageal exposure. The Wilcoxon signed rank test was applied to analyse the changes in the oesophageal contraction amplitude and number of heartburn episodes. The Pearson correlation was used to relate gastric emptying with the frequency of TLOSRs.

RESULTS

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

All of the patients completed the study successfully except for one who dropped out due to the discomfort caused by the catheter assembly.

Tolerability

The patients experienced more heartburn episodes during the placebo regimen; however, only the number of daytime episodes differed significantly (P=0.016). Less antacid tablets were needed to control the symptoms during cisapride treatment compared to the placebo regimen: 19.6 ± 6.5 tablets per patient weekly vs. 31.6 ± 8.0 (P=0.062).

Effect of cisapride on acid reflux parameters

Nocturnal oesophageal acid exposure to pH < 4.0 during sleep whilst patients were on cisapride decreased by 58% in comparison to the placebo regimen (Table 1). Overall, the total oesophageal exposure time below pH 4 declined from a value of 20.4 ± 8.6% whilst on placebo to 11.9 ± 4.0% during cisapride (P=0.20).

Table 1.  . Motility and pH monitoring parameters of patients treated with cisapride and placebo. See details in the text. All comparisons are performed vs. the corresponding placebo values. All values are presented as mean ± s.e., except for transient lower oesophageal sphincter relaxation (TLOSR) duration, which is expressed as median ± s.e Thumbnail image of

LOS pressure and oesophageal motility data

All patients showed preserved peristaltic oesophageal contractions at wet swallows. The mean pressure amplitude with cisapride was higher than with placebo (Table 1). The majority of patients revealed low LOS pressure (< 10 mmHg) or in the low to normal range (10–15 mmHg). The LOS tone was moderately increased with cisapride in comparison with the placebo regimen: from 12.7 ± 2.8 mmHg to 16.9 ± 3.9 mmHg (P=0.03).

Nocturnal TLOSR data

The mean duration of sleep assessed by electroencephalogram per patient per night did not differ significantly between the nights on the two regimens: 3.7 ± 1.9 h vs. 3.2 ± 2.3 h sleep (P=0.65). The total number of TLOSRs during the electroencephalogram-documented sleep was significantly reduced by cisapride to 1.21 ± 0.3/h compared with 2.67 ± 0.5/h on placebo. The total number of TLOSRs was 49% less during cisapride treatment (35 vs. 68), and the overnight acid contact time in the oesophagus was reduced by 58% (Table 1).

Gastric emptying time data

The gastric emptying retention for solids observed for 4 h was within the normal range: 68.5 ± 4.8% for the first hour, 39.9 ± 5.9% for the second hour, 13.9 ± 3.8% for the third hour and 1.2 ± 0.9% for the fourth hour.

No significant correlation was found between gastric emptying retention values and the number of TLOSRs per hour during sleep for both regimens.

Safety

Cisapride was well tolerated. Mild diarrhoea and abdominal cramps were the most frequent side-effects of cisapride treatment. None of the patients reported symptoms originating from the cardiovascular system.

DISCUSSION

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

Nocturnal reflux has a central role in the pathogenesis of gastro-oesophageal reflux disease.14, 15 The frequency of TLOSRs was shown to be an important factor in nocturnal oesophageal acid exposure in healthy subjects, and TLOSRs were demonstrated to be the major mechanism for gastro-oesophageal reflux disease.15–17 Freidin et al. reported that patients with gastro-oesophageal reflux disease had a higher frequency of TLOSRs associated with gastro-oesophageal reflux events during brief arousals from sleep.18 In our study, cisapride significantly reduced the daytime and substantially decreased the night-time heartburn episodes, which led to a 40% reduction in antacid consumption. Cisapride, 10 mg q.d.s., decreased the mean frequency of TLOSRs by 49%, with an accompanying 60% reduction in oesophageal acid contact time, and also exerted a modest, but statistically significant, increase in LOS baseline pressure, which varied from low to the low–normal range before treatment.

Because cisapride does not exert central effects, a possible explanation for the reduction of TLOSRs could be an enhancement of gastric emptying, causing less gastric distension and thus less TLOSRs post-prandially.19–23 All of the subjects enrolled in the present study had normal gastric emptying. However, cisapride could enhance normal emptying and reduce the retention time of the secreted gastric acid, refluxed bile and small bowel secretions that would be available to reflux, thus reducing the possibility of triggering TLOSRs.

One of the limitations of the study was the short duration of the patients' sleep, which is understandable in such a technically busy setting. Additionally, due to rare but very concerning side-effects explained by drug interactions, cisapride was removed from the USA market,24 which led to the premature closing of the study and the inability to enrol more patients to strengthen the statistical analysis of the data.

In conclusion, cisapride, a selective 5-HT4 receptor agonist, decreased the frequency of TLOSRs and the oesophageal acid contact time during sleep compared to placebo. A similar reduction of the number of post-prandial TLOSRs has been reported with a new 5-HT4 receptor agonist, tegaserod.25 Future developmental goals for prokinetics should take into consideration that TLOSRs can be reduced by a 5-HT4 receptor agonist.

ACKNOWLEDGEMENTS

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

We would like to express our gratitude to Michael Garrison and Chris McMillin for their help. This study was supported by a Janssen-Eisai research grant.

The authors report no conflict of interest with any device or pharmaceutical product described in this paper.

References

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