ABT-229, a motilin agonist without antibacterial activity, has been shown to enhance both lower oesophageal sphincter pressure in cats and gastric emptying in humans.
ABT-229, a motilin agonist without antibacterial activity, has been shown to enhance both lower oesophageal sphincter pressure in cats and gastric emptying in humans.
To investigate the effect of oral treatment with ABT-229 10 mg b.d., ABT-229 5 mg b.d. and cisapride 10 mg q.d.s. on gastro-oesophageal reflux, lower oesophageal sphincter pressure, transient lower oesophageal sphincter relaxations and symptoms in GERD patients.
Twenty-four GERD patients completed the study. A randomized, double-blind, placebo-controlled, three-period incomplete crossover design was used with three dosing periods of 7 days. All patients received ABT-229 10 mg b.d. and placebo during two of the three periods. In the remaining period 12 patients were given ABT-229 5 mg b.d. and 12 received cisapride 10 mg q.d.s. Ambulatory 24 h recordings of oesophageal pH and pharyngeal, oesophageal, lower oesophageal sphincter and gastric pressures were performed on day 7 using an assembly incorporating a Dent sleeve connected to a portable water-perfused manometric system.
Oesophageal acid exposure was not affected by ABT-229 or cisapride, but the incidence of reflux episodes was reduced by cisapride. None of the drugs affected oesophageal motility, lower oesophageal sphincter pressure or the incidence of transient lower oesophageal sphincter relaxations. Both ABT-229 10 mg b.d. and cisapride reduced the severity of daytime heartburn.
The value of ABT-229 in the treatment of GERD appears to be limited.
The most important mechanisms underlying gastro-oesophageal reflux disease (GERD) are transient lower oesophageal sphincter relaxations, hypotensive lower oesophageal sphincter pressure, and decreased oesophageal clearance as a result of oesophageal hypoperistalsis.1–3 Gastric acid antisecretory medication is currently the most effective medical treatment for patients with GERD, but these drugs do not address the underlying motility disorders. Drugs with prokinetic properties such as cisapride have been shown to be effective in the treatment of erosive oesophagitis. Cisapride heals low grade oesophagitis, prevents its recurrence, and reduces typical GERD symptoms.4–11 These effects of cisapride can be attributed to its stimulating effects on oesophageal motility, lower oesophageal pressure and gastric emptying.4 Apart from the 5HT4 agonist cisapride, motilin agonists have also been shown to have an effect on upper gastrointestinal motor function including the oesophagus.12
Erythromycin reduces gastro-oesophageal reflux, probably due to an increase in lower oesophageal sphincter pressure and acceleration of the gastric emptying rate.13–19 However, other studies have shown no effect of oral erythromycin on oesophageal reflux.20, 21 Erythromycin mimics the effects of motilin by binding to motilin receptors.22, 23
ABT-229 is a recently developed motilin agonist which, in contrast to erythromycin, is devoid of antibacterial properties. It has been demonstrated that ABT-229 has a much higher in vitro promotility effect than erythromycin.24 We have previously shown that a low dose of ABT-229 enhances gastric emptying in healthy subjects.25 These data suggest that in humans ABT-229 is also a very strong prokinetic agent. In cats, ABT-229 has been shown to increase basal lower oesophageal sphincter pressure.26 To date no studies on the effect of ABT-229 on oesophageal or lower oesophageal sphincter motor patterns have been performed in humans. We hypothesized that the effects of ABT-229 would also be of benefit in the treatment of GERD patients.
The primary aim of this study was to evaluate the pharmacodynamic effects of two different doses of ABT-229, as compared with placebo or cisapride, on oesophageal acid exposure and oesophageal and lower oesophageal sphincter motility, as assessed by 24 h ambulatory combined oesophageal pH and oesophageal and lower oesophageal sphincter pressure monitoring, in patients with heartburn. A secondary aim was to assess the pharmacodynamic effects of ABT-229, placebo and cisapride on symptom improvement, during 1-week treatment periods.
Twenty-four patients with symptomatic GERD (15 men, mean age 45.5 years, range 21–61 years) completed the study. Patients were recruited by advertisements in widely available national newspapers. Patients were included if they had a history of recurrent daytime and/or night-time heartburn, with or without regurgitation, for 3 months or more. In addition, heartburn symptoms had to interfere with concentration and/or daily activities for at least 3 out of 7 days during the screening period. Patients were excluded if they had (i) a history of any disease or operation that might influence gastrointestinal motility or gastric acid secretion, (ii) an oesophageal motility disorder not related to GERD, or (iii) oesophagitis grade 3 or 4. Nine patients had no oesophageal erosions, 11 patients had grade 1 and four patients grade 2 oesophagitis (modified Savary–Miller scale). Six patients without oesophageal erosions had acid reflux for at least 5.8% of the 24 h and/or acid-related symptoms. Macroscopic signs of Barrett’s oesophagus were observed in three patients and a hiatus hernia of at least 3 cm diameter in 14 patients. Five patients were H. pylori-positive by rapid urease test. Antisecretory drugs at treatment dose for GERD had to be stopped for at least 6 weeks prior to the start of the study. This applied to six of the 24 patients who used antisecretory drugs at maintenance dose. All drugs known to influence oesophageal or gastric motility were stopped at least 1 week before the screening period.
From the moment of screening onwards, antacids (Maalox) were provided but were taken only for the relief of intolerable pain or discomfort. Antacids were not permitted during the 24 h pH and manometric recordings and during the night preceding the 24 h recording. Smoking was prohibited from 23.00 hours on the evening before the 24 h study until the end of the 24 h study. The study was approved by the Ethics Committee for Research on Humans of the University Medical Center Utrecht and each subject gave their written informed consent.
Patients went through a screening period of 2 weeks prior to the study. During this period each patient kept a diary to assess the severity of daytime and night-time heartburn and regurgitation. An upper endoscopy was performed in the second week of the screening period in order to determine the grade of oesophagitis, to exclude other gastrointestinal disorders and to determine if a hiatus hernia was present. During the upper endoscopy one corpus and one antrum biopsy was taken to determine the H. pylori status using a urease test (H.pylorifast, GI Supply, Camp Hill). Stationary oesophageal manometry was also performed in order to detect oesophageal motility disorders not related to GERD,1 and to locate the proximal border of the lower oesophageal sphincter.
A randomized, double-blind, placebo-controlled, three-period incomplete crossover design was used with three treatment periods of 7 days each. Each patient received ABT-229 10 mg b.d. and placebo during two of the three treatment periods. For the remaining treatment period 12 patients were allocated to ABT-229 5 mg b.d. and 12 to cisapride 10 mg q.d.s. The doses of ABT-229 used in this study are based on a previous study in healthy subjects in which both ABT-229 5 mg b.d. and ABT-229 10 mg b.d. were shown to accelerate gastric emptying at breakfast, lunch and dinner (data on file at Abbott Laboratories).
Combined 24 h ambulatory oesophageal pH and manometric recordings were performed on day 7 of each treatment period. The treatment periods were separated by 7–14 day washout periods.
Patients were admitted to the research unit from the evening before until the end of the recording period. After an overnight fast, both catheters were introduced transnasally at 07.00 hours. The manometric catheter was positioned with the side hole at the proximal border of the sleeve at 1 cm above the lower oesophageal sphincter, so that the sleeve straddled the lower oesophageal sphincter. After positioning the manometric catheter, perfusion of the side hole at the proximal border of the sleeve was capped off. The two most optimal pharyngeal side holes were identified and perfusion of the other two pharyngeal channels was also discontinued.
The pH electrode was positioned at 5 cm proximal to the upper border of the lower oesophageal sphincter.
During the 24 h recording period standardized meals were provided as follows: (i) breakfast (42.2 g carbohydrate, 27.8 g protein, 20.8 g fat, 458 kcal), (ii) lunch (94.8 g carbohydrate, 30 g protein, 37.2 g fat, 869.5 kcal) and (iii) dinner (117.5 g carbohydrate, 57.4 g protein, 14.6 g fat, 831 kcal). These were given at 08.00, 12.30 and 18.30 hours, respectively. The patients were allowed to drink water ad libitum during the 24 h recording period and drank a cup of tea or decaffeinated coffee at 15.30 and 21.30 hours. The patients went to bed at 23.00 hours and were woken up at 07.30 hours. The catheters were removed directly after the patients woke up. Patients were not allowed to sleep before 23.00 hours, as this might influence the incidence of transient lower oesophageal sphincter relaxations.27 Eating and drinking periods and the incidence of complaints of heartburn were marked on the data logger and also noted in a diary.
Three containers of medication were supplied to each patient. ABT-229 5 mg or placebo (box X), ABT-229 10 mg or placebo (box Y) and cisapride 10 mg or placebo (box Z). All patients were instructed to take one capsule from boxes X and Y 15 min before breakfast and dinner and to take one capsule from box Z at 15 min before breakfast, lunch, dinner and bedtime.
During each of the treatment periods the patients kept a diary identical to that kept during the screening period. This diary recorded the severity of daytime and night-time regurgitation and heartburn. Each symptom was scored on a 7 point scale (0= absence of symptoms, 1=symptoms can easily be ignored, 2=symptoms cannot be ignored but do not interfere with everyday activities, 3=symptoms interfere with concentration and/or activities, 4=symptoms interfere with all activities except basic needs, 5=symptoms necessitate bed rest, and 6=symptoms need prompt medical advice).
Manometric recordings were performed using a silicone rubber water-perfused micromanometric assembly (Dentsleeve Pty Ltd, Belair, South Australia).28 This 12-channel assembly (OD 3.5 mm, ID 0.4 mm) incorporated four pharyngeal, three oesophageal and one intragastric side hole, a reversed water-perfused sleeve, and one side hole at the proximal border of the sleeve ( Figure 1). Each lumen was perfused with degassed water at a rate of 0.08 mL/min using hydraulic flow restrictors (Dentsleeve Pty Ltd) and a purpose-built portable low-compliance water pump. The external pressure transducers (Abbott, Chicago, IL) and hydraulic flow restrictors were mounted on a belt.29 The water pump consisted of a small gas cylinder and a 350 mL water reservoir was carried in a small back-pack. To investigate the recording fidelity of the portable manometric system we performed a study in eight healthy volunteers in which we compared lower oesophageal sphincter manometric recordings performed with the portable water-perfused system with those performed with the conventional water-perfused system. This study showed that the portable system records comparable basal lower oesophageal sphincter pressures [0.9 (0.2) vs. 0.9 (0.13) (kPa)] and both incidences [11.5 (3.8) vs. 10.8 (1.5)] and characteristics of transient lower oesophageal sphincter relaxations [relaxation rate: 0.3 (0.06) vs. 0.4 (0.06) kPa/s, nadir pressure: 0.09 (0.01) vs. 0.08 (0.02) kPa and duration: 18.5 (1.2) vs. 18.2 (1.5) s] as the conventional water-perfused manometric recording (unpublished data).
Oesophageal pH was recorded using a glass electrode (model LOT 440, Ingold AG, Urdorf, Switzerland). Before and after the study the pH electrode was calibrated at 37 °C using pH 4.0 and 7.0 buffered solutions (Radiometer Analytical A/S, Bagsvaerd, Copenhagen). The manometric catheter was calibrated at a level of 0 and 50 cm water (0 and 5 kPa). The manometric pressure transducers and the pH electrode were connected to a digital data logger (MMS, Enschede, Netherlands). The manometric data were sampled at a frequency of 4 Hz, except for the pharyngeal pressure sensors, which were sampled at 8 Hz. The pH sensor was sampled at a rate of 1 Hz. After the recording data were retrieved and stored on a personal computer.
For each week of treatment, mean daily severity scores for each of the four symptoms (daytime heartburn and regurgitation, and night-time heartburn and regurgitation) were calculated separately and for the sum of the four symptoms.
Locally developed software enabled automated correction of baseline fluctuations in the manometric tracings caused by body movements. Moving baselines for the pharyngeal and oesophageal signals were created by taking the 20th percentile over a period of 3.75 s (30 samples) and the 40th percentile over a period of 30 s (120 samples), respectively. A baseline for the lower oesophageal sphincter pressure was created automatically by taking the lowest value of the lower oesophageal sphincter pressure signal over a period of 4 min. This appeared to be the best estimation of the intragastric pressure. Secondly, the computer program calculated the end-expiratory lower oesophageal sphincter pressure curve by using an algorithm defined as the 10th percentile of the raw lower oesophageal sphincter pressure over a period of 10 s. The newly created curve was similar to the raw pressure curve but without the fluctuations caused by respiration. Mean basal end-expiratory lower oesophageal sphincter pressure was calculated from the end-expiratory lower oesophageal sphincter curve. In this procedure the time intervals from 4 s before to 6 s after a lower oesophageal sphincter relaxation were excluded. To validate the software for the analysis of the end-expiratory lower oesophageal sphincter pressure we used manometric lower oesophageal sphincter recordings from eight patients. Mean lower oesophageal sphincter pressures for 1 h postprandial, 1 h interprandial and 1 h supine was manually determined by three observers, by taking the visual mean of each 15-min period, and by the computer program. Mean lower oesophageal sphincter pressures calculated by the three observers and by the software were comparable [1.31 (0.17) vs. 1.24 (0.15); P=N.S.]. Finally, the computer program detected oesophageal contractions, and measured their mean amplitude and duration. The algorithms for the oesophageal manometric analysis were derived from a previously validated computer program.30
Transient lower oesophageal sphincter relaxations were analysed visually and were defined as lower oesophageal sphincter relaxations with a velocity of at least 0.4 kPa per 3 s, a duration longer than 10 s, a nadir pressure of <& 0.4 kPa, and with no pharyngeal contraction in the time interval from 5 s before to 2 s after the onset of the relaxation.
Mean lower oesophageal sphincter pressure and number of transient lower oesophageal sphincter relaxations/hour were determined for the 24 h, fasted, postprandial and supine periods. Oesophageal motility variables were calculated for the 24 h, preprandial, interprandial and supine periods. The postprandial period was defined as the sum of the three 2-h periods following the three meals. The fasted period was defined as the upright period (07.30–23.00 hours) minus the preprandial and postprandial periods. The supine period was defined as the time interval from 23.00 hours to 07.30 hours next morning.
The percentage of time with pH < 4, number of reflux episodes per hour and the mean duration of the reflux episodes were also calculated automatically. Acid reflux episodes were defined as a drop in oesophageal pH to a value below 4 lasting for at least 3 s. Reflux episodes separated by a period with oesophageal pH above 4 but with a duration of less than 3 s were considered as one episode. Oesophageal pH data were analysed for the 24 h, upright and supine periods.
Statistical analysis was performed using analysis of variance ( ANOVA).
With a sample size of 24 patients the comparison between ABT-229 10 mg and placebo had a power of 0.96 to detect a mean difference of 3.4 for the percentage of time with oesophageal pH < 4. The ANOVA analysed effects of patient, period and treatment. The comparisons between ABT-229 10 mg and ABT-229 5 mg, between ABT-229 10 mg and cisapride, between ABT-229 5 mg and placebo, and between cisapride and placebo had a power of 0.74 with a sample size of 12 patients. The ANOVA included effects of sequence, patients within sequence, period and treatment regimen. The comparison between ABT-229 5 mg and cisapride had a power of 0.25 with a sample size of 12 patients. This comparison was evaluated by one-way ANOVA with treatment regimen as the factor.
This study was not powered to observe treatment differences with regard to symptoms.
Significance was accepted with a P-value of < 0.05. Data are expressed as means and standard deviations.
Ten patients discontinued the study prematurely, five because of personal reasons and five because of intolerance to prolonged manometric recording. All 10 patients were replaced.
The effects of ABT-229 and cisapride on reflux time, incidence of reflux episodes, and mean reflux episode duration are shown in Table 1.
The percentage of time with oesophageal pH < 4 was not affected by ABT-229 10 mg b.d. or 5 mg b.d., or by cisapride ( Figure 2). Furthermore, the incidence of reflux episodes was not affected by ABT-229 10 mg b.d. or 5 mg b.d. However, in the upright position the number of reflux episodes per hour was statistically significantly lower during treatment with cisapride than during treatment with ABT-229 10 mg or placebo (P=0.03, P=0.04, respectively) ( Figure 3). During the night and the total 24 h period, however, the incidence of reflux episodes was not affected by cisapride (Table 1). None of the drugs affected the mean duration of the reflux episodes significantly (Table 1).
Amplitude and duration of the oesophageal contractions and the number of peristaltic contractions were not significantly affected by ABT-229 5 mg or 10 mg or cisapride during the 24 h, preprandial, interprandial or supine periods (data not shown). However, during cisapride treatment the number of peristaltic contractions was statistically significantly higher in the total 24 h and supine periods than with ABT-229 5 mg b.d. (2607.7 vs. 1662.4, P=0.045, and 523.6 vs. 283.8, P=0.006, respectively).
ABT-229 10 mg b.d., ABT-229 5 mg b.d. and cisapride had no significant effect on basal end-expiratory lower oesophageal sphincter pressure over the recorded 24 h, postprandial, interprandial and supine periods ( Figure 4, Table 2). None of the drugs had a significant effect on the incidence of transient lower oesophageal sphincter relaxations ( Figure 5, Table 3).
Table 4 shows that the severity of daytime heartburn was significantly less during treatment with both ABT-229 10 mg and cisapride compared with placebo. Night-time heartburn as well as daytime and night-time regurgitation was not significantly changed either by ABT-229 10 mg or by cisapride. None of the symptoms was affected by ABT-229 5 mg. The total symptom score was similar during all four treatment periods.
The main findings of our study are that: (i) both ABT-229 10 mg b.d. and ABT-229 5 mg b.d. failed to reduce the exposure of the oesophagus to acid reflux, and the incidence or duration of gastro-oesophageal reflux episodes; (ii) ABT-229, at doses of 10 mg b.d. and 5 mg b.d., did not affect oesophageal body motility; (iii) basal lower oesophageal sphincter pressure and the incidence of transient lower oesophageal sphincter relaxations were not affected by ABT-229 10 mg b.d. or 5 mg b.d.; (iv) cisapride reduced the incidence of reflux episodes during the daytime, but not during the night, and did not affect the percentage of time with oesophageal pH < 4; (v) cisapride did not affect oesophageal motility, basal lower oesophageal sphincter pressure or the incidence of transient lower oesophageal sphincter relaxations.
In the present study we compared the efficacy of ABT-229 with cisapride 10 mg q.d.s., as several studies have shown that cisapride is superior to placebo in healing oesophagitis and in preventing oesophagitis relapse.7–11 We observed no effect of ABT-229 on acid gastro-oesophageal reflux. We found a statistically significantly lower number of reflux episodes per hour in the upright position during dosing with cisapride compared to placebo and ABT-229 10 mg. However, this effect was not significant in the supine and in the total 24 h periods, and cisapride did not affect the mean time of exposure of the oesophagus to acid reflux. Previous studies on the effects of an oral dose of cisapride on oesophageal pH in adult GERD patients have yielded conflicting results.31–35 Two studies found that cisapride caused a reduction in oesophageal acid exposure.31, 32 In contrast, three other studies, in which a larger number of GERD patients were investigated, showed that cisapride had no effect on acid reflux.33–35
Motilin is a gastrointestinal hormone that is predominantly produced in the mucosa of the duodenum and jejunum and has a prokinetic effect on the upper gastric tract.19, 36–38 Motilin also affects basal lower oesophageal sphincter pressure and studies have shown that intravenous exogenous motilin stimulates lower oesophageal sphincter pressure in healthy subjects.39 More recently, some studies were performed on the effect of erythromycin on gastro-oesophageal reflux and oesophageal and lower oesophageal motility. Intravenously administered erythromycin increased lower oesophageal sphincter pressure in healthy subjects and patients with GERD and systemic sclerosis.15–17, 40 Furthermore, it decreased oesophageal reflux.13, 14 Oral erythromycin, however, had no effect on gastro-oesophageal reflux.20, 21 Intravenously administered ABT-229 has been shown to increase lower oesophageal sphincter pressure in cats dose-dependently, without affecting swallow-induced lower oesophageal sphincter relaxations or oesophageal peristalsis.26 Because ABT-229 has a much stronger prokinetic effect than erythromycin24, 25 and is devoid of antibacterial activity, it was worth testing in the treatment of GERD.
GERD is associated with increased reflux caused by transient lower oesophageal sphincter relaxations and low lower oesophageal sphincter pressure, and impaired oesophageal clearance.1–3 Therefore, 24 h manometric recordings were performed to investigate whether ABT-229 or cisapride influences oesophageal or lower oesophageal sphincter motility. Neither dose of ABT-229 affected oesophageal contraction amplitude, duration or peristaltic success. In addition, we observed no effect of ABT-229 on basal lower oesophageal sphincter pressure or on the number of transient lower oesophageal sphincter relaxations.
An intravenously administered bolus of cisapride increases lower oesophageal sphincter pressure in healthy volunteers, and in adults and children with GERD.41–46 However, repeated oral doses of cisapride appear to increase lower oesophageal sphincter pressure to a minimal extent only.34, 35, 41, 47, 48 In our study no significant effect of cisapride on basal lower oesophageal sphincter pressure was observed. It should be taken into consideration, however, that we opted in this study for an incomplete crossover design in which half of the patients were treated with cisapride. As a result, the statistical analysis concerning cisapride had a lower power.
Cisapride treatment did not affect the incidence of transient lower oesophageal sphincter relaxations. This finding is in agreement with the results of a study by Holloway et al. which also showed a lack of effect of cisapride on postprandial reflux induced by transient lower oesophageal sphincter relaxations, and therefore suggests that the number of transient lower oesophageal sphincter relaxations was also unaffected by cisapride.35
We observed that ABT-229 10 mg b.d. reduced daytime heartburn in patients with symptomatic GERD. In contrast, ABT-229 10 mg b.d. did not affect night-time heartburn, or daytime or night-time regurgitation. ABT-229 5 mg b.d. did not affect GERD symptoms. During cisapride treatment our patients experienced a similar symptom reduction as during ABT-229 10 mg b.d. This is in contrast to large placebo-controlled studies by Castell et al. and Richter et al. in which, in 398 and 177 GERD patients, respectively, a significant reduction in night-time heartburn and total regurgitation was also observed during 4 weeks of treatment with cisapride (dosed as 20 mg b.d. and 10 and 20 mg q.d.s.).5, 6 The difference may be explained by differences in numbers of patients studied. Our study was not statistically powered to reveal differences between drugs and placebo with regard to symptom improvement. Moreover, in our study the mean severity of night-time heartburn at entry was low and barely half that of daytime heartburn. In contrast to our study, night-time heartburn was one of the inclusion factors in both US studies.
In the present study a recently developed 24 h portable water-perfused manometric system and automated computer analysis were used. Until now, for practical reasons, most studies on the incidence of transient lower oesophageal sphincter relaxations have been carried out in recumbent patients and over a relatively short period. However, both lower oesophageal sphincter pressure and the incidence of transient lower oesophageal sphincter relaxations show marked diurnal variations.27, 49 The development of micromanometric catheters with smaller perfusion lumina that require low perfusion rates enabled us to develop a portable water-perfused manometric system,28, 29 facilitating prolonged manometric recording in ambulant patients.29, 50 With these micromanometric catheters and a low perfusion rate (0.08 mL/min), adequate manometric characteristics of the oesophagus can be achieved.51
Detailed manual calculation of lower oesophageal sphincter pressure is a time-consuming process. Therefore, most investigators estimate lower oesophageal sphincter pressure using relatively small parts of the tracing (i.e. each 15th minute). In contrast, by using an automated computer analysis we were able to calculate basal end-expiratory lower oesophageal sphincter pressure over the total recorded 24 h for each sample. The results of our validation studies illustrate that it is feasible to measure lower oesophageal sphincter pressure and transient lower oesophageal sphincter relaxations accurately with an ambulant water-perfused manometric system and by using computer analysis.
In summary, we have shown in this study that a 7 day treatment with oral ABT-229 (5 mg and 10 mg b.d.) has no effect on oesophageal reflux, oesophageal motility, lower oesophageal sphincter pressure or transient lower oesophageal sphincter relaxations in patients with GERD. The only positive effect of ABT-229 10 mg b.d. was a reduction in the severity of daytime heartburn. It must be concluded that the value of the motilin agonist ABT-229 in the treatment of GERD appears to be limited.
This study was supported by a grant from Abbott Laboratories, Abbott Park, Illinois, USA.
The authors would like to thank N. Neumann for her skilful assistance and P. Wozniak, D. Morris and E. Bedwell for expert statistical analysis and study conduct supervision.