The effect of motilin agonist ABT-229 on gastro-oesophageal reflux, oesophageal motility and lower oesophageal sphincter characteristics in GERD patients

BACKGROUND: 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. AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: The value of ABT-229 in the treatment of GERD appears to be limited.     

The effect of cholecystokinin antagonism on postprandial lower oesophageal sphincter function in asymptomatic volunteers and patients with reflux disease

BACKGROUND: Postprandial acid reflux is thought to be mediated by the increase in transient lower oesophageal sphincter relaxations (TLOSR) frequency and fall in lower oesophageal sphincter (LOS) pressure seen after ingestion of a meal. Studies in animals and healthy volunteers suggest that cholecystokinin (CCK) may play a role. AIM: To study the role of CCK in postprandial LOS function using the CCK antagonist loxiglumide. SUBJECTS: 10 asymptomatic volunteers (7 male, 20-29 years) and 9 patients with symptomatic gastro-oesophageal reflux (4 male, 33-66 years). METHODS: Oesophageal, LOS and gastric pressure and oesophageal pH readings were recorded for 1 h before and 2 h after intragastric infusion of a 200 kCal, 300 mL long chain triglyceride meal. Each subject underwent two studies and received intravenous loxiglumide or placebo infusion in randomized order. RESULTS: During placebo infusion, postprandial LOS pressure fell [volunteers: 17 (9-31) to 7 (1-19) mmHg (P < 0.01), patients: 15 (6-26) to 9 (2-21) mmHg (P=0.02)] and TLOSR frequency increased [volunteers: 0 (0-1) to 2 (0-7) per hour (P=0.01), patients: 0 (0-3) to 2 (0-10) per hour (P=0.03)]. Loxiglumide infusion attenuated the postprandial fall in LOS pressure and the postprandial increase in TLOSR frequency [volunteers: 0 (0-3) per hour (P=0.04 vs. placebo), patients: 0 (0-2) per hour (P=0.03 vs. placebo)], but it had only modest effects on postprandial acid exposure [volunteers: placebo 45 (0-1725) vs. loxiglumide 0 (0-443) seconds (N.S.), patients: placebo 60 (0-3442) seconds vs. loxiglumide 31 (0-1472) seconds (N.S.)]. CONCLUSIONS: Loxiglumide inhibits TLOSR and attenuates the fall in LOS pressure following a meal, but has only modest effects on postprandial gastro-oesophageal acid reflux.     

Systematic review: ageing and gastro-oesophageal reflux disease symptoms, oesophageal function and reflux oesophagitis

Background Gastro‐oesophageal reflux disease (GERD) is thought to become more prevalent with age. Aim To assess systematically how age affects the prevalence of GERD and its oesophageal complications. Methods Systematic PubMed searches were used to identify population‐based studies on the age‐related prevalence and incidence of GERD, and clinical studies on age‐related changes in oesophageal complications in GERD. Results Nine population‐based studies and seven clinical studies met the inclusion criteria. Four of seven prevalence studies observed no significant effect of age on GERD symptom prevalence, two did not report on statistical significance and one observed a significant age‐related increase in symptom prevalence. The two population‐based endoscopic surveys showed no significant effect of age on reflux oesophagitis prevalence. Clinical studies in patients with GERD showed an increase in reflux oesophagitis severity and a decrease in heartburn severity with age, and age‐related increases in oesophageal acid exposure and anatomical disruption of the gastro‐oesophageal junction. Conclusions Epidemiological studies do not show an increase in GERD symptom prevalence with age. However, in individuals with GERD, ageing is associated with more severe patterns of acid reflux and reflux oesophagitis; despite this, symptoms associated with GERD become less severe and more nonspecific with ageing. Thus, the real prevalence of GERD may well increase with age.     

Review article: the clinical relevance of transient lower oesophageal sphincter relaxations in gastro-oesophageal reflux disease

Aliment Pharmacol Ther 2011; 33: 650–661

Summary

Background Transient lower oesophageal sphincter relaxations (TLOSR) are considered the physiological mechanism that enables venting of gas from the stomach and appear as sphincter relaxations that are not induced by swallowing. It has become increasingly clear that most reflux episodes occur during TLOSRs and therefore play a key role in gastro‐oesophageal reflux disease (GERD). Aim To describe the current knowledge about TLOSRs and its clinical implications. Methods Search of the literature published in English using the PubMed database and relevant abstracts presented at international conventions. Results Several factors influence the rate of TLOSRs including anti‐reflux surgery, meal, body position, nutrition, lifestyle and a wide array of neurotransmitters. Ongoing insights in the neurotransmitters responsible for the modulation of TLOSRs, as well as the neural pathways involved in TLOSR induction, have lead to novel therapeutic targets. These therapeutic targets can serve as an add‐on therapy in patients with an unsatisfactory response to proton pump inhibitor by inhibiting TLOSRs and its associated reflux events. However, the TLOSR‐inhibiting drugs that are currently available still have significant side effects. Conclusion It is likely that in the future, selected GERD patients may benefit from transient lower oesophageal sphincter relaxation inhibition when compounds are found without significant side effects.     

Lack of effect of spearmint on lower oesophageal sphincter function and acid reflux in healthy volunteers

BACKGROUND: Spearmint is commonly used as an antispasmodic and as a flavouring in several medications including antacids. It can produce heartburn, presumably by lowering lower oesophageal sphincter (LES) tone, but the mechanism has not previously been objectively examined. AIM: To study the effect of spearmint on LES function, acid reflux and symptoms. METHODS: In healthy volunteers, a Dent Sleeve and a pH electrode were placed in the distal oesophagus. They were then given spearmint either in a flavouring (0.5 mg), or a high (500 mg) dose, or a placebo, using a double-blind randomized crossover design. LES pressure, oesophageal pH and symptoms were recorded for 30 min before and after administration. RESULTS: LES pressure was not affected by spearmint, either high dose (19.6 vs. 16.0 mmHg), flavouring dose (20.2 vs. 19.8 mmHg) or placebo (20.5 vs. 19.2 mmHg, all N.S.). There were no differences in reflux occurrence following high dose (mean = 0.65 vs. 0.85 episodes), low dose (0.4 vs. 0.5 episodes) or placebo (0.7 vs. 1.10 episodes, all N.S.). There was a significant increase in mean symptom scores following high-dose spearmint (0 vs. 0.35, P = 0.03), but not low dose (0 vs. 0.2) or placebo (0 vs. 0.5, both N.S.). One subject reported symptoms with placebo, one with low dose, and six with high dose; all without increased reflux episodes or decreased sphincter pressure. CONCLUSION: Spearmint has no effect on LES pressure or acid reflux. Flavouring doses of spearmint do not produce more symptoms than placebo while high doses can be associated with symptoms, presumably from direct mucosal irritation but not reflux.     

Effect of cisapride on nocturnal transient lower oesophageal sphincter relaxations and nocturnal gastro-oesophageal reflux in patients with oesophagitis: a double-blind, placebo-controlled study

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.     

Effect of non-selective gamma-aminobutyric acid receptor stimulation on motor function of the lower oesophageal sphincter and gastro-oesophageal reflux in healthy human subjects

BACKGROUND: Transient lower oesophageal sphincter relaxation and low lower oesophageal sphincter pressure are the main mechanisms of reflux. It has recently been shown that the stimulation of gamma-aminobutyric acid type B (GABAB) receptors by baclofen decreases the rate of transient lower oesophageal sphincter relaxation and increases the lower oesophageal sphincter pressure in healthy humans. Valproic acid increases synaptosomal GABA concentrations, thus affecting all types of GABA receptors. AIM: To evaluate the effect of valproic acid on transient lower oesophageal sphincter relaxation, lower oesophageal sphincter pressure and gastro-oesophageal reflux. METHODS: Thirteen healthy subjects underwent 2-h post-prandial oesophageal motility and pH monitoring on two separate occasions after the oral administration of 1 g valproic acid or placebo. RESULTS: Valproic acid increased the lower oesophageal sphincter pressure by 41% (14.0 +/- 2.1 mmHg vs. 9.9 +/- 2.0 mmHg after placebo, P<0.02), but did not affect the rate of transient lower oesophageal sphincter relaxation (7.9 +/- 1.0/h vs. 8.2 +/- 0.9/h after placebo), the number of reflux episodes or gastro-oesophageal reflux. CONCLUSIONS: Non-selective GABA receptor stimulation may be beneficial to reflux patients with low lower oesophageal sphincter pressure, but exerts a different modulation of transient lower oesophageal sphincter relaxation than the selective stimulation of GABAB receptors.     

Effect of caloric density of a meal on lower oesophageal sphincter motility and gastro-oesophageal reflux in healthy subjects

BACKGROUND: Patients with gastro-oesophageal reflux disease are advised to avoid the ingestion of large meals. In healthy volunteers, a relationship between the amount of postprandial gastro-oesophageal reflux and the volume of a liquid meal has been demonstrated. AIM: To evaluate whether the amount of postprandial gastro-oesophageal reflux is also related to the calorie content of a meal, a second parameter that will be reduced by avoidance of the ingestion of large meals. METHODS: Twelve healthy volunteers (six female, 19-31 years) received two solid-liquid meals with either 842 kcal (solid 582 kcal, liquid 260 kcal) or 582 kcal (31% reduction) in a randomized order. The nutritional components (10% fat, 76% carbohydrates, 14% protein) and the volume of the meals were identical in both meals. The lower oesophageal sphincter pressure was measured continuously in the first postprandial hour with a Dent sleeve, and pH-metry was performed for 3 h postprandially with a glass electrode in the distal oesophagus. Blinded to the type of ingested meal, we calculated the mean lower oesophageal sphincter pressure, the frequency of transient lower oesophageal sphincter relaxations, the number of reflux episodes, and the fraction of time for which pH < 4. RESULTS: A similar decrease in lower oesophageal sphincter pressure was observed after ingestion of the high calorie meal (median 10.9 mmHg, range 4.8-16.7 mmHg) and low calorie meal (median 9.9 mmHg, range 3.9-18.4 mmHg). No difference in the number of transient lower oesophageal sphincter relaxations (high calorie: median 9 per hour, range 5-13 per hour; low calorie: median 7 per hour, range 0-14 per hour) and of reflux episodes (high calorie: median 12 in 3 h, range 3-22 in 3 h; low calorie: median 12 in 3 h, range 3-30 in 3 h) was registered after intake of both types of meal. Additionally, no difference was identified regarding the fraction of time for which pH < 4 between the high calorie (mean 2.3%, 0.2-23.7%) and low calorie meal (3.3%, 0.5-17.8%). CONCLUSION: Reducing the caloric density of a meal neither influences postprandial lower oesophageal sphincter pressure nor decreases gastro-oesophageal reflux in healthy volunteers. Thus, the amount of gastro-oesophageal reflux induced by ingestion of a meal seems to depend on the volume but not on the caloric density of a meal.     

A double-blind placebo-controlled trial of BRL 24924 on lower oesophageal sphincter pressure and gastro-oesophageal reflux in healthy volunteers

BRL 24924 is a new gastrointestinal prokinetic agent with properties similar to metoclopramide but with increased potency and devoid of side-effects associated with blockade of dopamine receptors in the central nervous system. A double-blind placebo-controlled trial of the effect of a single oral dose of 2.2 mg BRL 24924 on lower oesophageal sphincter pressure and gastro-oesophageal reflux has been performed in 20 healthy volunteers. BRL 24924 significantly increased mean lower oesophageal sphincter pressure (21.9 cmH2O BRL; 15.9 cmH2O placebo: P less than 0.017) but failed to alter either the frequency or the duration of gastro-oesophageal reflux after provocation following a test meal. BRL 24924 has significant effects on lower oesophageal sphincter pressure but no effect on provoked post-prandial reflux in healthy volunteers. Further studies in patients with gastro-oesophageal reflux and oesophagitis are needed to evaluate the clinical efficacy of this compound.     

The effect of sildenafil on segmental oesophageal motility and gastro-oesophageal reflux

BACKGROUND: Sildenafil is an inhibitor of type 5 phosphodiesterase. It relaxes or inhibits contraction of smooth muscle by increasing cellular concentrations of cyclic guanosine monophosphate. Multichannel intraluminal impedance manometry/pH allow the precise evaluation of oesophageal bolus transit and acid/non-acid reflux. AIM: To investigate the effect of sildenafil on segmental oesophageal motor function and gastro-oesophageal reflux. METHODS: Eight healthy volunteers underwent multichannel intraluminal impedance manometry baseline, and 15, 30 and 45 min before and after a 50-mg dose of sildenafil successively. The subjects underwent 2-h multichannel intraluminal impedance/pH studies on two separate days after either water or sildenafil ingestion. RESULTS: Sildenafil decreased the resting lower oesophageal sphincter pressure and prolonged the duration of lower oesophageal sphincter relaxation for the 45 min following its ingestion. At 15 min, distal onset velocity, total bolus transit time, bolus presence time and segmental transit time were delayed in the mid to distal oesophagus. At 30 min, distal onset velocity was restored but bolus presence time and bolus presence time were still delayed in distal smooth muscle segment. At 45 min, total bolus transit time and distal onset velocity were restored but bolus presence time and segmental transit time were delayed more in the transition zone. Sildenafil did not alter the reflux. CONCLUSION: Sildenafil alters lower oesophageal sphincter function and oesophageal bolus transit, but not induce gastro-oesophageal reflux.     

The effect of mosapride, a novel prokinetic, on acid reflux variables in patients with gastro-oesophageal reflux disease

Background:

Mosapride is a novel prokinetic agent facilitating acetylcholine release from the enteric cholinergic neurones through a selective 5-HT₄ receptor agonistic action. It is also active through its main metabolite M1, which is a 5-HT₃ antagonist. The importance of motor dysfunction in the pathogenesis of gastro-oesophageal reflux disease (GERD) makes it interesting to examine the effect of mosapride on oesophageal acid exposure.

Methods:

The effect of mosapride on oesophageal 24-h acid reflux variables was studied in 21 patients with GERD symptoms and a pre-entry total acid exposure time (pH < 4) of more than 5%. Ambulatory pH monitoring was performed after treatment with 40 mg mosapride citrate or placebo q.d.s. for 2 days in random order, using a double-blind crossover technique, with a washout period of at least 5 days.

Results:

Mosapride was significantly more effective than placebo in decreasing the total number of reflux episodes, the total number of reflux episodes lasting more than 5 min and the total time, as well as the amount of day time, of intra-oesophageal pH below 4. Consequently, mosapride also significantly improved total acid clearance time.

Conclusion:

Mosapride 40 mg q.d.s. is effective in decreasing acid reflux in the oesophagus in patients with GERD and therefore has the potential to be effective in the treatment of this disease.

     

The effects of itopride on oesophageal motility and lower oesophageal sphincter function in man

Aliment Pharmacol Ther 2011; 33: 99–105

Summary

Background Itopride is a new prokinetic agent that combines antidopaminergic and cholinesterase inhibitory actions. Previous studies suggested that itopride improves heartburn in functional dyspepsia, and decreases oesophageal acid exposure in gastro‐oesophageal reflux disease. It remains unclear whether this effect is due to effects of itopride on the lower oesophageal sphincter (LES). Aims To study the effects of itopride on fasting and postprandial LES function in healthy subjects. Methods Twelve healthy volunteers (five men; 32.6 ± 2.0 years) underwent three oesophageal sleeve manometry studies after 3 days premedication with itopride 50 mg, itopride 100 mg or placebo t.d.s. Drug was administered after 30 min and a standardized meal was administered after 90 min, with measurements continuing to 120 min postprandially. Throughout the study, 10 wet swallows were administered at 30‐min intervals, and gastrointestinal symptoms were scored on 100 mm visual analogue scales at 15‐min intervals. Results Lower oesophageal sphincter resting pressures, swallow‐induced relaxations and the amplitude or duration of peristaltic contractions were not altered by both doses of itopride, at all time points. Itopride pre‐treatment inhibited the meal‐induced rise of transient LES relaxations (TLESRs). Conclusions Itopride inhibits TLESRs without significantly affecting oesophageal peristaltic function or LES pressure. These observations support further studies with itopride in gastro‐oesophageal reflux disease.     

Heartburn severity can predict pathologic oesophageal reflux in gastro-oesophageal reflux disease patients treated with a proton-pump inhibitor

BACKGROUND: In gastro-oesophageal reflux disease (GERD) subjects treated with a gastric anti-secretory agent, it is not known whether there is a relationship between heartburn severity and oesophageal acid exposure. METHODS: Oesophageal pH and heartburn severity were determined in 27 GERD subjects at baseline and on days 1, 2 and 8 of treatment with 20 mg omeprazole or 20 mg rabeprazole in a randomized, two-way crossover fashion. RESULTS: Receiver operating characteristic (ROC) analysis was used to determine values for heartburn severity that gave optimal cut-off points for distinguishing between normal and pathologic oesophageal reflux. Using these cut-off points, we found that the probability of no pathologic oesophageal reflux (Y) could be best fitted by an exponential equation: Y = a(e-bX) + c, where a, b and c are constants and X is the value of heartburn severity. There was close agreement between predicted and observed percentages of subjects with pathologic oesophageal reflux during different days of treatment. CONCLUSIONS: In GERD subjects treated with a proton-pump inhibitor, the value of heartburn severity following a single standard meal can predict the likelihood of pathologic oesophageal reflux over the entire 24-h period.     

Effect of hiatal hernia on proximal oesophageal acid clearance in gastro-oesophageal reflux disease patients

Summary

Background

Proximal acid reflux is common in gastro‐oesophageal reflux disease and is a determinant of symptoms. Patients with hiatal hernia complain of more symptoms than those without and are less responsive to proton‐pump inhibitors.

Aim

To evaluate the role of hiatal hernia on spatiotemporal characteristics of acid reflux.

Methods

Thirty seven consecutive gastro‐oesophageal reflux disease patients underwent endoscopy, videofluoroscopy, manometry and multichannel 24‐h pH test. Data were compared with those of 15 asymptomatic controls. Multivariate linear regression was used for statistical analysis.

Results

At videofluoroscopy, hiatal hernia was found in 16 of 37 patients. The mean size of hiatal hernia was 3.4 cm. Patients showed significantly prolonged acid clearance time, both at proximal and distal oesophagus, compared with controls. Hiatal hernia patients showed a significantly delayed acid clearance, along the oesophageal body, compared with non‐hiatal hernia patients. The prolonged acid exposure was maintained during upright and supine position. The presence of hiatal hernia significantly predicted acid clearance delay in the distal and proximal oesophagus [at 10 cm below upper oesophageal sphincter: Δ + 2.5 min (95% confidence interval: 0.4–4.5); P < 0.02].

Conclusions

The presence of hiatal hernia is a strong predictor of more prolonged proximal oesophageal acid exposure and clearance. Hiatal hernia is likely to play a role in the pathophysiology of gastro‐oesophageal reflux disease symptoms, and should be taken into greater consideration in the treatment strategies of the disease.

     

Effects of ABT-229, a motilin agonist,on acid reflux,oesophageal motility and gastric emptying in patients with gastro-oesophageal reflux disease

AIM: The effect of ABT-229, a new macrolide with no antibacterial activity, on gastro-oesophageal reflux, oesophageal motility and gastric emptying in patients with gastro-oesophageal reflux disease was investigated. METHODS: Twenty-one patients were treated with a placebo and ABT-229 (2.5, 5 or 10 mg b.d.) in a randomized, incomplete crossover study design. Ambulatory 24-h pH manometry was performed and gastric emptying was assessed by the 13C-octanoic acid breath test on the seventh day of treatment. RESULTS: A significant decrease was found in the mean (+/- s.e.) percentage of reflux time (intra-oesophageal pH < 4) for ABT-229 5 mg b.d. and 10 mg b.d., but not for 2.5 mg b.d., compared with placebo. For ABT-229 5 mg, it was 8.5 +/- 0.5% vs. 10.7 +/- 0.7% (P < 0.038) and, for ABT-229 10 mg, it was 6.6 +/- 0.5% vs. 8.4 +/- 0.5% (P < 0.019). There were no significant differences in any of the analysed manometric parameters. In addition, the gastric half-emptying time for all doses of ABT-229 did not differ significantly from that after placebo. CONCLUSIONS: ABT-229 is able to reduce slightly, but significantly, acid reflux in patients with gastro-oesophageal reflux disease. This effect does not appear to be due to a measurable improvement in oesophageal motility or gastric emptying.