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.     

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.     

The effects of tegaserod on oesophageal function and bolus transport in healthy volunteers: studies using concurrent high-resolution manometry and videofluoroscopy

BACKGROUND: Tegaserod is a partial 5-hydroxytryptamine 4 receptor agonist with prokinetic effects on the gastrointestinal tract, its effects on oesophageal function are unknown. AIM: A randomized, placebo controlled, double-blind trial assessed the effect of tegaserod on the oesophagus in healthy, asymptomatic subjects. METHOD: A 7-day course of tegaserod 6 mg b.d. vs. placebo was prescribed (n = 17/21 completed both phases of study). High-resolution manometry and pH measurements were performed before and after a test meal. Bolus transport of liquids and solids was studied by high-resolution manometry and videofluoroscopy. RESULTS: Tegaserod had no effect on lower oesophageal sphincter pressure compared with placebo, peristaltic velocity increased (P < 0.001) and distal contractile pressure decreased slightly (P < 0.05). Transient lower oesophageal sphincter relaxations and reflux were infrequent regardless of treatment. During the studies of bolus transport, high-resolution manometry revealed that tegaserod promoted mid-oesophageal contractility (P < 0.02) and shortened the 'proximal transition zone' (P < 0.05), the level where bolus escape occurred most frequently. These effects had no effect on liquid bolus transport; however a non-significant trend to improved solid bolus transport was observed (66% vs. 31%;P = 0.07). CONCLUSION: Tegaserod did not alter lower oesophageal sphincter pressure, but had significant effects on peristaltic function. High-resolution manometry promoted mid-oesophageal contractility during bolus transport. This effect was associated with a non-significant trend to improved solid bolus transit.     

The effect of baclofen on gastro-oesophageal reflux,lower oesophageal sphincter function and reflux symptoms in patients with reflux disease

BACKGROUND: Baclofen decreases gastro-oesophageal reflux episodes in healthy subjects by reducing the incidence of transient lower oesophageal sphincter relaxations. AIM: To investigate the effect of baclofen on reflux symptoms, oesophageal pH and lower oesophageal sphincter manometry in patients with gastro-oesophageal reflux disease. METHODS: A double-blind, placebo-controlled, two-way crossover design was used to study the effect of baclofen on heartburn and regurgitation 3 h after a provocation test meal in 37 patients with gastro-oesophageal reflux disease. Additionally, in 20 of these patients, the effect of baclofen on oesophageal pH, transient lower oesophageal sphincter relaxations and basal lower oesophageal sphincter pressure was studied. RESULTS: Baclofen significantly decreased the acid reflux time and the incidence of gastro-oesophageal reflux episodes (8.3 +/- 8.8% vs. 12.4 +/- 12.0%, P = 0.03 and 10.9 +/- 7.3 per 3 h vs. 18.7 +/- 12.4 per 3 h). The incidence of transient lower oesophageal sphincter relaxations was significantly lower with baclofen than with placebo (15.1 +/- 6.4 per 3 h vs. 22.8 +/- 5.4 per 3 h, P < 0.0001). Lower oesophageal sphincter pressure and the percentage of transient lower oesophageal sphincter relaxations associated with reflux were not affected by baclofen. No significant effect on symptom scores was observed. CONCLUSIONS: Baclofen decreases post-prandial acid reflux in patients with gastro-oesophageal reflux disease by reducing the incidence of transient lower oesophageal sphincter relaxations. No effect of a single dose of baclofen on reflux symptoms could be demonstrated in this 3-h post-prandial study.     

Effects of a 5-HT(4) receptor agonist on oesophageal function and gastro-oesophageal reflux: studies using combined impedance-manometry and combined impedance-pH

BACKGROUND: 5-HT(4) receptor agonists are used as promotility agents of the stomach, small and large intestine. There is limited information on the influence of 5-HT(4) receptor agonists on oesophageal function and gastro-oesophageal reflux. AIM: To evaluate the effects of tegaserod, a 5-HT(4) agonist on oesophageal function using impedance-manometry and postprandial reflux using impedance-pH monitoring. METHODS: Twenty healthy volunteers were enrolled in a double-blind randomized three-period crossover placebo-controlled study. Impedance-manometry and impedance-pH monitoring after a refluxogenic meal were performed at baseline and after 2 days of dosing with tegaserod 6 mg b.d. or placebo. Multichannel intraluminal impedance-EM recorded pressure and bolus transit data during standardized swallows. Multichannel intraluminal impedance-pH monitoring recorded the number of 2-h postprandial acid and non-acid reflux episodes. RESULTS: We found no significant difference in distal oesophageal amplitude when subjects received placebo (median 94.5; range: 53-243 mmHg) or tegaserod (93.6; 43-216 mmHg). Bolus transit time was similar during dosing with placebo (7.1; 5.3-9.4 s) and tegaserod (7.2; 5.9-11.1 s). We observed similar numbers of acid and non-acid reflux episodes during dosing with placebo (5; 0-15 and 3; 0-18, respectively) and tegaserod (2; 0-11 and 4; 0-19, respectively). CONCLUSION: Tegaserod, a 5-HT(4) receptor agonist does not change oesophageal motility and gastro-oesophageal reflux parameters in healthy volunteers.     

SR 48692, a specific neurotensin receptor antagonist, has no effect on oesophageal motility in humans

BACKGROUND: The administration of exogenous neurotensin can reduce the lower oesophageal sphincter pressure, but it is unclear whether this effect is pharmacological or physiological. AIM: A specific neurotensin receptor antagonist (SR 48692) was used to assess the effect of endogenous neurotensin on lower oesophageal sphincter function. METHODS: Twenty-four healthy male subjects were included in a double-blind, placebo-controlled, randomized, cross-over study designed to determine the effects of two single doses (90 and 300 mg, preceded by a loading dose) of SR 48692 on the resting lower oesophageal sphincter pressure, transient lower oesophageal sphincter relaxations, primary oesophageal peristalsis and oesophageal acid exposure. Oesophageal pH and motility recordings were performed during 1 h of fasting and 3 h post-prandially. Plasma neurotensin-like immunoreactivity release was determined by radioimmunoassay. RESULTS: During fasting, the lower oesophageal sphincter pressure, transient lower oesophageal sphincter relaxation rate and reflux episodes were similar with the two doses of SR 48692 and placebo. Meal ingestion induced a rise in plasma neurotensin-like immunoreactivity, a decrease in lower oesophageal sphincter pressure and an increase in both the transient lower oesophageal sphincter relaxation rate and the number of reflux episodes, which were not significantly modified by SR 48692. SR 48692 did not affect oesophageal primary peristalsis. CONCLUSION: This study shows that SR 48692, a specific neurotensin 1 receptor antagonist, has no effect on oesophageal motility in humans.     

Pharmacoeconomic issues of the treatment of gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) is one of the most common diagnoses in a gastroenterologist’s practice. Gastroesophageal reflux (GER) describes the retrograde movement of gastric contents through the lower oesophageal sphincter (LES) to the oesophagus. GER can occur physiologically and may be accompanied by symptoms. The introduction of endoscopes and ambulatory devices for continuous monitoring of oesophageal pH (24 h pH monitoring) has led to great improvement in the ability to diagnose reflux disease and reflux-associated complications. The development of pathological reflux and GERD can be attributed to many factors. Pathophysiology of GERD includes transient lower oesophageal sphincter relaxations (TLESRs), incompetent LES because of a decreased lower oesophageal sphincter pressure (LESP) and deficient or delayed oesophageal acid clearance. Uncomplicated GERD may be treated by modification of lifestyle and eating habits in an early stage of GERD. The various agents currently used for treatment of GERD include mucoprotective substances, antacids, H₂-blockers, prokinetics and proton pump inhibitors (PPIs). Although these drugs are effective, they do not necessarily influence the underlying causes of the disease by improving the oesophageal clearance, increasing the LESP or reducing the frequency of TLESRs. The following article gives an overview regarding current concepts of the pathophysiology and pharmacological treatment of GERD stressing on pharmacoeconomic issues of the treatment and discusses the advantages and disadvantages for step-up and step-down therapy.     

Pharmacoeconomic issues of the treatment of gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) is one of the most common diagnoses in a gastroenterologist's practice. Gastroesophageal reflux (GER) describes the retrograde movement of gastric contents through the lower oesophageal sphincter (LES) to the oesophagus. GER can occur physiologically and may be accompanied by symptoms. The introduction of endoscopes and ambulatory devices for continuous monitoring of oesophageal pH (24 h pH monitoring) has led to great improvement in the ability to diagnose reflux disease and reflux-associated complications. The development of pathological reflux and GERD can be attributed to many factors. Pathophysiology of GERD includes transient lower oesophageal sphincter relaxations (TLESRs), incompetent LES because of a decreased lower oesophageal sphincter pressure (LESP) and deficient or delayed oesophageal acid clearance. Uncomplicated GERD may be treated by modification of lifestyle and eating habits in an early stage of GERD. The various agents currently used for treatment of GERD include mucoprotective substances, antacids, H2-blockers, prokinetics and proton pump inhibitors (PPIs). Although these drugs are effective, they do not necessarily influence the underlying causes of the disease by improving the oesophageal clearance, increasing the LESP or reducing the frequency of TLESRs. The following article gives an overview regarding current concepts of the pathophysiology and pharmacological treatment of GERD stressing on pharmacoeconomic issues of the treatment and discusses the advantages and disadvantages for step-up and step-down therapy.     

Transient lower oesophageal sphincter relaxations—a pharmacological target for gastro‐oesophageal reflux disease?

The oesophago-gastric junction functions as an anti-reflux barrier preventing increased exposure of the oesophageal mucosa to gastric contents. Failure of this anti-reflux barrier results in gastro-oesophageal reflux disease, and may lead to complications such as oesophagitis, Barrett's oesophagus and eventually oesophageal carcinoma. Recent studies have suggested that transient lower oesophageal sphincter relaxation is the main mechanism underlying gastro-oesophageal reflux. It involves a prolonged relaxation of the lower oesophageal sphincter, mediated by a vago-vagal neural pathway, synapsing in the brainstem. Several drugs, such as atropine, baclofen and loxiglumide, have been shown to reduce the rate of transient lower oesophageal sphincter relaxations and concomitantly the number of reflux episodes. These findings illustrate that transient lower oesophageal sphincter relaxations may represent a potential new target for the pharmacological treatment of gastro-oesophageal reflux disease. It is possible that the reduction in the number of transient lower oesophageal sphincter relaxations may also contribute to the beneficial effect of fundoplication and new endoscopic anti-reflux procedures. It should be emphasized, however, that other factors, such as low lower oesophageal sphincter pressure, the presence of a hiatal hernia and impaired oesophageal peristalsis, are also of great importance. Therefore, whether the targeting of transient lower oesophageal sphincter relaxations is the 'golden bullet' in anti-reflux therapy remains to be proven, as evidence of an effective control of gastro-oesophageal reflux in reflux patients is still lacking.     

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.     

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.     

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.     

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.     

Effects of repeated administration of baclofen on transient lower esophageal sphincter relaxation in the dog

The metabotropic gamma-aminobutyric acid (GABA) receptor (GABA(B) receptor) agonist baclofen inhibits transient lower esophageal sphincter relaxation in dogs, ferrets, and humans. Since transient lower esophageal sphincter relaxations are the major cause of gastroesophageal reflux, GABA(B) receptor agonists may have a therapeutic value in the treatment of gastroesophageal reflux disease. However, repeated stimulation of the GABA(B) receptor may induce receptor desensitization which, depending on the magnitude, would limit the therapeutic effect. The aim of the present study was to follow the effects of baclofen on transient lower esophageal sphincter relaxation in the dog after repeated administration. The effect of 7 micromol/kg baclofen b.i.d. (given intragastrically) on transient lower esophageal sphincter relaxation and related parameters was determined in four dogs. Transient lower esophageal sphincter relaxations stimulated by infusion of liquid nutrient and insufflation of air were quantified after placebo and then after the 1st, 13th, and 27th dose. Baclofen reduced the number of transient lower esophageal sphincter relaxations without affecting their duration, and the latency to the first transient lower esophageal sphincter relaxation was prolonged. Basal sphincter pressure was unaffected by baclofen, and the number of reflux episodes and esophageal acid exposure decreased. There was a statistically insignificant numerical decrease (approximately 30%) in the effect of baclofen on transient lower esophageal sphincter relaxation after the seventh dose but this was not further accentuated after the 27th dose. The effect on latency was also reduced with repeated dosing, but again, the effects after the 1st, 13th, and 27th doses were not statistically significant. The attenuation of acid exposure and reflux episodes was unaltered after repeated dosing. Three of the dogs greatly reduced their food intake within the first 2-3 days but this side effect was resolved subsequently. It is concluded that repeated dosing of baclofen leads to mild tolerance development in terms of the effects on transient lower esophageal sphincter relaxation, but that the tolerance is much less pronounced than that previously reported in other animal models.     

Tegaserod coadministration does not alter the pharmacokinetics of theophylline in healthy subjects

Tegaserod (HTF 919), a selective 5-HT4 receptor partial agonist, is in development for the treatment of functional gastrointestinal motility disorders. Tegaserod has been found to inhibit cytochrome P-450 (CYP) 1A2, for which theophylline is a prototype substrate. This study was designed to assess the effect of tegaserod on the single-dose pharmacokinetic and safety profile of theophylline. Eighteen subjects were enrolled in a randomized, open-label, two-period crossover study. After an overnight fast, subjects were randomized to receive one of two treatments: (1) a single dose of controlled-release formulation of theophylline (Theo-Dur, 600 mg) on day 1 or (2) a single dose of tegaserod (6 mg) on day 1, concomitant administration of tegaserod (6 mg) and theophylline (600 mg) on the morning of day 2, followed by an additional dose of tegaserod (6 mg) 12 hours later. Four to 10 days later, the subjects received the alternative treatment regimen. The pharmacokinetic parameters of theophylline, including AUC, Cmax, and t(1/2lambda z), were similar for both treatment regimens, although the tmax of theophylline was statistically different between the treatments. Except for a decrease in partial metabolic formation clearance from theophylline to 1-methyluric acid, which is unlikely to be clinically relevant, there were no statistically significant differences in renal clearance of theophylline and partial metabolic formation clearances following the combined treatment compared with theophylline alone. The results of the current study indicate that no dose adjustment is required when drugs metabolized via CYP1A2 are coadministered with tegaserod.     

Review article: the pathophysiology of gastro-oesophageal reflux disease

BACKGROUND: Gastro-oesophageal reflux disease (GERD) is a common condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. AIM: To review the current knowledge on the underlying factors contributing to GERD, with particular emphasis on the most recent research. METHODS: Literature searches were conducted in Medline and EMBASE. The abstracts from recent large congresses were also reviewed to ensure coverage of the latest findings. RESULTS: The pathophysiological factors causing GERD can be split into those inducing greater exposure of the oesophagus to stomach contents, and those that provide increased perception of reflux or increased mucosal damage. Transient lower oesophageal sphincter relaxations, which are likely to be triggered by gastric distension, appear to be a key physiological cause of GERD. Excessive reflux may also be provoked by impaired oesophageal or gastric clearance mechanisms. Pre-epithelial, epithelial and post-epithelial defences all normally protect the oesophagus from injury, and may be compromised in individuals with GERD. Heartburn could also be caused by oesophageal hypersensitivity as a result of visceral neural pathway dysfunction. CONCLUSION: The pathophysiology of GERD is multifactorial, and abnormalities in the gastro-oesophageal junction, the stomach, the oesophagus and the nervous system may all contribute to this disease state.     

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.     

Effect of lesogaberan,a novel GABAB‐receptor agonist,on transient lower oesophageal sphincter relaxations in male subjects

Aliment Pharmacol Ther 31 , 1208–1217

Summary

Background Transient lower oesophageal sphincter relaxations (TLESRs) are a major mechanism behind gastro‐oesophageal reflux disease (GERD). Aim To assess the effect of lesogaberan (AZD3355) – a novel peripherally active GABA_B receptor agonist – on TLESRs. Methods Twenty‐four healthy men were enrolled in this single‐blind, placebo‐controlled, randomized, single‐centre, three‐period crossover phase 1 study. Subjects were randomized to receive single oral doses of lesogaberan (0.8 mg/kg), baclofen (40 mg) and placebo, separated by washout periods of ≤7 days. Subjects finished a meal 1 h after the dose. Oesophageal manometry and pH‐metry measurements were taken during the 3 h after the meal. Results Twenty‐one subjects completed the study. Compared with placebo, lesogaberan 0.8 mg/kg significantly reduced the number of TLESRs by 36% [geometric mean ratio (GMR): 0.64; 95% confidence interval (CI): 0.51–0.82] and significantly reduced the number of acid reflux episodes (mean reduction: 1.6; 95% CI: 0.34–2.9). Lesogaberan also significantly increased lower oesophageal sphincter (LES) pressure by 39% compared with placebo (GMR: 1.39; 95% CI: 1.18–1.64). Comparable results were observed with baclofen. Similar numbers of adverse events were reported by subjects taking lesogaberan and placebo. Conclusion Compared with placebo, lesogaberan significantly reduced TLESRs and acid reflux episodes and increased LES pressure.     

Cisapride in the treatment of gastro-oesophageal reflux disease

Prokinetic agents are being used increasingly in medical therapy for gastro-oesophageal reflux disease (GERD). This study examined the effect of 10 mg q.d.s., oral cisapride, or placebo, taken for 12 weeks, on 48 patients with symptoms and endoscopic evidence of GERD. Objective evaluation of benefit was obtained by endoscopy and biopsy, oesophageal manometry, acid reflux provocation test and 24-h oesophageal pH monitoring. Cisapride significantly increased lower oesophageal sphincter pressure (P= 0.003) against baseline and also against placebo, in patients (n= 9) with an hypotensive lower oesophageal sphincter pressure (P < 0.01). The frequency of dyspeptic symptoms was significantly improved in the cisapride group (P= 0.03). Antacid intake, global evaluation of symptoms and a VAS score for symptoms were all better than placebo but failed to reach significance (global evaluation by patients, P= 0.07). Overall, there was no significant improvement in oesophagitis at either 6 weeks (P < 0.05 > 0.3) or 12 weeks (P= 0.07). However, if patients with grades I and II oesophagitis at entry were excluded, cisapride had a significantly greater effect than placebo, 6 weeks (P= 0.05), 12 weeks (P= 0.04). In those with oesophageal ulceration, cisapride was significantly more effective than placebo in inducing healing. Gastro-oesophageal reflux was very variable on both 24-h pH monitoring and acid reflux provocation test. In spite of a 50% decrease in acid exposure on 24-h pH monitoring (cisapride group, mean % pH < 4 day: entry 18.9%, 12 weeks 9.6%), there were no significant intra- or intergroup differences for percentage of time < pH 4, or frequency and duration of episodes, neither pre- or post-prandially, day or night, except for the number of post-prandial episodes during acid reflux provocation tests, which decreased significantly more with cisapride than with placebo (P < 0.05). Thus, oral cisapride when taken for 12 weeks promoted healing of oesophagitis and improved symptoms in patients with GERD; although an increase in lower oesophageal sphincter pressure was observed and a reduction in acid reflux was measured, no significant decrease of acid exposure was seen.     

Baclofen decreases acid and non-acid post-prandial gastro-oesophageal reflux measured by combined multichannel intraluminal impedance and pH

BACKGROUND: Omeprazole controls acid but not non-acid reflux. The GABA B agonist baclofen decreases acid reflux through the inhibition of transient lower oesophageal sphincter relaxations (TLESRs) and should similarly decrease non-acid reflux. Using combined multichannel intraluminal impedance and pH (MII/pH), we compared acid and non-acid reflux after placebo and baclofen. METHODS: Nine healthy volunteers and nine heartburn patients underwent two 2-h studies of combined MII/pH in right lateral decubitus after a refluxogenic meal in random order: on placebo and after baclofen 40 mg p.o. Tracings were analysed for acid and non-acid reflux episodes, re-reflux and symptoms in the heartburn patients. RESULTS: In normal subjects baclofen significantly reduced the median number of episodes of acid (7 vs. 1, P = 0.02), non-acid (2 vs. 0, P = 0.005), and all reflux combined (10 vs. 2, P = 0.006); re-reflux was not reduced (0 vs. 0, P = N.S.). In heartburn patients, baclofen significantly decreased the median number of episodes of acid (15 vs. 6, P = 0.004), non-acid (4 vs. 2, P = 0.003), re-reflux (2 vs. 0, P = 0.02), and all reflux combined (23 vs. 8, P = 0.004); it also reduced the median number of acid-related (9 vs. 1, P = 0.008) and non-acid-related (1 vs. 0, P = 0.04) symptoms. CONCLUSIONS: Baclofen reduces post-prandial acid and non-acid reflux and their associated symptoms. GABA B agonists may have a role in treating GERD.