Intragastric infusion of denatonium benzoate attenuates interdigestive gastric motility and hunger scores in healthy female volunteers

Background: Denatonium benzoate (DB) has been shown to influence ongoing ingestive behavior and gut peptide secretion.Objective: We studied how the intragastric administration of DB affects interdigestive motility, motilin and ghrelin plasma concentrations, hunger and satiety ratings, and food intake in healthy volunteers.Design: Lingual bitter taste sensitivity was tested with the use of 6 concentrations of DB in 65 subjects. A placebo or 1 μmol DB/kg was given intragastrically to assess its effect on fasting gastrointestinal motility and hunger ratings, motilin and ghrelin plasma concentrations, satiety, and caloric intake.Results: Women (n = 39) were more sensitive toward a lingual bitter stimulus (P = 0.005) than men (n = 26). In women (n = 10), intragastric DB switched the origin of phase III contractions from the stomach to the duodenum (P = 0.001) and decreased hunger ratings (P = 0.04). These effects were not observed in men (n = 10). In women (n = 12), motilin (P = 0.04) plasma concentrations decreased after intragastric DB administration, whereas total and octanoylated ghrelin were not affected. The intragastric administration of DB decreased hunger (P = 0.008) and increased satiety ratings (P = 0.01) after a meal (500 kcal) in 13 women without affecting gastric emptying in 6 women. Caloric intake tended to decrease after DB administration compared with the placebo (mean ± SEM: 720 ± 58 compared with 796 ± 45 kcal; P = 0.08) in 20 women.Conclusions: Intragastric DB administration decreases both antral motility and hunger ratings during the fasting state, possibly because of a decrease in motilin release. Moreover, DB decreases hunger and increases satiety ratings after a meal and shows potential for decreasing caloric intak

Pharmacological and nutritional interventions to adapt gastrointestinal functions and improve functional gastrointestinal symptoms

Functional dyspepsia (FD) and irritable bowel syndrome (IBS) are two common functional gastrointestinal disorders (FGIDs). Both conditions have a considerable impact on quality of life and presumably result from a heterogeneous and multifactorial pathophysiology with several factors suggested to be involved. To date, no reliable biomarker to accurately diagnose these FGIDs has been identified. Consequently, the diagnosis of FD and IBS is primarily based on symptom features, reflected in the Rome criteria. Due to the heterogeneity of both disorders in terms of pathophysiology and symptoms, correctly diagnosing the disorders and finding efficient treatment options to successfully improve symptoms has been proven challenging. Furthermore, the currently available therapies remain suboptimal, resulting in increased health care utilization, increasing health care costs, for both the patient and the society. The medical need for efficient and cost-efficient therapies for FD and IBS is high. As a result, the interest in non-pharmacological treatment options for FD and IBS has increased over the last decades. This doctoral thesis aims to investigate the effects of several therapeutic options (pharmacological and non-pharmacological) used to treat FD and IBS on the function of the GI tract and on gastrointestinal symptoms. Compounds investigated in relation to FD are (1) acotiamide, a first-in-class compound developed to treat FD, (2) the combination of peppermint oil and caraway oil and (3) rikkunshito, a Japanese Kampo herbal medicine to treat upper GI complaints. For IBS, the low-FODMAP diet is a frequently used treatment option to alleviate symptoms. Therefore, the effects of FODMAPs on upper GI motility and brain activation are studied in this PhD project.status: publishe

Functional Constipation: Individualising Assessment and Treatment

Chronic constipation is one of the five most common symptoms seen by gastroenterologist. In the absence of alarm symptoms, a confident symptom-based diagnosis can often be made using the Rome criteria. Three different subtypes have been identified to date: normal transit constipation, defaecatory disorders and slow transit constipation. Differentiation between these subtypes can be made through functional testing using tests such as anorectal manometry with balloon expulsion and a radio-opaque marker test. In general, patients are initially advised to increase their fluid and fibre intake. When these general lifestyle recommendations do not improve patients' symptoms, a step-wise and add-on treatment approach should be applied. This review summarises the diagnostic criteria to differentiate functional constipation from other causes of chronic constipation. In addition, current drug treatment options, including discussion of new therapeutic targets are discussed. Further, practical treatment approaches (choice and dosing), include discussion of combination/augmentation, treatment failure (adherence/expectations), and relapse prevention are mentioned. Finally, treatment and management of pain and bloating aspects are included.status: publishe

Review article: treatment options for functional dyspepsia

BACKGROUND: Functional dyspepsia, consisting of epigastric pain syndrome and postprandial distress syndrome, is a prevalent functional gastrointestinal disorder. To date, only limited treatment options are available and conflicting results in terms of efficacy have been reported. Consequently, nonpharmacological treatment options are increasingly being explored for functional dyspepsia. AIM: To provide an overview of current pharmacological and nonpharmacological treatment options for functional dyspepsia. METHODS: A literature search was conducted on Pubmed and other sources to identify relevant studies. RESULTS: Acid suppressive therapy reduced symptoms in 30%-70% of the patients, with higher benefit in epigastric pain syndrome and superior effectiveness for proton pump inhibitors compared to H2 -antagonists. Prokinetic agents, primarily used to treat postprandial distress syndrome, showed variable efficiency: 59%-81% responder rate for dopamine receptor antagonists, 32%-91% for serotonin-4-receptor agonists and 31%-80% for muscarinic receptor antagonists. H Pylori eradication, recommended in infected patients, was effective in 24%-82%. Refractory symptoms are addressed with neuromodulators. However, their efficacy in functional dyspepsia remains incompletely elucidated, available data showing symptom reduction in 27%-71% of the patients. Regarding herbal agents, peppermint oil reduced symptoms in 66%-91%, rikkunshito in 29%-34% and iberogast in 20%-95%. Lastly, acupuncture, cognitive behavioural therapy and hypnotherapy may help to provide symptom control, but research on their efficacy remains sparse. CONCLUSIONS: None of the available therapies is effective in the majority of patients without being associated with major side effects. Developing new treatment options is challenging due to the heterogeneity of functional dyspepsia, the lack of readily identified target mechanisms and the poor association between pathophysiological disturbances and symptoms.status: publishe

Acotiamide affects antral motility, but has no effect on fundic motility, gastric emptying or symptom perception in healthy participants

BACKGROUND: Acotiamide, a prokinetic agent was shown to be efficacious in the treatment of functional dyspepsia (FD). The exact mechanism of action is incompletely elucidated. METHODS: This randomized, placebo-controlled, cross-over study aimed to examine the effect of acotiamide on gastric motility, measured as intragastric pressure, gastric emptying (GE) rate and gastrointestinal (GI) symptom perception in healthy volunteers (HVs). Participants were treated with acotiamide (100 mg tid) and placebo for 3 weeks, separated by a 1-week washout period. A daily symptom diary was collected during both treatments. At the end of each treatment period, GE rate and gastric motility were assessed with a 13 C-octanoic acid breath test and high-resolution manometry during nutrient infusion, respectively. GI symptom levels were scored during high-resolution manometry. Data were analyzed using mixed models. The study was registered as NCT03402984. KEY RESULTS: Twenty HVs (10 female, 25 ± 4.1 years, 22.58 ± 2.73 kg/m2 ) participated in the study. There was no difference in GE half time between both treatments (P = 0.92). Acotiamide had no effect on fundic pressures before and after nutrient infusion (P = 0.91). However, postprandial antral pressures remained significantly lower compared to placebo (P = 0.015). There was no significant difference in hunger, satiation and GI symptoms scores assessed during IGP measurement and by the daily diary (P > 0.12 for all). CONCLUSION: Acotiamide is associated with lower antral pressures after nutrient intake, whereas it has no effect on fundic pressures, GE rate and symptom perceptions in HVs. Studies in FD need to elucidate whether lower antral pressures induced by acotiamide underlie postprandial symptom improvement in FD.status: publishe

The effect of rikkunshito on gastrointestinal symptoms and gastric motor function: The first study in a Belgian functional dyspepsia population

BACKGROUND: Rikkunshito, a traditional Kampo medicine, has shown efficacy to treat functional dyspepsia (FD) in controlled trials in Japan. Its putative benefit for European patients and mechanism of action has not been established. METHODS: This study examined the effect of rikkunshito on gastric motility and GI symptom perception in FD-PDS patients in a randomized, placebo-controlled, cross-over study. After a 2-week run-in period, patients received rikkunshito or matching placebo (2.5 g t.i.d.) for 4 weeks, separated by a 4-week washout period. Symptoms were assessed by the Leuven Postprandial Distress Scale (LPDS) diary throughout the study. At baseline and after both treatment arms, intragastric pressure (IGP) was measured to evaluate gastric accommodation and gastric motility. Simultaneously, GI symptoms were scored on a 100 mm visual analogue scale. Validated symptom questionnaires (PAGI-SYM, VSI, DSS, and PHQ) were completed each study visit. KEY RESULTS: Twenty-three patients completed the study (33 ± 14 years, 22.7 ± 3.22 kg/m2 ). Intragastric pressure was numerically, but not significantly, lower after rikkunshito compared with baseline and placebo (P = .14). No differences were found in gastric accommodation, nutrient volume tolerance, and symptoms assessed during IGP measurements. Early satiation and postprandial fullness (daily diary) decreased after rikkunshito compared with baseline (P < .041 for both). Placebo also improved most other symptoms assessed. No significant changes in VSI scores occurred. No adverse reactions occurred. CONCLUSIONS: Rikkunshito did not alter gastric motility. Treatment with rikkunshito improved upper GI symptoms in FD patients but similarly high placebo effects were observed using the LPDS diary, PAGI-SYM, SF-NDI, and DSS scores. Rikkunshito was safe and well-tolerated.status: publishe

Exploring the Impact of Real-Life Dosing Conditions on Intraluminal and Systemic Concentrations of Atazanavir in Parallel With Gastric Motility Recording in Healthy Subjects

This work strived to explore gastrointestinal (GI) dissolution, supersaturation and precipitation of the weakly basic drug atazanavir in humans under different ‘real-life’ intake conditions. The impact of GI pH and motility on these processes was thoroughly explored. In a cross-over study, atazanavir (Reyataz®) was orally administered to 5 healthy subjects with (i) a glass of water, (ii) a glass of Coca-Cola® and (iii) a glass of water under hypochlorhydric conditions (induced by concomitant intake of a proton-pump inhibitor (PPI)). After intake, GI fluids were aspirated from the stomach and the duodenum and, subsequently, analyzed for atazanavir. In parallel, blood samples were collected to assess systemic concentrations. In general, the results of this study revealed that the acidic gastric pH in combination with gastric residence time played a crucial role in the dissolution of atazanavir along the GI tract. After intake of atazanavir with a glass of water (i.e., reference condition), complete gastric dissolution was observed. After GI transfer, supersaturation was noticed for a limited amount of time (1.25 h). With respect to the Coca-Cola® condition, complete gastric dissolution was also observed. A delay in gastric emptying, highly likely caused by the caloric content (101 kcal), was responsible for delayed arrival of atazanavir into the upper small intestine, creating a longer time window of supersaturated concentrations in the duodenal segment (3.25 h) compared to the water condition. The longer period of supersaturated concentrations resulted in a slightly higher systemic exposure of atazanavir compared to the condition when atazanavir was taken with a glass of water. A remarkable observation was the creation (when the drug was given in the migrating motor complex (MMC) phase 2) or maintenance (when the drug was given in MMC phase 1) of a quiescent phase for up to 80 min. With respect to the PPI condition, negligible gastric and intestinal concentrations were observed, resulting in minimal systemic exposure for all subjects. It can be concluded that gastric pH and residence time play a pivotal role in the intestinal disposition of atazanavir in order to generate sufficiently high concentrations further down in the intestinal tract for a sufficient period of time, thus creating a beneficial driving force for intestinal absorption.status: Published onlin

The influence of gastric motility on the intraluminal behavior of fosamprenavir

In fasting conditions, the gastrointestinal system contracts according to the interdigestive migrating motor complex (MMC), in which phases of quiescence (MMC phase I) alternate with phases of medium (MMC phase II) to very strong (MMC phase III) contractions. The time of drug intake relative to this cyclic motility pattern may cause variations in formulation behavior. To explore this hypothesis, a cross-over study was performed in healthy volunteers with an immediate release tablet of fosamprenavir (Telzir) which was administered in either MMC phase I or MMC phase II, as determined by high-resolution manometry. In the intestinal tract, fosamprenavir is rapidly hydrolyzed to the active compound amprenavir by alkaline phosphatases. Drug concentrations of both prodrug and drug were determined in the stomach and duodenum and linked to simultaneously assessed systemic concentrations. In 5 out of 6 healthy volunteers, the gastric release of fosamprenavir and the systemic uptake of amprenavir were affected by the MMC phase in which the tablet was administered. The intragastric disintegration of the tablet was faster and less variable after administration in MMC phase II, resulting in faster and less variable uptake of amprenavir in the systemic circulation. Mean plasma tmax values were 157 (±72.0) and 73.3 (±27.3) min after administration in MMC phase I and MMC phase II, respectively. The study clearly identified the time of oral drug intake relative to the interdigestive motility pattern as a possible source of variation in gastrointestinal drug behavior and absorption.status: publishe

Editorial: effects of vildagliptin on GLP-1 levels, gastric motor functions and food intake - authors' reply

Editorial - an autor's replystatus: publishe