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The endocrine effects of bitter tastant administration in the gastrointestinal system: intragastric versus intraduodenal administration.
Verbeure, W, Deloose, E, Tóth, J, Rehfeld, JF, Van Oudenhove, L, Depoortere, I, Tack, J
American journal of physiology. Endocrinology and metabolism. 2021;(1):E1-E10
Abstract
Bitter tastants are recently introduced as potential hunger-suppressive compounds, the so-called "Bitter pill." However, the literature about bitter administration lacks consistency in methods and findings. We want to test whether hunger ratings and hormone plasma levels are affected by: 1) the site of administration: intragastrically (IG) or intraduodenally (ID), 2) the bitter tastant itself, quinine hydrochloride (QHCl) or denatonium benzoate (DB), and 3) the timing of infusion. Therefore, 14 healthy, female volunteers participated in a randomized, placebo-controlled six-visit crossover study. After an overnight fast, DB (1 µmol/kg), QHCl (10 µmol/kg), or placebo were given IG or ID via a nasogastric feeding tube. Blood samples were taken 10 min before administration and every 10 min after administration for a period of 2 h. Hunger was rated at the same time points on a visual analogue scale. ID bitter administration did not affect hunger sensations, motilin, or acyl-ghrelin release compared with its placebo infusion. IG QHCl infusion tended to suppress hunger increase, especially between 50 and 70 min after infusion, simultaneously with reduced motilin values. Here, acyl-ghrelin was not affected. IG DB did not affect hunger or motilin, however acyl-ghrelin levels were reduced 50-70 minutes after infusion. Plasma values of glucagon-like peptide 1 and cholecystokinin were too low to be properly detected or to have any physiological relevance. In conclusion, bitter tastants should be infused into the stomach to reduce hunger sensations and orexigenic gut peptides. QHCl has the best potential to reduce hunger sensations, and it should be infused 60 min before food intake.NEW & NOTEWORTHY Bitter tastants are a potential new weight-loss treatment. This is a noninvasive, easy approach, which should be received with considerable enthusiasm by the public. However, literature about bitter administration lacks consistency in methods and findings. We summarize how the compound should be given based on: the site of administration, the best bitter compound to use, and at what timing in respect to the meal. This paper is therefore a fundamental step to continue research toward the further development of the "bitter pill."
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Gastric emptying of "clear liquid drinks" assessed with gastric ultrasonography: a blinded, randomized pilot study.
Pai, SL, Bojaxhi, E, Logvinov, II, Porter, S, Feinglass, NG, Robards, CB, Torp, KD
Minerva anestesiologica. 2020;(2):165-171
Abstract
BACKGROUND Protein-containing liquids may delay gastric emptying and increase risk of aspiration. Commercial whey protein nutritional drinks (WPNDs) are advertised as "clear liquid nutritional drinks" and can be mistaken for protein-free, carbohydrate-based clear liquids. We used gastric ultrasonography to compare gastric emptying of a protein-free, carbohydrate-based clear liquid with that of a WPND in healthy volunteers. METHODS We recruited 19 adult (age ≥18 years) volunteers with a body mass index less than 40 kg/m2 and without a history of diabetes mellitus, dysphagia, prior gastric surgery, or allergy to the ingredients of apple juice (AJ) or a WPND. After fasting for eight hours, the volunteers randomly received 474 mL of AJ or a WPND. Gastric ultrasonographic measurements were obtained at baseline and at 0, 30, 60, and 120 minutes after ingestion of the liquid. RESULTS We enrolled 19 volunteers. At 120 minutes after consumption, volunteers who ingested a WPND had a larger estimated gastric volume (GV) than volunteers who ingested AJ (median [interquartile range], 101.3 [70.0-137.4] vs. 50.6 [43.9-81.8] mL; P=.08). By using the 2-sample t test and an α level of .05, we determined that the study had 40% power to detect a significant difference in GV. Future studies need to include 24 participants per group to detect a significant difference. CONCLUSIONS Although consumption of a WPND was associated with a larger estimated GV in this pilot study, a larger study is necessary to conclude whether patients must fast longer than two hours after consumption of a WPND.
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Application of the GastroDuo to study the interplay of drug release and gastric emptying in case of immediate release Aspirin formulations.
Schick, P, Sager, M, Voelker, M, Weitschies, W, Koziolek, M
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V. 2020;:9-17
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Abstract
The process of gastric emptying is of major importance for the in vivo performance of immediate release dosage forms. In the fed state, this process consists of two phases: the rapid emptying of water along the "Magenstrasse" and the continuous emptying of the chyme. The relevance of these phases for the pharmacokinetic (PK) profile of a drug depends on the release behavior from its dosage form. It was the aim of this study to investigate the role of gastric emptying for the pharmacokinetics of a fast disintegrating and dissolving Aspirin® tablet (FDDT). For this purpose, a three way pharmacokinetic study with 30 healthy volunteers was performed to investigate the performance of the FDDT under fasted and fed conditions and compare it to a regular Aspirin® tablet (RT) administered in the fed state. Plasma samples were taken at predetermined time points and analyzed by LC MS/MS. In the second part of this work, both products were tested in a biorelevant dissolution test device - the GastroDuo. To simulate the occurrence of the Magenstrasse at different time points, two test programs have been applied. The results of the PK study clearly demonstrated the superiority of the FDDT over the RT. We observed an earlier tmax (0.39 h vs. 2.00 h) and a higher Cmax (6.33 ± 2.37 μg/mL vs. 3.23 ± 1.28 μg/mL), whereas the AUC was only slightly different between both formulations. The administration of the FDDT together with food had no marked effect on tmax (0.34 h vs. 0.39 h), but caused a decrease in Cmax compared to fasted intake (14.76 ± 4.81 μg/mL vs. 6.33 ± 2.37 μg/mL). This effect could be explained by the in vitro data collected with the GastroDuo. The FDDT showed a faster drug release and improved emptying kinetics in the GastroDuo. In contrast, the RT showed incomplete emptying in both test programs. Thus, the early tmax observed for the FDDT under fed conditions could be related to the presence of the Magenstrasse. In contrast, drug release from the RT was insufficient to allow gastric emptying via the Magenstrasse, which resulted in later tmax. This study highlighted the importance of gastric emptying for immediate release dosage forms and illustrated that the application of suitable formulation techniques provides a strategy to generate a fast and reliable onset of drug plasma concentrations even in the fed state.
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Acute Effects of Lixisenatide on Energy Intake in Healthy Subjects and Patients with Type 2 Diabetes: Relationship to Gastric Emptying and Intragastric Distribution.
Jalleh, R, Pham, H, Marathe, CS, Wu, T, Buttfield, MD, Hatzinikolas, S, Malbert, CH, Rigda, RS, Lange, K, Trahair, LG, et al
Nutrients. 2020;(7)
Abstract
Glucagon-like peptide-1 receptor agonists induce weight loss, which has been suggested to relate to the slowing of gastric emptying (GE). In health, energy intake (EI) is more strongly related to the content of the distal, than the total, stomach. We evaluated the effects of lixisenatide on GE, intragastric distribution, and subsequent EI in 15 healthy participants and 15 patients with type 2 diabetes (T2D). Participants ingested a 75-g glucose drink on two separate occasions, 30 min after lixisenatide (10 mcg) or placebo subcutaneously, in a randomised, double-blind, crossover design. GE and intragastric distribution were measured for 180 min followed by a buffet-style meal, where EI was quantified. Relationships of EI with total, proximal, and distal stomach content were assessed. In both groups, lixisenatide slowed GE markedly, with increased retention in both the proximal (p < 0.001) and distal (p < 0.001) stomach and decreased EI (p < 0.001). EI was not related to the content of the total or proximal stomach but inversely related to the distal stomach at 180 min in health on placebo (r = -0.58, p = 0.03) but not in T2D nor after lixisenatide in either group. In healthy and T2D participants, the reduction in EI by lixisenatide is unrelated to changes in GE/intragastric distribution, consistent with a centrally mediated effect.
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The influence of gastric motility on the intraluminal behavior of fosamprenavir.
Braeckmans, M, Brouwers, J, Masuy, I, Servais, C, Tack, J, Augustijns, P
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2020;:105117
Abstract
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.
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Transcutaneous electrical acustimulation synchronized with inspiration improves gastric accommodation impaired by cold stress in healthy subjects.
Ma, G, Hu, P, Zhang, B, Xu, F, Yin, J, Yang, X, Lin, L, Chen, JDZ
Neurogastroenterology and motility. 2019;(2):e13491
Abstract
BACKGROUND The aim of this study was to investigate whether transcutaneous electrical acustimulation (TEA) synchronized with inspiration (STEA), a method known to enhance vagal activity, was more effective than TEA in improving cold stress-induced impairment in gastric accommodation (GA) and dyspeptic symptoms in healthy subjects. METHODS Each of fifteen healthy subjects was studied in five randomized sessions: control (warm nutrient liquid), cold nutrient liquid (CNL), CNL+sham-TEA, CNL+TEA, and CNL+STEA. The subjects were requested to drink Ensure until reaching maximum satiety. STEA was performed using the same parameters as TEA but asking the subjects to breathe in when they sensed each stimulation train. The electrogastrogram (EGG) and electrocardiogram (ECG) were recorded to assess gastric slow waves (GSW) and autonomic functions, respectively. KEY RESULTS GA was reduced with the CNL in comparison with the warm drink but increased with TEA and STEA; STEA was more potent than TEA in improving GA; STEA was more potent in improving GSW than TEA; STEA significantly increased vagal activity and decreased sympathetic activity compared with TEA. CONCLUSIONS AND INFERENCES TEA synchronized with inspiration is more potent than TEA in improving cold stress-induced impairment in GA and GSW and dyspeptic symptoms and might be a novel noninvasive therapy for treating stress-induced dysmotility and dyspeptic symptoms.
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Gastric administration of garlic powder containing the trpa1- agonist allicin induces specific epigastric symptoms and gastric relaxation in healthy subjects.
Führer, M, Dejaco, C, Kopp, B, Hammer, J
Neurogastroenterology and motility. 2019;(1):e13470
Abstract
BACKGROUND TRPA1 is an excitatory ion channel and is involved in sensory processes including thermal nociception and inflammatory pain. The allicin in garlic is a strong activator of the TRPA1 channel. AIM: To evaluate the effect of intragastric garlic powder containing allicin on perception, gastric tone, and mechanosensitivity. METHODS An infusion-barostat balloon assembly was used for infusion of test solutions, for distension, and to measure proximal gastric compliance and tone. After an initial open label dose finding with 1 g, 2 g, 3.75 g, and 7.5 g commercially available garlic powder, a bolus of 2 g garlic powder (11 mg allicin)/60 mL H2 O was considered to induce moderate but constant sensation and was used hereafter in a placebo-controlled, single-dose, double-blind, randomized study in 7 volunteers to evaluate gastric sensation, tone, and mechanosensitivity. KEY RESULTS Bolus injection of garlic caused immediate epigastric symptoms, mean aggregate symptom scores (AUC in 15 minutes) were 106 ± 49 vs. 35 ± 30 after placebo (P = 0.01). Garlic induced significant epigastric pressure, stinging, and warmth (P < 0.01 vs. placebo), while intensity of cramps, satiety, nausea, and pain was not significantly different to placebo (P > 0.05). Garlic induced an immediate, short lived fundic relaxation (balloon volume 627 ± 349 mL vs. -145 ± 120 mL; P < 0.02). No effect of allicin on proximal gastric mechanosensitivity and compliance was observed (NS). CONCLUSION AND INFERENCES Garlic containing allicin induces immediate epigastric symptoms of pressure, stinging, and warmth and induces fundic relaxation but does not influence mechanosensitivity or compliance. TRPA1 is a receptor that is involved in gastric sensation and motility.
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Roux-en-Y or Billroth II Reconstruction After Radical Distal Gastrectomy for Gastric Cancer: A Multicenter Randomized Controlled Trial.
So, JB, Rao, J, Wong, AS, Chan, YH, Pang, NQ, Tay, AYL, Yung, MY, Su, Z, Phua, JNS, Shabbir, A, et al
Annals of surgery. 2018;(2):236-242
Abstract
OBJECTIVE The aim of the study was to compare the clinical symptoms between Billroth II (B-II) and Roux-en-Y (R-Y) reconstruction after distal subtotal gastrectomy (DG) for gastric cancer. BACKGROUND Surgery is the mainstay of curative treatment for gastric cancer. The technique for reconstruction after DG remains controversial. Both B-II and R-Y are popular methods. METHODS This is a prospective multicenter randomized controlled trial. From October 2008 to October 2014, 162 patients who underwent DG were randomly allocated to B-II (n = 81) and R-Y (n = 81) groups. The primary endpoint is Gastrointestinal (GI) Symptoms Score 1 year after surgery. We also compared the nutritional status, extent of gastritis on endoscopy, and quality of life after surgery between the 2 procedures at 1 year. RESULTS Operative time was significantly shorter for B-II than for R-Y [mean difference 21.5 minutes, 95% confidence interval (95% CI) 3.8-39.3, P = 0.019]. The B-II and R-Y groups had a peri-operative morbidity of 28.4% and 33.8%, respectively (P = 0.500) and a 30-day mortality of 2.5% and 1.2%, respectively (P = 0.500). GI symptoms score did not differ between R-Y versus B-II reconstruction (mean difference -0.45, 95% CI -1.21 to 0.31, P = 0.232). R-Y resulted in a lower median endoscopic grade for gastritis versus B-II (mean difference -1.32, 95% CI -1.67 to -0.98, P < 0.001). We noted no difference in nutritional status (R-Y versus B-II mean difference -0.31, 95% CI -3.27 to 2.65, P = 0.837) and quality of life at 1 year between the 2 groups too. CONCLUSION Although BII is associated with a higher incidence of heartburn symptom and higher median endoscopic grade for gastritis, BII and RY are similar in terms of overall GI symptom score and nutritional status at 1 year after distal gastrectomy.
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Linking the Gastrointestinal Behavior of Ibuprofen with the Systemic Exposure between and within Humans-Part 2: Fed State.
Paixão, P, Bermejo, M, Hens, B, Tsume, Y, Dickens, J, Shedden, K, Salehi, N, Koenigsknecht, MJ, Baker, JR, Hasler, WL, et al
Molecular pharmaceutics. 2018;(12):5468-5478
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Abstract
Exploring the intraluminal behavior of an oral drug product in the human gastrointestinal (GI) tract remains challenging. Many in vivo techniques are available to investigate the impact of GI physiology on oral drug behavior in fasting state conditions. However, little is known about the intraluminal behavior of a drug in postprandial conditions. In a previous report, we described the mean solution and total concentrations of ibuprofen after oral administration of an immediate-release (IR) tablet in fed state conditions. In parallel, blood samples were taken to assess systemic concentrations. The purpose of this work was to statistically evaluate the impact of GI physiology (e.g., pH, contractile events) within and between individuals (intra and intersubject variability) for a total of 17 healthy subjects. In addition, a pharmacokinetic (PK) analysis was performed by noncompartmental analysis, and PK parameters were correlated with underlying physiological factors (pH, time to phase III contractions postdose) and study parameters (e.g., ingested amount of calories, coadministered water). Moreover, individual plasma profiles were deconvoluted to assess the fraction absorbed as a function of time, demonstrating the link between intraluminal and systemic behavior of the drug. The results demonstrated that the in vivo dissolution of ibuprofen depends on the present gastric pH and motility events at the time of administration. Both intraluminal factors were responsible for explaining 63% of plasma Cmax variability among all individuals. For the first time, an in-depth analysis was performed on a large data set derived from an aspiration/motility study, quantifying the impact of physiology on systemic behavior of an orally administered drug product in fed state conditions. The data obtained from this study will help us to develop an in vitro biorelevant dissolution approach and optimize in silico tools in order to predict the in vivo performance of orally administered drug products, especially in fed state conditions.
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Gastric Residual Volumes Versus Abdominal Girth Measurement in Assessment of Feed Tolerance in Preterm Neonates: A Randomized Controlled Trial.
Thomas, S, Nesargi, S, Roshan, P, Raju, R, Mathew, S, P, S, Rao, S
Advances in neonatal care : official journal of the National Association of Neonatal Nurses. 2018;(4):E13-E19
Abstract
BACKGROUND Preterm neonates often have feed intolerance that needs to be differentiated from necrotizing enterocolitis. Gastric residual volumes (GRV) are used to assess feed tolerance but with little scientific basis. PURPOSE To compare prefeed aspiration for GRV and prefeed measurement of abdominal girth (AG) in the time taken to reach full feeds in preterm infants. METHODS This was a randomized controlled trial. Infants with a gestational age of 27 to 37 weeks and birth weight of 750 to 2000 g, who required gavage feeds for at least 48 hours, were included. Infants were randomized into 2 groups: infants in the AG group had only prefeed AG measured. Those in the GRV group had prefeed gastric aspiration obtained for the assessment of GRV. The primary outcome was time to reach full enteral feeds at 150 mL/kg/d, tolerated for at least 24 hours. Secondary outcomes were duration of hospital stay, need for parenteral nutrition, episodes of feed intolerance, number of feeds withheld, and sepsis. RESULTS Infants in the AG group reached full feeds earlier than infants in the GRV group (6 vs 9.5 days; P = .04). No significant differences were found between the 2 groups with regard to secondary outcomes. IMPLICATIONS FOR PRACTICE Our research suggests that measurement of AG without assessment of GRV enables preterm neonates to reach full feeds faster than checking for GRV. IMPLICATIONS FOR RESEARCH Abdominal girth measurement as a marker for feed tolerance needs to be studied in infants less than 750 g and less than 26 weeks of gestation.