The endocrine effects of bitter tastant administration in the gastrointestinal system - Intragastric versus intraduodenal administration

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 (1µmol/kg), QHCl (10µmol/kg) or placebo were given IG or ID via a nasogastric feeding tube. Blood samples were taken 10 min prior to administration and every 10 min after administration for a period of 2 hours. Hunger was rated at the same timepoints on a visual analogue scale (VAS). ID bitter administration did not affect hunger sensations, motilin or acyl-ghrelin release compared with its PLC infusion. IG QHCl infusion tended to suppress hunger increase, especially between 50-70 minutes 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 minutes before food intake.

Dose-Dependent Pharmacokinetics of Tofacitinib in Rats: Influence of Hepatic and Intestinal First-Pass Metabolism

This study investigated the pharmacokinetics of tofacitinib in rats and the effects of first-pass metabolism on tofacitinib pharmacokinetics. Intravenous administration of 5, 10, 20, and 50 mg/kg tofacitinib showed that the dose-normalized area under the plasma concentration-time curve from time zero to infinity (AUC) was significantly higher at 50 mg/kg than at lower doses, a difference possibly due to saturation of the hepatic metabolism of tofacitinib. Oral administration of 10, 20, 50, and 100 mg/kg tofacitinib showed that the dose-normalized AUC was significantly higher at 100 mg/kg than at lower doses, a difference possibly due to saturation of the intestinal metabolism of tofacitinib. Following oral administration of 10 mg/kg tofacitinib, the unabsorbed fraction from the rat intestine was 3.16% and the bioavailability (F) was 29.1%. The AUC was significantly lower (49.3%) after intraduodenal, compared to intraportal, administration, but did not differ between intragastric and intraduodenal administration, suggesting that approximately 46.1% of orally administered tofacitinib was metabolized through an intestinal first-pass effect. The AUC was also significantly lower (42%) after intraportal, compared to intravenous, administration, suggesting that the hepatic first-pass effect on tofacitinib after entering the portal vein was approximately 21.3% of the oral dose. Taken together, these findings suggest that the low F of tofacitinib is due primarily to intestinal first-pass metabolism.

Effects of intraduodenal administration of lauric acid and L-tryptophan, alone and combined, on gut hormones, pyloric pressures, and energy intake in healthy men

ABSTRACT Background The fatty acid, lauric acid (‘C12’), and the amino acid, L-tryptophan (‘Trp’), modulate gastrointestinal functions including gut hormones and pyloric pressures, which are important for the regulation of energy intake, and both potently suppress energy intake. Objective We hypothesized that the intraduodenal administration of C12 and Trp, at loads that do not affect energy intake individually, when combined will reduce energy intake, which is associated with greater modulation of gut hormones and pyloric pressures. Design Sixteen healthy, lean males (age: 24 ± 1.5 y) received 90-min intraduodenal infusions of saline (control), C12 (0.3 kcal/min), Trp (0.1 kcal/min), or C12 + Trp (0.4 kcal/min), in a randomized, double-blind, cross-over study. Antropyloroduodenal pressures were measured continuously, and plasma cholecystokinin (CCK), ghrelin, and glucagon-like peptide-1 (GLP-1) concentrations, appetite perceptions, and gastrointestinal symptoms at 15-min intervals. Immediately after the infusions, energy intake from a standardized buffet meal was quantified. Results C12 + Trp markedly reduced energy intake (kcal; control: 1,232 ± 72, C12: 1,180 ± 82, Trp: 1,269 ± 73, C12 + Trp: 1,056 ± 106), stimulated plasma CCK (AUC(area under the curve)0–90 min, pmol/L*min; control: 21 ± 8; C12: 129 ± 15; Trp: 97 ± 16; C12 + Trp: 229 ± 22) and GLP-1 (AUC0–90 min, pmol/L*min; control: 102 ± 41; C12: 522 ± 102; Trp: 198 ± 63; C12 + Trp: 545 ± 138), and suppressed ghrelin (AUC0–90 min, pg/mL*min; control: −3,433 ± 2,647; C12: −11,825 ± 3,521; Trp: −8,417 ± 3,734; C12 + Trp: −18,188 ± 4,165) concentrations, but did not stimulate tonic, or phasic, pyloric pressures, compared with the control (all P < 0.05), or have adverse effects. C12 and Trp each stimulated CCK (P < 0.05), but to a lesser degree than C12 + Trp, and did not suppress energy intake or ghrelin. C12, but not Trp, stimulated GLP-1 (P < 0.05) and phasic pyloric pressures (P < 0.05), compared with the control. Conclusion The combined intraduodenal administration of C12 and Trp, at loads that individually do not affect energy intake, substantially reduces energy intake, which is associated with a marked stimulation of CCK and suppression of ghrelin. The study was registered as a clinical trial at the Australian and New Zealand Clinical Trial Registry (www.anzctr.org.au,) as 12613000899741.

Effects of intraduodenal administration of the artificial sweetener sucralose on blood pressure and superior mesenteric artery blood flow in healthy older subjects

ABSTRACTBackgroundPostprandial hypotension (PPH) occurs frequently, particularly in older people and those with type 2 diabetes, and is associated with increased morbidity and mortality. The magnitude of the decrease in blood pressure (BP) induced by carbohydrate, fat, and protein appears to be comparable and results from the interaction of macronutrients with the small intestine, including an observed stimulation of mesenteric blood flow. It is not known whether artificial sweeteners, such as sucralose, which are widely used, affect BP.ObjectiveThe aim of this study was to evaluate the effects of intraduodenal sucralose on BP and superior mesenteric artery (SMA) blood flow, compared with intraduodenal glucose and saline (control), in healthy older subjects.DesignTwelve healthy subjects (6 men, 6 women; aged 66–79 y) were studied on 3 separate occasions in a randomized, double-blind, crossover design. After an overnight fast, subjects had concurrent measurements of BP and heart rate (HR; automated device), SMA blood flow (Doppler ultrasound), and blood glucose (glucometer) during intraduodenal infusion of 1) glucose (25% wt:vol, ∼1400 mOsmol/L), 2) sucralose (4 mmol/L, ∼300 mOsmol/L), or 3) saline (0.9% wt:vol, ∼300 mOsmol/L) at a rate of 3 mL/min for 60 min followed by intraduodenal saline for a further 60 min.ResultsThere was a decrease in mean arterial BP (P < 0.001) during intraduodenal glucose [baseline (mean ± SEM): 91.7 ± 2.6 mm Hg compared with t = 60 min: 85.9 ± 2.8 mm Hg] but not during intraduodenal saline or intraduodenal sucralose. The HR (P < 0.0001) and SMA blood flow (P < 0.0001) also increased during intraduodenal glucose but not during intraduodenal saline or intraduodenal sucralose. As expected, blood glucose concentrations increased in response to glucose (P < 0.0001) but not saline or sucralose.ConclusionsIn healthy older subjects, intraduodenal administration of the artificial sweetener sucralose was not associated with changes in BP or SMA blood flow. Further studies are therefore warranted to determine the potential role for artificial sweeteners as a therapy for PPH. This trial was registered at http://www.ANZCTR.org.au as ACTRN12617001249347.

The gastroprotective effect of Memora nodosa roots against experimental gastric ulcer in mice

ABSTRACT Memora nodosa is popularly known as "caroba" and widely found in the Cerrado regions of Brazil. In traditional medicine, the leaves and stems are used for the healing of external ulcer and the roots for abdominal pain. This study investigated the effect of ethanolic roots extract of Memora nodosa (EMN) on the gastric mucosa of mice. In the indomethacin induced gastric ulcer model, the treatments of the animals with EMN at doses of 100, 300 and 1000 mg/kg, p.o., markedly reduced the index of lesions. In the gastric ulcer models induced by ethanol and cold restraint-stress the previous treatment with EMN at dose of 300 mg/kg showed 69% and 43% of protection, respectively. Seven days after food-restriction, the animals treated with EMN (300 mg/kg p.o.) showed reduction in the index of lesion by 65% as compared to control group. The intraduodenal administration of EMN (300 mg/kg) did not alter the gastric acid secretion parameters. The treatment with EMN (300 mg/kg p.o.) did not alter glutathione levels (GSH), but showed an increase of adhered gastric mucus as compared to the control group with lesion. These results showed that EMN has gastroprotective activity probably due with an increase of adhered gastric mucus.

Thermotropic behavior of celecoxib-loaded beta-casein micelles: relevance to the improved bioavailability

The physico-chemical characterization of novel celecoxib-loaded beta-casein micelles (Cx/bCN) was recently described and its superiority in enhancing celecoxib bioavailability after intraduodenal administration to pigs was demonstrated. Here, using solution differential scanning calorimetry (DSC) combined with analysis of size distribution by DLS, zeta potential and changes in composition we demonstrate that the above superiority may be related to the thermotropic behavior of these micelles under physiological conditions. DSC of Cx/bCN reveals a characteristic irreversible exotherm upon heating, having its temperature of maximal change in heat capacity (T

Anti-ulcerogenic and antisecretory effects of Celtis iguanaea (Jacq.) Sargent hexane leaf extract

The Celtis iguanaea (Jacq.) Sargent (Cannabaceae) is one of the native species of the Cerrado region of Brazil widely used in folk medicine to treat dyspepsia. The objective of the present study was to evaluate the gastroprotective effect of the Celtis iguanaea (Jacq.) Sargent (HE) hexane leaf extract in the lesion and gastric secretion models.Antiulcerogenic activity of the Celtis iguanaea (HE) hexane leaf extract was observed with the experimental models, such as indomethacin and pyloric ligation-induced gastric ulcers. In order to evaluate the antisecretory activity of this extract, isolated Rana catesbeiana mucosa and pyloric ligation in mice were used. The HE treatment reduced the lesion index of indomethacin and pyloric ligation-induced ulcer. This extract also reduced the gastric acid secretion and total acidity (increasing the gastric pH) in mice. The secretion of H+ was reduced in the basal values (15.58 ± 1.99 µEq H+/g/15 min) when isolated Rana catesbeiana mucosa was incubated with HE. Intraduodenal administration of HE reduced the gastric secretion produced by bethanecol or histamine. The antiulcerogenic and antisecretory efficacy of HE in this study suggest anticholinergic and antihistaminergic mechanism or interruption of intracellular events that are linked to acid secretion.

A Single Intraduodenal Administration of Human Adenovirus 40 Vaccine Effectively Prevents Anaphylactic Shock

ABSTRACTVaccine administration into the intestine is known to induce mucosal tolerance most efficiently. Therefore, developing a delivery system that targets the intestinal mucosa is expected to improve the efficiency of immunosuppression. Human enteric adenovirus serotype 40 (Ad40)-based vectors have the advantage of targeting intestinal mucosa, making them prime candidates as mucosal vaccine carriers for immunosuppression. Here, after both oral and intraduodenal administrations, the vector distribution of replication-defective recombinant Ad40 vectors (rAd40) was significantly higher than that of a conventional Ad vector based on human adenovirus 5 (Ad5) in ilea containing Peyer's patches. Single intraduodenal administration of rAd40 induced antigen-specific mucosal immunoreaction mediated by intestinal mucosal and systemic immunity. In ovalbumin-induced allergy mouse models, this approach inhibited antigen-specific delayed-type hypersensitivity reactions, diarrhea occurrence, and systemic anaphylaxis. Thus, a single intraduodenal administration of rAd40 provides a potent method of inducing allergen-specific mucosal tolerance and a new allergen-specific immunotherapy for overcoming problems with current therapies against life-threatening allergic reactions, including anaphylaxis.