Low-fat Meal Research Articles

Novel Gastroretentive Controlled Release Formulations for Once-Daily Administration: Assessment of Clinical Feasibility and Formulation Concept for Raltegravir.

Raltegravir is an integrase strand transfer inhibitor indicated in combination with other anti-retroviral medicinal products for the treatment of HIV-1 infection, given twice daily. Although a BCS class II compound, raltegravir exhibits low colonic absorption, thus making development of modified release formulations challenging. It was hypothesized that a gastroretentive (GR) formulation would increase trough (C24 h) concentrations of raltegravir, hence being amenable to a once-daily (QD) regimen. Iterative prototype GR formulations were developed in monolithic, bilayer, and trilayer tablet designs. Four phase I studies in healthy subjects were conducted to provide proof of formulation concept. Raltegravir C24 h was increased by a GR formulation with scintigraphy data supporting gastric retention. Single-dose exposures from a trilayer tablet administered in the morning with a high-fat meal resulted in acceptable C24 h values. However, C24 h values for evening dosing with a high-fat meal did not meet the success criteria for QD administration. Raltegravir C24 h and area under the curve (AUC) values after AM dosing with a low-fat meal were significantly lower than after dosing with a moderate-fat meal. Skipping, delaying, or giving a low-fat, low-calorie lunch after dosing with a high-calorie breakfast also resulted in an unacceptable decline in C24 h values. The requirements for consistent product performance under varying conditions of diet, timing of dosing, and dose were not favorable when given as GR tablets. The findings from these studies offer valuable insights into modifying the absorption of candidate drugs with limiting colonic permeability and solubility characteristics and the interplay between meal, dose timing, and GR formulation performance.

Effect of Low‐ and High‐Fat Meals on the Pharmacokinetics of Venetoclax, a Selective First‐in‐Class BCL‐2 Inhibitor

Venetoclax is a selective, first-in-class, B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in several hematological malignancies. Two studies evaluated the relative bioavailability of venetoclax in healthy subjects: (1) a bioequivalence study to compare the bioavailability of the film-coated tablet with that of an earlier uncoated tablet and (2) a food effect study to evaluate the effect of food on venetoclax pharmacokinetics. Both studies were open-label, single-dose, crossover studies. In the bioequivalence study, 15 subjects received a single dose of venetoclax 50mg under nonfasting conditions, in each of 2periods; one period used the uncoated tablet, and the other used the film-coated tablet. In the food effect study, 24subjects received a single dose of venetoclax film-coated 100-mg tablet under fasting conditions, after a low-fat breakfast or after a high-fat breakfast in different periods. The venetoclax film-coated tablet was bioequivalent to the uncoated tablet, which indicates that the film coating does not affect bioavailability. The median Tmax of venetoclax was delayed by about 2 hours when administered with food. Compared with fasting conditions, Cmax and AUC increased by approximately 3.4-fold following a low-fat breakfast. High-fat meals increased Cmax and AUC by approximately 50% relative to low-fat meals. The mean terminal half-life was comparable between the high-fat meal and fasting conditions (19.1 versus 16.1hours). Based on these results and the venetoclax exposure-response profile, venetoclax should be administered with food and without specific recommendations for fat content to ensure adequate and consistent bioavailability.

Effects of High- and Low-Fat Meals on the Pharmacokinetics of Ozanimod, a Novel Sphingosine 1-Phosphate Receptor Modulator

Introduction: Ozanimod (RPC1063) is an oral, selective sphingosine 1-phosphate (S1P) 1 and 5 receptor modulator in clinical development for the treatment of relapsing multiple sclerosis and inflammatory bowel disease. Since food has the potential to significantly influence the rate and extent of drug absorption, we designed and conducted a food-effect study with ozanimod. Methods: The objective of this study was to characterize the effects of high-fat and low-fat meals on the pharmacokinetics (PK) of a single oral dose of ozanimod in healthy adult subjects. This was a randomized, open-label, 3-period, 6-sequence, crossover study. Twenty-four healthy adult subjects were enrolled to receive a single 1-mg oral dose of ozanimod under 3 different conditions separated by washout periods of 7 days: fasted (treatment A), with a standard FDA high-fat meal (treatment B), and with a low-fat meal (treatment C). PK parameters for ozanimod and its two active metabolites (RP101988 [major] and RP101075 [minor]) were calculated. Point estimates and 90% confidence intervals (CIs) about the geometric mean ratio between treatments for maximum concentration (Cmax) and overall exposure (AUC0-inf or AUC0-last) were determined using linear mixed-effects models. Results: Twenty subjects completed both treatments A and B and 23 subjects completed both treatments A and C and provided PK data for the pair-wise comparison of fed vs fasted. The 90% CIs between fed (high-fat or low-fat) and fasted treatments for the Cmax and AUC0-inf of ozanimod and RP101988 were all within the no-effect boundary of 0.80 to 1.25. For the minor metabolite RP101075, the 90% CIs between high-fat and fasted for AUC0-last and the 90% CIs between low-fat and fasted for Cmax and AUC0-last were within the no-effect boundary. While the 90% CI between high-fat and fasted treatments for RP101075 Cmax (0.76 to 0.88) fell outside the lower bound of the no-effect boundary, this decrease was not considered to be clinically meaningful. Median time to reach Cmax (Tmax) for ozanimod was delayed following a high-fat meal (12 hours) compared to fasted and lowfat meal conditions (8 hours), but the range (6 to 12 hours) was the same. Mean elimination half-life (t1/2) values for ozanimod and its active metabolites ranged from 17-21 hours and were similar across all 3 treatments. Overall, single oral doses of 1 mg ozanimod were considered generally well tolerated. Conclusion: Ozanimod may be taken with or without food.

Postprandial Plasma Concentrations of Individual Bile Acids and FGF-19 in Patients With Type 2 Diabetes.

Bile acids regulate lipid and carbohydrate metabolism by interaction with membrane or intracellular proteins including the nuclear farnesoid X receptor (FXR). Postprandial activation of ileal FXR leads to secretion of fibroblast growth factor 19 (FGF-19), a gut hormone that may be implicated in postprandial glucose metabolism. To describe postprandial plasma concentrations of 12 individual bile acids and FGF-19 in patients with type 2 diabetes (T2D) and healthy controls. Descriptive study, performed at the Center for Diabetes Research, Gentofte Hospital, Hellerup, Denmark. Fifteen patients with T2D and 15 healthy matched controls with normal glucose tolerance. A 75-g oral glucose tolerance test and three isocaloric and isovolemic liquid meals with low, medium, and high fat content, respectively. Bile acid and FGF-19 concentrations. Postprandial total bile acid concentrations increased with increasing meal fat content (P < .05), peaked after 1-2 hours, and were higher in T2D patients vs controls (oral glucose tolerance test, low and medium fat meals, P < .05; high fat meal, P = .30). Differences reflected mainly unconjugated and glycine-conjugated forms of deoxycholic acid (DCA) and to a lesser extent cholic acid (CA) and ursodeoxycholic acid (UDCA), whereas chenodeoxycholic acid (CDCA) concentrations were comparable in the two groups. FGF-19 concentrations tended to be lower in T2D patients vs controls, but differences were not statistically significant due to considerable variation. Postprandial plasma patterns of bile acids with FXR agonistic properties (CDCA, DCA, and CA) and FXR antagonistic properties (UDCA) in T2D patients support the notion of a "T2D-bile acid-FGF-19" phenotype with possible pathophysiological implications.

Effect of the Level of Dietary Fat and Fat Type on Postprandial Calciuria and Involvement of Insulin

Postprandial calciuric responses to high and low protein meals are usually involves making meals isocalorific by adding extra fat to the low protein meals. In this study the effect of high fat meals and the type of fat on calciuria is examined to evaluate any effect it can have on evaluating protein induced hypercalciuria. Changes in urinary calcium, creatinine and phosphate are compared with serum calcium, creatinine, urea, protein and insulin. Group result show that the average postprandial calciuria was affected by the high fat meals compared to low fat meals and the type of fat had little effect. However the increase in calciuria in every case showed a plateau effect during the time of maximum insulinemia. Examination of individual results show that the individuals with less insulinemia exhibited greatest hypercalciuria and individuals with exaggerated insulinemia responses showed reduced hypercalciuria. Discussion is providing regarding the significance of the insulin in regard to hypercalciuria and possible mechanisms for it cause. A suggestion is made that diet induced calciuria could be used as a non-invasive measure of insulin insensitivity.

The acute effects of time-of-day-dependent high fat feeding on whole body metabolic flexibility in mice.

Background:Both circadian disruption and timing of feeding have important roles in the development of metabolic disease. Despite growing acceptance that the timing of food consumption has long-term impact on metabolic homeostasis, little is known regarding the immediate influence on whole body metabolism, or the mechanisms involved. We aimed to examine the acute effects of time-of-day-dependent high fat feeding on whole body substrate metabolism and metabolic plasticity, and to determine the potential contribution of the adipocyte circadian clock.Methods:Mice were fed a regimen of 4-h meal at the beginning and end of the dark (waking) cycle, separated by 4 h of fasting. Daily experimental conditions consisted of either an early very high fat or high fat (EVHF or EHF, 60 or 45% kcals from fat, respectively) or late (LVHF or LHF) meal, paired with a low fat (LF, 10% kcals from fat) meal. Metabolic parameters, glucose tolerance, body fat composition and weight were assessed. To determine the role of the adipocyte circadian clock, an aP2-CLOCK mutant (ACM) mouse model was used.Results:Mice in the EVHF or EHF groups showed a 13.2 or 8.84 higher percentage of caloric intake from fat and had a 0.013 or 0.026 lower daily average respiratory exchange ratio, respectively, compared with mice eating the opposite feeding regime. Changes in glucose tolerance, body fat composition and weight were not significant at the end of the 9-day restricted feeding period. ACM mice did not exhibit different metabolic responses to the feeding regimes compared with wild-type littermates. Circadian clock disruption did not influence the short-term response to timed feeding.Conclusions:Both the total fat composition of diet and the timing of fat intake may differentially mediate the effect of timed feeding on substrate metabolism, but may not induce acute changes in metabolic flexibility.

Salt Promotes Passive Overconsumption of Dietary Fat in Humans

Background: Excess fat consumption has been linked to the development of obesity. Fat and salt are a common and appetitive combination in food; however, the effect of either on food intake is unclear. Fat taste sensitivity has been negatively associated with dietary fat intake, but how fat taste sensitivity influences the intake of fat within a meal has, to our knowledge, not yet been investigated.Objectives: Our objectives were, first, to investigate the effects of both fat and salt on ad libitum food intake and, second, to investigate the effects of fat taste sensitivity on satiation responses to fat and whether this was affected by salt.Methods: Forty-eight healthy adults [16 men and 32 women, aged 18–54 y, body mass index (kg/m2): 17.8–34.4] were recruited and their fat taste sensitivity was measured by determination of the detection threshold of oleic acid (18:1n–6). In a randomized 2 × 2 crossover design, participants attended 4 lunchtime sessions after a standardized breakfast. Meals consisted of elbow macaroni (56%) with sauce (44%); sauces were manipulated to be 1) low-fat (0.02% fat, wt:wt)/low-salt (0.06% NaCl, wt:wt), 2) low-fat/high-salt (0.5% NaCl, wt:wt), 3) high-fat (34% fat, wt:/wt)/low-salt, or 4) high-fat/high-salt. Ad libitum intake (primary outcome) and eating rate, pleasantness, and subjective ratings of hunger and fullness (secondary outcomes) were measured.Results: Salt increased food and energy intakes by 11%, independent of fat concentration (P = 0.022). There was no effect of fat on food intake (P = 0.6), but high-fat meals increased energy intake by 60% (P < 0.001). A sex × fat interaction was found (P = 0.006), with women consuming 15% less by weight of the high-fat meals than the low-fat meals. Fat taste sensitivity was negatively associated with the intake of high-fat meals but only in the presence of low salt (fat taste × salt interaction on delta intake of high-fat − low-fat meals; P = 0.012).Conclusions: The results suggest that salt promotes passive overconsumption of energy in adults and that salt may override fat-mediated satiation in individuals who are sensitive to the taste of fat. This trial was registered at the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12615000048583.

Effects of meal type on the oral bioavailability of the ALK inhibitor ceritinib in healthy adult subjects.

Ceritinib is a potent inhibitor of anaplastic lymphoma kinase (ALK), which has shown acceptable safety and substantial antitumor activity in ALK-positive non-small cell lung cancer (NSCLC) patients. Two food-effect studies were conducted in healthy adults to investigate the influence of food on the oral bioavailability of ceritinib: a study with low- or high-fat meals at 500 mg and a study with a light snack at 750 mg. Compared with the fasted state, AUC0-∞ (90%CI) of ceritinib was increased by 58% (34%, 86%) after the intake of a low-fat meal, by 73% (46%, 105%) after the intake of a high-fat meal, and by 54% (19%, 99%) after the intake of a light snack. Safety assessments also suggested that food may improve gastrointestinal (GI) tolerability after a single ceritinib dose. Based on the pharmacokinetic results, it is essential to avoid any type of meal during dosing of ceritinib because the intake of food may increase the occurrence of exposure-dependent, non-GI toxicities at the labeled dose of 750 mg daily during fasting. A randomized trial is ongoing to determine an alternative way to give ceritinib (450 mg or 600 mg with food) that may enhance GI tolerability in ALK-positive NSCLC patients.

Assessment of Gastric Accommodation in Patients with Functional Dyspepsia by 99mTc-Pertechtenate Single Photon Emission Computed Tomography Imaging: Practical but not Widely Accepted.

Objective:Impaired gastric accommodation is one of the main symptoms in patients with functional dyspepsia. The aim of the present study was to assess gastric accommodation in patients with functional dyspepsia using single photon emission computed tomography (SPECT) imaging.Methods:Twenty-four patients with functional dyspepsia and 50 healthy volunteers as control group were enrolled in this study. All participants were given 5 mCi 99mTc-pertechtenate intravenously, served with a low fat meal, and underwent SPECT scanning 20 minutes after the meal.Results:Based on the scintigraphic data, gastric volumes were found to be significantly increased after food ingestion in both patient and control groups. We also found that while there was no significant difference between patient and control groups in terms of fasting gastric volumes, postprandial gastric volume was significantly lower in patients as compared to healthy individuals (p<0.05).Conclusion:Measuring gastric volume by using SPECT can be a valuable method in the detection of functional dyspepsia and in differentiation of this entity from other organic disorders.

Providing food to treat adolescents at risk for cardiovascular disease.

ObjectiveDiet modification is recommended to treat childhood cardiovascular (CV) risk factors; however, the optimal dietary strategy is unknown.MethodsIn a randomized trial the effect of a low-fat (LF) and a low-glycemic-load (LGL) reduced-calorie diet were examined in youth with overweight/obesity with CV risk factors. Using a novel intervention, we delivered LF or LGL meals and nutrition education to the home for 8 weeks (Intensive Phase), followed by 4-months Maintenance without food provision. Between-group differences in the change in insulin area-under-the-curve (InsAUC) by oral glucose tolerance test and other risk factors were analyzed.ResultsOverall, participants (n=27) showed substantial improvement during the Intensive Phase, including InsAUC (−59±18.2 µU/mL*120mins, p=0.004), total cholesterol (−9.9±3.6mg/dL, p=0.01), weight (−2.7±0.5kg, p<0.001), waist circumference (−3.1±0.8cm, p<0.001), HOMA-IR (−1.7±0.4, p<0.001), systolic BP (−5±1.4 mmHg, p=0.002) and CRP (−0.1±0.1mg/dL, p=0.04). There were minimal between-group differences; the LF group showed greater declines in HDL-C (p=0.005) and fasting glucose (p=0.01) compared to the LGL group. Improvements waned during Maintenance.ConclusionsHome delivery of LF or LGL diets resulted in rapid and clinically important improvements in CV risk factors that diminished without food delivery, and did not differ based on dietary intervention. If scalable, food provision may represent an alternative nutrition treatment strategy.

Clinical pharmacology characterization of RG7112, an MDM2 antagonist, in patients with advanced solid tumors

RG7112, the first selective small-molecule MDM2 antagonist in clinical testing, is a non-genotoxic oral p53 activator. To optimize its dose and schedule, a number of clinical pharmacology characteristics were explored in this multicenter trial in patients with advanced solid tumors. In part 1, the impact of high-energy/high-fat meal and formulations (crystalline and amorphous) on relative bioavailability was examined in single-dose crossover designs. In part 2, schedule optimization (4 schedules of drug administration under fasting condition and 2 cohorts with liquid supplementation) was investigated in parallel, dose escalation designs. Clinical endpoints were pharmacokinetics (PK), pharmacodynamics (PD) including MIC-1 elevation and platelet reduction, and safety/tolerability. With a single-dose treatment, a high-fat/high-energy meal and a new formulation under fasting condition, respectively, enhanced overall bioavailability of RG7112 slightly over twofold. Following multiple-dose administrations, all four schedules yielded the comparable per-cycle (28-d) exposure (AUC), as designed; liquid supplements also enhanced bioavailability. High-dose treatments of consecutive daily dosing for 5 and 3 days resulted in higher on-treatment-day exposure to RG7112 than both weekly and low-dose/long-duration (20-day) daily schedules. Serum MIC-1 and blood platelet profiles showed similar patterns to those of PK when the clinical pharmacology conditions were varied, suggesting the relative importance of treatment-day exposure than overall per-cycle AUC. Food (both high-fat and low-fat meals) and new formulation enhanced bioavailability. High-dose consecutive daily treatment for 3-5 days is superior to weekly and low-dose/long-duration (20-day) daily schedules in yielding the sufficiently high drug exposure and PD effects potentially required for cancer treatment efficacy.

Evaluation of food effect on the oral bioavailability of pradigastat, a diacylglycerol acyltransferase 1 inhibitor.

Pradigastat, a diacylglycerol acyltransferase 1 inhibitor, is being developed for the treatment of familial chylomicronemia syndrome. The results of two studies that evaluated the effect of food on the oral bioavailability of pradigastat using randomized, open-label, parallel group designs in healthy subjects (n=24/treatment/study) are presented. In study 1, a single dose of 20 mg pradigastat was administered under the fasted condition or with a high-fat meal. In study 2, a single dose of 40 mg pradigastat was administered under the fasted condition or with a low- or high-fat meal. At the 20 mg dose, the pradigastat Cmax and AUClast increased by 38% and 41%, respectively, with a high-fat meal. When 40 mg pradigastat was administered with a low-fat meal, the Cmax and AUClast increased by 8% and 18%, respectively, whereas with a high-fat meal the increase was 20% and 18%, respectively. The population pharmacokinetic analysis with the pooled data from 13 studies indicated that administration of pradigastat with a meal resulted in an increase of 30% in both the Cmax and AUC parameters. Based on these results, food overall increased pradigastat exposure in the range of less than 40%, which is not considered clinically significant. Both 20 and 40 mg doses of pradigastat were well tolerated under fasted or fed conditions.

Abstract 629: Sensing Nutrient Overload: The Role of the Endothelium

Recent data suggest that leukocyte accumulation into visceral fat depots occurs within 72 following high fat feeding. At this early stage, neutrophils have been found to be the predominant leukocyte population to infiltrate the visceral fat. Other studies have shown that deletion of the high affinity counter-receptor for P-selectin, P-selectin glycoprotein ligand-1 (PSGL-1), attenuate immune cell infiltration into fat depots of chronically high fat fed mice. Accordingly, we tested the hypothesis that endothelial, expressed P-selectin serves as a molecular sensor for initiating inflammatory responses in the microcirculation of the visceral fat following nutrient overload. Wild-type (WT) and P-sel-/- C57BL/6 mice were given either a low fat (10% fat) or a high fat (60% fat) meal by gavage. All mice were studied 1, 2, 3, 4 and 24 hours post gavage by intravital microscopy (IVM) to measure postprandial kinetics of leukocyte rolling (LR) and leukocyte adhesion (LA) in the microcirculation of the mesenteric fat pads. In WT mice, administration of high fat meals acutely and transiently increased LR and LA in the visceral fat microcirculation (p&lt;0.001 vs low fat meal). In contrast, high fat meals failed to increase LR and LA in P-sel-/- mice (NS vs low fat meal WT). Immunofluorescence studies demonstrated that fat meals upregulate cell surface expression of P-selectin in the visceral fat microcirculation, but not in the subcutaneous one. Flow cytometry studies demonstrated that neutrophils are the main leukocyte population to acutely infiltrate visceral fat depots after lipid overload. Mechanistic studies were also undertaken using palmitate, a postprandially elevated, unsaturated free fatty acid. Superfusion of (dose) palmitate during IVM acutely increased LR and LA in the microcirculation of the mesenteric fat pads of WT mice (p&lt;0.01 vs control), a response that was prevented in vivo by P-selectin antibody blockade. Taken together, these data demonstrate that endothelial P-selectin plays a key role in the early inflammatory responses to fat overload by promoting neutrophil trafficking in the microcirculation of the visceral fat. These data first uncover a novel nutrient-sensory role of the vascular endothelium, which warrants further investigation.

INFLUENCE OF HERBAL EXTRACTS ON METABOLIC DISTURBANCES IN DIABETES MELLITUS AND INSULIN RESISTANCE MODEL

The aim of this research was to assess the influence on metabolic processes of herbal extracts, used in diets with different fat content, in diabetes mellitus and insulin resistance model.Material and methods. The experiments were performing on 90 noninbred male albino rats. Diabetes mellitus was modeling with twice-repeated intraperitoneal streptozotocine (30 mg/kg) injections. For the insulin resistance formation animals were fad meal with 30% fat content. Against the background rats were administering into the stomach nettle leafs (Urtica dioica L., 100 mg/kg), burdock roots (Arctium lappa L., 25 mg/kg) extracts or intraperitoneal insulin preparation Actrapide HM Penfill (3 mg/kg) daily during 10 days. During period of agents introduction one-half of animals continued to receive food with high fat content, the other half received diet with 8% fat content. The third rats group received only food with low fat content without extracts or insulin administration. In blood was measured the glucose, glycosylated hemoglobin, creatinine, urea, uric acid content, in liver homogenates – glycogen, protein content, aminotransferases and glucose-6phosphatase activity, in muscle homogenates – glycogen and protein content.Results. After streptozotocine injections and diet with 30% fat content the blood glucose level became by 4.0–5.3 fold more than level of intact animals, increased the hemoglobin glycosylation, also creatinine, urea, uric acid blood content, in liver and muscle homogenates raised glycogen content, decreased protein quantity, in liver homogenates increased aminotranferases and glucose-6-phosphatase activity. In animals only feeding with 8% fat diminished hyperglycemia, creatinine blood retention, the liver glycogen content and recovered its protein resources. The nettle or burdock extracts administrating to animals that continued to receive high fat meal decreased the blood glucose, glycosylated hemoglobin and creatinine content, the liver glucose-6-phosphatase activity, increased the muscle protein content, the nettle extract also prevented from hyperuricemia and liver protein deficiency, the burdock extract caused the liver glycogen accumulation. In animals feeding with low fat meal the nettle extract caused hyperglycemia parameters regression and changed in the direction of the norm the liver and muscle glycogen content, the burdock extract decreased only hemoglobin glycosylation, both herbal extracts decreased the blood creatinine level and increased the muscle protein level. Independently of diet the nettle extract increased the insulin sensitivity after 60 and 120 min after insulin injection, the burdock extract – after 120 min.Conclusion. The nettle and burdock extracts have in diabetes mellitus and insulin resistance model hypoglycemic action, prevent from hemoglobin glycosylation, improve creatinine excretion, recover the muscle sensitivity to insulin effect.

Su1452 Analyses of Long-Term Follow-Up of Gastric Electrical Stimulation Therapy and Pyloroplasty for Refractory Gastroparesis

G A A b st ra ct s amplitude of antral contractions Luminal obliteration Motility index Characterize antral contractility and identify its role in patients with rapid gastric emptying (RGE) and delayed gastric emptying (DGE). Describe antral contractility patterns in patients with UGIMD and normal gastric emptying (NGE) and role in explaining symptoms. METHODS Age, clinical presentation, gender, diabetes mellitus, other comorbidities, and ethnicity were documented in 10 patients who underwent GES and DAS from October to November of 2014. All patients ingested a standardized low-fat meal (255 kCal) labeled with 2 mCi of Tc-99m SC, obtaining 1-minute static images in the anterior and posterior projections at 30, 60, 120, 180 and 240 minutes. The DAS methodology involved 512 dynamic images at 0.5 second per frame acquired in the anterior projection at 15, 30, 45, 60, 90, 180 and 240 minutes. The data was analyzed to derive the following mean parameters of antral motility: a) Frequency, rhythm, coordination and amplitude of contractions, representing the cyclic variation of labeled meal, b) Obliteration or fraction of labeled meal that leaves the antrum during each contraction and c) Motility index or fraction of contents leaving the antrum per minute (product of obliteration and frequency). RESULTS The mean age was 53 years (21-67), 8 females, 3 had diabetes mellitus. Two patients with DGE (1 diabetic and 1 idiopathic) had the highest contraction frequency, but the lowest contraction amplitude, obliteration and motility index (Fig. 1). Two patients with RGE (1 diabetic and 1 idiopathic) had the lowest contraction frequency, but the highest amplitude, obliteration, and motility index. The remaining 6 patients (5 idiopathic and 1 diabetic) had normal GEwith contraction parameters values in between those of the DGE and RGE patients (Table 1). CONCLUSION 1) In patients with UGIMD and DGE, the antral contraction parameters as assessed by DAS are less than 1/2 the values of NGE patients; 2) RGE patients had nearly 3 times higher contraction parameters than DGE patients, specifically having longer and more coordinated forceful contractions resulting in powerful motility index and faster gastric emptying and 3) DAS data complements GES results offering important additional assessment of gastric motility characteristics and parameters that have direct application to patient care and treatment decisions. Table 1: Quantitative parameters of antral motility in patients with upper GI motility disorder

Pharmacokinetics of Mirabegron, a β3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy East Asian Subjects

PurposeThe objective of these studies was to evaluate the pharmacokinetic profile, safety, and tolerability of mirabegron, a β3-adrenoceptor agonist for the treatment of overactive bladder, including food effects (low- or high-fat meals) and sex, in healthy East Asian subjects. MethodsIn total, 5 pharmacokinetic studies of mirabegron were conducted in healthy East Asian subjects. Food effects were assessed in 3 randomized, single-dose studies in young Japanese male subjects (study 1), male and female subjects (study 2), and young Taiwanese male and female subjects (study 3). In the other 2 single- and multiple-dose studies in young Chinese male and female subjects (study 4 and study 5), mirabegron was administered as a single dose under fasted conditions. After the washout period, mirabegron was administered once daily under fed conditions for 8 days. Pharmacokinetic parameters were determined using noncompartmental methods. Safety and tolerability assessments included physical examinations, vital signs, 12-lead ECG, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse event monitoring. FindingsAfter administration of single oral doses of mirabegron, exposure under fed conditions was lower than under fasted conditions in Japanese and Taiwanese subjects. In Japanese subjects, a greater reduction in mirabegron Cmax and AUC0–∞ was observed after a low-fat meal compared with a high-fat meal. In Chinese subjects, Cmax was reached at approximately 4.0 hours after single oral doses. Mirabegron accumulated 2- to 3-fold on once-daily dosing of multiple-dose relative to single-dose data. Steady state was reached within 7 days. After administration of mirabegron, mean values for Cmax and AUC in female subjects were higher than those in male subjects. Mirabegron was well tolerated in Japanese, Taiwanese, and Chinese subjects. ImplicationsOur studies confirm the higher exposure levels of mirabegron in female compared with male East Asian subjects as found earlier in Western subjects. Furthermore, the effects of food on the pharmacokinetic profiles appeared to be similar among the 3 populations tested in our studies. The findings suggest that there are no significant pharmacokinetic differences among the Japanese, Taiwanese, and Chinese populations.

Postprandial adiponectin and gelatinase response to a high-fat versus an isoenergetic low-fat meal in lean, healthy men

ObjectiveEvidence suggests that an acute systemic inflammatory response is invoked after consumption of a high-energy meal. Postprandial regulation of adiponectin, an adipose tissue-derived, anti-inflammatory hormone, and the gelatinases, matrix metalloproteinase (MMP)-2 and MMP-9, endopeptidases implicated in a diverse range of inflammatory processes, remain inconclusive. The aim of this study was to assess the postprandial effect of a high-energy (1212 kcal) meal on plasma adiponectin, MMP-2 and MMP-9 activity, glucose, insulin, triacylglycerols, total cholesterol, high-density lipoprotein cholesterol, and the differential effects on these parameters depending on whether the test meal was high fat (HF; 46 g fat, 1210 kcal) or isoenergetic and low fat (LF; 15 g fat, 1214 kcal energy). MethodsTest meals were consumed by 17 lean, healthy men on two separate occasions with blood samples collected by venipuncture at baseline (0 h) and 1 and 3 h after consumption of each test meal. ResultsAt baseline, no significant difference was seen in the parameters between the two groups, except for MMP-2, MMP-9, and total cholesterol. Over the 3-h postprandial period, no significant differential effect of the HF versus the LF test meal was observed on adiponectin, MMP-2, MMP-9, or on metabolic markers other than triacylglycerol, which increased significantly in response to the HF test meal (time × treatment, P = 0.002). When analyzed independent of time, MMP-2 (treatment, P = 0.006), MMP-9 (treatment, P = 0.022), and glucose (treatment, P = 0.026) were lower after consumption of the HF meal compared with the LF test meal. When analyzed independent of treatment, adiponectin increased over the 3-h postprandial period (time, P = 0.031), but there was no change in MMP-2 or MMP-9 (time, P = 0.503 and P = 0.525, respectively). Over the 3-h postprandial period, insulin (time, P < 0.001) and total cholesterol (time, P = 0.002) increased, whereas glucose (time, P < 0.001) and high-density lipoprotein cholesterol (time, P < 0.001) decreased. ConclusionNo differential effects of a HF versus a LF isoenergetic meal were seen on postprandial adiponectin or the gelatinases. Adiponectin increased in response to a high-energy meal independent of treatment, and the gelatinases were lower in response to the HF versus the LF isoenergetic meal, independent of time point. Given the considerable amount of time that humans spend in the postprandial state, additional research is necessary to further understand inflammatory changes in this state.

Effect of dietary fat and food consistency on gastroparesis symptoms in patients with gastroparesis.

Nutrition therapy for gastroparesis focuses on reducing meal size, fiber, fat intake, and increasing liquids intake relative to solid foods. Evidence to support these dietary interventions has been anecdotal. The aim of this study was to determine the effect of fat intake and solid/liquid meal consistency on symptoms in gastroparesis. Twelve patients with gastroparesis were studied on four separate days receiving one of four meals each day in a randomized order: high-fat solid, high-fat liquid, low-fat liquid, and low-fat solid meal. At each visit, eight gastrointestinal symptoms were rated from 0 (none) to 4 (very severe) every 15 min, before and for 4 h after meal ingestion. There was an increase in the total symptom score in the following order: high-fat solid > low-fat solid > high-fat liquid > low-fat liquid. For the high-fat solid meal, symptoms remained elevated throughout the 4 h postprandial period. Severity of nausea more than doubled after the high-fat solid meal, whereas the low-fat liquid meal caused the least increase in nausea. A high-fat solid meal significantly increased overall symptoms among individuals with gastroparesis, whereas a low-fat liquid meal had the least effect. With respect to nausea, low-fat meals were better tolerated than high-fat meals, and liquid meals were better tolerated than solid meals. These data provide support for recommendations that low-fat and increased liquid content meals are best tolerated in patients with symptomatic gastroparesis.

Effects of a High Carbohydrate and High Protein Formula Diet On Body Composition and Metabolic Risk Parameters in Obese Subjects

Background: In obese subject’s weight loss is known to improve blood lipid profiles, glycemic control and other conditions that may contribute to the development of metabolic syndrome or cardiovascular diseases. However, the optimal dietary carbohydrate and protein composition to facilitate weight loss and improving potential adverse effects is still in debate. Therefore, the aim of this study was to compare the effect of two low-fat formula diets either high in carbohydrate or high in protein, on body composition and metabolic risk factors. Methods: 154 obese (BMI 32.5 ± 0.14 kg/m2) men and women were included in this randomized clinical trial and classified in two groups (highcarbohydrateformula diet (HC) and high protein formula diet (HP)) of 80 matched subjects. They underwent an intervention for eight weeks, which consisted of two phases: (1) week 1 and 2: total replacement of three meals by a formula diet and (2) six week partial formula diet (replacement of 1-2 meals). Measurements were taken prior and post intervention for analysis of body composition and parameters of lipid and glucose metabolism. Results: After eight weeks both groups lost significantly body fat mass (HC: -5.11 ± 0.51 kg, p<0.001; HP: -5.81 ± 0.54 kg, p<0.001), while only for subjects of HP group no change of lean body mass and body cell mass was observed. Metabolic risk parameters were reduced in both the HC and HP group; however, subjects in the HC group showed a higher reduction in triacylglycerol concentration (-29.1 mg/dl vs. -14.0 mg/dl, p<0.04). Further, the prevalence of the metabolic syndrome was reduced in both groups without difference (HC: -17.9%, p=0.004; HP: -18.4%, p=0.003). Conclusion: Our data demonstrate, that even in a short period of time, a low-fat meal replacement diet high in carbohydrate or high in protein is effective in improving body composition and reducing metabolic risk parameters.

Age-related changes in the diurnal variation of ketogenesis in patients with type 2 diabetes and relevance to hypoglycemic medications.

To assess the significance of ketogenesis in the management of diabetes mellitus, we analyzed the factors associated with the diurnal variation of the plasma ketone body levels. The subjects consisted of 220 patients with type 2 diabetes, aged 60 ± 15 years, without advanced complications. They ate a standardized, low-fat meal at 8:00, 12:00, and 18:00. The plasma levels of 3-hydroxybutyrate (3HB) and free fatty acid (FFA) were increased before breakfast and before dinner. The plasma glucose concentration was almost the same at any blood sampling time point among age quartiles. However, the 3HB levels were significantly decreased with age, which was most obvious before dinner. The FFA levels also decreased with age, but the decline was mild. A multiple regression analysis with stepwise selection revealed that age was an independent, negative contributor and that the pre-breakfast FFA concentration was an independent, positive contributor to the pre-breakfast 3HB levels. Regarding the pre-dinner 3HB levels, in addition to age and the pre-dinner FFA concentration, the uses of sulfonylurea and dipeptidyl peptidase-4 inhibitors were independent negative contributors. The metabolism of ketone bodies is an alternative energy source for the brain under conditions of starvation. While excessive ketogenesis leads to critical ketoacidosis, inadequate ketone body production could be associated with a propensity to develop neurohypoglycemia in elderly patients treated with insulin secretagogues. Because age-related changes in ketogenesis were the most significant before dinner, attention should be paid not only to fasting but also to the pre-dinner levels of 3HB.