Low-fat Meal Research Articles

Characteristics of Patients With Chronic Unexplained Nausea and Vomiting and Normal Gastric Emptying

Chronic nausea and vomiting with normal gastric emptying is a poorly understood syndrome; we analyzed its characteristics. We collected and analyzed data from 425 patients with chronic nausea and vomiting, enrolled at 6 centers by the Gastroparesis Clinical Research Consortium in the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Registry. Among the patients, 319 (75%) had delayed emptying, defined by the results of a standardized, low-fat meal, and 106 had normal gastric emptying. Patients with or without delayed emptying did not differ in age, sex, or race, although those with normal gastric emptying were less likely to be diabetic. Symptom severity indexes were similar between groups for nausea, retching, vomiting, stomach fullness, inability to complete a meal, feeling excessively full after meals, loss of appetite, bloating, and visibly larger stomach. There were no differences in health care utilization, quality of life indexes, depression, or trait anxiety scores. However, state anxiety scores were slightly higher among patients with delayed gastric emptying. Total gastroparesis cardinal symptom index scores were not correlated with gastric retention after 2 or 4 hours in either group. Patients with the syndrome were not adequately captured by the stand-alone criteria for the Rome III diagnoses of chronic idiopathic nausea and functional vomiting. With rare exceptions, the diagnosis remained stable after a 48-week follow-up period. Patients with nausea and vomiting with normal gastric emptying represent a significant medical problem and are, for the most part, indistinguishable from those with gastroparesis. This syndrome is not categorized in the medical literature--it might be a separate clinical entity.

A high-fat challenge increases airway inflammation and impairs bronchodilator recovery in asthma

Dietary fat activates systemic innate immune responses, but the effect on airway responses is unknown. To examine effects of a high-fat versus low-fat meal on systemic and airway inflammation in asthma. Nonobese subjects with asthma were randomized to consume a high-fat (n= 19; 48% [49 g] fat) or low-fat (n= 18; 15% [3 g] fat) meal. Fourteen obese patients with asthma and 21 healthy controls also consumed a high-fat meal. Another group of patients with asthma consumed a high-trans (n= 5; 5.2 g trans fat) or nontrans (n= 5, <0.3 g trans fat) fatty acid meal. Lung function was measured at baseline (prebronchodilator) and 2, 3, and 4 hours after bronchodilator. Airway inflammation was assessed by using induced sputum cell counts and Toll-like receptor 4 mRNA expression by real-time PCR. Systemic inflammation was measured by ELISA quantification of plasma TNF-α, high-sensitivity C-reactive protein, and IL-6 concentrations. In patients with asthma, at 4 hours postmeal, increases in sputum % neutrophils and Toll-like receptor 4 mRNA expression were higher and increases in FEV(1)/forced vital capacity (FVC) were lower in the high-fat versus low-fat groups. Changes in plasma fatty acids correlated with changes in sputum % neutrophils and were negatively associated with changes in % FEV(1), % FVC, and FEV(1)/FVC. After the high-trans fatty acid meal, sputum % neutrophils were significantly higher than after the nontrans meal. A high-fat meal augments neutrophilic airway inflammation, with the effect dependent on the type of fatconsumed. Ahigh-fat meal also suppresses bronchodilator recovery in asthma. Modifying dietary fat intake may beuseful in asthma.

Sugars and fat have different effects on postprandial glucose responses in normal and type 1 diabetic subjects

Background and aims We aimed to determine the effects on glycemic responses and potential risk of hypoglycaemia in type 1 diabetic subjects of replacing half the starch in a meal with sugars, and of adding fat to the low-sugar and high-sugar meals. Methods and results We studied overnight fasted subjects with type 1 diabetes ( n = 11) and age-, BMI- and ethnicity-matched controls ( n = 11) using a 2 × 2 factorial design. The low-sugar/low-fat meal was 110 g white-bread. In the high-sugar/low-fat meal half the white-bread starch replaced by sugars (jam and orange juice). The high-fat meals consisted of the low-fat meals plus 20 g fat (margarine). The significance of the main effects of sugars and fat and the sugar × fat, group × sugar and group × fat interactions were determined by ANOVA. In control and diabetic subjects, respectively, high-sugar significantly reduced time to peak rise by 13% ( P = 0.004) and 32% ( P = 0.004; group × sugar: P = 0.01) and increased peak rise by 14% and 10% (ns). Adding fat increased time to peak rise by 17-19% in both groups ( P = 0.003), reduced peak rise by 31% in normal ( P < 0.001) but increased peak rise in diabetic subjects by 3% (ns) (group × fat: P = 0.022). Blood glucose nadir and occurrence of hypoglycaemia were similar among the 4 meals. Conclusions In type 1 diabetes, insulin adjustment to avoid hypoglycemia may be useful for meals in which the proportion of carbohydrate absorbed as glucose is <0.75, however the precise level which increases hypoglycaemic risk requires further research. The results suggest that people with type 1 diabetes should not be advised to add fat to meals to reduce glycemic responses.

The relationship among adiponectin, high sensitive C reactive protein and triacylglycerol level in healthy young persons

BackgroundThe elevated postprandial triacylglycerol (TG) concentration is associated with elevated coronary artery disease. Oral fatty tolerant test (OFTT) is less performed in the health. This study was to evaluate the effect of sex and body mass index (BMI) on postprandial TG concentration of the low fat meal in healthy young persons. This study included 112 healthy college students (18.8+/-1.6y). Their body height and weight were measured for body mass index (BMI). According to BMI, 27 subjects were in the under-weight subgroup, 60 in the normal weight subgroup and 25 in the over-weight subgroup. After overnight fasting low fat OFTT (27 g fat, 600 kcal) was performed and the plasma TG and glucose concentrations were measured before and at 2, 4 and 6 hour after a fat meal. The area under the curve (AUC) of TG was calculated.ResultsThe fasting TG levels were similar and the fasting TG levels gradually increased as BMI increased in both sexes. The postprandial TG levels at 2 and 4 h decreased in female, but did not significant change in male. In female, the TG curves of 3 BMI subgroups showed saddle type, but in male the TG curve of the over-weight subgroup had a peak at 2 h, on the other hand the TG curve of under- weight subgroup had a dip at 2 h.ConclusionsGender and BMI are important influencing factors for TG metabolism after fat meal in the youth. The young male persons with over-BMI have abnormal TG metabolism.

Effect of High- versus Low-Fat Meal on Serum 25-Hydroxyvitamin D Levels after a Single Oral Dose of Vitamin D: A Single-Blind, Parallel, Randomized Trial

Background/Aims. Vitamin D3 is liposoluble, so dietary fat could increase its oral absorption. Our aim was to compare serum 25-hydroxyvitamin D [25(OH)D] after the oral intake of cholecalciferol with a high- or low-fat meal. Methods. In a single-blind, parallel clinical trial, 32 healthy physicians were divided into two groups. In the same day, they ingested 50,000 IU (1.25 mg) of vitamin D3 with food: group 1 (G1): lipids: 25.6 g and group 2 (G2) lipids: 1.7 g. Serum 25(OH)D (0, 7, and 14 days), and parathyroid hormone (PTH), and calcium (0 and 14 days) were measured. Results. Baseline mean serum 25(OH)D levels were 42.7 ± 19.0 nmol/L in G1 and 36.4 ± 19.0 nmol/L in G2 (P = 0.38). After cholecalciferol, mean serum 25(OH)D was higher in G1 (P < 0.001): 7 days: G1 = 46.2 (38.4–53.9) nmol/L and G2 = 33.7 (25.4–40.1) nmol/L; 14 days: G1 = 53.7 (45.2–62.1) nmol/L and G2 = 33.7 (25.2–42.2) nmol/L. Serum PTH and 25(OH)D were negatively correlated before and after the intake of vitamin D3, respectively, r = −0.42 (P = 0.02) and r = −0.52 (P = 0.003). Conclusions. A high-fat meal increased the absorption of vitamin D3, as measured by serum 25(OH)D.

A Phase I Study of the Pharmacokinetic and Safety Profiles of Oral Pazopanib With a High-Fat or Low-Fat Meal in Patients With Advanced Solid Tumors

Pazopanib is an oral angiogenesis inhibitor of vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor, and cytokine receptor. This open-label, randomized, crossover, phase I study evaluated the effect of low- and high-fat meals on the pharmacokinetics (PK) of pazopanib in patients with advanced solid tumors. Patients participated in either the lead-in cohort or randomized food-effect cohort. Patients in the lead-in cohort were administered a single dose of pazopanib 400 mg with a high-fat meal. Patients in the food-effect cohort were randomized to receive single doses of pazopanib 800 mg in fed condition (high- or low-fat meal) or fasting condition, in random sequence 14 days apart. After completion of the study, patients were given the opportunity to continue treatment with daily pazopanib 800 mg. Administration of pazopanib with both low- and high-fat meals increased maximum observed plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) by approximately twofold as compared with the corresponding values when administered to patients in the fasted condition. Therefore, pazopanib should be administered to patients in the fasted state so as to minimize within- and between-day variability in the systemic exposure to pazopanib in patients with cancer.

Effects of Four Different Meal Types on the Population Pharmacokinetics of Single-Dose Rifapentine in Healthy Male Volunteers

Rifapentine and its primary metabolite, 25-desacetyl rifapentine, are active against mycobacterium tuberculosis. The objectives of this study were to describe the population pharmacokinetics of rifapentine and 25-desacetyl rifapentine in fasting and fed states. Thirty-five male healthy volunteers were enrolled in an open-label, randomized, sequential, five-way crossover study. Participants received a single 900-mg dose of rifapentine after meals with high fat (meal A), bulk and low fat (meal B), bulk and high fat (meal C), high fluid and low fat (meal D), or 200 ml of water (meal E). Venous blood samples were collected over 72 h after each rifapentine dose, and plasma was analyzed for rifapentine and 25-desacetyl rifapentine using high-performance liquid chromatography. Pharmacokinetic data were analyzed by nonlinear mixed-effect modeling using NONMEM. Compared with the fasting state, meal A had the greatest effect on rifapentine oral bioavailability, increasing it by 86%. Meals B, C, and D resulted in 33%, 46%, and 49% increases in rifapentine oral bioavailability, respectively. Similar trends were observed for 25-desacetyl rifapentine. As meal behavior has a substantial impact on rifapentine exposure, it should be considered in the evaluation of optimal dosing approaches.

Metabolic Responses To A Single Low-carbohydrate And Low-fat Meal At Rest And During Exercise In Adult Females

PURPOSE: The present study examined the metabolic response to a single low-carbohydrate (LC) and low-fat (LF) meal at rest and during exercise in females. METHODS: All data are reported as the mean + standard deviation. Subjects included 8 premenopausal females who engaged in aerobic activity for > 3 days/week for at least 6 months (age 33.0 + 6.3 years, BMI 26.8 + 3.5 kg/m2, body fat 30.9 + 6.1%, and peak oxygen consumption (VO2peak) 41.8 + 5.7 ml/kg/min). Subjects completed a LC and LF testing session administered in random order and after a 12 hr fast. Respiratory gas exchange (RER) measurements were taken for 20 min fasted before the test meal was consumed, for 55 min postprandial (PP), and during 30 min of treadmill exercise performed at 60 to 65% of VO2peak. Blood was collected for assessment of glucose (G), insulin (IN), triglycerides (TG), and free fatty acids (FFA) during the final 10 min of the fasting and PP time periods and immediately post-exercise (PE). G, FFA, and TG were analyzed using enzymatic assays. IN was analyzed using the ELISA technique. The LF meal provided 396 kcal (78% carbohydrate, 7% fat, and 15% protein). The LC meal provided 392 kcal (15% carbohydrate, 68% fat, and 18% protein). Repeated Measures Factorial ANOVAs were computed for LC and LF over time. RESULTS: No significant differences (p > 0.05) existed between test meals for fasting values of RER, G, IN, TG, or FFA. PP IN (µU/ml) levels were significantly lower (p < 0.05) following LC compared to LF (10.7 + 6.1 vs. 26.0 + 21.0). PE FFA (mEq/L) levels were significantly greater (p < 0.05) following LC (1.1 + 0.3 vs. 0.5 + 0.3). PE TG (mg/dL) levels were significantly greater (p < 0.05) following LC (152.0 + 53.1 vs. 114.4 + 40.9). RER was significantly lower (p < 0.05) from 0 to 25 min PP and from 25 to 55 min PP after LC (0.72 + 0.04 vs. 0.80 + 0.04 and 0.75 + 0.03 vs. 0.86 + 0.04). RER during exercise was significantly lower (p < 0.05) after LC (0.81 + 0.04 vs. 0.86 + 0.04). CONCLUSIONS: In moderately active adult females, ingestion of a single LC meal resulted in greater lipid oxidation at rest and during exercise as compared to a single LF meal. Although macronutrient distribution appears to have dictated substrate utilization in the present study, more research is needed regarding the long-term effects of macronutrient redistribution with and without exercise on substrate utilization.

Effects of Fat Supplementation on Postprandial GIP, GLP-1, Ghrelin and IGFBP-1 Levels: A Pilot Study on Adolescents with Type 1 Diabetes

Aims: To compare the responses of GIP, GLP-1, ghrelin and IGFBP-1 between meals with different fat and energy content in adolescents with type 1 diabetes (T1DM) and to relate them to gastric emptying and glycaemia. Methods: On different days and in a random order, 7 adolescents with T1DM ingested a high- and low-fat meal (fat content: 38 and 2 g, energy content: 640 and 320 kcal, respectively). At normoglycaemia, the same prandial insulin dose was given at both meals and to all subjects. Postprandial blood samples were taken repeatedly over 4 hours. Gastric emptying was estimated by the paracetamol absorption method. Results: The area under the curve (AUC) for GIP_{0–240 min} and for GLP-1_{0–120 min} was larger, but smaller for relative ghrelin_{0–240 min}, after the high-fat meal (p = 0.002, 0.030 and 0.043, respectively). IGFBP-1 decreased significantly, but not differently, after the meals. Larger GLP-1 secretion correlated with slower gastric emptying (p = 0.029) and higher fasting ghrelin levels correlated with lower postprandial glycaemia (p = 0.007). Conclusion: In adolescents with T1DM, the postprandial responses of GIP, GLP-1 and ghrelin, but not that of IGFBP-1, depend more on meal size than on insulin.

A high protein low fat meal does not influence glucose and insulin responses in obese individuals with or without type 2 diabetes

When substituted for carbohydrate in a meal, dietary protein enhances glycaemic control in subjects with type 2 diabetes (DM2). It is unknown whether the effect is a result of increased protein or reduced carbohydrate. The present study aimed to compare the effects of two meals differing in protein to fat ratios on post-prandial glucose and insulin responses. This was a crossover, blind study in which obese subjects with (n = 23) and without (n = 26) DM2 consumed two meals in random order with equal amounts of energy (3.1 MJ, 741 kcal), fibre and carbohydrates and a 1-week washout period. Meals were a high protein, low fat (30% protein, 51% carbohydrates, 19% fat) meal and a low protein, high fat (15% protein, 51% carbohydrates, 34% fat) meal. Subjects were matched for age and body mass index. Plasma glucose and insulin were measured at fasting, 30, 60, 90, 120 min post-prandially. Insulin resistance and insulin sensitivity were assessed. There was no significant meal effect on glucose and insulin responses within groups. Glucose response was higher in diabetic (120 min 11 +/- 0.7 mmol L(-1)) compared to nondiabetic (120 min 5 +/- 0.2; P < 0.001) subjects. Diabetic subjects had significantly higher insulin resistance (P < 0.001) and lower insulin sensitivity (P < 0.001) than nondiabetics. Although peak insulin levels, 60 min post-prandially, did not differ between groups (81 +/- 9 pmol L(-1) for diabetic versus 79 +/- 7 pmol L(-1) for nondiabetic subjects), they were achieved much later, 90 min post-prandially, in diabetic, (99 +/- 8 pmol L(-1)) compared to nondiabetic (63 +/- 7 pmol L(-1), P = 0.002) subjects. Manipulating protein to fat ratio in meals does not affect post-prandial plasma blood glucose or insulin responses in obese people with and without DM2.

Energy and macronutrient composition of breakfast affect gastric emptying of lunch and subsequent food intake, satiety and satiation

Satiety and food intake are closely related to gastrointestinal transit and specifically gastric emptying. High-fat (HF) meals empty more slowly from the stomach yet are less satiating than isoenergetic low-fat (LF) meals. The current study examines how gastric emptying and satiety at lunch are affected by energy and macronutrient content of breakfast. Nine male volunteers consumed either (1) a HF breakfast, (2) a LF breakfast isoenergetic to HF (LFE) or (3) a LF breakfast of equal mass to HF (LFM). Gastric emptying half time measured using the sodium [13C] acetate breath test was delayed after HF compared to LF meals (HF: 102±11, LFE: 96±13, LFM: 95±13min, mean±SD). Fullness increased and desire to eat decreased following the LFE breakfast measured using visual analogue scales. Eating a HF breakfast increased the energy, fat and protein from an ad libitum buffet meal given 4h after lunch. In conclusion, eating a HF breakfast delayed gastric emptying of lunch and increased food intake 7h later compared to a LFM breakfast. These data suggest both mass and energy content of food regulate subsequent appetite and feeding and demonstrate the hyperphagic effect of a single HF meal.

Acute Molecular Mechanisms Responsive to Feeding and Meal Constitution in Mesenteric Adipose Tissue

To identify the acute effects of feeding on mesenteric fat, we have performed a transcriptomic study in the mesenteric adipose tissue after low-fat (LF) and high-fat (HF) meal ingestion. After fasting, one group of mice was killed and the others were fed ad libitum with HF or LF meal, and killed 3 h after the ingestion. Serial analysis of gene expression (SAGE) was performed, generating approximately 150,000 tags/sample. The results were confirmed using quantitative real-time PCR (qRT-PCR). Transcripts involved in lipid biosynthesis were upregulated only by LF meal, whereas intracellular lipid catabolism was repressed by feeding. Apoptotic genes were downregulated, whereas antiapoptosis and proteolysis were upregulated by feeding. The expression levels of genes coding for adiponectin and ribosomal proteins were decreased by HF meal, as well as transcripts involved in mRNA processing, cytoskeleton, and extracellular matrix. Several other fat-responsive genes were identified, including diverse uncharacterized transcripts. These results revealed that mesenteric adipose tissue transcriptome was responsive to food intake and was affected differently according to meal constitution. The identification of uncharacterized transcripts regulated by LF and HF meals is a first step toward further understanding the early mechanisms of diet-induced obesity as well as discovering new therapeutic targets for obesity-related diseases.

The effect of food with varying fat content on the clinical pharmacokinetics of gabapentin after oral administration of gabapentin enacarbil

Gabapentin enacarbil, an actively transported prodrug of gabapentin, provides sustained and dose-proportional exposure to gabapentin. To evaluate the effect of food of varying fat content on the pharmacokinetics and tolerability of gabapentin enacarbil. METHODS, MATERIALS AND SUBJECTS: A randomized, open-label, crossover study of 1,200 mg gabapentin enacarbil was conducted in 12 healthy adults, under four conditions: fasted, or following low-fat (200 - 300 kcal total, approximately 6% from fat), moderate-fat (500 - 600 kcal total, approximately 30% from fat) or high-fat meals (1,000 kcal total, approximately 50% from fat), separated by a washout period of >or= 5 days. Ten subjects completed treatment under all four conditions. Data from all subjects were used for pharmacokinetic and safety analyses unless stated otherwise. Mean (standard deviation) bioavailability (based on urinary recovery) of gabapentin from gabapentin enacarbil was 42.0 (6.1)% (fasted), 64.3 (13.2)% (low-fat meal), 64.9 (16.9)% (moderate-fat meal), and 76.1 (14.4)% (high-fat meal). Gabapentin exposures (AUC(inf)) in fed conditions were 23% (low-fat meal), 31% (moderate-fat meal), and 40% (high-fat meal) greater than the exposure under fasted condition. Fed conditions did not significantly delay median t(max), but a trend for delayed gabapentin enacarbil absorption was seen in t(max) ranges following moderate- and high-fat meals compared with the fasted state or low-fat meal. The most commonly reported treatment-emergent adverse events (TEAEs) were dizziness (4 subjects), balance disorder (4 subjects) and somnolence (3 subjects). All TEAEs were rated as mild in intensity. Administration of gabapentin enacarbil with food enhanced gabapentin exposure compared with fasted conditions, regardless of the fat or caloric content, and gabapentin enacarbil was generally well tolerated.

Feeding Regulates the Expression of Pancreatic Genes in Gastric Mucosa

The ineffective short-term control of feeding behavior compromises energy homeostasis and can lead to obesity. The gastrointestinal tract secretes several regulatory peptides. However, little is known about the stomach peptide contribution to the acute regulation of intake. In an attempt to identify new gastric signals, the serial analysis of gene expression (SAGE) method was used for the transcription profiling of stomach mucosa in 7 groups of mice: fasting and sacrificed 30 minutes, 1 hour, 3 hours after a low-fat (LF) or high-fat (HF) ad libitum meal. In total, 35 genes were differentially modulated by LF and HF meals compared to fasting, including 15 mRNAs coding for digestive enzymes/secretory proteins, and 10 novel transcripts. Although the basic expression profile did not undergo substantial variations, both LF and HF meals influenced the transcription. This study represents the first global analysis of stomach transcriptome as induced by different nutritional stimuli. Further studies including the characterization of novel genes may help to identify new targets for the therapy and prevention of obesity.

Effects of a low-fat meal on the oral bioavailability of UFT and leucovorin in patients with colorectal cancer

UFT is composed of tegafur, a prodrug of 5-fluorouracil, and uracil, at a fixed ratio of 1: 4. UFT is widely used with leucovorin as adjuvant chemotherapy in patients with colon cancer. As reported, UFT/leucovorin should not be taken simultaneously with food because a high fat content will reduce the systemic exposure to the active cytotoxic moiety of UFT. In this single-dose, randomized, two-way crossover study, we investigated the effects of a low-fat Japanese meal on the pharmacokinetics and oral bioavailability of UFT (2 x 100-mg capsules; dose in terms of tegafur) and leucovorin (1 x 25-mg tablet). Patients (n = 12) were randomly assigned to receive both drugs after an overnight fast or 5 min after eating a standard Japanese breakfast (641 kcal), with a 3-day washout period between treatments. Pharmacokinetics (n = 12) were determined for tegafur, 5-fluorouracil, uracil, leucovorin, and 5-methyltetrahydrofolate (an active metabolite of leucovorin). For 5-fluorouracil pharmacokinetics, the maximum plasma concentration and the area under the curve were reduced by 73.7% and 47.4%, respectively, when UFT was taken postprandially, and the maximum plasma concentration and the area under the curve for uracil were reduced by 84.1% and 68.9%, respectively, compared with dosing on an empty stomach. These decreases in the systemic exposure to 5-fluorouracil were quite marked and may have an impact on its antitumor effect. A low-fat meal affects the pharmacokinetics of UFT similarly to a high-fat meal.

A Phase I and Pharmacokinetic Study of Oral Lapatinib Administered Once or Twice Daily in Patients with Solid Malignancies

This study determined the range of tolerable doses, clinical safety, pharmacokinetics, and preliminary evidence of clinical activity following once or twice daily administration of lapatinib in patients with solid malignancies. Cancer patients (n = 81) received oral doses of lapatinib ranging from 175 to 1,800 mg once daily or 500 to 900 mg twice daily. Clinical assessments of safety and antitumor activity were recorded and blood was sampled for pharmacokinetic assessments. The effect of a low-fat meal on lapatinib pharmacokinetics was assessed in a subset of patients. Lapatinib was well tolerated, such that dose escalation was limited at 1,800 mg once daily only by pill burden. Twice-daily dosing was implemented to further explore tolerability, and was limited by diarrhea to 500 mg twice daily. The most commonly reported adverse events with once-daily dosing were diarrhea (48%), nausea (40%), rash (40%), and fatigue (38%) and with twice-daily dosing were diarrhea (85%), rash (54%), and nausea (34%). Lapatinib serum concentrations accumulated upon repeated dosing, increasing nearly in proportion with dose, and were significantly increased when dosed with food or administered twice daily. One patient with head and neck cancer achieved a confirmed complete response and 22 patients had stable disease of >or=8 weeks including three patients with stable disease of >10 months (renal, lung, and salivary gland cancers). Lapatinib was well tolerated following once and twice daily administration. Systemic exposure to lapatinib was dependent on the dose, duration and frequency of dosing, and prandial state. Clinical activity was observed.

Single-dose pharmacokinetics and pharmacodynamics of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

Anacetrapib is an orally active and potent inhibitor of CETP in development for the treatment of dyslipidaemia. These studies endeavoured to establish the safety, tolerability, pharmacokinetics and pharmacodynamics of rising single doses of anacetrapib, administered in fasted or fed conditions, and to preliminarily assess the effect of food, age, gender and obesity on the single-dose pharmacokinetics and pharmacodynamics of anacetrapib. Safety, tolerability, anacetrapib concentrations and CETP activity were evaluated. Anacetrapib was rapidly absorbed, with peak concentrations occurring at approximately 4 h post-dose and an apparent terminal half-life ranging from approximately 9 to 62 h in the fasted state and from approximately 42 to approximately 83 h in the fed state. Plasma AUC and C(max) appeared to increase in a less than approximately dose-dependent manner in the fasted state, with an apparent plateau in absorption at higher doses. Single doses of anacetrapib markedly and dose-dependently inhibited serum CETP activity with peak effects of approximately 90% inhibition at t(max) and approximately 58% inhibition at 24 h post-dose. An E(max) model best described the plasma anacetrapib concentration vs CETP activity relationship with an EC(50) of approximately 22 nm. Food increased exposure to anacetrapib; up to approximately two-three-fold with a low-fat meal and by up to approximately six-eight fold with a high-fat meal. Anacetrapib pharmacokinetics and pharmacodynamics were similar in elderly vs young adults, women vs men, and obese vs non-obese young adults. Anacetrapib was well tolerated and was not associated with any meaningful increase in blood pressure. Whereas food increased exposure to anacetrapib significantly, age, gender and obese status did not meaningfully influence anacetrapib pharmacokinetics and pharmacodynamics.

Características y utilidad de los sustitutos de la comida: análisis de los productos comercializados de uso habitual en nuestro entorno

Obesity has become a serious health problem. It is nowadays considered a pandemia and it is therefore a priority to develop different strategies on its prevention and treatment: lifestyle changes, community interventions as well as pharmacological and non-pharmacological activities. In this way, meal replacement products (energy reduced products designed to replace one or two regular meals providing a supously nutritionally balanced low fat meal) can be an alternative to traditional reduced calorie diet. Our aim was to revise the literature on meal replacement and compare the nutritional composition and the different forms of presentation of the main meal replacement products commercialised in Spain. We made a research in pharmacies, weight loss centers and big supermarkets of food products specially designed to replace a meal. We compared the nutritional composition regarding macronutrients and micronutrients of the thirty-two different products founded, including their different form of presentation (bars, powder, drink-shakes and crackers). In order to judge their nutritional composition, we compared one meal replaced with these products with the Recommended Dietary Allowances (RDA). The most common form of meal replacement products were bars (23 of 32 analyzed products), followed by powder for making shakes (6 products), bricks (2 products) and crackers (1 product). When we analysed a single meal replaced with these products, we founded that the global distribution of macronutrients was: 45% as carbohydrates, 29% as fats, 26% as proteins, and 4.45 grams of fiber. Their average energy was 266 Kcal per meal. Regarding micronutrients (vitamins and minerals), there was a great variability among the different products, but in average their composition was above the 33% of the RDA per meal specially in iron and vitamins B1, B6 and D. Calcium, magnesium, folic acid and vitamin B12 were the micronutrients less plentiful. Partial meal replacement can be an alternative or a complementary therapeutic option to conventional hipocaloric diets in obesity since they appear to have an easier understanding and follow up. It is therefore important to consider them in weight management programs and more studies are required to establish strict criteria on their nutritional composition by a legal normative.

Positive relationship between dietary fat, ethanol intake, triglycerides, and hypothalamic peptides: counteraction by lipid-lowering drugs

Studies in both humans and animals suggest a positive relationship between the intake of ethanol and intake of fat, which may contribute to alcohol abuse. This relationship may be mediated, in part, by hypothalamic orexigenic peptides such as orexin (OX), which stimulate both consumption of ethanol and fat, and circulating triglycerides (TGs), which stimulate these peptides and promote consummatory behavior. The present study investigated this vicious cycle between ethanol and fat, to further characterize its relation to TGs and to test the effects of lowering TG levels. In Experiment 1, the behavioral relationship between fat intake and ethanol was confirmed. Adult male Sprague-Dawley rats, chronically injected intraperitoneally with ethanol (1 g/kg) and tested in terms of their preference for a high-fat diet (HFD) compared with low-fat diet (LFD), showed a significant increase in their fat preference, compared with rats injected with saline, in measures of 2 h and 24 h intake. Experiment 2 tested the relationship of circulating TGs in this positive association between ethanol and fat, in rats chronically consuming 9% ethanol versus water and given acute meal tests (25 kcal) of a HFD versus LFD. Levels of TGs were elevated in response to both chronic drinking of ethanol versus water and acute eating of a high-fat versus low-fat meal. Most importantly, ethanol and a HFD showed an interaction effect, whereby their combination produced a considerably larger increase in TG levels (+172%) compared to ethanol with a LFD (+111%). In Experiment 3, a direct manipulation of TG levels was found to affect ethanol intake. After intragastric administration of gemfibrozil (50 mg/kg) compared with vehicle, TG levels were lowered by 37%, and ethanol intake was significantly reduced. In Experiment 4, the TG-lowering drug gemfibrozil also caused a significant reduction in the expression of the orexigenic peptide, OX, in the perifornical lateral hypothalamus. These results support the existence of a vicious cycle between ethanol and fat, whereby each nutrient stimulates intake of the other. Within this vicious cycle, ethanol and fat act synergistically to increase TG levels, which in turn stimulate peptides that promote further consumption, and these phenomena are reversed by gemfibrozil, which lowers TG levels.

Circulating triglycerides after a high-fat meal: Predictor of increased caloric intake, orexigenic peptide expression, and dietary obesity

Recent studies in normal-weight rats have linked circulating triglycerides (TG), when elevated by a high-fat (HF) compared to equicaloric low-fat (LF) meal, to an increase in subsequent food intake and hypothalamic expression of orexigenic peptides. The present study tested whether natural variations between rats in their TG levels after a small HF meal can also be related to their individual patterns of eating and peptide expression. In tail vein blood collected on three separate days 60 min after a HF meal, levels of TG were found to be strongly, positively correlated within rats from day to day but were highly variable between rats (75–365 mg/dl), allowing distinct subgroups (33% lowest or highest) to be formed. Compared to “Low-TG responders” with post-meal levels averaging 109 mg/dl, “High-TG responders” with 240 mg/dl showed in two separate experiments a significant increase in caloric intake in a subsequent laboratory chow meal. Before this larger meal, these rats with elevated TG consistently exhibited higher expression levels and synthesis of the orexigenic peptides, enkephalin, orexin and melanin-concentrating hormone, as revealed using real-time quantitative PCR, radiolabeled in situ hybridization, and immunofluorescence histochemistry. Over the long-term, the High-TG responders also showed an increased propensity to overeat, gain weight and accumulate excess body fat on a chronic HF diet. This simple measure of TG levels after a HF meal may offer a useful tool for identifying subpopulations with increased risk for overeating and dietary obesity and detecting early signs of brain disturbances that may contribute to this high-risk phenotype.