On the usefulness of compendial setups and tiny-TIM system in evaluating the in vivo performance of oral drug products with various release profiles in the fasted state: Case example sodium salt of A6197.

We evaluated the usefulness of quality control dissolution data collected with compendial Apparatus I and II, biorelevant dissolution data collected with compendial apparatus IV, and bioaccessibility data collected with the non-compendial tiny-TIM system in screening modified release formulations during the development of BCS Class I compounds using a Boehringer Ingelheim model experimental compound, A6197. Four products were investigated: an immediate release tablet, an extended release tablet, modified release mini-tablets, and extended release pellets. Data with modified release products collected with the compendial apparatus were evaluated vs.

Appetite ratings of foods are predictable with an in vitro advanced gastrointestinal model in combination with an in silico artificial neural network.

The expected increase of global obesity prevalence makes it necessary to have information about the effects of meal intakes on the feeling of appetite. Because human clinical studies are time and cost intensive, there is a need for a reliable alternative. The aim of this study was to develop and evaluate an in vitro-in silico technology to predict the feelings of fullness and hunger after consumption of different types of meals.

Survival of Mycobacterium bovis BCG oral vaccine during transit through a dynamic in vitro model simulating the upper gastrointestinal tract of badgers.

In developing an oral bait BCG vaccine against tuberculosis in badgers we wanted to understand the conditions of the gastrointestinal tract and their impact on vaccine viability. Conditions mimicking stomach and small-intestine caused substantial reduction in BCG viability. We performed in vivo experiments using a telemetric pH monitoring system and used the data to parameterise a dynamic in vitro system (TIM-1) of the stomach and small intestine.

Can dynamic digestion systems mimic the physiological reality?

During the last decade, there has been a growing interest in understanding the fate of food during digestion in the gastrointestinal tract in order to strengthen the possible effects of food on human health. Ideally, food digestion should be studied on humans but this is not always ethically and financially possible. Therefore simple static digestion models mimicking the gastrointestinal tract have been proposed as alternatives to experiments but these models are quite basic and hardly recreate the complexity of the digestive tract.

Protein Digestion and Quality of Goat and Cow Milk Infant Formula and Human Milk Under Simulated Infant Conditions.

Objective: The aim of this study was to determine the kinetics of true ileal protein digestion and digestible indispensable amino acid score (DIAAS) of a goat milk-based infant formula (GIF), a cow milk-based infant formula (CIF), and human milk (HM).

Methods: The GIF, CIF, and HM were investigated in an in vitro gastrointestinal model simulating infant conditions. Digested compounds were dialyzed from the intestinal compartment as bioaccessible fraction.

Herring roe protein has a high digestible indispensable amino acid score (DIAAS) using a dynamic in vitro gastrointestinal model.

It is hypothesized that the digestible indispensable amino acid score (DIAAS) can be determined based on dynamic in vitro gastrointestinal digestion experiments as replacement for invasive animal studies. We determined the in vitro DIAAS for immature herring eggs (roe) proteins in comparison with reference proteins. The true ileal digestibility of protein and indispensable amino acids (IAA) was measured under human conditions simulated in a gastrointestinal model (tiny-TIM).

Malondialdehyde and 4-hydroxy-2-hexenal are formed during dynamic gastrointestinal in vitro digestion of cod liver oils.

Marine long-chain polyunsaturated fatty acids (LC n-3 PUFA) are associated with reduced risk for inflammatory diseases, such as cardiovascular diseases and rheumatoid arthritis. These fatty acids, however, are rapidly oxidized, generating highly reactive malondialdehyde (MDA), 4-hydroxy-2-hexenal (HHE) and 4-hydroxy-2-nonenal (HNE). These oxidation products may interact with DNA and proteins, thus possibly leading to impaired cell functions.

Formation of malondialdehyde (MDA), 4-hydroxy-2-hexenal (HHE) and 4-hydroxy-2-nonenal (HNE) in fish and fish oil during dynamic gastrointestinal in vitro digestion.

Marine lipids contain a high proportion of polyunsaturated fatty acids (PUFA), including the characteristic long chain (LC) n-3 PUFA. Upon peroxidation these lipids generate reactive products, such as malondialdehyde (MDA), 4-hydroxy-2-hexenal (HHE) and 4-hydroxy-2-nonenal (HNE), which can form covalent adducts with biomolecules and thus are regarded as genotoxic and cytotoxic. PUFA peroxidation can occur both before and after ingestion.

Increased bioavailability of celecoxib under fed versus fasted conditions is determined by postprandial bile secretion as demonstrated in a dynamic gastrointestinal model.

The objective of this study was to utilize physiologically relevant dynamic dissolution testing with the TNO intestinal model (TIM-1) in vitro gastrointestinal model to investigate the bioaccessibility of celecoxib. A single 200-mg dose of celecoxib was evaluated under average adult human physiological conditions simulated in the TIM-1 system. The in vitro data were compared with the clinically established pharmacokinetic data.

Evaluation of two dynamic in vitro models simulating fasted and fed state conditions in the upper gastrointestinal tract (TIM-1 and tiny-TIM) for investigating the bioaccessibility of pharmaceutical compounds from oral dosage forms.

Pharmaceutical research needs predictive in vitro tools for API bioavailability in humans. We evaluated two dynamic in vitro gastrointestinal models: TIM-1 and tiny-TIM. Four low-soluble APIs in various formulations were investigated in the TIM systems under fasted and fed conditions.

The bioaccessibility of eicosapentaenoic acid was higher from phospholipid food products than from mono- and triacylglycerol food products in a dynamic gastrointestinal model.

The bioaccessibility of eicosapentaenoic acid (EPA) in the forms of monoacylglycerol (EPA-MAG), triacylglycerol (EPA-TAG), and phospholipid (EPA-PL) during gastrointestinal passage was compared in this study using a dynamic gastrointestinal model (TIM system). The TIM system simulated the average upper gastrointestinal tract conditions of healthy human adults after intake of a meal (fed state conditions). In this study, the three EPA-rich oils were separately homogenized with full fat milk to obtain oil-in-water emulsions.

Effects of a high fat meal matrix and protein complexation on the bioaccessibility of blueberry anthocyanins using the TNO gastrointestinal model (TIM-1).

The TNO intestinal model (TIM-1) of the human upper gastrointestinal tract was used to compare intestinal absorption/bioaccessibility of blueberry anthocyanins under different digestive conditions. Blueberry polyphenol-rich extract was delivered to TIM-1 in the absence or presence of a high-fat meal. HPLC analysis of seventeen anthocyanins showed that delphinidin-3-glucoside, delphinidin-3-galactoside, delphinidin-3-arabinoside and petunidin-3-arabinoside were twice as bioaccessible in fed state, whilst delphinidin-3-(6″-acetoyl)-glucoside and malvidin-3-arabinoside were twice as bioaccessible under fasted conditions, suggesting lipid-rich matrices selectively effect anthocyanin bioaccessibility.

In vitro gastrointestinal model (TIM) with predictive power, even for infants and children?

There is a need for information on the bioavailability in pediatric patients of drugs from manipulated dosage forms when applied in combination with food and/or co-medication under realistic daily practice circumstances. We describe the development, validation and application of a dynamic, computer-controlled in vitro system mimicking the conditions in the upper gastrointestinal tract of neonates, infants and toddlers: TIMpediatric. Paracetamol and diclofenac in age-related food matrices and with esomeprazole co-medication were tested.

Digestibility of transglutaminase cross-linked caseinate versus native caseinate in an in vitro multicompartmental model simulating young child and adult gastrointestinal conditions.

Aim of this study was to investigate the digestion of transglutaminase cross-linked caseinate (XLC) versus native caseinate (NC) in solution and in cheese spread under digestive conditions for adults and children mimicked in a gastrointestinal model. Samples were collected for gel electrophoresis and nitrogen analysis. The results showed no relevant differences between XLC and NC for total and α-amino nitrogen in digested fraction under adult and child conditions.

Complementary approaches to gauge the bioavailability and distribution of ingested berry polyphenolics.

Two different strategies for investigating the likely fate, after ingestion, of natural, bioactive berry constituents (anthocyanins and other non-nutritive flavonoids) are compared. A model of the human gastrointestinal tract (TIM-1) that mimicked the biological environment from the point of swallowing and ingestion through the duodenum, jejunum, and ileum (but not the colon) was used to monitor the stability and bioaccessibility of anthocyanins from both maqui berry and wild blueberry. TIM-1 revealed that most anthocyanins were bioaccessible between the second and third hours after intake.

Effect of bioprocessing of wheat bran in wholemeal wheat breads on the colonic SCFA production in vitro and postprandial plasma concentrations in men.

The health benefits of whole grain consumption can be partly attributed to the inclusion of the bran or outer-layers of the grain rich in dietary fibre. Fibre is fermented in the colon, leading to the production of beneficial metabolites, such as short-chain fatty acids (SCFA). The effect of five different types of bread on the SCFA production was studied in an in vitro model of human colon.

Intestinal health functions of colonic microbial metabolites: a review.

This review tries to find a scientific answer on the following two questions: (1) to what extent do we understand the specific role of colonic microbial metabolites, especially short-chain fatty acids (SCFA), in maintaining the health status and prevention of diseases of the colon and the host; (2) to what extent can we influence or even control the formation of colonic microbial metabolites which are beneficial for the health status. The review focuses on the following topics: energy source, intestinal motility, defence barrier, oxidative stress with special attention for antiinflammatory and anti-carcinogen functions, and satiety. Also the risk of overproduction of SCFA is discussed.

Bioprocessing of wheat bran in whole wheat bread increases the bioavailability of phenolic acids in men and exerts antiinflammatory effects ex vivo.

Whole grain consumption has been linked to a lower risk of metabolic syndrome, which is normally associated with a low-grade chronic inflammation. The benefits of whole grain are in part related to the inclusion of the bran, rich in phenolic acids and fiber. However, the phenols are poorly bioaccessible from the cereal matrix.

Bioprocessing of wheat bran improves in vitro bioaccessibility and colonic metabolism of phenolic compounds.

Ferulic acid (FA) is the most abundant phenolic compound in wheat grain, mainly located in the bran. However, its bioaccessibility from the bran matrix is extremely low. Different bioprocessing techniques involving fermentation or enzymatic and fermentation treatments of wheat bran were developed aiming at improving the bioaccessibility of phenolic compounds in bran-containing breads.

Ferulic acid from aleurone determines the antioxidant potency of wheat grain (Triticum aestivum L.).

Grain is an important source of phytochemicals, which have potent antioxidant capacity. They have been implicated in the beneficial health effect of whole grains in reducing cardiovascular disease and type 2 diabetes. The aim of the present study was to identify the most important antioxidant fractions of wheat grain.

Assessment of the multi-mycotoxin-binding efficacy of a carbon/aluminosilicate-based product in an in vitro gastrointestinal model.

A laboratory model, set to simulate the in vivo conditions of the porcine gastrointestinal tract, was used to study the small intestinal absorption of several mycotoxins and the effectiveness of Standard Q/FIS (a carbon/aluminosilicate-based product) in reducing mycotoxin absorption when added to multitoxin-contaminated diets. Mycotoxins were quickly absorbed in the proximal part of the small intestine at levels of 105 and 89% for fumonisins B1 and B2, respectively, 87% for ochratoxin A, 74% for deoxynivalenol, 44% for aflatoxin B1, and 25% for zearalenone. Addition of Standard Q/FIS to the diet (up to 2%, w/w) significantly reduced mycotoxin absorption, in a dose-dependent manner, up to 88% for aflatoxin B1, 44% for zearalenone, and 29% for the fumonisins and ochratoxin.

Efficient degradation of gluten by a prolyl endoprotease in a gastrointestinal model: implications for coeliac disease.

Background: Coeliac disease is caused by an immune response to gluten. As gluten proteins are proline rich they are resistant to enzymatic digestion in the gastrointestinal tract, a property that probably contributes to the immunogenic nature of gluten.

Aims: This study determined the efficiency of gluten degradation by a post-proline cutting enzyme, Aspergillus niger prolyl endoprotease (AN-PEP), in a dynamic system that closely mimics the human gastrointestinal tract (TIM system).

Predicted serum folate concentrations based on in vitro studies and kinetic modeling are consistent with measured folate concentrations in humans.

The nutritional quality of new functional or fortified food products depends on the bioavailability of the nutrient(s) in the human body. Bioavailability is often determined in human intervention studies by measurements of plasma or serum profiles over a certain time period. These studies are time and cost consuming and often appear to lack an optimal study design, leading to follow-up intervention trials.

Research goals for folate and related B vitamin in Europe.

In the past decade, the understanding of folate bioavailability, metabolism and related health issues has increased, but several problems remain, including the difficulty of delivering the available knowledge to the populations at risk. Owing to the low compliance of taking folic acid supplements, for example, among women of child-bearing age who could lower the risk of having a baby with a neural tube defect, food-based strategies aimed at increasing the intake of folate and other B-group vitamins should be a priority for future research. These should include the development of a combined strategy of supplemental folate (possibly with vitamin B(12)), biofortification using engineered plant-derived foods and micro-organisms and food fortification for increasing folate intakes in the general population.