Iron absorption in adults with sickle cell anemia: a stable-isotope approach.

PURPOSE: Iron absorption in sickle cell anemia (SCA) remains unclear and studies in adults with SCA are scarce. The aim of this study was to evaluate the iron absorption SCA adults and its association with iron status and hepcidin concentration. METHODS: SCA patients (n = 13; SCAtotal) and control participants (n = 10) ingested an oral stable iron isotope (57Fe). Iron absorption was measured by inductively coupled plasma mass spectrometry (ICP-MS) 14 days after isotope administration. Patients with ≥ 1000 ng/mL serum ferritin were considered to present iron overload (IO) (SCAio+; n = 3) and others classified without IO (SCAio-; n = 10). RESULTS: Iron absorption in the control group ranged from 0.3 to 26.5% (median = 0.9%), while it varied from 0.3 to 5.4% in SCAio+ (median = 0.5%) and from 0.3 to 64.2% in the SCAio- (median = 6.9%). Hepcidin median values were 14.1 ng/mL (3.0-31.9 ng/mL) in SCAio-, 6.2 ng/mL (3.3-7.8 ng/mL) in SCAio + and 6.2 ng/mL (0.6-9.3 ng/mL) in control. Iron absorption was associated with ferritin level (r = - 0.641; p = 0.018) and liver iron concentration (LIC; r = - 0.786; p = 0.036) in the SCAtotal group. CONCLUSION: Our data suggest that SCAio- individuals may be at risk of developing primary IO. Simultaneously, secondary IO may induce physiological adaptation, resulting in reduced iron absorption. Further studies evaluating intestinal iron absorption using larger sample sizes should be conducted to help establish a safe nutrition approach to be adopted and to ensure the security of food-fortifying public policies for these patients. TRIAL REGISTRATION: This trial was registered at www.ensaiosclinicos.gov.br (Identifier RBR-4b7v8pt).

Endurance exercise associated with a fructooligosaccharide diet modulates gut microbiota and increases colon absorptive area.

BACKGROUND AND AIM: Fructooligosaccharide (FOS) supplementation can stimulate beneficial intestinal bacteria growth, but little is known about its influence on training performance. Therefore, this study analyzed FOS and exercise effects on gut microbiota and intestinal morphology of C57Bl/6 mice. METHODS: Forty male mice were divided into four groups: standard diet-sedentary (SDS), standard diet-exercised (SDE), FOS supplemented (7.5% FOS)-sedentary (FDS), and FOS supplemented-exercised (FDE), n = 10 each group. Exercise training consisted of 60 min/day, 3 days/week, for 12 weeks. RESULTS: SDE and FDE groups had an increase in aerobic performance compared to the pretraining period and SDS and FDS groups (P < 0.01), respectively. Groups with FOS increased colonic crypts size (P < 0.05). The FDE group presented rich microbiota (α-diversity) compared to other groups. The FDE group also acquired a greater microbial abundance (ß-diversity) than other groups. The FDE group had a decrease in the Ruminococcaceae (P < 0.002) and an increase in Roseburia (P < 0.003), Enterorhabdus (P < 0.004) and Anaerotruncus (P < 0.006). CONCLUSIONS: These findings suggest that aerobic exercise associated with FOS supplementation modulates gut microbiota and can increase colonic crypt size without improving endurance exercise performance.

Adult and pediatric physiologically-based biopharmaceutics modeling to explain lamotrigine immediate release absorption process.

Physiologically-based biopharmaceutics modeling (PBBM) has potential to accelerate the development of new drug and formulations. An important application of PBBM is for special populations such as pediatrics that have pharmacokinetics dependent on the maturation process. Lamotrigine (LTG) is a Biopharmaceutics Classification System (BCS) II drug and is widely prescribed. Therefore, the goal of this study was to assess the biopharmaceutics risk of the low-soluble drug LTG when the ontogeny on gastrointestinal tract (GIT) physiological parameters are considered. An oral physiologically-based pharmacokinetic model and a PBBM were developed and verified using GastroPlus™ software for both adults and children (2-12 years old, 12-52 kg). The biopharmaceutics properties and GIT physiological parameters were evaluated by sensitivity analysis. High doses were simulated assuming a worst case scenario, that is, the dose of 200 mg for adults and 5 mg/kg (up to the maximum of 200 mg) for 2-year-old children. Although several authors have suggested that ontogeny may have an effect on gastrointestinal fluid volume, our study found no evidence of interference between fluid and dose volumes with in vivo dissolution of LTG. The most impactful parameter was found to be the gastric transit time. Therefore, the hypothesis is developed to examine whether LTG exhibits characteristics of a BCS II classification in vitro while showing BCS I-like behavior in vivo. This hypothesis could act as a base for conducting novel studies on model-informed precision dosing, tailored to specific populations and clinical conditions. In addition, it could be instrumental in assessing the influence of various release profiles on in vivo performance for both adult and pediatric populations.

Exploring in vitro solubility of lamotrigine in physiologically mimetic conditions to prospect the in vivo dissolution in pediatric population.

Pediatric drugs knowledge still leaves several gaps to be filled, all the while many biopharmaceutic properties applied to adults do not work in pediatrics. The solubility in many cases is extrapolated to pediatrics; however, sometimes it may not represent the real scenario. In this context, the aim of this study was to assess the possibility of the extrapolation of the solubility data assumed for adults to children aged 2-12 years using lamotrigine (LTG) as a model. LTG showed that its solubility is dependent on the pH of the medium, no precipitate formation was seen, and biomimetic media showed a greater capacity to solubilize it. Based on the dose number (D0 ) in adults, the LTG was soluble in acidic pH media and poorly soluble in neutral to basic. Similar behavior was found in conditions which mimic children aged 10-12 years at a dose of 5 and 15 mg/kg. The D0 for 5-year-old children at a dose of 15 mg/kg showed different behaviors between biorelevant and pharmacopeial buffers media. For children aged 2-3 years, LTG appeared to be poorly soluble under both gastric and intestinal conditions. Solubility was dependent on the volume of fluid calculated for each age group, and this may impact the development of better pharmaceutical formulations for this population, better pharmacokinetic predictions in tools as PBPK, and physiologically-based biopharmaceutics modeling, greater accuracy in the justifications for biowaiver, and many other possibilities.

Bioaccessibility and uptake/epithelial transport of vitamin E: Discoveries and challenges of in vitro and ex vivo assays.

Vitamin E comprises compounds consisting of a chromanol ring and an isoprenoid side-chain, and is an essential lipid-soluble nutrient with several physiological functions. Vitamin E intake has been reported as inadequate for some populations. Only a fraction of dietary vitamin E is effectively released from the food matrix (bioaccessible fraction), absorbed (enterocyte uptake/epithelial transport) and transported in lipoproteins to reach the target tissues (bioavailable fraction), depending on the food structure, composition, and processing. Therefore, research concerning the fate of vitamin E through the gastrointestinal tract is of paramount importance for developing healthy foods and guiding effective public policies. The combination of simulated in vitro gastrointestinal digestion followed by intestinal epithelial transport and/or enterocyte uptake assays using ex vivo cell models has been successfully used to mimic the physiological conditions and predict the bioaccessibility and epithelial transport of compounds. The objective of this review was to summarize the current knowledge and challenges for predicting the bioaccessibility and uptake/epithelial transport of vitamin E by in vitro and ex vivo assays. Here, we revisited the metabolism of vitamin E and introduced in vitro and ex vivo methods for estimating the bioaccessibility and intestinal absorption of vitamin E. This review compiles data on vitamin E bioaccessibility in vitro and uptake/epithelial transport ex vivo for different food matrices, and discusses the factors that can affect their measurement. Additionally, co-culture approaches using hepatic lineages to assess vitamin E bioavailability are further presented.

Lactobacillus acidophilus BIOTECH 1900 decreases the transepithelial mucosal-to-serosal transport of colchicine in an ex vivo non-everted gut sac model.

Colchicine (COL) is a permeability-glycoprotein (P-gp) substrate drug used for familial Mediterranean fever, acute pericarditis, and the management of acute gout. It has a narrow therapeutic index which implies that a small change in the drug's absorption profile may lead to either toxicity or therapeutic failure. Absorption can be altered by modulating the function of P-gp via the concomitant use of drugs, herbal medicines, or food supplements such as probiotics. Here, we investigated the effect of probiotic Lactobacillus acidophilus BIOTECH 1900 on COL's transepithelial mucosal-to-serosal transport in the jejunum of ICR mice. A high-performance liquid chromatography-photodiode array (HPLC-PDA) method for the assay of COL was developed and validated. The HPLC-PDA method was applied in an ex vivo non-everted gut sac model to measure COL's cumulative mucosal-to-serosal transport and apparent permeability (Papp). Treatment of L. acidophilus BIOTECH 1900 resulted to a significantly lower COL transport and Papp value compared to the control group. Additionally, the activity of L. acidophilus BIOTECH 1900 was found to be similar to dexamethasone, a known P-gp inducer. We report that L. acidophilus BIOTECH 1900 decreases the transepithelial mucosal-to-serosal transport of COL, suggesting possible P-gp induction. Further studies are recommended to substantiate this transporter-based drug-probiotic interaction.

Calcium is a noncompetitive inhibitor of DMT1 on the intestinal iron absorption process: empirical evidence and mathematical modeling analysis.

Iron absorption is a complex and highly controlled process where DMT1 transports nonheme iron through the brush-border membrane of enterocytes to the cytoplasm but does not transport alkaline-earth metals such as calcium. However, it has been proposed that high concentrations of calcium in the diet could reduce iron bioavailability. In this work, we investigate the effect of intracellular and extracellular calcium on iron uptake by Caco-2 cells, as determined by calcein fluorescence quenching. We found that extracellular calcium inhibits iron uptake by Caco-2 cells in a concentration-dependent manner. Chelation of intracellular calcium with BAPTA did not affect iron uptake, which indicates that the inhibitory effect of calcium is not exerted through intracellular calcium signaling. Kinetic studies performed, provided evidence that calcium acts as a reversible noncompetitive inhibitor of the iron transport activity of DMT1. Based on these experimental results, a mathematical model was developed that considers the dynamics of noncompetitive inhibition using a four-state mechanism to describe the inhibitory effect of calcium on the DMT1 iron transport process in intestinal cells. The model accurately predicts the calcein fluorescence quenching dynamics observed experimentally after an iron challenge. Therefore, the proposed model structure is capable of representing the inhibitory effect of extracellular calcium on DMT1-mediated iron entry into the cLIP of Caco-2 cells. Considering the range of calcium concentrations that can inhibit iron uptake, the possible inhibition of dietary calcium on intestinal iron uptake is discussed.

Absorción mineral y retención ósea en ratas normales en crecimiento por el consumo de un yogur experimental reducido en lactosa que contiene galactooligosacáridos (GOS) / Mineral absorption and bone retention in normal growing rats by consumption of an experimental lactose-reduced yogurt containing galactooligosaccharides (GOS)

Introducción: Los GOS son prebióticos naturales presentes en la leche materna que pue-den obtenerse enzimáticamente a partir de la lactosa de leche de vaca durante la fabricación de yogur. El producto lácteo resultante será reducido en lactosa y contendrá prebióticos y bacterias potencialmente probióticas. Sin embargo, mantendrá la baja relación Ca/Pi que aporta la leche de vaca, lo que podría alterar el remodelamiento óseo y la mineralización. Objetivo: comparar si un yogur reducido en lactosa que contiene GOS (YE) ofrece ventajas adicionales respecto de un yogur regular sin GOS (YR) sobre las absorciones (Abs) de Ca y Pi, retención y calidad ósea durante el crecimiento normal. Al destete, ratas machos fueron divididas en 3 grupos alimentados con AIN ́93-G (C), YE o YR durante 28 días. Resultados: YE mostró el mayor aumento de lactobacilos fecales; producción de ácidos grasos de cadena corta especialmente p, profundidad de las criptas colónicas y menor pH cecal. El %AbsCa y %AbsPi aumentó en el siguiente órden: YE> YR> C (p < 0,05). El contenido de Ca y Pi en fémur, la densidad y contenido mineral óseos y los parámetros biomecánicos fueron similares en YE y C, mientras que YR mostró valores significativa-mente menores (p < 0,05). Conclusiones: YE aumentó las Abs y biodisponibilidad de minerales, alcanzando la retención y calidad ósea de C. El aumento en las Abs observado en YR no logró obtener la retención y calidad ósea de C. Conclusión: YE habría contrarrestado el efecto negativo del mayor aporte de Pi de la leche de vaca y sería una buena estrategia para lograr el pico de masa ósea y calidad del hueso adecuados, especialmente en individuos intolerantes a la lactosa. (AU)

Breast milk contains an optimal calcium/phosphate (Ca/Pi) ratio and GOS. These natural prebiotics can be enzymatically produced via cow's milk lactose inyogurt manufacture. This milk product is low in lactose and contains prebiotics and potentially probiotic bacteria but maintains a low Ca/Pi ratio that could alter bone remodeling and mineralization. We evaluated if a lactose-reduced yogurt containing GOS (YE) offers additional advantages over regular yogurt without GOS (YR) on Ca and Pi absorption (Abs), bone retention and quality during normal growth. Weaning male rats were divided into 3 groups fed AIN'93-G (C), YE or YR for 28 days. Results: YE showed the highest increase in fecal lactobacilli; short-chain fatty acids production, especially propionate and butyrate; intestine crypt depth, and the lowest cecal pH. AbsCa% and AbsPi% increased in this order: YE> YR> C (p <0.05). Ca and Pi content in femur, bone density and mineral content, and biomechanical parameters were similar in YE and C, while YR showed the significantly lowest value (p < 0.05). Conclusions: YE increased mineral Abs reaching the retention and bone quality of C. Although YR increased Abs, bone retention and quality did not achieve C values. Seemingly, YE compensated for the negative effect of the higher Pi supply and would be a good strategy to achieve adequate peak bone mass and bone quality, especially in lactose intolerant individuals. (AU)

Biopharmaceutics studies applied to goyazensolide: a drug candidate from Lychnophora species.

OBJECTIVES: To predict the substance's behaviour in vivo and determine the viability of the bioactive substance to become a drug, this work aimed to evaluate the biopharmaceutics characteristics of goyazensolide. METHODS: Differential scanning calorimetry (DSC) and thermogravimetry (TG) were applied for the characterization of goyazensolide. The biopharmaceutics characteristics were evaluated using in-silico and in-vitro (shake-flask and Parallel Artificial Membrane Permeability Assay) methods. KEY FINDINGS: DSC curve showed a single endothermic peak. According to the TG curve, goyazensolide has thermal stability close to 221.0°C and 210.0°C, under a nitrogen and oxygen atmosphere, respectively. In-silico data indicated that goyazensolide has high solubility and low permeability. The high solubility was confirmed by equilibrium solubility studies determined by the shake-flask method. The dose/solubility ratio values were 175.16 ml (pH 1.2), 194.99 ml (pH 4.5) and 222.07 ml (pH 6.8). The effective permeability of 0.03 × 10-6 cm/s was obtained for goyazensolide. This value is lower than furosemide (1.03 × 10-6 cm/s), confirming the low permeability of goyazensolide. CONCLUSIONS: Biopharmaceutics characteristics of goyazensolide are similar to drugs available on the market and attest to the feasibility of starting the process of developing a formulation containing this substance.

Ceftriaxone causes dysbiosis and changes intestinal structure in adjuvant obesity treatment.

BACKGROUND: Obesity is still a worldwide public health problem, requiring the development of adjuvant therapies to combat it. In this context, modulation of the intestinal microbiota seems prominent, given that the composition of the intestinal microbiota contributes to the outcome of this disease. The aim of this work is to investigate the treatment with an antimicrobial and/or a potential probiotic against overweight. METHODS: Male C57BL/6J mice were subjected to a 12-week overweight induction protocol. After that, 4-week treatment was started, with mice divided into four groups: control, treated with distilled water; potential probiotic, with Lactobacillus gasseri LG-G12; antimicrobial, with ceftriaxone; and antimicrobial + potential probiotic with ceftriaxone in the first 2 weeks and L. gasseri LG-G12 in the subsequent weeks. RESULTS: The treatment with ceftriaxone in isolated form or in combination with the potential probiotic provided a reduction in body fat. However, such effect is supposed to be a consequence of the negative action of ceftriaxone on the intestinal microbiota composition, and this intestinal dysbiosis may have contributed to the destruction of the intestinal villi structure, which led to a reduction in the absorptive surface. Also, the effects of L. gasseri LG-G12 apparently have been masked by the consumption of the high-fat diet. CONCLUSIONS: The results indicate that the use of a ceftriaxone in the adjuvant treatment of overweight is not recommended due to the potential risk of developing inflammatory bowel disease.

Evaluation of antihyperglycemic activity of plants in northeast mexico.

iabetes mellitus is one of the most common non-contagious diseases. In 2017, The International Diabetes Federation reported that around 425 million people suffer from diabetes worldwide. Medications used for the treatment of diabetes lead to unwanted side effects, and thus, new safe drugs are necessary. Some natural plant-based products exhibit anti hyperglycemic activity and low toxicity. The aim of this study was to evaluate the antihyperglycemic activity (using both in vitro and in vivo models) as well as cytotoxicity of the extracts obtained from various plants. Nine extracts from a total of eight plant species were subjected to in vitro α-amylase and α-glucosidase inhibition assays. Subsequently, they were assessed through the ex vivo everted sac assay, and finally, the in vivo antihyperglycemic activity was evaluated. The extracts obtained from Ceanothus coeruleus, Chrysactinia mexicana and Zanthoxylum fagara inhibited the activities of α-amylase and α-glucosidase in the in vitro assays. Ethyl acetate and hydroalcoholic extracts from Jatropha dioica, hydroalcoholic extract from Salvia ballotaeflora and Chrysactinia mexicana, as well as methanolic extract from Ricinus communis and Zanthoxylum fagara significantly reduced the glucose uptake in the ex vivo everted intestinal sac test. All the eight extracts showed antihyperglycemic effect through the in vivo model of the Glucose Tolerance Test, using starch as the carbohydrate source.  The antihyperglycemic effect of the extracts could be mediated through the inhibition of digestive enzymes and/or the absorption of glucose through the intestine. However, the mechanism of action for the hydroalcoholic extract of Salvia texana and the methanolic extract of Turnera diffusa, which showed a strong in vivo antihyperglycemic effect, is unclear.

Eficacia y seguridad de colestiramina para el tratamiento de diarrea por malabsorción de ácidos biliares secundaria a resección ileal en población pediátrica / Efficacy and safety of cholestyramine for treatment of diarrhea by acid malabsorption bile ducts secondary to ileal resection in population pediatric

INTRODUCCIÓN: Este documento técnico se realizó en el marco de la Guía de Práctica Clínica para pacientes pediátricos con falla intestinal; la pregunta PICO fue la siguiente: P: pacientes de 0-18 años con resección ileal por cualquier causa; I: colestiramina; C: placebo, colestipol, colesevelam, dietas modificadas o suplementos dietéticos; O: frecuencia de deposiciones, cambio en el peso o masa de las heces y eventos adversos. a. Cuadro clínico: Los ácidos biliares son moléculas cuya función principal es ayudar en la digestión y absorción de lípidos. En personas sanas, más del 95% de ácidos biliares se reabsorben en el íleon terminal. La reabsorción insuficiente de ácidos biliares en el íleon terminal incrementa la concentración en el colon, produciendo diarrea secretora. Se estima que la malabsorción de ácidos biliares (MAB) afecta al 1% de la población de países occidentales y cerca del 90% de pacientes con resección ileal. El tratamiento de la diarrea por MAB consiste en un manejo dietético y farmacológico. Los pacientes con diarrea y esteatorrea moderada deben someterse a una dieta baja en grasas (30 g/día) con o sin adición de triglicéridos de cadena media. El tratamiento farmacológico se basa en secuestrantes de ácidos biliares como colestiramina, colestipol o colesevelam. b. Tecnología sanitaria: Colestiramina es un secuestrante de ácidos biliares que se une con alta afinidad a los ácidos biliares en el intestino para formar un complejo estable e insoluble que se excreta en las heces. Pese a no ser una indicación aprobada, se emplea hace varias décadas para el tratamiento de MAB. Su forma de presentación consiste en sachets conteniendo 4 gr de polvo. Las dosis empleadas para la diarrea por MAB deben adaptarse a la respuesta del paciente, con una dosis máxima de 36 gr al día. Los eventos adversos suelen ser dependientes de la dosis, siendo los más frecuentes: malestar gastrointestinal, dispepsia, flatulencia, estreñimiento, náuseas y vómitos. Colestiramina cuenta en Perú con un registro sanitario vigente. Según el observatorio de precios de medicamentos de DIGEMID, el costo más bajo en el sector privado de 100 sobres de colestiramina asciende a S/. 13.00 (S/. 0.13 por cada sobre) mientras que no se hallaron precios disponibles en el sector público. OBJETIVO: Describir la evidencia científica sobre la eficacia y seguridad de colestiramina para el tratamiento de diarrea por malabsorción de ácidos biliares secundaria a resección ileal en población pediátrica. METODOLOGÍA: La búsqueda de evidencia se desarrolló en Medline, Web of Science, The Cochrane Library y LILACS hasta el 04 de octubre de 2021, limitado a estudios en español o inglés. La búsqueda de guías de práctica clínica (GPC) y evaluaciones de tecnología sanitaria (ETS) se desarrolló en repositorios digitales de agencias elaboradoras de estos documentos. Adicionalmente, se realizó una búsqueda de GPC en PubMed. Se valoró el riesgo de sesgo empleado la herramienta de la Colaboración Cochrane. RESULTADOS: No se identificó ningún estudio en población pediátrica. Se consideró como evidencia indirecta cuatro estudios primarios desarrollados en adultos. Frecuencia de deposiciones: El estudio de Hofmann (1969) reportó una reducción en la frecuencia diaria de deposiciones (p<0.05) durante el tratamiento con colestiramina en pacientes con <100 cm de resección ileal, comparado con placebo. En pacientes con >100 cm de íleon resecado (n=8) no se observaron diferencias. Un segundo estudio de Hofmann (1972) reportó una disminución en la frecuencia de deposiciones diarias de pacientes con resección ileal <100 cm tratados con colestiramina y triglicéridos de cadena larga (TCL) o media (TCM), en comparación con solo TCL o TCM. En pacientes con resección ileal >100 cm, colestiramina redujo la frecuencia de deposiciones, aunque la mayor reducción se observó cuando se reemplazó TCL por TCM, ambos sin colestiramina (p<0.025). El estudio de Jacobsen reportó una reducción del número de evacuaciones fecales durante el tratamiento con colestiramina comparado con placebo (15 vs 23, p<0.05). El estudio de Williams reportó una disminución del número de deposiciones al día en pacientes tratados colestiramina comparado con una dieta control (2.3 vs 4.6; p=0.027). Volumen de masa fecal El estudio de Hofmann (1969) reportó que 4 de 6 pacientes con <100 cm de resección ileal alcanzaron una reducción significativa de la masa fecal comparado con placebo (p<0.05). En pacientes con >100 cm de íleon resecado (n=3), colestiramina no produjo reducción significativa de la masa fecal en ningún participante. El estudio de Jacobsen reportó una reducción del volumen de masa fecal durante el tratamiento con colestiramina comparado con placebo (p<0.05). El estudio de Williams reportó una disminución significativa de la masa fecal en pacientes tratados colestiramina comparado con una dieta control de 2000 Kcal con TCL (media: 394 gr/día vs 568 gr/día; p=0.027). Eventos adversos: Ningún estudio informó sobre la presencia de eventos adversos. Recomendaciones en GPC: Las GPC de la Asociación Argentina de Nutrición Enteral y Parenteral (AANEP) y de la Canadian Association of Gastroenterology (CAG) recomiendan colestiramina para el manejo de la MAB. Las GPC de la European Society for Clinical Nutrition and Metabolism (ESPEN), Cleveland Clinic, British Society of Gastroenterology (BSG), y American Gastroenterological Association (AGA) no recomiendan su uso en pacientes con resección ileal extensa. Evaluaciones de Tecnología Sanitaria: Una ETS desarrollada por IETSI concluyó con evidencia limitada aprobar el uso de colestiramina para el tratamiento de pacientes con diarrea crónica por MAB. Sin embargo, su aprobación fue revocada un año después por tratarse de una indicación terapéutica "fuera de etiqueta". Evaluación de la calidad metodológica: Tres estudios tuvieron alto riesgo de sesgo de selección. Dos estudios tuvieron alto riesgo de sesgo de realización y detección. El riesgo de sesgo de reporte fue considerado poco claro en todos los estudios. Todos los estudios fueron considerados como alto riesgo de otro tipo de sesgos por un reporte insuficiente o nulo de las fuentes de financiamiento y el conflicto de interés de los autores. CONCLUSIONES: Los hallazgos sobre la eficacia de colestiramina no fueron concluyentes. Dos estudios reportaron una reducción en la frecuencia de deposiciones y volumen fecal en pacientes tratados con colestiramina, mientras que otros dos estudios mostraron una reducción significativa solo en pacientes con resección ileal <100 cm, y un efecto limitado o nulo en pacientes con resección ileal extensa (>100 cm). No se informaron resultados sobre la seguridad de colestiramina. Los estudios incluidos enrolaron un número pequeño de participantes, con periodos cortos de seguimiento, presentaron alta heterogeneidad en el diseño, características de los participantes e intervenciones, y tuvieron un alto riesgo de sesgo en la mayoría de dimensiones evaluadas. Dos GPC consideran el uso de colestiramina como terapia para pacientes con diarrea por MAB, mientras que cuatro GPC recomiendan limitar su uso en pacientes con resección ileal extensa. Una ETS realizada por IETSI (Perú) concluyó aprobar el uso de colestiramina para el tratamiento de pacientes con diarrea crónica por MAB. Sin embargo, su aprobación fue revocada un año después por tratarse de una indicación terapéutica "fuera de etiqueta".

Effect of Early Feeding on Intestinal Permeability and Inflammation Markers in Infants with Genetic Susceptibility to Type 1 Diabetes: A Randomized Clinical Trial.

OBJECTIVES: To assess whether weaning to an extensively hydrolyzed formula (EHF) decreases gut permeability and/or markers of intestinal inflammation in infants with HLA-conferred diabetes susceptibility, when compared with conventional formula. STUDY DESIGN: By analyzing 1468 expecting biological parent pairs for HLA-conferred susceptibility for type 1 diabetes, 465 couples (32 %) potentially eligible for the study were identified. After further parental consent, 332 babies to be born were randomized at 35th gestational week. HLA genotyping was performed at birth in 309 infants. Out of 87 eligible children, 73 infants participated in the intervention study: 33 in the EHF group and 40 in the control group. Clinical visits took place at 3, 6, 9, and 12 months of age. The infants were provided either EHF or conventional formula whenever breastfeeding was not available or additional feeding was required over the first 9 months of life. The main outcome was the lactulose to mannitol ratio (L/M ratio) at 9 months. The secondary outcomes were L/M ratio at 3, 6, and 12 months of age, and fecal calprotectin and human beta-defensin 2 (HBD-2) levels at each visit. RESULTS: Compared with controls, the median L/M ratio was lower in the EHF group at 9 months (.006 vs .028; P = .005). Otherwise, the levels of intestinal permeability, fecal calprotectin, and HBD-2 were comparable between the two groups, although slight differences in the age-related dynamics of these markers were observed. CONCLUSIONS: It is possible to decrease intestinal permeability in infancy through weaning to an extensively hydrolyzed formula. This may reduce the early exposure to dietary antigens. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01735123.

Plant origin prebiotics affect duodenal brush border membrane functionality and morphology, in vivo (Gallus Gallus).

The intra-amniotic administration approach has been used to evaluate the effects of plant origin prebiotics on intestinal health and on brush border membrane functionality and morphology. Prebiotics are fermentable dietary fibers, which can positively affect the host by selectively stimulating the growth and activity of colon bacteria, thus improving intestinal health. The consumption of prebiotics increases digestive tract motility, which leads to hyperplasia and/or hypertrophy of intestinal cells, increasing nutrient digestive and absorptive surface area. This review collates information about the effects and relationship between prebiotic consumption on small intestinal brush border membrane functionality and morphology by utilizing the intra-amniotic administration approach. To date, research has shown that the intra-amniotic administration of prebiotics affects the expression of key brush border membrane functional proteins, intestinal surface area (villi height/width), and goblet cell number/size. These effects may improve brush border membrane functionality and digestive/absorptive capabilities.

Antibacterial and antibiotic modifying activity, ADMET study and molecular docking of synthetic chalcone (E)-1-(2-hydroxyphenyl)-3-(2,4-dimethoxy-3-methylphenyl)prop-2-en-1-one in strains of Staphylococcus aureus carrying NorA and MepA efflux pumps.

A large number of infections are caused by multi-resistant bacteria worldwide, adding up to a figure of around 700,000 deaths per year. Because of that many strategies are being developed in order to combat the resistance of microorganisms to drugs, in recent times, chalcones have been studied for this purpose. Chalcones are known as α, ß-unsaturated ketones, characterized by having the presence of two aromatic rings that are joined by a three-carbon chain, they are a class of compounds considered an exceptional model due to chemical simplicity and a wide variety of biological activities, which include anticancer, anti-inflammatory, antioxidants, antimicrobials, anti-tuberculosis, anti-HIV, antimalarial, anti-allergic, antifungal, antibacterial, and antileishmanial. The objective of this work was evaluate the antibacterial and antibiotic modifying activity of chalcone (E)-1-(2-hydroxyphenyl)-3-(2,4-dimethoxy-3-methylphenyl)prop-2-en-1-one against the bacteria Staphylococcus aureus carrying a NorA and MepA efflux pump. The results showed that chalcone was able to synergistically modulate the action of Norfloxacin and Ethidium Bromide against the bacteria Staphylococcus aureus 1199B and K2068, respectively. The theoretical physicochemical and pharmacokinetic properties of chalcone showed that the chalcone did not present a severe risk of toxicity such as genetic mutation or cardiotoxicity, constituting a good pharmacological active ingredient.

Eremantholide C from aerial parts of Lychnophora trichocarpha, as drug candidate: fraction absorbed prediction in humans and BCS permeability class determination.

BACKGROUND: Lychnophora trichocarpha (Spreng.) Spreng. ex Sch.Bip has been used in folk medicine to treat pain, inflammation, rheumatism and bruises. Eremantholide C, a sesquiterpene lactone, is one of the substances responsible for the anti-inflammatory and anti-hyperuricemic effects of L. trichocarpha. OBJECTIVES: Considering the potential to become a drug for the treatment of inflammation and gouty arthritis, this study evaluated the permeability of eremantholide C using in situ intestinal perfusion in rats. From the permeability data, it was possible to predict the fraction absorbed of eremantholide C in humans and elucidate its oral absorption process. METHODS: In situ intestinal perfusion studies were performed in the complete small intestine of rats using different concentrations of eremantholide C: 960 µg/ml, 96 µg/ml and 9.6 µg/ml (with and without sodium azide), in order to verify the lack of dependence on the measured permeability as a function of the substance concentration in the perfusion solutions. RESULTS: Eremantholide C showed Peff values, in rats, greater than 5 × 10-5 cm/s and fraction absorbed predicted for humans greater than 85%. These results indicated the high permeability for eremantholide C. Moreover, its permeation process occurs only by passive route, because there were no statistically significant differences between the Peff values for eremantholide C. CONCLUSION: The high permeability, in addition to the low solubility, indicated that eremantholide C is a biologically active substance BCS class II. The pharmacological activities, low toxicity and biopharmaceutics parameters demonstrate that eremantholide C has the necessary requirements for the development of a drug product, to be administered orally, with action on inflammation, hyperuricemia and gout.

Enteric reabsorption processes and their impact on drug pharmacokinetics.

Enteric reabsorption occurs when a drug is secreted into the intestinal lumen and reabsorbed into the systemic circulation. This distribution process is evidenced by multiple peaks in pharmacokinetic profiles. Commonly, hepatobiliary drug secretion is assumed to be the underlying mechanism (enterohepatic reabsorption, EHR), neglecting other possible mechanisms such as gastric secretion (enterogastric reabsorption, EGR). In addition, the impact of drug reabsorption on systemic clearance, volume of distribution and bioavailability has been a subject of long-standing discussions. In this work, we propose semi-mechanistic pharmacokinetic models to reflect EHR and EGR and compare their respective impact on primary pharmacokinetic parameters. A simulation-based analysis was carried out considering three drug types with the potential for reabsorption, classified according to their primary route of elimination and their hepatic extraction: (A) hepatic metabolism-low extraction; (B) hepatic metabolism-intermediate/high extraction; (C) renal excretion. Results show that an increase in EHR can significantly reduce the clearance of drugs A and B, increase bioavailability of B drugs, and increase the volume of distribution for all drugs. Conversely, EGR had negligible impact in all pharmacokinetic parameters. Findings provide background to explain and forecast the role that this process can play in pharmacokinetic variability, including drug-drug interactions and disease states.

The effect of food and nutrients on iron overload: what do we know so far?

There has been no established food and nutrition guidance for diseases characterized by the presence of iron overload (IOL) yet. Hepcidin is a hormone that diminishes iron bioavailability. Its levels increase in response to increased iron stores. Hence, IOL conditions could hypothetically trigger a self-regulatory mechanism for the reduction of the intestinal absorption of iron. In addition, some food substances may modulate intestinal iron absorption and may be useful in the dietary management of patients with IOL. This scoping review aimed to systematize studies that support dietary prescriptions for IOL patients. It was carried out according to the method proposed by the Joanna Briggs Institute and the preferred reporting items for systematic reviews and meta-analyses (PRISMA). Although the need to restrict iron in the diet of individuals with hemochromatosis is quite clear, there is a consensus that IOL diminishes the rate of iron absorption. Reduced iron absorption is also present and has been reported in some diseases with transfusion IOL, in which serum hepcidin is usually high. The consumption of polyphenols and 6-shogaol seems to reduce iron absorption or serum ferritin concentration, while procyanidins do not cause any changes. Vitamin C deficiency is often found in IOL patients. However, vitamin C supplementation and alcohol consumption should be avoided not only because they increase iron absorption, but also because they provoke toxic oxidative reactions when the iron is excessive. Dietary approaches must consider the differences in the pathophysiology and treatment of IOL diseases.

Insights on the intestinal absorption of chlorophyll series from microalgae.

The bioaccessibility and subsequent uptake by Caco-2 human intestinal cells of chlorophyll pigments from Scenedesmus obliquus were determined for the first time. In order to evaluate the impact of different types of the matrix on bioaccessibility of chlorophyll from microalgae, three different products were evaluated: isolated chlorophyll extract (ICE); wet ultrasonicated biomass (WUB); and whole dried biomass (WDB). The samples were submitted to in vitro digestion model according to the INFOGEST protocol, and Caco-2 cells determined the intestinal uptake. Chlorophyll pigments were determined by HPLC-PDA-MS/MS. A total of ten chlorophyll pigments (8,318.48 µg g-1) were separated in S. obliquus biomass, with chlorophyll a (3,507.76 µg g-1) and pheophytin a' (1,598.09 µg g-1) the major ones. After in vitro digestion, all tested products showed bioaccessible chlorophylls. However, the total bioaccessibility results were as follows: ICE (33.45%), WUB (2.65%), WDB (0.33%). Five compounds were bioaccessible in ICE, three in WUB, and one in WDB. The hydroxypheophytin a showed the highest bioaccessibility (212%) in ICE, while pheophytin a' in WUB (11%) and WDB (2%). As a result, bioavailability estimates of ICE using the Caco-2 cell showed hydroxypheophytin a (102.53%), followed by pheophytin a' (64.69%) as the chlorophyll pigments most abundant in intestinal cells. In summary, from a nutritional perspective, these three types of the matrix (WDB, WUB, and ICE) influence the promotion of chlorophyll bioaccessibility. In this way, the data suggest that chlorophylls bioaccessibility from ICE is greater than that in WDB and WUB. Therefore, ICE should be considered a product that provides bioavailable chlorophyll and could be the best choice, such as ingredients in the development of functional foods chlorophyll-based.

Bioaccessibility and In Vitro Intestinal Permeability of a Recombinant Lectin from Tepary Bean (Phaseolus acutifolius) Using the Everted Intestine Assay.

Tepary bean (Phaseolus acutifolius) lectins exhibit differential in vitro and in vivo biological effects, but their gastrointestinal interactions and digestion have not yet been assessed. This work aimed to evaluate the changes of a recombinant Tepary bean lectin (rTBL-1) through an in vitro and ex vivo gastrointestinal process. A polyclonal antibody was developed to selectively detect rTBL-1 by Western blot (WB) and immunohistochemical analysis. Everted gut sac viability was confirmed until 60 min, where protein bioaccessibility, apparent permeability coefficient, and efflux ratio showed rTBL-1 partial digestion and absorption. Immunoblot assays suggested rTBL-1 internalization, since the lectin was detected in the digestible fraction. The immunohistochemical assay detected rTBL-1 presence at the apical side of the small intestine, potentially due to the interaction with the intestinal cell membrane. The in silico interactions between rTBL-1 and some saccharides or derivatives showed high binding affinity to sialic acid (-6.70 kcal/mol) and N-acetylglucosamine (-6.10 kcal/mol). The ultra-high-performance liquid chromatography-electron spray ionization-quantitative time-of-flight coupled to mass spectrometry (UHPLC-ESI-QTOF/MS) analysis showed rTBL-1 presence in the gastric content and the non-digestible fraction after intestinal simulation conditions. The results indicated that rTBL-1 partially resisted the digestive conditions and interacted with the intestinal membrane, whereas its digestion allowed the absorption or internalization of the protein or the derivative peptides. Further purification of digestion samples should be conducted to identify intact rTBL-1 protein and digested peptides to assess their physiological effects.