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BACKGROUND: Peru is one of the most biodiverse countries in the world, which is reflected in its wealth of knowledge about medicinal plants. However, there is a lack of information regarding intestinal absorption and the permeability of natural products. The human colon adenocarcinoma cell line (Caco-2) is an in vitro assay used to measure apparent permeability. This study aims to develop a quantitative structure-property relationship (QSPR) model using machine learning algorithms to predict the apparent permeability of the Caco-2 cell in natural products from Peru. METHODS: A dataset of 1817 compounds, including experimental log Papp values and molecular descriptors, was utilized. Six QSPR models were constructed: a multiple linear regression (MLR) model, a partial least squares regression (PLS) model, a support vector machine regression (SVM) model, a random forest (RF) model, a gradient boosting machine (GBM) model, and an SVM-RF-GBM model. RESULTS: An evaluation of the testing set revealed that the MLR and PLS models exhibited an RMSE = 0.47 and R2 = 0.63. In contrast, the SVM, RF, and GBM models showcased an RMSE = 0.39-0.40 and R2 = 0.73-0.74. Notably, the SVM-RF-GBM model demonstrated superior performance, with an RMSE = 0.38 and R2 = 0.76. The model predicted log Papp values for 502 natural products falling within the applicability domain, with 68.9% (n = 346) showing high permeability, suggesting the potential for intestinal absorption. Additionally, we categorized the natural products into six metabolic pathways and assessed their drug-likeness. CONCLUSIONS: Our results provide insights into the potential intestinal absorption of natural products in Peru, thus facilitating drug development and pharmaceutical discovery efforts.
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Beeswax oleogels (OGs), with a mechanical strength similar to pork backfat, were formulated with avocado (A), sunflower (S), and linseed (L) oils, applying a central composite design plus star point, and were evaluated as oral delivery vehicles of curcuminoids (OGACur, OGSCur, OGLCur). The incorporation of curcumin into the OG matrix significantly delayed both the formation of peroxides and conjugated trienes (K268 values), and the degradation rate of curcumin decreased with the increase of the oil polyunsaturated fatty acids (PUFA) content. The oil structuring did not affect the bioaccessibility of curcuminoids (>55% in all the OGs, regardless of the oil type), but it did reduce the release of fatty acids (~10%) during in vitro gastrointestinal digestion. The intestinal absorption, evaluated in Caco-2 cell monolayers, was higher for the micelle-solubilized curcumin from the digested OG than from unstructured oils, and it showed high anti-inflammatory potential by inhibiting the tumor necrosis factor-α (TNF-α) production compared to the positive control, both before and after the stimulation of ThP-1 cells with LPS. Regardless of the oil type, these beeswax-based OGs with gel-like behavior designed as fat replacers may be promising vehicles for the oral delivery of curcuminoids.
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Objective: Intestinal failure refers to a reduction in intestinal function that necessitates intravenous supplementation of macronutrients, water, or electrolytes due to the intestine's inability to absorb these substances adequately to maintain health and growth. This study aims to explore the experiences and challenges faced by patients enrolled in the intestinal rehabilitation program at Hospital Pablo Tobón Uribe in Medellín. Methodology: This qualitative study adopts a hermeneutic approach and utilizes grounded theory techniques. The sampling process involved both selective and theoretical sampling. A total of 20 semi-structured interviews were conducted, with eight interviews including contributions from family members. The data analysis commenced with open coding, followed by the grouping of codes into descriptive categories. Dimensions and properties were identified within these categories, and analytical categories were subsequently developed through axial and selective coding. This iterative process led to the emergence of the final paradigm matrix. Results: The study revealed that the healthcare system inadequately addresses the needs and expectations of patients with intestinal failure, leading to increased uncertainty about the disease's origin and future prognosis. Intestinal failure and its treatment disrupt various aspects of patients' lives, including personal, family, and work domains. Social stigmatization and rejection are prominent, underscoring the importance of support from family and close individuals in facilitating adaptation and revaluing life. Conclusions: Coping with the challenges of intestinal failure entails embracing the necessity of relying on parenteral nutrition, which is perceived as a prison that paradoxically enables survival.
Objetivo: la insuficiencia intestinal es la reducción de la función intestinal que requiere la suplementación intravenosa de macronutrientes, agua o electrolitos, pues el intestino no logra la absorción mínima para mantener la salud y el crecimiento. El objetivo es comprender el significado que tiene afrontar la condición de insuficiencia intestinal en pacientes que pertenecen al programa de rehabilitación intestinal del Hospital Pablo Tobón Uribe de Medellín. Metodología: estudio cualitativo con enfoque hermenéutico que utilizó técnicas de la teoría fundamentada. El muestreo fue primero selectivo y luego teórico. Se realizó un total de 20 entrevistas semiestructuradas; 8 de las cuales tuvieron el aporte de familiares. El análisis inició por la codificación abierta. Los códigos obtenidos se agruparon en categorías descriptivas, y en ellas se identificaron dimensiones y propiedades que se utilizaron para elaborar categorías analíticas mediante la codificación axial y selectiva que permitió emerger la matriz del paradigma final. Resultados: las necesidades y expectativas de los pacientes con insuficiencia intestinal no son suficientemente atendidas por el sistema de salud, lo que genera mayor incertidumbre sobre el origen de la enfermedad y aún más sobre su futuro. La insuficiencia intestinal y su tratamiento trastornan la vida personal, familiar y laboral. El rechazo social es marcado, por lo que el apoyo familiar y de las personas cercanas es fundamental para lograr la adaptación que les permite revalorar la vida. Conclusiones: afrontar la condición de insuficiencia intestinal representa la experiencia de requerir necesariamente de nutrición parenteral, la cual se percibe como una prisión que paradójicamente permite sobrevivir.
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RESUMEN El manejo de la hiperfosfatemia de los pacientes con insuficiencia renal crónica en diálisis permanece como un desafío. A pesar de utilizar un enfoque multifacético que incluye la restricción dietética, la remoción de fósforo por la diálisis y el uso de quelantes de fósforo, esta estrategia múltiple no logra reducir los niveles de fósforo en más de 2 mg/dl. El control de fósforo de los pacientes en diálisis es fundamental en razón de la relación monotónica entre los niveles séricos de fosfato y el incremento del riesgo cardiovascular. Por lo tanto, hay una necesidad de explorar nuevas estrategias para reducir los niveles séricos de fosfato a niveles normales. Recientes avances en nuestra compresión de los mecanismos que subyacen a la homeostasis del fósforo sugieren que el transporte gastrointestinal del fósforo podría ser un objetivo. Recientemente se han desarrollado inhibidores de los cotransportadores sodio fosfato del intestino y se ha revalorizado el uso de la nicotinamida, en su formulación de liberación prolongada, que también actuaria por ese mecanismo. También se han drogas como el tenapanor, que inhibiendo el intercambiador sodio/hidrogeno isoforma 3 del enterocito, disminuyen la absorción paracelular de fósforo.
ABSTRACT Management of hyperphosphatemia in patients with chronic renal failure on dialysis remains challenging. Despite using a multifaceted approach that includes dietary restriction, phosphorus removal by dialysis, and phosphate binders, these multiple strategies fail to reduce phosphorus levels by more than 2 mg/dL. Phosphorus control in dialysis patients is essential due to the monotonic relationship between serum phosphate levels and increased cardiovascular risk. Therefore, there is a need to explore new strategies to reduce serum phosphate levels to normal levels. Recent advances in understanding the mechanisms underlying phosphorus homeostasis suggest that the gastrointestinal transport of phosphorus could be a target. Inhibitors of intestinal sodium phosphate cotransporters recently developed, and using of nicotinamide, in its prolonged release formulation, which would also act by this mechanism, has been revalued. There have also been drugs such as tenapanor, which, by inhibiting the isoform three sodium/hydrogen exchanger of the enterocyte, decreases the paracellular absorption of phosphorus.
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BACKGROUND: Increased cholesterol absorption and reduced synthesis are processes that have been associated with cardiovascular disease risk in a controversial way. However, most of the studies involving markers of cholesterol synthesis and absorption include conditions, such as obesity, diabetes, dyslipidemia, which can be confounding factors. The present study aimed at investigating the relationships of plasma cholesterol synthesis and absorption markers with cardiovascular disease (CVD) risk factors, cIMT (carotid intima-media thickness), and the presence of carotid plaques in asymptomatic subjects. METHODS: A cross-sectional study was carried out in 270 asymptomatic individuals and anthropometrical parameters, fasting plasma lipids, glucometabolic profiles, high-sensitivity C-reactive protein (hs-CRP), markers of cholesterol synthesis (desmosterol and lathosterol), absorption (campesterol and sitosterol), cIMT, and the presence of atherosclerotic plaques were analyzed. RESULTS: Among the selected subjects aged between 19 and 75 years, 51% were females. Age, body mass index, systolic and diastolic blood pressure, total cholesterol, non-HDL-C, triglycerides, glucose, and lathosterol/sitosterol ratios correlated positively with cIMT (p ≤ 0.05). Atherosclerotic plaques were present in 19% of the subjects. A direct association of carotid plaques with campesterol, OR = 1.71 (95% CI = 1.04-2.82, p ≤ 0.05) and inverse associations with both ratios lathosterol/campesterol, OR = 0.29 (CI = 0.11-0.80, p ≤ 0.05) and lathosterol/sitosterol, OR = 0.45 (CI = 0.22-0.95, p ≤ 0.05) were observed in univariate logistic regression analysis. CONCLUSIONS: The findings suggested that campesterol may be associated with atherosclerotic plaques and the lathosterol/campesterol or sitosterol ratios suggested an inverse association. Furthermore, synthesis and absorption of cholesterol are inverse processes, and the absorption marker, campesterol, may reflect changes in body cholesterol homeostasis with atherogenic potential.
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Doenças Cardiovasculares , Fitosteróis , Placa Aterosclerótica , Adulto , Idoso , Biomarcadores/metabolismo , Proteína C-Reativa , Espessura Intima-Media Carotídea , Colesterol/análogos & derivados , Colesterol/metabolismo , Estudos Transversais , Desmosterol , Feminino , Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Sitosteroides , Triglicerídeos , Adulto JovemRESUMO
Psoralen (PSO) and 5-methoxypsoralen (5-MOP) are widely used drugs in oral photochemotherapy against vitiligo and major bioactive components of root bark extract of Brosimum gaudichaudii Trécul (EBGT), previously standardized by LC-MS. However, the exceptionally low water solubility of these psoralens can cause incomplete and variable bioavailability limiting their applications and patient adherence to treatment. Therefore, the purpose of this work was to investigate the effects of 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) inclusion complex on the solubility and jejunal permeability of PSO and 5-MOP from EBGT. Characterization of inclusion complexes were evaluated by current methods in nuclear magnetic resonance studies on aqueous solution, Fourier transform infrared spectroscopy, thermal analysis, and scanning electron microscopy in solid state. Ex vivo rat jejunal permeability was also investigated and compared for both pure psoralens and plant extract formulation over a wide HP-ß-CD concentration range (2.5 to 70 mM). Phase solubility studies of the PSO- and 5-MOP-HP-ß-CD inclusion complex showed 1:1 inclusion complex formation with small stability constants (Kc < 500 M−1). PSO and 5-MOP permeability rate decreased after adding HP-ß-CD by 6- and 4-fold for pure standards and EBGT markers, respectively. Nevertheless, the complexation with HP-ß-CD significantly improved solubility of PSO (until 10-fold) and 5-MOP (until 31-fold). As a result, the permeability drop could be overcome by solubility augmentation, implying that the HP-ß-CD inclusion complexes with PSO, 5-MOP, or EBGT can be a valuable tool for designing and developing novel oral drug product formulation containing these psoralens for the treatment of vitiligo.
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Furocumarinas , Moraceae , Vitiligo , beta-Ciclodextrinas , 2-Hidroxipropil-beta-Ciclodextrina/química , Animais , Varredura Diferencial de Calorimetria , Permeabilidade , Extratos Vegetais/farmacologia , Ratos , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X , beta-Ciclodextrinas/químicaRESUMO
Resumen Tras el descubrimiento de que el transporte del sodio y el transporte de la glucosa están acoplados en el intestino delgado, de manera que la glucosa acelera la absorción de soluto y agua, destacó la hidratación oral junto con otros hitos del siglo XX como el desarrollo de la penicilina y los cultivos virales que anteceden la vacuna contra la poliomielitis; este artículo de opinión se refiere a la participación de Costa Rica en el exitoso desarrollo de un estudio de investigación aplicada sobre un problema prioritario de Salud: la hidratación oral en las diarreas provocadas por virus.
Abstract Following the discovery that sodium transport and glucose transport are coupled in the small intestine, such that glucose accelerates solute and water absorption, highlighted oral hydration), along with other 20th-century milestones like the development of penicillin and viral cultures that preceded the polio vaccine; this opinion article refers to the participation of Costa Rica in the successful development of an applied research study on a priority health problem: oral rehydration in diarrhea caused by viruses.
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Diarreia/diagnóstico , HidrataçãoRESUMO
BACKGROUND: The oral route is the most frequently used and the most convenient route of drug administration since it has several advantages, such as ease of use, patient compliance, and better costeffectiveness. However, physicochemical and biopharmaceutical limitations of various active pharmaceutical ingredients (API) hinder suitability for this route, including degradation in the gastrointestinal tract, low intestinal permeability, and low bioavailability. To overcome these problems, while maintaining therapeutic efficacy, polymeric nanoparticles have attracted considerable attention for their ability to increase drug solubility, promote the controlled release, and improve stability. In addition, the functionalization of nanocarriers can increase uptake and accumulation at the target site of action, and intestinal absorption, making it possible to obtain more viable, safe and efficient treatments for oral administration. OBJECTIVE: This systematic review aimed to seek recent advances in the literature on the use of polymeric nanoparticles functionalization to increase intestinal permeability of APIs that are intended for oral administration. METHODS: Two bibliographic databases were consulted (PubMed and ScienceDirect). The selected publications and the writing of this systematic review were based on the guidelines mentioned in the PRISMA statement. RESULTS: Out of a total of 3036 studies, 22 studies were included in this article based on our eligibility criteria. The results were consistent for the application of nanoparticle functionalization to increase intestinal permeability. CONCLUSION: The functionalized polymeric nanoparticles can be considered as carrier systems that improve the intestinal permeability and bioavailability of APIs, with the potential to result, in the future, in the development of oral medicines.
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Produtos Biológicos , Nanopartículas , Administração Oral , Disponibilidade Biológica , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Humanos , Permeabilidade , Preparações Farmacêuticas , Polímeros/metabolismoRESUMO
Insects are unable to synthesize cholesterol and depend on the presence of sterols in the diet for cell membrane composition and hormone production. Thus, cholesterol absorption, transport, and metabolism are potential targets for vector and pest control strategies. Here, we investigate the dietary cholesterol absorption and tissue distribution in the kissing bug Rhodnius prolixus using radiolabeled cholesterol. Both the anterior and posterior midguts absorbed cholesterol from the ingested blood, although the anterior midgut absorbed more. We also observed esterified cholesterol labeling in the epithelium, indicating that midgut cells can metabolize and store cholesterol. Only a small amount of labeled cholesterol was found in the hemolymph, where it was mainly in the free form and associated with lipophorin (Lp). The fat body transiently accumulated cholesterol, showing a labeled cholesterol peak on the fifth day after the blood meal. The ovaries also incorporated cholesterol, but cumulatively. The insects did not absorb almost half of the ingested labeled cholesterol, and radioactivity was present in the feces. After injection of 3H-cholesterol-labeled Lp into females, a half-life of 5.5 ± 0.7 h in the hemolymph was determined. Both the fat body and ovaries incorporated Lp-associated cholesterol, which was inhibited at low temperature, indicating the participation of active cholesterol transport. These results help describe an unexplored part of R. prolixus lipid metabolism.
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Roots´ bark extract of Brosimum gaudichaudii Trécul (EBGT) is traditionally used for photochemotherapy of vitiligo due to the presence of furanocoumarins psoralen (PSO) and 5-methoxypsoralen (5-MOP) as major compounds. Though plant extracts may provide additional highly permeable psoralens-like substances which may act synergically on vitiligo's therapy. Thus, the aim of this work was to develop an LC-MS/MS method for screening new highly permeable furanocoumarins from B. gaudichaudii and to compare biomarkers permeability and solubility provided as single compounds or as crude extract, according to BCS. An optimized LC-MS/MS method showed twelve permeable and bioactive compounds, among which 9 furanocoumarins, 2 pyranocoumarins and 1 dihydrocinnamic acid derivative were detected in EBGT samples. Solubility of PSO and 5-MOP was found to be, respectively, six- and eleven-fold higher in crude extract than as pure compounds. Permeability (Papp) of PSO and 5-MOP in EBGT were higher than metoprolol, the low/high BCS permeability class boundary reference compound. Hence, both biomarkers were considered as highly permeable (BCS2) compounds. Their permeability were concentration-dependent displaying values from 30.26 ± 5.13-8.21 ± 2.16 × 10-6 cm/s and 10.72 ± 1.73-6.07 ± 1.27 × 10-6 cm/s, respectively, over a wide range (2.3-200.0 mg mL-1). Thus, a carrier-mediated absorption process is suggested as the main mechanism. Accordingly, all additional permeated coumarins, identified by LC-MS/MS, showed to be at comparable amount of biomarkers in the permeated samples inferring similar high permeability rate. Moreover, biomarkers and other highly absorbable and bioactive linear furanocoumarins from EBGT may be used for vitiligo´s photochemotherapy. Taken together, these findings bring additional evidences for using crude plant extract when aiming synergistic effects of bioactive compounds on melanogenic therapies.
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Moraceae , Vitiligo , Cromatografia Líquida , Absorção Intestinal , Permeabilidade , Extratos Vegetais , Espectrometria de Massas em TandemRESUMO
The adrenal cortical carcinoma (ACC) treatment, for which mitotane (o,p'-DDD) is the drug of choice, still remains a challenge both because of the well-known solubility problems of the drug, and its serious side effects. Mitotane is currently administered as oral tablets. The loading of mitotane into nanocarriers has been suggested as a way to circumvent the low solubility of the drug and its limited oral bioavailability. In this work, we have developed liposomes containing mitotane to enhance its intestinal absorption and oral bioavailability. Liposomes were produced by spray-drying of a mixture of phospholipids and the developed formulation was optimized by studying the degree of crystallinity, spray-drying conditions, phospholipid/mitotane ratio, and influence of mannitol in the hydrating ethanolic solution. An optimal liposomal formulation was produced with a phospholipid:mitotane combination (3.34:1), exhibiting a mean hydrodynamic diameter around 1 µm and spherical shape. The produced mitotane liposomes were re-suspended by hydrating the spray-dried powders in a stirred tank, and tested their intestinal permeability (ex vivo) and relative bioavailability (in vivo), against a free drug solution (with or without Trigliceril®CM). Our results support the conclusion that the loading of mitotane in liposomes enhanced its intestinal absorption and relative bioavailability.
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Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Lipossomos/farmacologia , Mitotano/metabolismo , Mitotano/farmacologia , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/metabolismo , Animais , Disponibilidade Biológica , Química Farmacêutica/métodos , Absorção Intestinal/efeitos dos fármacos , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Fosfolipídeos/metabolismo , Fosfolipídeos/farmacologia , Pós/farmacologia , Ratos , Ratos Wistar , Solubilidade/efeitos dos fármacos , Comprimidos/metabolismo , Comprimidos/farmacologiaRESUMO
Endopleura uchi, is used for the treatment of inflammatory disease and related to the female reproductive tract. The aim of this study was to evaluate the acute toxicity of the Endopleura uchi stem bark hydroethanolic extract (EEu) in zebrafish, emphasizing the histopathological and biochemical parameters, as well as evaluating the in silico pharmacokinetic and toxicological parameters of the phytochemical/pharmacological marker, bergenin, as their metabolites. The animals were orally treated with EEu at a single dose of 75 mg/kg, 500 mg/kg, 1000 mg/kg and 3000 mg/kg. the oral LD50 of the EEu higher to the dose of 3000 mg/kg. Behavioral, biochemical and histopathological changes were dose dependent. In silico pharmacokinetic predictions for bergenin and its metabolites showed moderate absorption in high human intestinal absorption (HIA) and Caco-2 models, reduced plasma protein binding, by low brain tissue binding and no P-glycoprotein (P-Gp) inhibition. Their metabolism is defined by the CYP450 enzyme, in addition to bergenin inhibition of CYP2C9, CYP3A4 and CYP2C19. In the bergenin and its metabolites in silico toxicity test it have been shown to cause carcinogenicity and a greater involvement of the bergenin with the CYP enzymes in the I and II hepatic and renal metabolism's phases was observed. It is possible to suggest that the histopathological damages are involved with the interaction of this major compound and its metabolites at the level of the cellular-biochemical mechanisms which involve the absorption, metabolization and excretion of these possible prodrug and drug.
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Weaning results in intestinal dysfunction, mucosal atrophy, transient anorexia, and intestinal barrier defects. In this study, the effect of prodigiosin (PG) on the intestinal inflammation of weaned rats was investigated by using 1H-NMR spectroscopy and biochemistry indexes to regulate the intestinal metabolism. After administration for 14 days, the body mass of the PG group was increased by 1.29- and 1.26-fold compared with those of the control and alcohol groups, respectively, using a dose of 200 µg PG·kg-1 body weight per day. PG increased organic acid content and decreased moisture, pH values, and free ammonia in feces. In addition, PG alleviated the intestinal inflammation of weaned rats. The analysis of 1H-NMR signal peak attribution and the model validation of metabolic data of feces contents showed that PG significantly affected the metabolism of small molecular compounds in the intestinal tract of weaned rats. This study presents the promising alternative of using PG to alleviate intestinal inflammation effectively in the intestinal tract of weaned rats.
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Animais , Masculino , Ratos , Prodigiosina/efeitos adversos , Desmame , Bioquímica/classificação , Espectroscopia de Prótons por Ressonância Magnética/métodos , Inflamação/classificação , Anorexia , Dosagem/efeitos adversos , Concentração de Íons de Hidrogênio , Metabolismo/efeitos dos fármacosRESUMO
Studies have shown the positive effects of prebiotics on the intestinal absorption of Ca and Fe. The present study evaluated the effect of fructo-oligosaccharide (FOS) supplementation in soya beverage (SB) on absorption mechanisms of Ca and Fe in recently weaned rats. Male Wistar rats were divided into four groups: lactose-free cows' milk (CM), lactose-free CM with FOS (0·8 g/100 ml) (CMF), SB and soya beverage with FOS (0·8 g/100 ml) (SBF). These rats were euthanised after 1 week of treatment. Organ weight, pH of the caecal content and absorption mechanisms of Ca and Fe were evaluated. The results showed that the weight of the caecal contents increased in the CMF and SBF groups, and the pH of the caecal contents was lower in these groups. The Hb levels of the CMF and SB groups were higher when compared with that of the CM group and lower in relation to the SBF group. The apparent Ca and Fe absorption and apparent Ca retention in the CM group were higher when compared with the SB group, whereas in the CMF group, they were higher in relation to the SBF group. Divalent metal transporter 1 (DMT1) protein expression in the duodenum was higher in the SBF group than in the SB and CMF groups. SB resulted in lower intestinal Ca absorption and higher Hb concentration, despite the lower apparent Fe absorption in relation to CM. Supplementation with FOS provided beneficial effects on Hb and DMT1 protein expression in the duodenum, in addition to improving the absorption process.
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Bebidas , Cálcio da Dieta/metabolismo , Suplementos Nutricionais , Glycine max , Ferro/metabolismo , Oligossacarídeos/administração & dosagem , Ração Animal , Animais , Proteínas de Transporte de Cátions/metabolismo , Duodeno/metabolismo , Hematócrito , Hemoglobinas/análise , Concentração de Íons de Hidrogênio , Absorção Intestinal , Intestinos , Fígado/metabolismo , Masculino , Leite , Minerais/metabolismo , Prebióticos/análise , Ratos , Ratos Wistar , Vitamina D/análogos & derivados , Vitamina D/metabolismo , DesmameRESUMO
BACKGROUND: Species beloging to the genus Pomacea (Ampullariidae), often referred as apple snails, are freshwater, amphibious snails native to South, Central and North America. Some species such as P. canaliculata have become a driver of ecosystem changes in wetlands and an important rice and taro pest after its introduction to Asia and other parts of the world. Females deposit colored egg clutches above the waterline, a reproductive strategy that exposes the eggs to harsh conditions and terrestrial predation. However, eggs have no reported predators in their native range, probably because of the acquisition of unparalleled biochemical defenses provided by a set of proteins (perivitellins) that nourish embryos and protect them from predators and abiotic factors. Notably, ingestion of egg perivitelline fluid (PVF) decreases rat growth rate and alters their gastrointestinal morphology. The aim of the study is to determine the effect of apple snail egg PVF on mice gut digestive activity, morphology and nutrient absorption. METHODS: Carbohydrate digestion by intestinal disaccharidases (sucrase-isomaltase and maltase-glucoamylase) was evaluated ex vivo in mice gavaged with 1 or 4 doses of PVF. Changes in gut morphological and absorptive surface were measured. In addition, alteration on nutrient absorption rates, transport pathways and intestinal permeability was evaluated by luminal perfusions of small intestine with radiolabeled L-proline (absorbed by paracellular and transcellular pathways) and L-arabinose (absorbed exclusively by paracellular pathway). RESULTS: Perivitelline fluid affected mice displayed significant morphological changes in the small intestine epithelium inducing the appearance of shorter and wider villi as well as fused villi. This resulted in a diminished absorptive surface, notably in the proximal portion. Likewise, the activity of disaccharidases diminished in the proximal portion of the intestine. Total absorption of L-proline increased in treated mice in a dose-dependent manner. There were no differences neither in the ratio of paracellular-to-transcellular absorption of L-proline nor in gut permeability as revealed by the clearance of L-arabinose. DISCUSSION: Oral administration of apple snail PVF to mice adversely alters gut morphophysiology by reducing the intestinal absorptive surface, affecting enzymes of sugar metabolism and increasing the absorption rate of nutrients without affecting the relative contribution of the absorption pathways or gut permeability. These results further support the role of PVF in passive anti-predator defenses in Pomacea snail eggs that target the digestive system.
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The purpose of this work was to describe the closed loop in situ perfusion method in rats and to compare the difficulties and advantages with other methods proposed by regulatory agencies for BCS classification and finally to illustrate its application to evaluate the permeability of digoxin at relevant clinical concentrations. Digoxin was evaluated at two concentration levels: 1.0⯵g/ml (with and without sodium azide 65.0⯵g/ml) and 6.0⯵g/ml. These concentrations correspond to the ratio of the highest dose strength (0.25â¯mg) and the highest single dose administered (1.5â¯mg) and the 250â¯ml of water. In situ closed loop perfusion studies in rats were performed in the whole small intestine and also in duodenum, jejunum and ileum segments to evaluate the relevance of P-gp secretion in the overall permeability. A kinetic modelling approach involving passive permeation and efflux transport mechanism allowed the estimation of the passive diffusional component and the Michaelis-menten parameters. The estimated Km value demonstrated that at clinical luminal concentrations the efflux process is not saturated and then it could be inhibited by other drugs, excipients or food components leading to the already reported clinical drug-drug and drug-food interations. The present data confirms from a mechanistic point of view these interactions.
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Cardiotônicos/classificação , Cardiotônicos/farmacocinética , Digoxina/classificação , Digoxina/farmacocinética , Absorção Intestinal , Modelos Biológicos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Biofarmácia , Intestino Delgado/metabolismo , Masculino , Perfusão , Ratos WistarRESUMO
In the small intestine transcellular and paracellular pathways are implicated in water-soluble nutrient absorption. In small birds the paracellular pathway is quantitatively important while transcellular pathway is much more important in terrestrial mammals. However, there is not a clear understanding of the mechanistic underpinnings of the differences among taxa. This study was aimed to test the hypothesis that paracellular permeability in perfused intestinal segments is higher in passerine birds than rodents. We performed in situ intestinal perfusions on individuals of three species of passerine birds (Passer domesticus, Taeniopygia guttata and Furnarius rufus) and two species of rodents (Mus musculus and Meriones ungiculatus). Using radio-labelled molecules, we measured the uptake of two nutrients absorbed by paracellular and transcellular pathways (L-proline and 3-O-methyl-D-glucose) and one carbohydrate that has no mediated transport (L-arabinose). Birds exhibited ~2 to ~3 times higher L-arabinose clearance per cm2 epithelium than rodents. Moreover, paracellular absorption accounted for proportionally more of 3-O-methyl-D-glucose and L-proline absorption in birds than in rodents. These differences could be explained by differences in intestinal permeability and not by other factors such as increased retention time or higher intestinal nominal surface area. Furthermore, analysis of our results and all other existing data on birds, bats and rodents shows that insectivorous species (one bird, two bats and a rodent) had only 30% of the clearance of L-arabinose of non-insectivorous species. This result may be explained by weaker natural selection for high paracellular permeability in animal- than in plant-consumers. Animal-consumers absorb less sugar and more amino acids, whose smaller molecular size allow them to traverse the paracellular pathway more extensively and faster than glucose.
Assuntos
3-O-Metilglucose/farmacocinética , Arabinose/farmacocinética , Gerbillinae/fisiologia , Mucosa Intestinal/fisiologia , Camundongos/fisiologia , Passeriformes/fisiologia , Prolina/farmacocinética , Animais , Transporte Biológico , Permeabilidade , Especificidade da EspécieRESUMO
El principal producto derivado de la yuca en Venezuela es el casabe, valorado por su contenido calórico y de Fibra Dietética (FD). Objetivo: determinar el efecto del consumo de diferentes variedades de casabe sobre la absorción y retención aparente de proteínas en un modelo experimental con ratas. Métodos: se utilizaron 20 ratas machos adultas, cepa Sprague Dawley®, las cuales fueron divididas en 4 grupos: un control sin fibra y tres grupos experimentales en los que se sustituyó el almidón de maíz por una variedad de casabe, identificados por su procedencia como: "Casabe Miranda", "Casabe Sucre" y "Casabe Amazonas". Resultados: el contenido de FD total y su fracción soluble fueron significativamente mayores en las variedades de casabe Amazonas y Sucre (p<0,05). La inclusión de casabe a las dietas produjo un aumento en el peso de las heces así como en su contenido de nitrógeno (p<0,05), sin presentar diferencias significativas en la excreción de nitrógeno urinaria. La absorción de proteínas y la retención aparente de nitrógeno disminuyeron significativamente (p<0,05) hasta el día 14 del período experimental. Sin embargo, se pudo apreciar que al final del ensayo (día 21) la retención aparente de nitrógeno no mostró diferencia entre los controles y los grupos experimentales. Conclusiones: la inclusión de casabe a las dietas no produjo una reducción en la utilización de proteínas como para afectar el crecimiento de los animales. Se plantea la necesidad de seguir realizando estudios en esta área ya que la literatura es muy escasa(AU)
The main product derived from cassava in Venezuela is cassava bread, valued for its caloric content and Dietary Fiber (DF). Objective: to determine the effect of the consumption of different varieties cassava bread on the absorption and retention of proteins in a rat experimental model. Methods: Twenty male adult rats, Sprague Dawley ® strain, were divided into four groups: a control without fiber and three experimental groups in which corn starch was substituted for a variety of cassava bread, identified by their origin as: "Cassava bread Miranda", "Cassava bread Sucre" and "Cassava bread Amazonas". Results: The total DF content and soluble fraction were significantly higher in the varieties of cassava breads varieties Amazonas and Sucre (p <0.05). The inclusion of cassava bread in diets produced an increase in stool weight as well as in nitrogen content (p <0.05), without presenting significant differences in the excretion of urinary nitrogen. Protein absorption and apparent nitrogen retention decreased significantly (p <0.05) until day 14 of the experimental period. However, it could be seen that at the end of the trial (day 21) the apparent nitrogen retention showed no difference between the controls and the experimental groups. Conclusions: the inclusion of cassava bread in the diets did not produce a reduction in the use of proteins to affect the growth of the animals. The need to continue conducting studies in this area is considered, since the literature is very scarce(AU)
Assuntos
Animais , Ratos , Fibras na Dieta , Proteínas , Manihot/metabolismo , Nutrientes , Sistema Digestório , Alimentos, Dieta e NutriçãoRESUMO
We propose an in vitro permeability assay by using a modified lipid membrane to predict the in vivo intestinal passive permeability of drugs. Two conditions were tested, one with a gradient pH (pH 5.5 donor/pH 7.4 receptor) and the other with an iso-pH 7.4. The predictability of the method was established by correlating the obtained apparent intestinal permeability coefficients (Papp) and the oral dose fraction absorbed in humans (fa) of 16 drugs with different absorption properties. The Papp values correlated well with the absorption rates under the two conditions, and the method showed high predictability and good reproducibility. On the other hand, with this method, we successfully predicted the transport characteristics of oral sulfadiazine (SDZ). Also, the tradeoff between the increase in the solubility of SDZ by its complex formation with cyclodextrins and/or aminoacids and its oral permeability was assessed. Results suggest that SDZ is transported through the gastrointestinal epithelium by passive diffusion in a pH-dependent manner. These results support the classification of SDZ as a high/low borderline permeability compound and are in agreement with the Biopharmaceutics Classification Systems (BCS). This conclusion is consistent with the in vivo pharmacokinetic properties of SDZ.
Assuntos
Ciclodextrinas/química , Absorção Intestinal , Sulfadiazina/metabolismo , Administração Oral , Transporte Biológico , Permeabilidade da Membrana Celular , Difusão , Humanos , Concentração de Íons de Hidrogênio , Metabolismo dos Lipídeos , Membranas Artificiais , Reprodutibilidade dos Testes , Solubilidade , Sulfadiazina/administração & dosagem , Sulfadiazina/química , Sulfadiazina/farmacocinéticaRESUMO
Hyperphosphatemia is a common condition in patients with chronic kidney disease (CKD) and can lead to bone disease, vascular calcification, and increased risks of cardiovascular disease and mortality. Inorganic phosphate (Pi) is absorbed in the intestine, an important step in the maintenance of homeostasis. In CKD, it is not clear to what extent Pi absorption is modulated by dietary Pi. Thus, we investigated 5/6 nephrectomized (Nx) Wistar rats to test whether acute variations in dietary Pi concentration over 2 days would alter hormones involved in Pi metabolism, expression of sodium-phosphate cotransporters, apoptosis, and the expression of matrix extracellular phosphoglycoprotein (MEPE) in different segments of the small intestine. The animals were divided into groups receiving different levels of dietary phosphate: low (Nx/LPi), normal (Nx/NPi), and high (Nx/HPi). Serum phosphate, fractional excretion of phosphate, intact serum fibroblast growth factor 23 (FGF-23), and parathyroid hormone (PTH) were significantly higher and ionized calcium was significantly lower in the Nx/HPi group than in the Nx/LPi group. The expression levels of NaPi-IIb and PiT-1/2 were increased in the total jejunum mucosa of the Nx/LPi group compared with the Nx/HPi group. Modification of Pi concentration in the diet affected the apoptosis of enterocytes, particularly with Pi overload. MEPE expression was higher in the Nx/HPi group than in the Nx/NPi. These data reveal the importance of early control of Pi in uremia to prevent an increase in serum PTH and FGF-23. Uremia may be a determining factor that explains the expressional modulation of the cotransporters in the small intestine segments.