RESUMEN
DNA gyrase and topoisomerase IV play significant role in maintaining the correct structure of DNA during replication and they have been identified as validated targets in antibacterial drug discovery. Inadequate pharmacokinetic properties are responsible for many failures during drug discovery and their estimation in the early phase of this process maximizes the chance of getting useful drug candidates. Passive gastrointestinal absorption of a selected group of thirteen dual DNA gyrase and topoisomerase IV inhibitors was estimated using two in vitro tests - parallel artificial membrane permeability assay (PAMPA) and biopartitioning micellar chromatography (BMC). Due to good correlation between obtained results, passive gastrointestinal absorption of remaining ten compounds was estimated using only BMC. With this experimental setup, it was possible to identify compounds with high values of retention factors (k) and highest expected passive gastrointestinal absorption, and compounds with low values of k for which low passive gastrointestinal absorption is predicted. Quantitative structure-retention relationship (QSRR) modelling was performed by creating multiple linear regression (MLR), partial least squares (PLS) and support vector machines (SVM) models. Descriptors with the highest influence on retention factor were identified and their interpretation can be used for the design of new compounds with improved passive gastrointestinal absorption.
Asunto(s)
Absorción Gastrointestinal , Relación Estructura-Actividad Cuantitativa , Inhibidores de Topoisomerasa II , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/farmacocinética , Micelas , Modelos Lineales , Membranas Artificiales , Girasa de ADN/metabolismo , Girasa de ADN/química , Humanos , Topoisomerasa de ADN IV/metabolismo , Topoisomerasa de ADN IV/antagonistas & inhibidores , Topoisomerasa de ADN IV/químicaRESUMEN
Upon dissolution, amorphous solid dispersions (ASDs) of poorly water-soluble compounds can generate supersaturated solutions consisting of bound and free drug species that are in dynamic equilibrium with each other. Only free drug is available for absorption. Drug species bound to bile micelles, polymer excipients, and amorphous and crystalline precipitate can reduce the drug solute's activity to permeate, but they can also serve as reservoirs to replenish free drug in solution lost to absorption. However, with multiple processes of dissolution, absorption, and speciation occurring simultaneously, it may become challenging to understand which processes lead to an increase or decrease in drug solution concentration. Closed, nonsink dissolution testing methods used routinely, in the absence of drug removal, allow only for static equilibrium to exist and obscure the impact of each drug species on absorption. An artificial gut simulator (AGS) introduced recently consists of a hollow fiber-based absorption module and allows mass transfer of the drug from the dissolution media at a physiological rate after tuning the operating parameters. In the present work, ASDs of varying drug loadings were prepared with a BCS-II model compound, ketoconazole (KTZ), and hypromellose acetate succinate (HPMCAS) polymer. Simultaneous dissolution and absorption testing of the ASDs was conducted with the AGS, and simple analytical techniques were utilized to elucidate the impact of bound drug species on absorption. In all cases, a lower amount of crystalline precipitate was formed in the presence of absorption relative to the nonsink dissolution "control". However, formation of HPMCAS-bound drug species and crystalline precipitate significantly reduced KTZ absorption. Moreover, at high drug loading, inclusion of an absorption module was shown to enhance ASD dissolution. The rank ordering of the ASDs with respect to dissolution was significantly different when nonsink dissolution versus AGS was used, and this discrepancy could be mechanistically elucidated by understanding drug dissolution and speciation in the presence of absorption.
Asunto(s)
Absorción Gastrointestinal , Polímeros , Solubilidad , Cristalización , Liberación de Fármacos , Polímeros/químicaRESUMEN
Extemporaneous preparation (EP) formulation is an attractive strategy to accelerate the formulation development of new chemical entities for first entry into human study. In this work, an EP suspension formulation for a development drug candidate GDC-6599 was successfully developed. The formulation spanned a wide concentration range from 0.1 to 2.0 mg/mL. A non-solubilizing vehicle, 0.6 % (w/v) methylcellulose solution was used to suspend GDC-6599. An aversive agent denatonium benzoate at an extremely low level (6 ppm) was applied as a taste masking agent. This enabled a simple matrix for the analysis of related substances from GDC-6599 during all stability studies. Microcrystalline cellulose at 10 mg/mL concentration was added to the EP formulation to generate a suspension appearance, leading to the success of using a single placebo for matching active formulation at all concentrations. The developed formulation demonstrated excellent homogeneity, sufficient stability and passed microbiological enumeration test. Rinsing performance test demonstrated that greater than 99.8 % amount of drug was successfully recovered by rinsing with water twice, providing guidance for clinical dosing. Biopharmaceutical assessment was conducted by both in silico simulation and in vitro tests. Greater than 90 % bioaccessibility of the EP suspension formulation was obtained via an in vitro system mimicking the human gastrointestinal absorption, consistent with the result from the in silico modeling. The developed EP formulation was successfully used to support the early single ascending dose (SAD) cohorts of GDC-6599 Phase I clinical study. The formulation matrix and assessment workflow developed in this work are generalizable as a platform for EP formulation development of new chemical entities for early phase clinical studies.
Asunto(s)
Celulosa , Absorción Gastrointestinal , Humanos , Composición de Medicamentos , Administración Oral , Percepción del Gusto , Estabilidad de MedicamentosRESUMEN
This review is a revisit of various oral drug absorption models developed in the past decades, focusing on how to incorporate the physiological dynamics in the upper gastrointestinal (GI) tract. For immediate-release oral drugs, GI absorption is a critical input of drug exposure and subsequent human body response, yet difficult to model largely due to the complex GI environment. One of the biggest hurdles lies at capturing the high within-subject variability (WSV) of bioavailability measures, which can be mechanistically explained by the GI physiological dynamics. A thorough summary of how GI dynamics is handled in the absorption models would promote the development of mechanism-based oral drug absorption models, aid in the design of clinical studies regarding dosing regimens and bioequivalence studies based on WSV, and advance the decision-making on formulation selection.
Asunto(s)
Tracto Gastrointestinal , Tracto Gastrointestinal Superior , Adulto , Humanos , Tracto Gastrointestinal/metabolismo , Solubilidad , Administración Oral , Absorción Gastrointestinal , Absorción Intestinal/fisiologíaRESUMEN
Aquaporins (AQPs), transmembrane proteins permeable to water, are involved in gastrointestinal secretion. The secretory products of the glands are delivered either to some organ cavities for exocrine glands or to the bloodstream for endocrine glands. The main secretory glands being part of the gastrointestinal system are salivary glands, gastric glands, duodenal Brunner's gland, liver, bile ducts, gallbladder, intestinal goblet cells, exocrine and endocrine pancreas. Due to their expression in gastrointestinal exocrine and endocrine glands, AQPs fulfill important roles in the secretion of various fluids involved in food handling. This review summarizes the contribution of AQPs in physiological and pathophysiological stages related to gastrointestinal secretion.
Asunto(s)
Acuaporinas , Líquidos Corporales , Absorción Intestinal , Absorción Gastrointestinal , Tracto GastrointestinalRESUMEN
Celiac disease (CD) accompanying autoimmune endocrine diseases (AED) is generally asymptomatic. This study aimed to evaluate the frequency of clinically overt or silent CD in patients diagnosed with autoimmune endocrinopathy and the clinical effects of silent CD in these endocrinopathies. The study included 166 patients with known or newly diagnosed mono-/polyglandular AED and 90 age- and gender-matched healthy controls. The patients were classified into four groups: type 1 diabetes mellitus (DM) (n=44), Hashimoto's thyroiditis (HT) (n=68), Addison's disease (AD) (n=17), and autoimmune polyglandular syndrome (APS) (n=37). All subjects were serologically screened for tissue transglutaminase antibody (tTG) IgA and IgG. In addition, to evaluate the possible systemic consequences of CD, serum parathormone (PTH), 25-hydroxicholecalsiferol (25-OH-Vit D), vitamin B12, folic acid, iron, iron-binding capacity (IBC), and ferritin levels were measured. In the total series, 193 (75.4%) individuals were females, and 63 (24.6%) were males. TTG IgA antibody positivity was found in 23 among 166 patients, while no positivity was encountered in the healthy control group. The highest rates of positive tTg IgA frequency were detected in AD, with 29.4% (5/17). Serum 25-OH-Vit D, vitamin B12, folic acid, iron, and ferritin levels were significantly lower in AEDs compared to controls (p<0.001), and the lowest these parameters were detected in patients with AD. The serologic CD prevalence is higher in autoimmune mono-/and polyglandular endocrine diseases than in the control group. The data support recommends regular screening for CD in all patients with AEDs.
Asunto(s)
Enfermedad de Addison , Enfermedad Celíaca , Diabetes Mellitus Tipo 1 , Masculino , Femenino , Humanos , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/diagnóstico , Autoanticuerpos , Inmunoglobulina A , Vitamina B 12 , Ácido Fólico , Hierro , Absorción Gastrointestinal , FerritinasRESUMEN
Gastrointestinal absorption is a key factor amongst the ADME-related (absorption, distribution, metabolism and excretion) pharmacokinetic properties; therefore, it has a major role in drug discovery and drug safety determinations. The Parallel Artificial Membrane Permeability Assay (PAMPA) can be considered as the most popular and well-known screening assay for the measurement of gastrointestinal absorption. Our study provides quantitative structure-property relationship (QSPR) models based on experimental PAMPA permeability data for almost four hundred diverse molecules, which is a great extension of the applicability of the models in the chemical space. Two- and three-dimensional molecular descriptors were applied for the model building in every case. We have compared the performance of a classical partial least squares regression (PLS) model with two major machine learning algorithms: artificial neural networks (ANN) and support vector machine (SVM). Due to the applied gradient pH in the experiments, we have calculated the descriptors for the model building at pH values of 7.4 and 6.5, and compared the effect of pH on the performance of the models. After a complex validation protocol, the best model had an R2=0.91 for the training set, and R2= 0.84 for the external test set. The developed models are capable for the robust and fast prediction of new compounds with an excellent accuracy compared to the previous QSPR models.
Asunto(s)
Algoritmos , Absorción Gastrointestinal , Absorción Intestinal , Permeabilidad , Relación Estructura-Actividad Cuantitativa , Aprendizaje AutomáticoRESUMEN
Absorption in the gastrointestinal tract is a key factor determining the bioavailability of chemicals after oral exposure but is frequently assumed to have a conservative value of 100% for environmental chemicals, particularly in the context of high-throughput toxicokinetics for in vitro-to-in vivo extrapolation (IVIVE). For pharmaceutical compounds, the physiologically based advanced compartmental absorption and transit (ACAT) model has been used extensively to predict gut absorption but has not generally been applied to environmental chemicals. Here we develop a probabilistic environmental compartmental absorption and transit (PECAT) model, adapting the ACAT model to environmental chemicals. We calibrated the model parameters to human in vivo, ex vivo, and in vitro datasets of drug permeability and fractional absorption by considering two key factors: (1) differences between permeability in Caco-2 cells and in vivo permeability in the jejunum, and (2) differences in in vivo permeability across different gut segments. Incorporating these factors probabilistically, we found that given Caco-2 permeability measurements, predictions of the PECAT model are consistent with the (limited) available gut absorption data for environmental chemicals. However, the substantial chemical-to-chemical variability observed in the calibration data often led to wide probabilistic confidence bounds in the predicted fraction absorbed and resulting steady state blood concentration. Thus, while the PECAT model provides a statistically rigorous, physiologically based approach for incorporating in vitro data on gut absorption into toxicokinetic modeling and IVIVE, it also highlights the need for more accurate in vitro models and data for measuring gut segment-specific in vivo permeability of environmental chemicals.
Asunto(s)
Absorción Gastrointestinal , Modelos Biológicos , Humanos , Disponibilidad Biológica , Células CACO-2RESUMEN
OBJECTIVES: To compare the rate and extent of absorption of a launched generic calcium dobesilate capsule versus the branded reference formulation under fasting and fed conditions in healthy Chinese subjects, and to assess their bioequivalence and tolerability. METHODS: This single-dose, open-label, randomized-sequence, 2-period crossover bioequivalence study was conducted on healthy Chinese volunteers aged 18 to 45 years. Subjects received a single 0.5 g dose of calcium dobesilate capsule under fasting or fed conditions, with a 3-day washout period between doses of the test (T) and reference (R) formulations. Blood samples were collected before and up to 24 hours after administration. The plasma concentration of calcium dobesilate was determined by a validated Liquid chromatography-tandem mass spectrometry method. Non-compartmental analysis was applied to identify the pharmacokinetic (PK) properties. The primary PK parameters including the maximal plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC0-t), and the AUC extrapolated to infinity (AUC0-inf) were used for bioequivalence evaluation. RESULTS: The mean of PK parameters for T and R capsules under fasting (fed) condition were: Cmax, 13.57 (6.71) and 12.59 (7.25) µg/mL; AUC0-t, 97.32 (79.74) and 96.97 (80.71) h*µg/mL; AUC0-inf, 101.68 (88.01) and 101.64 (87.81) h*µg/mL. The 90% confidence intervals (CIs) of GMRs under fasting (fed) condition were: Cmax, 97.91%-116.62% (88.63%-96.53%); AUC0-t, 97.15%-104.00% (96.58%-101.39%); and AUC0-inf, 97.19%-102.89% (98.67%-103.99%). These 90% CIs were all within the bioequivalence range of 80%-125%. All adverse events were mild. CONCLUSION: In this study, the T calcium dobesilate 0.5 g capsule was bioequivalent to the reference product under both fasting and fed conditions. Taking food would slow down its rate and reduce its amount of absorption. Both formulations were generally well tolerated.
Asunto(s)
Dobesilato de Calcio , Medicamentos Genéricos , Pueblos del Este de Asia , Conducta Alimentaria , Medicamentos bajo Prescripción , Humanos , Área Bajo la Curva , Dobesilato de Calcio/sangre , Dobesilato de Calcio/farmacocinética , Cápsulas , Estudios Cruzados , Ayuno/sangre , Ayuno/fisiología , Conducta Alimentaria/fisiología , Voluntarios Sanos , Equivalencia Terapéutica , Medicamentos Genéricos/farmacocinética , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Absorción Gastrointestinal/fisiología , Medicamentos bajo Prescripción/farmacocinéticaRESUMEN
Supersaturation is a promising strategy to improve gastrointestinal absorption of poorly water-soluble drugs. Supersaturation is a metastable state and therefore dissolved drugs often quickly precipitate again. Precipitation inhibitors can prolong the metastable state. Supersaturating drug delivery systems (SDDS) are commonly formulated with precipitation inhibitors, hence the supersaturation is effectively prolonged for absorption, leading to improved bioavailability. This review summarizes the theory of and systemic insight into supersaturation, with the emphasis on biopharmaceutical aspects. Supersaturation research has developed from the generation of supersaturation (pH-shift, prodrug and SDDS) and the inhibition of precipitation (the mechanism of precipitation, the character of precipitation inhibitors and screening precipitation inhibitors). Then, the evaluation approaches to SDDS are discussed, including in vitro, in vivo and in silico studies and in vitro-in vivo correlations. In vitro aspects involve biorelevant medium, biomimetic apparatus and characterization instruments; in vivo aspects involve oral absorption, intestinal perfusion and intestinal content aspiration and in silico aspects involve molecular dynamics simulation and pharmacokinetic simulation. More physiological data of in vitro studies should be taken into account to simulate the in vivo environment. The supersaturation theory should be further completed, especially with regard to physiological conditions.
Asunto(s)
Absorción Gastrointestinal , Absorción Intestinal , Solubilidad , Preparaciones Farmacéuticas , Sistemas de Liberación de Medicamentos , Precipitación Química , Administración OralRESUMEN
For supersaturating formulations of BCS-II compounds, which by definition have high intestinal permeability, a closed USP apparatus does not provide the necessary absorptive conditions during dissolution. To address this, an artificial gut simulator (AGS) has been constructed consisting of a 2.5 mL donor compartment in which a hollow fiber-based absorption module is suspended. Drug from donor diffuses across the hollow fiber membrane to be absorbed by the continuously flowing intraluminal receiver fluid. The membrane surface area and intraluminal fluid flow rate are tuned to obtain the physiologically observed absorption rate constant for a weakly basic, poorly water-soluble model compound, ketoconazole (KTZ). Supersaturated solutions of KTZ were generated in the donor in pH 6.5 phosphate buffer by the pH-shift method in the absence (closed system, control) and presence (open system, biorelevant) of an optimally or suboptimally tuned absorption module. Drug concentrations in the donor and intraluminal fluids were determined by in-line UV spectroscopy. The presence of an absorptive sink reduced the supersaturated solution's crystallization propensity, more so in the case of the optimally tuned AGS. This study demonstrates the significance of simulating absorption of drug at a physiological rate during dissolution studies, especially to predict the performance of formulations of BCS-II drugs.
Asunto(s)
Absorción Gastrointestinal , Cetoconazol , Cetoconazol/química , Solubilidad , Composición de Medicamentos , Absorción Intestinal/fisiología , Administración OralRESUMEN
Aim: This study aimed to evaluate if there is a dose-response relationship between toothpaste chemically soluble fluoride absorbed in the gastrointestinal tract and fluoride secreted by saliva, giving support to the use of saliva as surrogate for plasma fluoride. Methods: A 4-phase single blind study was conducted, in which 10 participants were subjected in each phase to one of the assigned treatment groups: group I: fresh sample of a Na2FPO3/CaCO3-based toothpaste with 1,334 µg F/g of total soluble fluoride (TSF) and groups IIIV: aged samples of this toothpaste presenting TSF concentrations of 1,128, 808, and 687 µg F/g, respectively. In all phases, the participants ingested an amount of toothpaste equivalent to 70.0 µg F/Kg body weight, as total fluoride (TF). Saliva and blood samples were collected before (baseline) and up to 180 min after toothpaste ingestion as indicator of fluoride bioavailability. F concentration in saliva and blood plasma was determined with a fluoride ion-specific electrode. The areas under the curve (AUC) of F concentration versus time (AUC = ng F/mL × min) and the peaks of fluoride concentration (Cmax) in saliva and plasma were calculated. Results: A significant correlation between mg of TSF ingested and the AUC (r=0.47; p<0.01), and Cmax (r=0.59; p<0.01) in saliva was found; for TF, the correlation was not significant (p>0.05). In addition, the correlations between plasma and saliva fluoride concentrations were statistically significant for AUC (r=0.55; p<0.01) as for Cmax (r=0.68; p<0.01). Conclusion: The findings support that saliva can be used as a systemic biomarker of bioavailable fluoride present in Na2FPO3/CaCO3-based toothpaste
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Adulto Joven , Pastas de Dientes/farmacocinética , Absorción Gastrointestinal , Eliminación Salival , Fluoruros/farmacocinética , Pastas de Dientes/administración & dosificación , Método Simple Ciego , Riesgo , Relación Dosis-Respuesta a Droga , Fluoruros/administración & dosificación , Fluoruros/sangre , Fluorosis DentalRESUMEN
Computer searches of the PubMed, Cochrane Library, and Embase databases for randomized controlled studies on the effects of intensive nutrition on clinical outcomes in patients with severe craniocerebral injury were conducted from the time of database creation to June 11, 2022, along with manual searches of the relevant literature. Two investigators independently screened the literature, extracted data, and evaluated the risk of bias of the included studies before the effect sizes were combined using RevMan 5.3 statistical software provided by the Cochrane Collaboration Network, and publication bias was detected using Stata 12.0 software. Meta-analysis showed that total protein levels were higher in the intensive nutrition group than in the regular nutrition group (WMD = 4.96 g/L (1.57-8.34), P < 0.001); IgA levels were significantly higher in the intensive nutrition group than in the regular nutrition group (SMD = 0.79 (0.51-1.07), P < 0.001; SMD = 0.98 (0.58-1.38), P < 0.001); IgG levels were significantly higher in the fortified group than in the regular group (SMD = 0.98 (0.58-1.38), P < 0.001); CD4/CD8 was significantly higher in the fortified patients than in the regular patients with a combined effect size of WMD = 0.33 (0.18-0.48) (P < RR = 0.45 (0.27-0.75), P = 0.002). The results show that effective support of early enteral nutrition can reduce the occurrence of gastrointestinal complications in patients, give them a better adaptation process to the gastrointestinal tract, and ensure the degree of tolerance of their gastric mucosa, thus absorbing more nutrition. Fortification significantly reduced the incidence of gastric retention in patients with craniocerebral injury (RR = 0.19 (0.07-0.49), P < 0.001). In the subgroup analysis of the three groups, it was shown that, depending on the starting time, the total protein level and IgG level were better in the early nutrition at 24 h than in the late nutrition above 24h and that, depending on the starting dose, the total protein level, IgA, IgG, and CD4/CD8 were better in the intervention at doses above 30 mL/h, using the starting dose of 30 mL/h as the cut-off point. In the subgroup analysis based on different nutrition methods (enteral and parenteral nutrition), IgA levels and the incidence of bloating and diarrhea were better than those of parenteral nutrition in the indicators of enteral nutrition.
Asunto(s)
Extubación Traqueal , Coma , Traumatismos Craneocerebrales , Nutrición Enteral , Nutrición Parenteral , Extubación Traqueal/efectos adversos , Coma/complicaciones , Coma/diagnóstico , Coma/terapia , Traumatismos Craneocerebrales/complicaciones , Diarrea/complicaciones , Absorción Gastrointestinal , Humanos , Inmunoglobulina A , Inmunoglobulina G , Resultado del TratamientoRESUMEN
OBJECTIVE: To establish the pharmacokinetics of a single 2-mg oral dose of chlorambucil in cats with indolent lymphoproliferative malignancies. ANIMALS: 24 client-owned cats. PROCEDURES: Cats were assigned to 1 of 4 groups, with each group having a total of 3 sample collection time points over 12 hours after receiving a single 2-mg oral dose of chlorambucil. Each time point combined to generate 6 full patient plasma chlorambucil concentration-time curves from the 24 cats. Chlorambucil treatment was continued every other day and a single, variably timed sample collection was obtained on day 14. Population parameter estimates were obtained by nonlinear mixed-effects modeling. Covariates investigated included age, sex, baseline serum cobalamin, study location, weight, and body condition score. RESULTS: Chlorambucil administered orally to cats was found to have a peak plasma concentration of approximately 170 ng/mL (SE, 31.1 ng/mL), percent coefficient of variation (%CV) of 18.4% within 15 minutes, and a terminal half-life of 1.8 hours (SE, 0.21 hour; %CV, 12.4). At the 4-hour mark, a smaller secondary peak in plasma chlorambucil was found. Day 14 samples were similar to those of the initial dose. No covariates showed a significant effect in the population model. CLINICAL RELEVANCE: In these cats, chlorambucil at a 2-mg dose administered every other day undergoes rapid gastrointestinal absorption and plasma clearance with no drug accumulation between doses. These data are critical to inform future work investigating the association of chlorambucil drug exposure with adverse events and outcome of cats with lymphoproliferative diseases.
Asunto(s)
Enfermedades de los Gatos , Neoplasias , Gatos , Animales , Clorambucilo/uso terapéutico , Cinética , Área Bajo la Curva , Absorción Gastrointestinal , Neoplasias/veterinaria , Administración OralRESUMEN
Resumen La marihuana o cannabis es la sustancia psicoactiva ilícita de mayor consumo. Una consecuencia no deseada de la regulación de su cultivo y la difusión popular de su uso medicinal y recreativo, es su asociación con el aumento de la disponibilidad de cultivos en la población general y de productos, como alimentos y fármacos elaborados con infusiones de esta planta, con concentraciones desconocidas de delta-9-tetrahidrocannabinol (A9THC), su principal componente psicoactivo. Se presenta una serie de 3 pacientes expuestos a esta sustancia de forma no intencional, por vía digestiva, asistidos de forma presencial por los servicios de Toxicología y Emergencias del Hospital Interzonal de Agudos Especializado en Pediatría "Sor María Ludovica" de La Plata. A diferencia de la absorción por vía inhalatoria, por vía digestiva se producen concentraciones mucho más variables y ciclos temporales mayores de A9THC y sus metabolitos, que ejercen sus efectos sobre los receptores CB1, dispuestos en el sistema nervioso central, incluido tronco encefálico, región con mayor presencia de éstos en niños, lo que justifica las manifestaciones neurológicas frecuentes y de mayor gravedad en este grupo etario, en relación a los adultos. La sospecha clínica, la anamnesis y la detección temprana de cannabinoides en orina son los pilares fundamentales para establecer el diagnóstico temprano. El tratamiento consiste en medidas de sostén y sintomáticas, que se implementan según la gravedad del cuadro. Debe considerarse la posibilidad de exposición a esta sustancia frente a cuadros de letargo o somnolencia de aparición brusca, con ataxia, modificaciones del humor, alteraciones sensoperceptivas, convulsiones o coma, con o sin insuficiencia respiratoria, con taquicardia o bradicardia. Es de fundamental importancia la educación y concientización de los adultos a cargo de niños sobre estos riesgos.
Abstract Marijuana or cannabis is the illicit psychoactive substance most widely used. An unwanted consequence of the regula-tion of its cultivation and the popular diffusion of its medicinal and recreational use, is the association with an increase in the avail-ability of crops in the general population, products, foods and medicines made with cannabis infusions, with unknown concentra-tions of delta-9-tetrahydrocannabinol (A9THC), the most important psychoactive component. We present a series with 3 patients with unintentional exposure to this substance through the digestive tract, assisted by the Toxicology and Emergency services of the Interzonal Hospital for Acute Specialized in Pediatrics "Sor María Ludovica". Unlike absorption through the inhalation route, more variable concentrations and greater temporal cycles of A9THC and its metabolites are produced through the digestive route, which exert their effects on CB1 receptors, arranged in the central nervous system, including brainstem, the region with greatest presence of this receptors in children, that justifies the frequent and more serious neurological manifestations in children, compared to adults. Clinical suspicion, anamnesis and early detection of cannabinoids in urine are the fundamental pillars to establish an early diagnosis. Treatment consists in supportive and symptomatic measures, that are implemented according to the severity of the condition. The possibility of exposure to this substance must be estimated in the face of sudden onset of lethargy or drowsi-ness, with ataxia, mood modifications, sensory-perceptual disturbances, seizures or coma, with or without respiratory failure, with tachycardia or bradycardia. The education and awareness of caretakers adults, about these risks is of fundamental importance.
Asunto(s)
Humanos , Masculino , Femenino , Lactante , Preescolar , Cannabis/envenenamiento , Cannabis/toxicidad , Absorción Gastrointestinal , Uso de la Marihuana/efectos adversosRESUMEN
The purpose of this study was to develop and validate a simultaneous dissolution and absorption testing tool, the "artificial gut simulator" (AGS), for oral drug formulations. The AGS was constructed using hollow fibers and housed in a 3-mL UV spectrophotometric cuvette that provided a large surface area-to-volume ratio to simulate absorption at a physiological rate. A quasi-steady-state model describing absorption was developed and validated using a high aqueous solubility, BCS-I model compound, caffeine. This model was used to optimize the AGS operating parameters to simulate physiological gastric emptying and caffeine absorption, which was further input into a one-compartment pharmacokinetic (PK) model. The in vivo caffeine plasma concentration-time profiles matched those predicted by the PK model with in vitro input from the AGS. This work provides a framework for establishing an in vitro/in vivo correlation with high-permeability, BCS-II supersaturating drug formulations, which will be explored in the future studies.
Asunto(s)
Cafeína , Absorción Gastrointestinal , Administración Oral , Absorción Intestinal , Modelos Biológicos , Permeabilidad , SolubilidadRESUMEN
El arándano (Vaccinium corymbosum L.) posee un alto contenido de compuestos fenólicos los cuales han sido estudiados principalmente por su actividad antioxidante, antiobesogénica, antiinflamatoria, entre otras. Objetivo. Evaluar el efecto de la digestión gastrointestinal in vitro sobre la bioaccesibilidad de compuestos fenólicos y actividad antioxidante de una formulación nutracéutica de arándano (cápsula), comparado con arándano fresco y polvo. Materiales y métodos. Se obtuvieron extractos metanólicos de muestras de arándano fresco y liofilizado y se determinó su contenido de fenoles, flavonoides y antocianinas totales, así como también actividad antioxidante. Se llevó a cabo un ensayo de simulación de digestión gastrointestinal para evaluar la bioaccesibilidad de los compuestos fenólicos presentes en las muestras. Resultados. Los resultados mostraron que la digestión gástrica de arándano en polvo y en cápsula promovió una mayor bioaccesibilidad de fenoles (42% y 40%), flavonoides (52% y 33%) y antocianinas (45% y 40%) comparado con digestos de arándano fresco. Posterior a la digestión intestinal, la bioaccesibilidad de fenoles (63%) y flavonoides (67%) fue mayor en la cápsula de arándano comparada con su contraparte arándano en polvo. Las condiciones de digestión intestinal afectaron negativamente la bioaccesibilidad de las antocianinas independientemente del tipo de muestra evaluada. Conclusión. Las condiciones de digestión gástrica promueven una mayor estabilidad de los compuestos fenólicos en arándano en polvo y en cápsula lo que pudiera ser relevante para el mantenimiento de un ambiente antioxidante a este nivel. Las condiciones de digestión intestinal afectaron de manera particular a los compuestos fenólicos de arándano fresco y polvo, pero no a la cápsula, lo que puede sugerir que el encapsulamiento protegió de las condiciones alcalinas a los fenoles presentes. Se sugieren estudios posteriores sobre absorción in vitro de los componentes remanentes en intestino y sus posibles efectos sobre biomarcadores de estrés oxidativo en modelos in vivo(AU)
Blueberry (Vaccinium corymbosum L.) has a high content of phenolic compounds which have been studied mainly for their antioxidant, antiobesogenic, anti-inflammatory activity, among others. Objetive. The objective of the present study was to evaluate the effect of in vitro gastrointestinal digestion on the bioaccessibility of phenolic compounds and antioxidant activity of a nutraceutical formulation of blueberry (capsule), compared to fresh and powder blueberry. Materials and methods. Methanolic extracts of fresh and lyophilized blueberry were obtained and determined its total phenols, flavonoids, anthocyanins content, as well as antioxidant activity. A gastrointestinal digestion simulation test also was carried out to assess the bioaccessibility of the phenolic compounds found in samples. Results. The results showed that gastric digestion of powder and capsule blueberry promoted greater bioaccessibility of phenols (42% and 40%), flavonoids (52% and 33%) and anthocyanins (45% and 40%), compared to fresh blueberry digests. After intestinal digestion, the bioaccessibility of phenols (63%) and flavonoids (67%) was higher in the blueberry capsule compared to its powdered blueberry counterpart. The intestinal digestion conditions negatively affected the bioaccessibility of anthocyanins regardless of the type of sample evaluated. Conclusion. Gastric digestion conditions promote greater stability of phenolic compounds in powdered and capsule blueberries, which could be relevant for the maintenance of an antioxidant environment at this level. The intestinal digestion conditions particularly affected the phenolic compounds of fresh and lyophilized blueberry, but not the capsule, which may suggest that encapsulation protected the phenols present from alkaline conditions. Further studies on in vitro absorption of the remaining components in the intestine and their possible effects on oxidative stress biomarkers in in vivo models are suggested(AU)
Asunto(s)
Taninos , Flavonoides , Arándanos Azules (Planta) , Compuestos Fenólicos , Absorción Gastrointestinal , Técnicas In Vitro , Enfermedad Crónica , Digestión , LiofilizaciónRESUMEN
The gut microbiota, an often forgotten organ, have a tremendous impact on human health. It has long been known that the gut microbiota are implicated in cancer development, and more recently, the gut microbiota have been shown to influence cancer metastasis to distant organs. Although one of the most common sites of distant metastasis is the bone, and the skeletal system has been shown to be a subject of interactions with the gut microbiota to regulate bone homeostasis, little research has been done regarding how the gut microbiota control the development of bone metastasis. This review will discuss the mechanisms through which the gut microbiota and derived microbial compounds (i) regulate gastrointestinal cancer disease progression and metastasis, (ii) influence skeletal remodeling and potentially modulate bone metastasis, and (iii) affect and potentially enhance immunotherapeutic treatments for bone metastasis.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Sistemas de Liberación de Medicamentos/métodos , Microbioma Gastrointestinal/fisiología , Neoplasias Gastrointestinales/metabolismo , Animales , Neoplasias Óseas/tratamiento farmacológico , Disbiosis/complicaciones , Disbiosis/tratamiento farmacológico , Disbiosis/metabolismo , Absorción Gastrointestinal/efectos de los fármacos , Absorción Gastrointestinal/fisiología , Microbioma Gastrointestinal/efectos de los fármacos , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/etiología , HumanosRESUMEN
BACKGROUND: Gastric ulcer (GU) belongs to gastric mucosal irritation and damage. 20(S)-ginsenoside Rg3 (Rg3) has shown anti-oxidant, antiinflammation, and tissue repair effects which are essential for GU treatment. However, the solubility of Rg3 is poor and low gastrointestinal absorption may limit its anti-ulcer effects. As a result, we aim to increase the gastric retention time and gastric absorption of Rg3 to achieve better GU treatment efficacy. METHODS: The mPEG-b-P(Glu-co-Phe) nanoparticles loaded with Rg3 (Rg3-NPs) were developed. The characteristics of Rg3-NPs, including the morphology, diameter, and stability were analyzed. The Rg3 release profiles, gastric retention of Rg3, in vitro cytotoxicity, and pharmacokinetics of Rg3 were assessed. An alcohol-induced rats GU model was performed, and the rats were randomly separated into five treatment groups. Biochemical analysis, gross evaluation, histopathology, and immunohistochemical analysis were applied to further analyze the anti-ulcer effects of Rg3-NPs. RESULTS: Rg3-NPs were successfully prepared and the Rg3 release was pH sensitive. The gastric retention time of Rg3 is longer in Rg3-NPs group than that in Rg3 group. By slightly increasing nitric oxide (NO), obviously increasing epidermal growth factor (EGF), EGF receptor (EGFR), and superoxide dismutase (SOD), and decreasing endothelin-1 (ET-1) and nitric oxide synthase (NOS2), Rg3-NPs possess better GU treatment efficacy than Rg3. CONCLUSIONS: Rg3-NPs can increase gastric retention time and gastric absorption of Rg3 and promote its GU treatment efficacy.
Asunto(s)
Ginsenósidos/farmacocinética , Ácido Glutámico/análogos & derivados , Fenilalanina/análogos & derivados , Polietilenglicoles/farmacocinética , Úlcera Gástrica/patología , Animales , Receptores ErbB/efectos de los fármacos , Mucosa Gástrica/metabolismo , Absorción Gastrointestinal , Ginsenósidos/administración & dosificación , Ácido Glutámico/administración & dosificación , Ácido Glutámico/farmacocinética , Nanopartículas/metabolismo , Fenilalanina/administración & dosificación , Fenilalanina/farmacocinética , Polietilenglicoles/administración & dosificación , Ratas , Ratas WistarRESUMEN
This collection of contributions from the European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP) community assembly aims to provide information on some of the current and newer methods employed to study the behaviour of medicines. It is the product of interactions in the immediate pre-Covid period when UNGAP members were able to meet and set up workshops and to discuss progress across the disciplines. UNGAP activities are divided into work packages that cover special treatment populations, absorption processes in different regions of the gut, the development of advanced formulations and the integration of food and pharmaceutical scientists in the food-drug interface. This involves both new and established technical approaches in which we have attempted to define best practice and highlight areas where further research is needed. Over the last months we have been able to reflect on some of the key innovative approaches which we were tasked with mapping, including theoretical, in silico, in vitro, in vivo and ex vivo, preclinical and clinical approaches. This is the product of some of us in a snapshot of where UNGAP has travelled and what aspects of innovative technologies are important. It is not a comprehensive review of all methods used in research to study drug dissolution and absorption, but provides an ample panorama of current and advanced methods generally and potentially useful in this area. This collection starts from a consideration of advances in a priori approaches: an understanding of the molecular properties of the compound to predict biological characteristics relevant to absorption. The next four sections discuss a major activity in the UNGAP initiative, the pursuit of more representative conditions to study lumenal dissolution of drug formulations developed independently by academic teams. They are important because they illustrate examples of in vitro simulation systems that have begun to provide a useful understanding of formulation behaviour in the upper GI tract for industry. The Leuven team highlights the importance of the physiology of the digestive tract, as they describe the relevance of gastric and intestinal fluids on the behaviour of drugs along the tract. This provides the introduction to microdosing as an early tool to study drug disposition. Microdosing in oncology is starting to use gamma-emitting tracers, which provides a link through SPECT to the next section on nuclear medicine. The last two papers link the modelling approaches used by the pharmaceutical industry, in silico to Pop-PK linking to Darwich and Aarons, who provide discussion on pharmacometric modelling, completing the loop of molecule to man.