RESUMEN
Percutaneous delivery is explored as alternative pathway for addressing the drawbacks associated with the oral administration of otherwise efficacious drugs. Short of breaching the skin by physical means, the preference goes to formulation strategies that augment passive diffusion across the skin. One such strategy lies in the use of skin penetration and permeation enhancers notably of hydroxylated solvents like propylene glycol (PG), ethanol (EtOH), and diethylene glycol monoethyl ether (Transcutol®, TRC). In a previous publication, we focused on the role of Transcutol® as enhancer in neat or diluted systems. Herein, we explore its' role in complex formulation systems, including patches, emulsions, vesicles, solid lipid nanoparticles, and micro or nanoemulsions. This review discusses enhancement mechanisms associated with hydroalcoholic solvents in general and TRC in particular, as manifested in multi-component formulation settings alongside other solvents and enhancers. The principles that govern skin penetration and permeation, notably the importance of drug diffusion due to solubilization and thermodynamic activity in the vehicle (formulation), drug solubilization and partitioning in the stratum corneum (SC), and/or solvent drag across the skin into deeper tissue for systemic absorption are discussed. Emphasized also are the interplay between the drug properties, the skin barrier function and the formulation parameters that are key to successful (trans)dermal delivery.
Asunto(s)
Administración Cutánea , Glicoles de Etileno , Permeabilidad , Absorción Cutánea , Piel , Solventes , Absorción Cutánea/fisiología , Absorción Cutánea/efectos de los fármacos , Glicoles de Etileno/química , Humanos , Piel/metabolismo , Animales , Solventes/química , Química Farmacéutica/métodos , Solubilidad , Sistemas de Liberación de Medicamentos/métodos , Emulsiones/química , Nanopartículas/química , Etanol/química , Etanol/administración & dosificaciónRESUMEN
This single blind placebo-controlled study has as its main objectives to investigate the influence of dark sweet cherries (DSC) consumption on obesity-related dysbiosis, metabolic endotoxemia, and intestinal permeability. Participants (>18 years old, BMI: 30-40 kg m-2) consumed 200 mL of DSC juice with 3 g of DSC powder (n = 19) or a placebo drink (n = 21) twice per day for 30 days. The gut microbiota abundance was investigated using 16S ribosomal RNA sequencing on fecal DNA. Metabolic endotoxemia was evaluated by measuring lipopolysaccharide-binding protein (LBP) in fasting plasma samples. Intestinal permeability was assessed using the lactulose/mannitol (L/M) test and by measuring regeneration islet-derived protein 4 (REG4), and interleukin-22 (IL-22) mRNA levels in stool samples. Results showed that DSC supplementation decreased the abundance of Anaerostipes hadrus (p = 0.02) and Blautia (p = 0.04), whose changes were significant in BMI ≥ 35 participants (p = 0.004 and p = 0.006, respectively). Additionally, DSC prevented the increase of Alistipes shahii (p = 0.005) and Bilophila (p = 0.01) compared to placebo. Notably, DSC intervention favored the abundance of bacteria supporting a healthy gut ecosystem such as Roseburia intestinalis (p = 0.01), Turicibacter (p = 0.01), and Bacteroides vulgatus (p = 0.003) throughout the intervention, along with Clostridium leptum (p = 0.03) compared to placebo. The LBP, L/M ratio, REG-4 and IL-22 mRNA levels remained unchanged in placebo and cherry groups, implying that participants did not experience alterations in intestinal permeability. These findings highlight the potential gut-health benefits of DSC and encourage future research among individuals with BMI ≥ 35 and increased intestinal permeability.
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Suplementos Dietéticos , Endotoxemia , Heces , Microbioma Gastrointestinal , Obesidad , Permeabilidad , Prunus avium , Humanos , Microbioma Gastrointestinal/efectos de los fármacos , Masculino , Heces/microbiología , Obesidad/microbiología , Obesidad/metabolismo , Obesidad/dietoterapia , Adulto , Femenino , Persona de Mediana Edad , Método Simple Ciego , Interleucina-22 , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Mucosa Intestinal/metabolismo , Adulto Joven , Funcion de la Barrera IntestinalRESUMEN
BACKGROUND/OBJECTIVES: Dietary fats have been linked to the increasing incidence of chronic diseases, including inflammatory bowel diseases (IBD), namely, Crohn's disease (CD). METHODS: This study investigated the impact of pentadecanoic acid (C15:0), a type of an odd-numbered chain saturated fatty acid, for its potential anti-inflammatory properties in different mouse models of experimental IBD using the SAMP1/YitFc (SAMP) mouse line (14- or 24-week-old), including chronic ileitis and DSS-induced colitis. To quantitively assess the effect of C:15, we tested two dosages of C:15 in selected experiments in comparison to control mice. Intestinal inflammation and intestinal permeability were used as primary outcomes. RESULTS: In ileitis, C:15 supplementation showed an anti-inflammatory effect in SAMP mice (e.g., a reduction in ileitis severity vs. control p < 0.0043), which was reproducible when mice were tested in the DSS model of colitis (e.g., reduced permeability vs. control p < 0.0006). Of relevance, even the short-term C:15 therapy prevented colitis in mice by maintaining body weight, decreasing inflammation, preserving gut integrity, and alleviating colitis signs. CONCLUSIONS: Collectively, the findings from both ileitis and colitis in SAMP mice indicate that C:15 may have therapeutic effects in the treatment of IBD (colitis in the short term). This promising effect has major translational potential for the alleviation of IBD in humans.
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Antiinflamatorios , Suplementos Dietéticos , Modelos Animales de Enfermedad , Enfermedades Inflamatorias del Intestino , Animales , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/administración & dosificación , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Masculino , Permeabilidad , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/dietoterapia , Ileítis/tratamiento farmacológico , Ileítis/prevención & controlRESUMEN
The gut barrier is essential for protection against pathogens and maintaining homeostasis. Macrophages are key players in the immune system, are indispensable for intestinal health, and contribute to immune defense and repair mechanisms. Understanding the multifaceted roles of macrophages can provide critical insights into maintaining and restoring gastrointestinal (GI) health. This review explores the essential role of macrophages in maintaining the gut barrier function and their contribution to post-inflammatory and post-infectious responses in the gut. Macrophages significantly contribute to gut barrier integrity through epithelial repair, immune modulation, and interactions with gut microbiota. They demonstrate active plasticity by switching phenotypes to resolve inflammation, facilitate tissue repair, and regulate microbial populations following an infection or inflammation. In addition, tissue-resident (M2) and infiltration (M1) macrophages convert to each other in gut problems such as IBS and IBD via major signaling pathways mediated by NF-κB, JAK/STAT, PI3K/AKT, MAPK, Toll-like receptors, and specific microRNAs such as miR-155, miR-29, miR-146a, and miR-199, which may be good targets for new therapeutic approaches. Future research should focus on elucidating the detailed molecular mechanisms and developing personalized therapeutic approaches to fully harness the potential of macrophages to maintain and restore intestinal permeability and gut health.
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Microbioma Gastrointestinal , Inflamación , Macrófagos , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Animales , Inflamación/metabolismo , Inflamación/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/inmunología , Transducción de Señal , MicroARNs/genética , MicroARNs/metabolismo , Tracto Gastrointestinal/microbiología , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/metabolismo , PermeabilidadRESUMEN
Efficient telmisartan delivery for hypertension management requires the incorporation of meglumine and/or sodium hydroxide as an alkalizer in the formulation. Long-term use of powerful alkalis with formulation as part of chronic therapy can cause metabolic alkalosis, ulcers, diarrhea, and body pain. Here, we aimed to design a telmisartan formulation without alkalizers. Telmisartan properties were tailor-made by microfluidizer-based physical modification. After microfluidization, telmisartan nanosuspension was lyophilized to obtain telmisartan premix powder. The optimized telmisartan nanosuspension had an average particle size of 579.85 ± 32.14 nm. The lyophilized premix was characterized by FT-IR, DSC, and PXRD analysis to ensure its physicochemical characteristics. The solubility analysis of premix showed 2.2 times, 2.3 times, and 6 times solubility improvement in 0.1 N HCl, phosphate buffer pH 7.5, and pH 6.8 compared to pure telmisartan. A 3D in-vitro Caco-2 model was developed to compare apparent permeability of API and powder premix. It showed that the powder premix was more permeable than pure API. The tablet formulation prepared from the telmisartan premix showed a dissolution profile comparable to that of the marketed formulation. The technique present herein can be used as a platform technology for solubility and permeability improvement of similar classes of molecules.
Asunto(s)
Tamaño de la Partícula , Permeabilidad , Solubilidad , Telmisartán , Telmisartán/administración & dosificación , Telmisartán/farmacocinética , Telmisartán/química , Humanos , Células CACO-2 , Composición de Medicamentos/métodos , Absorción Intestinal/efectos de los fármacos , Polvos/química , Concentración de Iones de Hidrógeno , Nanopartículas/química , Química Farmacéutica/métodos , Liberación de Fármacos , Funcion de la Barrera IntestinalRESUMEN
Hydrogels with sustained lubrication, high load-bearing capacity, and wear resistance are essential for applications in soft tissue replacements and soft material devices. Traditional tough or lubricious hydrogels fail to balance the lubrication and load-bearing functions. Inspired by the gradient-ordered multilayer structures of natural tissues (such as cartilage and ligaments), a tough, smooth, low-permeability, and low-friction anisotropic layered electrospun fiber membrane-reinforced hydrogel was developed using electrospinning and annealing recrystallization. This hydrogel features a stratified porous network structure of varying sizes with tightly bonded interfaces, achieving an interfacial bonding toughness of 1.6 × 103 J/m2. The anisotropic fiber membranes, mimicking the orderly fiber structures within soft tissues, significantly enhance the mechanical properties of the hydrogel with a fracture strength of 20.95 MPa, a Young's modulus of 29.64 MPa, and a tear toughness of 37.94 kJ/m2 and reduce its permeability coefficient (6.1 × 10-17 m4 N-1 s-1). Meanwhile, the hydrogel demonstrates excellent solid-liquid phase load-bearing characteristics, which can markedly improve the tribological performance. Under a contact load of 4.1 MPa, the anisotropic fiber membrane-reinforced hydrogel achieves a friction coefficient of 0.036, a 219% reduction compared with pure hydrogels. Thus, the superior load-bearing and lubricating properties of this layered hydrogel underscore its potential applications in soft tissue replacements, medical implants, and other biomedical devices.
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Hidrogeles , Permeabilidad , Hidrogeles/química , Anisotropía , Materiales Biocompatibles/química , Ensayo de Materiales , Membranas Artificiales , Módulo de Elasticidad , HumanosRESUMEN
Luteolin (LN), is an herbal bioactive flavone and exhibits many pharmacological activities. However, the bioavailability of LN is limited due to its inadequate solubility and significant first-pass metabolism. The present study developed transdermal LN-loaded invasomes (IVM) gel to improve the therapeutic efficacy. The LN-IVM was prepared and optimized by 2 3 factorial designs. LN-IVM was characterized for physicochemical parameters. The optimized LN-IVM (LN-IVMopt) was incorporated into HPMC-K4M gel and evaluated for viscosity, spreadability, and irritation. Further LN-IVM gel was evaluated for drug release, ex-vivo permeation, pharmacokinetic and pharmacodynamics study. LN-IVMopt showed 300.8±2.67 nm of VS, 0.258 of PDI, 89.92±1.29% of EE, and a zeta potential of -18.2 mV. LN-IVM exhibited spherical morphology. FTIR and XRD results demonstrated that LN was encapsulated into IVM matrix. The optimized IVM gel (LN-IVMoptG2) exhibited excellent viscosity, spreadability, and sustained release of LN (91.32±2.95% in 24 h). LN-IVMoptG2 exhibited statistically significant (p < 0.05) higher flux (5.79 µg/h/cm2 ) than LN-gel (2.09 µg/h/cm2 ). The apparent permeability coefficient of plain LN gel and LN- IVMoptG was 1.15×10-5 cm/min and 3.22×10-5 cm/min respectively. LN-IVMoptG2 showed no irritation (score 0.0) throughout the study (60 min). The relative bioavailability of LN from LN-IVMopt-G2 (transdermal) was 2.38±0.19 fold as compared to LN-Sus (oral) and 1.81±0.15-fold than plain LN-gel (transdermal). The LN-IVMoptG2 showed a substantial lessening in the paw volume up to 12 h (17.48±1.94% swelling) than plain LN-gel (44.77±2.82% swelling). The finding concluded that the IVM gel is a novel, effective, and safe approach for the delivery of LN transdermally to improve its therapeutic efficacy.
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Administración Cutánea , Liberación de Fármacos , Geles , Luteolina , Animales , Luteolina/administración & dosificación , Luteolina/farmacocinética , Viscosidad , Absorción Cutánea/efectos de los fármacos , Solubilidad , Masculino , Disponibilidad Biológica , Sistemas de Liberación de Medicamentos , Fenómenos Químicos , Permeabilidad , Ratas Sprague-DawleyRESUMEN
Patients on left ventricular assist devices (LVAD) are prone to excessive hemostasis disturbances due to permanent contact of artificial pump surfaces with blood components. We aimed to investigate if fibrin clot permeability is altered in patients on long-term continuous-flow LVAD therapy and if the clot permeability is associated with clinical characteristics and adverse events. We investigated 85 end-stage heart failure patients (90.6% men, age 48.6-63.8 years) scheduled for continuous flow long-term LVAD support according to current clinical indications. The patients were assessed periodically: prior to LVAD implantation (T1), 3-6 months (T2) after LVAD implantation, 6-12 months after (T3) and then every 6 months. We tested the first three blood samples (T1-T3) and the last available blood sample (T4), but no longer than 5 years after LVAD implantation. We assessed hemostasis parameters (Activated Partial Thromboplastin Time (APTT) Prothrombin Time, Activated Partial Thromboplastin Time, Fibrinogen, D-dimer, Antithrombin, Thrombin Time, Factor VIII, and von Willebrand Factor, aspirin-induced platelet inhibition, adenosine-diphosphate test) changes during the study period. Fibrin Clot Permeability was evaluated using a pressure system and Permeability Coefficient (Ks) was calculated. We observed a decrease in fibrin clot permeability (Ks) between T1, T2, T3 and T4 time periods; P < 0.01 for each comparison. Fibrin clot permeability was negatively correlated with fibrinogen concentration: r = - 0.51, P < 0.001, factor VIII activity r = - 0.42, P < 0.001. There was no association of Ks with age, Left Ventricular Ejection Fraction (LVEF) and medications P > 0.001, however cumulative measurements in patients on aspirin showed shortening of Ks in this group P = 0.0123. Major adverse cardiac and cerebrovascular events (MACCE) occurred in 36.5% patients, bleeding events in 25.9%, Net Adverse Clinical Events (NACE) in 62.4%; 31.7% patients died, and 17.6% underwent transplantation. The transplantation was considered as the endpoint. Discrepancies in Ks were observed between patients with MACCE, bleeding, and NACE, and patients without adverse events. Ks showed a constant trend towards normalization (P < 0.01) only in patients without adverse events. Patients with advanced heart failure have disturbed clot structure. A trend towards normalization of the Ks values is associated with fewer thromboembolic and bleeding complications in this group of patients.
Asunto(s)
Fibrina , Insuficiencia Cardíaca , Corazón Auxiliar , Humanos , Corazón Auxiliar/efectos adversos , Persona de Mediana Edad , Masculino , Femenino , Fibrina/metabolismo , Insuficiencia Cardíaca/terapia , Insuficiencia Cardíaca/metabolismo , Permeabilidad , Coagulación Sanguínea , HemostasisRESUMEN
It is becoming increasingly important to have starch sources with different physicochemical properties to meet the needs of new applications in food, packaging, bioplastic, and pharmaceutical industries. The first part of this study dealt with the isolation of starch from culturally, geographically, nutritionally esteemed, and high-yielding Assam Joha rice. Fine and uniform particle size (6.3 ± 0.09 µm), high amylose content (28 ± 1.03 %), swelling behavior, viscoelastic rheological behavior, moderate gelatinization temperature (66 ± 1.7 °C), thermostable nature, type A crystallographic pattern with high (45 ± 3.3 %) crystallinity, and suitable microbial quality make the Joha rice derived starch physico-chemically and functionally suitable for potential applications in diverse domains. The latter part of the study focuses on one of the applications of derived starch as a suitable matrix for intelligent packaging films with the incorporation of betanin-enriched beetroot extract (BRE) as a bio-based pH sensor. The addition of 1.0 % w/v BRE to the starch film (starch-BRE III) significantly increased its functionality by reducing UV-visible light transmittance and water vapor permeability, along with enhancing flexibility and hydrophobicity due to intermolecular bonding between BRE and the starch film matrix. Moreover, starch-BRE films with different BRE concentrations were successfully used to monitor the real-time freshness of white meat (chicken and fish) and Indian cottage cheese samples. Overall, the results indicated that starch-BRE III has great potential as an intelligent packaging material for monitoring food freshness.
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Beta vulgaris , Embalaje de Alimentos , Oryza , Extractos Vegetales , Almidón , Almidón/química , Embalaje de Alimentos/métodos , Beta vulgaris/química , Oryza/química , Extractos Vegetales/química , Amilosa/química , Amilosa/análisis , Permeabilidad , Reología , Concentración de Iones de Hidrógeno , TemperaturaRESUMEN
In this work, an attempt has been made to develop a novel natural polysaccharide-based composite packaging biofilm prepared through a solution casting method. The biofilm is prepared from guar gum (GG) and agar-agar (AA) beeswax (BE). The incorporation of 20 % wt./wt.glycerol BE in the blended polymer GG/AA (50:50) (GG/AA/BE20 (50:50)) film shows a reduction in water solubility (66.67 %), water vapour permeability (69.28 %) and oxygen permeability (72.23 %). Moreover, GG/AA/BE20 (50:50) shows an increment in the tensile strength and elongation of a break by 48.32 % and 26.05 %, respectively, compared to pristine GG film. The scanning electron microscopy (SEM) image reveals defects-free smooth surfaces of the film. The Fourier transform-infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) demonstrated the strong hydrogen bonding between GG, AA, and BE. The biodegradable film shows 99 % degradation within 28 days when placed in the soil. The developed film plays a crucial role in extending the shelf life of cheese, effectively maintaining its moisture content, texture, colour, and pH over a span of up to two months from the point of packaging. These results suggest that GG/AA/BE20 (50:50) composite film is a promising packaging film for cheese preservation.
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Agar , Queso , Embalaje de Alimentos , Galactanos , Mananos , Gomas de Plantas , Ceras , Gomas de Plantas/química , Galactanos/química , Mananos/química , Embalaje de Alimentos/métodos , Ceras/química , Agar/química , Permeabilidad , Conservación de Alimentos/métodos , Vapor , Resistencia a la Tracción , SolubilidadRESUMEN
In this work, the modification of poly(butylene adipate-co-terephthalate) (PBAT) was combined with the development of active packaging films. PBAT, starch, plasticizer, and tea polyphenols (TP) were compounded and extrusion-blown into thermoplastic starch (TPS)/PBAT-TP active films. Effects of TPS contents on physicochemical properties, functional activities, biodegradability, and release kinetics of PBAT-based active films were explored. Starch interacted strongly with TP through hydrogen bonding and induced the formation of heterogeneous structures in the films. With the increase in TPS contents, surface hydrophilicity and water vapor permeability of the films increased, while mechanical properties decreased. Blending starch with PBAT greatly accelerated degradation behavior of the films, and the T30P70-TP film achieved complete degradation after 180 days. As TPS contents increased, swelling degree of the films increased and TP release were improved accordingly, resulting in significantly enhanced antioxidant and antimicrobial activities. This work demonstrated that filling starch into PBAT-based active films could achieve different antioxidant and antimicrobial activities of the films by regulating film swelling and release behavior.
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Poliésteres , Polifenoles , Almidón , Té , Almidón/química , Polifenoles/química , Polifenoles/farmacología , Té/química , Poliésteres/química , Antioxidantes/química , Antioxidantes/farmacología , Permeabilidad , Fenómenos Químicos , Embalaje de Alimentos/métodos , Interacciones Hidrofóbicas e Hidrofílicas , Antiinfecciosos/química , Antiinfecciosos/farmacologíaRESUMEN
In recent years, there has been a significant increase in the prevalence of thyroid diseases, particularly hypothyroidism. In this study, we investigated the impact and mechanisms of Chemical permeation enhancement(CPE) on transdermal permeation of levothyroxine sodium (L-T4) patches.We found that the combination of oleic acid (OA) and Azone (NZ) yielded the best transdermal permeation effect for L-T4.Subsequently, we also investigated the relevant propermeability mechanism.The results demonstrate that the combined application of OA and NZ significantly enhances the transdermal permeation of L-T4 compared to individual applications,it is attributed to two mechanisms: firstly, OA improves drug release by increasing the flowability of the pressure-sensitive adhesive (PSA) matrix; secondly, both OA and NZ act on the stratum corneum, especially facilitating L-T4 permeation through the hair follicle pathway. No skin irritation or cytotoxicity is observed with these final patches, which exhibit a remarkable therapeutic effect on hypothyroidism. this study contributes to the development of transdermal formulations of L-T4.
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Administración Cutánea , Ácido Oléico , Absorción Cutánea , Tiroxina , Ácido Oléico/química , Tiroxina/administración & dosificación , Tiroxina/farmacología , Tiroxina/farmacocinética , Animales , Absorción Cutánea/efectos de los fármacos , Parche Transdérmico , Piel/metabolismo , Piel/efectos de los fármacos , Liberación de Fármacos , Ratones , Permeabilidad , Hipotiroidismo/tratamiento farmacológico , Hipotiroidismo/metabolismo , Humanos , Química Farmacéutica/métodos , MasculinoRESUMEN
Palbociclib and ribociclib an orally bioavailable, potent cyclin-dependent kinase 4/6 inhibitors, with low oral bioavailability due to substrate specificity towards CYP3A and P-glycoprotein. Thus, current research aims to examine the effect of a bioenhancer (naringin), on oral pharmacokinetics of palbociclib and ribociclib. Naringin's affinity for CYP3A4 and P-glycoprotein was studied using molecular docking; its impact on palbociclib/ribociclib CYP3A metabolism and P-glycoprotein-mediated efflux was examined using in vitro preclinical models; and its oral pharmacokinetics in rats were assessed following oral administration of palbociclib/ribociclib in presence of naringin (50 and 100 mg/kg). Naringin binds optimally to both proteins with the highest net binding energy of - 1477.23 and - 1607.47 kcal/mol, respectively. The microsomal intrinsic clearance of palbociclib and ribociclib was noticeably reduced by naringin (5-100 µM), by 3.0 and 2.46-folds, respectively. Similarly, naringin had considerable impact on the intestinal transport and efflux of both drugs. The pre-treatment with 100 mg/kg naringin increased significantly (p < 0.05) the oral exposure of palbociclib (2.0-fold) and ribociclib (1.95-fold). Naringin's concurrent administration of palbociclib and ribociclib increased their oral bioavailability due to its dual inhibitory effect on CYP3A4 and P-glycoprotein; thus, concurrent naringin administration may represent an innovative strategy for enhancing bioavailability of cyclin-dependent kinase inhibitors.
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Disponibilidad Biológica , Quinasa 6 Dependiente de la Ciclina , Flavanonas , Inhibidores de Proteínas Quinasas , Animales , Humanos , Ratas , Administración Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacología , Aminopiridinas/administración & dosificación , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Biopotenciadores/farmacología , Células CACO-2 , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Citocromo P-450 CYP3A/metabolismo , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Inhibidores Enzimáticos del Citocromo P-450/administración & dosificación , Flavanonas/administración & dosificación , Flavanonas/farmacología , Simulación del Acoplamiento Molecular , Permeabilidad , Piperazinas/farmacocinética , Piperazinas/farmacología , Piperazinas/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Purinas/farmacocinética , Purinas/administración & dosificación , Purinas/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Piridinas/administración & dosificación , Ratas Sprague-DawleyRESUMEN
Winlevi® (clascoterone) topical cream (1%, w/w) was approved by the U.S. FDA for the treatment of acne vulgaris in patients 12 years of age and older. The active ingredient, clascoterone, is not stable in physiological solutions and can hydrolyze to cortexolone at body temperature. Instability of clascoterone poses a significant challenge in accurately assessing the rate and extent of clascoterone permeation in vitro. Therefore, the purpose of this study was to develop an in vitro skin permeation test (IVPT) method, and a robust analytical method, that can minimize hydrolyzation of clascoterone during the study for quantification of clascoterone. Two IVPT methods, using either vertical diffusion cells or flow-through cells, were developed and compared to evaluate in vitro permeation of clascoterone from Winlevi. A liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was developed to monitor the level of clascoterone and cortexolone in the IVPT samples. The analytical method features a 2-min high-throughput analysis with good linearity, selectivity, and showed a lower limit of quantitation (LLOQ) of 0.5 ng/mL for both clascoterone and cortexolone. The in vitro skin permeation of clascoterone and cortexolone was observed as early as 2 h in both IVPT methods. A substantive amount of clascoterone was found to hydrolyze to cortexolone when using the vertical static diffusion cells with aliquot sampling. Conversely, degradation of clascoterone was significantly minimized when using the flow-through diffusion cells with fractional sampling. The data enhanced our understanding of in vitro permeation of clascoterone following topical application of the Winlevi topical cream, 1% and underscores the importance of IVPT method development and optimization during product development.
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Cortodoxona , Absorción Cutánea , Crema para la Piel , Espectrometría de Masas en Tándem , Absorción Cutánea/efectos de los fármacos , Absorción Cutánea/fisiología , Crema para la Piel/farmacocinética , Crema para la Piel/administración & dosificación , Cortodoxona/administración & dosificación , Cortodoxona/farmacocinética , Cortodoxona/metabolismo , Cortodoxona/análogos & derivados , Espectrometría de Masas en Tándem/métodos , Piel/metabolismo , Administración Cutánea , Cromatografía Liquida/métodos , Animales , Permeabilidad , Porcinos , Humanos , PropionatosRESUMEN
Many patients with irritable bowel syndrome (IBS) have a compromised intestinal barrier associated with low-grade inflammation. Polyunsaturated fatty acids (PUFAs) are potential mediators of inflammation: omega-6 PUFAs are pro-inflammatory, while omega-3 PUFAs are antioxidant and anti-inflammatory. Zonulin is a potential biomarker for small intestinal permeability (s-IP). This study investigated the relationship between PUFAs and gastrointestinal (GI) barrier integrity in IBS patients with predominant diarrhea (IBS-D). We evaluated GI barrier function indicators in the urine and bloodstream and erythrocyte membrane PUFA composition in 38 IBS-D patients (5 men, 33 women, 44.11 ± 1.64 years), categorized at baseline by fecal zonulin levels into high (≥107 ng/mL, H-FZ) and normal (<107 ng/mL N-FZ) groups. Evaluations were conducted prior to and following a 12-week diet low in FODMAPs (LFD). At baseline, H-FZ patients had s-IP significantly higher than the reference value, lower n-3 PUFAs levels, and higher n-6/n-3 PUFAs and arachidonic acid (AA) to eicosapentaenoic acid (EPA) ratios than N-FZ. After LFD, H-FZ patients showed significant increases in n-3 PUFAs levels; decreases in n-6 PUFAs, n-6/n-3 PUFAs and AA/EPA ratios; and improved s-IP. The n-6/n-3 PUFAs ratio positively correlated with fecal zonulin levels in all subjects. These findings highlight the relationship between PUFAs and the intestinal barrier, suggesting their role in IBS-D pathophysiology and confirming the positive effects of LFD in managing IBS-D.
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Biomarcadores , Diarrea , Membrana Eritrocítica , Haptoglobinas , Síndrome del Colon Irritable , Humanos , Femenino , Síndrome del Colon Irritable/dietoterapia , Masculino , Adulto , Diarrea/etiología , Haptoglobinas/metabolismo , Biomarcadores/orina , Membrana Eritrocítica/metabolismo , Membrana Eritrocítica/química , Persona de Mediana Edad , Permeabilidad , Heces/química , Ácidos Grasos Omega-3/análisis , Ácidos Grasos Insaturados/análisis , Precursores de Proteínas/metabolismo , Mucosa Intestinal/metabolismo , Toxina del Cólera , Dieta FODMAPRESUMEN
High-fat diet (HFD) feeding is known to cause intestinal barrier disruption, thereby triggering severe intestinal inflammatory disease. Indole-3-aldehyde (IAld) has emerged as a potential candidate for mitigating inflammatory responses and maintaining intestinal homeostasis. However, the role of IAld in the HFD-related intestinal disruption remains unclear. In this study, 48 7 week-old male C57BL/6J mice were assigned to four groups: the normal chow diet (NCD) group received a NCD; the HFD group was fed an HFD; the HFD + IAld200 group was supplemented with 200 mg/kg IAld in the HFD; and the HFD + IAld600 group was supplemented with 600 mg/kg IAld in the HFD. The results showed that dietary IAld supplementation ameliorated fat accumulation and metabolic disorders, which are associated with reduced intestinal permeability. This reduction potentially led to decreased systemic inflammation and enhanced intestinal barrier function in HFD-fed mice. Furthermore, we found that IAld promoted intestinal stem cell (ISC) proliferation by activating aryl hydrocarbon receptors (AHRs) in vivo and ex vivo. These findings suggest that IAld restores the HFD-induced intestinal barrier disruption by promoting AHR-mediated ISC proliferation.
Asunto(s)
Proliferación Celular , Dieta Alta en Grasa , Indoles , Mucosa Intestinal , Ratones Endogámicos C57BL , Células Madre , Animales , Dieta Alta en Grasa/efectos adversos , Masculino , Ratones , Indoles/farmacología , Células Madre/metabolismo , Células Madre/efectos de los fármacos , Células Madre/citología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Intestinos/efectos de los fármacos , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hidrocarburo de Aril/genética , PermeabilidadRESUMEN
BACKGROUND: Inflammatory bowel disease, particularly Crohn's disease (CD), has been associated with alterations in mesenteric adipose tissue (MAT) and the phenomenon termed "creeping fat". Histopathological evaluations showed that MAT and intestinal tissues were significantly altered in patients with CD, with these tissues characterized by inflammation and fibrosis. AIM: To evaluate the complex interplay among MAT, creeping fat, inflammation, and gut microbiota in CD. METHODS: Intestinal tissue and MAT were collected from 12 patients with CD. Histological manifestations and protein expression levels were analyzed to determine lesion characteristics. Fecal samples were collected from five recently treated CD patients and five control subjects and transplanted into mice. The intestinal and mesenteric lesions in these mice, as well as their systemic inflammatory status, were assessed and compared in mice transplanted with fecal samples from CD patients and control subjects. RESULTS: Pathological examination of MAT showed significant differences between CD-affected and unaffected colons, including significant differences in gut microbiota structure. Fetal microbiota transplantation (FMT) from clinically healthy donors into mice with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced CD ameliorated CD symptoms, whereas FMT from CD patients into these mice exacerbated CD symptoms. Notably, FMT influenced intestinal permeability, barrier function, and levels of proinflammatory factors and adipokines. Furthermore, FMT from CD patients intensified fibrotic changes in the colon tissues of mice with TNBS-induced CD. CONCLUSION: Gut microbiota play a critical role in the histopathology of CD. Targeting MAT and creeping fat may therefore have potential in the treatment of patients with CD.
Asunto(s)
Enfermedad de Crohn , Modelos Animales de Enfermedad , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Enfermedad de Crohn/microbiología , Enfermedad de Crohn/terapia , Enfermedad de Crohn/patología , Enfermedad de Crohn/metabolismo , Animales , Humanos , Ratones , Femenino , Masculino , Adulto , Heces/microbiología , Ácido Trinitrobencenosulfónico , Colon/microbiología , Colon/patología , Colon/inmunología , Fibrosis , Mesenterio , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Persona de Mediana Edad , Ratones Endogámicos C57BL , Estudios de Casos y Controles , Adulto Joven , Permeabilidad , Tejido Adiposo , Adipoquinas/metabolismoRESUMEN
Obesity is often associated with sex-dependent metabolic complications, in which altered intestinal barrier function and gut microbiota contribute. We aimed to characterize in mice the sex-dependent effects of a high fat diet on these parameters. Male and female C57BL/6 mice received a standard (SD) or high fat diet (HFD; 60% kcal from fat) during 14 weeks (W14). Body composition, glucose tolerance, insulin sensitivity, intestinal permeability, colonic expression of 44 genes encoding factors involved in inflammatory response and gut barrier function, cecal microbiota, plasma adipokines and white adipose tissue response have been assessed. Both male and female HFD mice exhibited an increase of body weight and fat mass gain and glucose intolerance compared to SD mice. However, only male HFD mice tended to develop insulin resistance associated to increased Tnfα and Ccl2 mRNA expression in perigonadal adipose tissue. By contrast, only female HFD mice showed significant intestinal hyperpermeability that was associated with more markedly altered colonic inflammatory response. Cecal microbiota richness was markedly reduced in both sexes (Observed species) with sex-dependent modifications at the phyla or family level, e.g. decreased relative abundance of Bacillota and Lachnospiraceae in females, increased of Bacteroidaceae in males. Interestingly, some of these microbiota alterations were correlated with peripheral metabolic and inflammatory markers. In conclusions, male and female mice exhibit different responses to a high fat diet with specific changes of gut microbiota, intestinal barrier function, colonic and white adipose tissue inflammation, metabolic markers and body weight gain. The underlying mechanisms should be deciphered in further investigations.
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Dieta Alta en Grasa , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Animales , Dieta Alta en Grasa/efectos adversos , Femenino , Masculino , Ratones , Resistencia a la Insulina , Enfermedades Metabólicas/microbiología , Enfermedades Metabólicas/etiología , Enfermedades Metabólicas/metabolismo , Obesidad/microbiología , Obesidad/metabolismo , Factores Sexuales , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Permeabilidad , Tejido Adiposo Blanco/metabolismo , Peso Corporal , Funcion de la Barrera IntestinalRESUMEN
The formulation and delivery of macromolecules through the oral route pose considerable challenges due to factors such as large molecular weight, pH sensitivity, and limited formulation approaches. This challenge is compounded if the drug is poorly permeable, necessitating innovative drug delivery strategies. Vancomycin, a widely prescribed glycopeptide antibiotic, has an oral bioavailability of less than 10%, leading to predominantly intravenous administration and potential patient discomfort. This study explores the potential of the buccal route as a non-invasive, highly vascularised alternative route of administration, offering a rapid onset of action while bypassing the first-pass metabolism. In this study, vancomycin was coated with L-glutamic acid using an isothermal dry particle coater to modulate permeation through the buccal cell line, TR146. Results confirm significant impact of both amino acid concentration and dry particle coating on the rate and extent of drug permeability. With the introduction of L-glutamic acid and utilisation of the isothermal dry particle coater, vancomycin's permeation profile increased six-fold compared to the control due to the formation of drug ion-pair complex. Imaging studies showed the presence of layered micronized glutamic acid particles on the surface of dry coated vancomycin particles which confirms the role of dry coating and amino acid concentration in modulating drug permeation. Microbiology experiments in Staphylococcus aureus, minimum inhibitory concentration and biofilm disruption studies, provided confirmatory evidence of antimicrobial activity of dry coated glutamic acid-vancomycin ion pair particulate structure. This study demonstrates, for the first-time, buccal delivery of dry coated large molecule drug, vancomycin, through controlled deposition of amino acid using innovative particle coating strategy.
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Antibacterianos , Vancomicina , Vancomicina/administración & dosificación , Vancomicina/farmacocinética , Humanos , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Antibacterianos/farmacocinética , Aminoácidos/química , Aminoácidos/metabolismo , Staphylococcus aureus/efectos de los fármacos , Mucosa Bucal/metabolismo , Permeabilidad/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Línea Celular , Ácido Glutámico/metabolismoRESUMEN
BACKGROUND: Older subjects are at risk of elevated intestinal permeability (IP) which can lead to immune system activation and low-grade systemic inflammation. Dietary changes are a potential strategy to reduce IP. The MaPLE project evaluated the hypothesis that increasing (poly)phenol intake would beneficially impact on several important markers and pathways related to IP. The objective of the present study was to assess the effects of the MaPLE (poly)phenol-rich diet (PR-diet) on additional IP-related biomarkers and any relationships between biomarker responses. METHODS: A randomised, controlled, crossover study was performed involving 51 participants (≥ 60 y) with increased IP, as determined by serum zonulin levels. Participants were randomly assigned to one of two intervention groups: a control diet (C-diet) or a PR-diet. Each intervention lasted 8 weeks and was separated by an 8-week washout period. For the present study, serum and faecal samples were used to measure zonula occludens-1 (ZO-1), occludin, adiponectin, calprotectin, faecal calprotectin, soluble cluster of differentiation 14 (sCD14), interleukin-6 receptor (IL-6R), and vascular endothelial-cadherin (VEC) levels using quantitative ELISA assays. Data were analysed using ANOVA, and Spearman and network correlation analysis were performed to identify the relationship among biomarkers at baseline. RESULTS: Among the different markers analysed, a significant reduction was observed for faecal and serum calprotectin (p = 0.0378 and p = 0.0186, respectively) following the PR-diet, while a significant increase in ZO-1 was found (p = 0.001) after both the intervention periods (PR-diet and C-diet). In addition, a time effect was observed for VEC levels showing a reduction (p = 0.038) following the PR-diet. Based on network correlation analysis, two clusters of correlations were identified: one cluster with high levels of serum calprotectin, faecal calprotectin, sCD14, interleukin (IL)-6, tumor necrosis factor (TNF)-α, C-reactive protein (CRP) and bacterial DNAemia (16 S rRNA gene copies), with potential inflammatory-induced intestinal permeability. Differently, the other cluster had high levels of serum occludin, IL-6R, soluble intercellular adhesion molecule-1 (sICAM-1) and VEC, with potential inflammatory-induced endothelial dysfunction. CONCLUSIONS: Overall, this study provides further support to the hypothesis that a (poly)phenol-rich diet may help to ameliorate intestinal permeability-associated conditions. In this regard, calprotectin might represent a promising biomarker since it is a protein that typically increases with age and it is considered indicative of intestinal and systemic inflammation. Further research is needed to develop targeted (poly)phenol-rich diets against age-related gut dysfunction and inflammation. TRIAL REGISTRATION: 28/04/2017; ISRCTN10214981; https://doi.org/10.1186/ISRCTN10214981 .