RESUMEN
Human activities in the areas of high altitude have increased significantly recently. Brain is highly sensitive to changing of oxygen pressure due to high altitude, and this physiological response may lead to serious brain injury, such as learning and memory disabilities. Puerarin is a phytoestrogen with many pharmacological activities, such as treatment of neurological disorders. However, most of current drugs can not easily enter brain through the blood-brain barrier (BBB). The nose-to-brain route can bypass BBB for brain-targeting. Here, thermosensitive in situ hydrogels (TISGs) of puerarin were prepared with poloxamers 407, poloxamers 188 and propylene glycol to improve bioavailability and brain targeting. In vitro drug release in simulated nasal fluids, rheological properties and cilia toxicity of puerarin TISGs were explored. The pharmacodynamics and pharmacokinetics of puerarin by intranasal (i.n.) and oral (p.o.) administrations were also evaluated. The viscosity of puerarin TISGs tended to increase obviously with increased temperature. The puerarin release profile and transmucosal process of puerarin TISGs could be described with the first-order kinetics equation, depending on drug diffusion. The cilia toxicity of puerarin TISGs was not obvious. Rat models of hypobarism/hypoxia-induced brain injury were established with a hypobaric simulation chamber. Morris water maze and open filed tests indicated that puerarin TISGs improved the spatial memory and spontaneous exploratory behavior of the rats suffering from hypoxia-induced brain injury. Furthermore, puerarin TISGs decreased the level of oxidative stress cytokines (malondialdehyde (MDA) and glutathione (GSH)) in the peripheral circulation, alleviated the cerebral histological lesions, and relieved the expression of hypoxia-inducible factor-1α (HIF-1α). Intranasal puerarin TISGs were absorbed quickly with a shorter Tmax (10.0 ± 5.7 min) compared to that of oral puerarin (36 ± 13.4 min). In addition, the relative bioavailability of i.n. puerarin TISGs was high to 300% compared to oral administration of puerarin. The area under the curve (AUC) of brain after i.n. administration of puerarin TISGs was 954.5 ± 335.1 h.ng/mL, while no puerarin was detected in the brain after oral administration. Therefore, i.n. puerarin TISGs led to excellent brain targeting effect. Puerarin TISGs are an effective neuroprotector formulation for prevention of brain injury induced by acute high-altitude hypoxia.
Asunto(s)
Mal de Altura , Lesiones Encefálicas , Administración Intranasal , Animales , Lesiones Encefálicas/tratamiento farmacológico , Hipoxia , Isoflavonas , RatasRESUMEN
The transdermal route is a convenient non-invasive way for drug delivery, however, the hydrophobic compact nature of stratum corneum (SC) forms an obstacle hindering the diffusion of drugs particularly hydrophilic ones. Hence, the purpose of this study was to develop novel soft nano-vesicles, entitled Flexosomes, amalgamating two penetration enhancers, ethanol and one edge activator (EA) from various types and different hydrophilic-lipophilic balances. The tailored vesicles were loaded with tropisetron hydrochloride (TRO), a potent highly-soluble anti-emetic, and compared with ethosomes. Aiming to preclude the formation of rigid non-deformable mixed micelles, all critical parameters; EA type, phosphatidylcholine-to-EA molar ratio, and cholesterol concentration, were optimized proving their influences on vesicle-to-micelle transitions. The prepared formulations were characterized in terms of visual inspection, particle size, polydispersity, zeta potential, turbidity measurements, entrapment efficiency, and vesicle morphology. The permeation mechanisms were assessed by differential scanning calorimetry on isolated SC. The modified vesicles, based on ethanol and either vitamin E or PEGylated castor oil derivatives exhibited the highest transdermal fluxes confirmed by a deeply tracking to dermis using confocal laser microscopy. Both vesicles demonstrated higher bioavailability relative to ethosomes, topical and oral aqueous solutions. The findings endorsed the effectiveness of tailored nano-vesicles in boosting TRO skin transport suggesting their applicability with various drug entities for enhanced transdermal delivery.
Asunto(s)
Antieméticos/administración & dosificación , Sistemas de Liberación de Medicamentos , Nanopartículas , Tropisetrón/administración & dosificación , Administración Cutánea , Animales , Antieméticos/farmacocinética , Disponibilidad Biológica , Rastreo Diferencial de Calorimetría , Química Farmacéutica/métodos , Etanol/química , Excipientes/química , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Micelas , Microscopía Confocal , Tamaño de la Partícula , Ratas , Piel/metabolismo , Absorción Cutánea , Tropisetrón/farmacocinéticaRESUMEN
Yerba mate tea contains various biochemically active substances. However, it can contain toxic metals. Thus, this work reports the total concentrations of Cd, Cu, Pb and Al in the commercial products, as well as the concentrations in infusions prepared. The bioaccessibility of these metals in these infusions was determined for the first time by in vitro digestion. For Al, its bioaccessibility was estimated in the presence of other ingredients used in tea consumption. In addition, the concentrations of phenolic compounds in infusions were also determined. All metals studied were detected in the samples ranging from 76â¯ngâ¯g-1 (Cd) to 526⯵gâ¯g-1 (Al). In general, Cd and Cu were the most bioaccessible metals, while Al was found in a relatively inert form. The addition of sugar and honey in infusions decreased the Al bioaccessibility. The relationship between the phenolic and the leaching of Al for the beverages was observed.
Asunto(s)
Tracto Gastrointestinal/metabolismo , Ilex paraguariensis/química , Metales/análisis , Tés Medicinales/análisis , Aluminio/análisis , Brasil , Cadmio/análisis , Cobre/análisis , Digestión , Análisis de los Alimentos , Contaminación de Alimentos/análisis , Plomo/análisisRESUMEN
The lungs have potential as a means of systemic drug delivery of macromolecules. Systemic delivery requires crossing of the air-blood barrier, however with molecular size-dependent limitations in lung absorption of large molecules. Systemic availability after inhalation can be improved by absorption enhancers, such as bile salts. Enhancers may potentially interfere with the different constituents of the lungs, e.g. the lung surfactant lining the alveoli or the lung epithelium. We used two in vitro models to investigate the potential effects of bile salts on lung surfactant function (with the constrained drop surfactometer) and on the epithelium in the proximal airways (with the MucilAir™ cell system), respectively. In addition, we measured direct effects on respiration in mice inhaling bile salt aerosols. The bile salts inhibited lung surfactant function at different dose levels, however they did not affect the integrity of ciliated cells at the tested doses. Furthermore, the bile salt aerosols induced changes in the breathing pattern of mice indicative of pulmonary irritation. The bile salts were ranked according to potency in vitro for surfactant function disruption and in vivo for induction of pulmonary irritation. The ranking was the same, suggesting a correlation between the interference with lung surfactant and the respiratory response.
Asunto(s)
Ácidos y Sales Biliares , Sistemas de Liberación de Medicamentos , Administración por Inhalación , Aerosoles , Animales , Ácidos y Sales Biliares/administración & dosificación , Ácidos y Sales Biliares/química , Epitelio/efectos de los fármacos , Pulmón/efectos de los fármacos , Masculino , Ratones , Surfactantes Pulmonares/antagonistas & inhibidoresRESUMEN
The objective of the present study was to formulate eprosartan mesylate loaded nano-bilosomes and investigates its potential for controlling streptozotocin induced diabetes nephropathy in Wistar rats. The eprosartan mesylate loaded nano-bilosomes comprising of various ratios of soybean phosphatidylcholine/sodium deoxycholate were prepared by thin film hydration technique. The prepared formulations were evaluated for vesicles size, polydispersity index, zeta potential and entrapment efficiency. Further the optimized formulation was characterized for vesicles morphology, and its efficacy for the management of diabetic nephropathy in Wistar rats. The optimized eprosartan mesylate loaded nano-bilosomes exhibited vesicles size, polydispersity index, zeta potential and entrapment efficiency of 63.88±3.46nm, 0.172±0.026, -30.40±2.75mV and 61.19±0.88% respectively. In vivo activity demonstrated that the prepared eprosartan mesylate loaded nano-bilosomes formulation demonstrated a nephro-protecting outcome as shown by the substantial decrease in serum creatinine, urea, lactate dehydrogenase, total albumin, and malondialdehyde. Additionally, an oral administration of eprosartan mesylate loaded nano-bilosomes decreases the raised expressions of Angiotensin II type 1 receptor, inducible nitric oxide synthase, and transforming growth factor-ß1 in Wistar rats. Further, histopathological examination established the nephro-protective effect of prepared formulation. In conclusion, the research work in the paper suggests that the prepared eprosartan mesylate loaded nano-bilosomes could serve as a practical oral formulation for diabetic nephropathy in future therapy and may offer potential benefits in cases with hypertension and renal disease.
Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Nefropatías Diabéticas/prevención & control , Imidazoles/química , Imidazoles/farmacología , Tiofenos/química , Tiofenos/farmacología , Administración Oral , Bloqueadores del Receptor Tipo 1 de Angiotensina II/química , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Ácidos y Sales Biliares , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Liposomas , Masculino , Nanoestructuras , Tamaño de la Partícula , RatasRESUMEN
Since microglia-associated neuroinflammation plays a pivotal role in the progression of neurodegenerative diseases, controlling microglial activation has been suggested as a potential therapeutic strategy. Here, we investigated the anti-inflammatory effects of galangin (3,5,7-trihydroxyflavone) in microglia and analyzed the underlying molecular mechanisms. Galangin inhibited the expression of inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines and enhanced the expression of anti-inflammatory interleukin (IL)-10 in lipopolysaccharide (LPS)-stimulated BV2 microglia. Galangin also suppressed microglial activation and the expression of pro-inflammatory markers in LPS-injected mouse brains. The results of mechanistic studies have shown that galangin inhibited LPS-induced phosphorylation of p38 mitogen activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), phosphatidylinositol 3-kinase (PI3K)/Akt, and nuclear factor (NF)-κB activity. On the contrary, galangin increased the activity of transcription factors, such as nuclear factor-E2-related factor 2 (Nrf2), cAMP response element-binding protein (CREB), and peroxisome proliferator-activated receptor (PPAR)-γ, known to play an anti-inflammatory role. In addition, galangin showed antioxidant effects by suppressing the expression of NADPH oxidase subunits p47phox and gp91phox, and by enhancing hemeoxygenase-1. We then investigated whether PPAR-γ was involved in the anti-inflammatory function of galangin. Pretreatment with a PPAR-γ antagonist or siRNA significantly blocked galangin-mediated upregulation of IL-10 and attenuated the inhibition of tumor necrosis factor (TNF)-α, nitric oxide (NO), and IL-6 in LPS-stimulated microglia. Moreover, the PPAR-γ antagonist reversed the effects of galangin on NF-κB, Nrf2, and CREB. Altogether, our data suggest that PPAR-γ plays a key role in mediating the anti-inflammatory effects of galangin by modulating the NF-κB and Nrf2/CREB signaling pathways.
Asunto(s)
Antiinflamatorios/farmacología , Flavonoides/farmacología , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/toxicidad , Microglía/metabolismo , PPAR gamma/fisiología , Animales , Línea Celular Transformada , Relación Dosis-Respuesta a Droga , Mediadores de Inflamación/antagonistas & inhibidores , Masculino , Ratones , Ratones Endogámicos ICR , Microglía/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
Metformin is an oral hypoglycemic agent used in the type 2 diabetes, whose poor bioavailability and short half-life make the development of effective extended-release formulations highly desirable. Different metformin-loaded chitosomal and niosomal formulations were developed and suitably characterized, but were unable to provide the desired sustained release. The entrapment of both kinds of colloidal dispersions in calcium alginate beads enabled to strongly reduce the amount of drug released at gastric level (from 18 up to a maximum of 30%), and to obtain a sustained release in simulated intestinal fluid, which was properly tuned by varying the percentage of calcium alginate in the beads. In vivo studies on rats revealed a significant improvement of metformin hypoglycemic effect when orally administered as chitosomal and even more as niosomal dispersion entrapped in alginate beads, not only with respect to the drug as such, but also to the alginate beads loaded with the plain drug. The more intense and sustained therapeutic effect with time provided by the drug-in niosomes-in alginate bead formulation could be very profitable for maintaining tight blood glucose levels over prolonged period of time after oral administration, allowing a reduction of its dose and related collateral effects, and improving patient compliance.
Asunto(s)
Alginatos/química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Metformina/administración & dosificación , Animales , Ácido Glucurónico/química , Ácidos Hexurónicos/química , Liposomas , Masculino , Microesferas , Tamaño de la Partícula , Ratas , Ratas Sprague-DawleyRESUMEN
In vitro studies were conducted to evaluate the particular nutritional benefits of whole faba bean seed (WFB) and fava bean seed coat (FBSC). Total dietary fiber contents of WFB and FBSC were 27.5% and 82.3%, respectively. FBSC were contained much higher total phenolic substances, condensed tannins, and total antioxidant activity than WFB. Bile acid (BA)-binding capacities of in vitro digested samples and nutritionally important products produced by in vitro fermentation of digestion residues were also studied. The BA-binding capacities of WFB and FBSC were 1.94 and 37.50µmol/100mg, respectively. Total BA bound by FBSC was even higher than the positive standard cholestyramine. Lignin and other constituents of the Klason residue were found to influence BA-binding properties. Moreover, the extent of the in vitro fermentation process showed that, fermentability of FBSC residue was significantly lower than that of WFB residue. Overall, faba bean, especially its seed coat, has great potential as a functional food.
Asunto(s)
Alimentos Funcionales/análisis , Semillas/química , Vicia faba/química , Técnicas In Vitro , Fenoles/análisisRESUMEN
Lipoamino acid-based micelles have been developed as delivery vehicles for the hydrophobic drug amphotericin B (AmB). The micellar solubilisation of AmB by a gemini lipoamino acid (LAA) derived from cysteine and its equimolar mixtures with the bile salts sodium cholate (NaC) and sodium deoxycholate (NaDC), as well as the aggregation sate of the drug in the micellar systems, was studied under biomimetic conditions (phosphate buffered-saline, pH 7.4) using UV-vis spectroscopy. Pure surfactant systems and equimolar mixtures were characterized by tensiometry and important parameters were determined, such as critical micelle concentration (CMC), surface tension at the CMC (γCMC), maximum surface excess concentration (Γmax), and minimum area occupied per molecule at the water/air interface (Amin). Rheological behaviour from viscosity measurements at different shear rates was also addressed. Solubilisation capacity was quantified in terms of molar solubilisation ratio (χ), micelle-water partition coefficient (KM) and Gibbs energy of solubilisation (ΔGs°). Formulations of AmB in micellar media were compared in terms of drug loading, encapsulation efficiency, aggregation state of AmB and in vitro antifungal activity against Candida albicans. The LAA-containing micellar systems solubilise AmB in its monomeric and less toxic form and exhibit in vitro antifungal activity comparable to that of the commercial formulation Fungizone.
Asunto(s)
Anfotericina B/administración & dosificación , Cisteína/química , Ácido Desoxicólico/química , Portadores de Fármacos/química , Micelas , Colato de Sodio/química , Anfotericina B/farmacología , Antifúngicos/administración & dosificación , Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Química Farmacéutica , Interacciones Hidrofóbicas e Hidrofílicas , Pruebas de Sensibilidad Microbiana , Reología , Solubilidad , Tensión Superficial , ViscosidadRESUMEN
Apigenin is a flavonoid compound with diverse pharmacological functions which could develop health benefit products, but its formulation is hampered by its poor water solubility and bioavailability. In this paper, in order to overcome these difficulties, apigenin was encapsulated in LLC formed by polyoxyethylene-10-oleyl ether (Brij 97) and sodium deoxycholate (NaDC) mixtures. The hexagonal liquid crystalline phase (H) and the cubic liquid crystalline phase (C) were found in this system. The shear rheology was used to study the structure change with temperature. It was shown that C3 (Brij 97-NaDC/IPM-PEG400/H2O=36:9:55) was C at low temperature. But above 35.6°C, the matrix of C3 completely transformed to polymer solution. The matrix of H3 was H (Brij 97-NaDC:IPM-PEG 400:H2O=50:9:41) below 50°C, but the structural strength change was obvious. Vitro release experiment was used to study drug release kinetics. It was indicated that apigenin encapsulated in LLC conformed to the concentration diffusion model, and cumulative percentage of apigenin released from C3 and H3 had corresponding relationship with the shear rheology at different temperatures.
Asunto(s)
Apigenina/análisis , Ácido Desoxicólico/química , Liberación de Fármacos , Cristales Líquidos/química , Polietilenglicoles/química , Reología , Apigenina/química , Cinética , Modelos Químicos , Solubilidad , TemperaturaRESUMEN
Oral drug delivery is the most preferred route for patients; however, the low solubility of drugs and the resultant poor absorption compromise the benefits of oral administration. On the other hand, for years, the overwhelmingly accepted mechanism for enhanced oral absorption using lipid nanocarriers was based on the process of lipid digestion and drug solubilization in the small intestine. Few reports indicated that other bypass pathways are involved in drug absorption in the gastrointestinal tract (GIT) for oral delivery of nanocarriers. Herein, we report a new nanoemulsion system with a denatured globular protein with a diameter of 30 nm, soybean protein isolates (SPI), and bile salt as emulsifiers, aiming to enhance the absorption of insoluble drugs and explore other pathways for absorption. A BCS class II drug, fenofibrate (FB), was used as the model drug. The SPI and bile salt-coated Ns with a diameter of approximately 150 nm were prepared via a high-pressure homogenizing procedure. Interestingly, the present Ns could be converted to solid dosage form using fluid-bed coating technology, maintaining a nanoscale size. Most importantly, in a model of in situ rat intestinal perfusion, Ns could penetrate across the intestinal epithelial barrier into the systemic circulation and then obtain biodistribution into other tissues. In addition, Ns significantly improved FB oral absorption, exhibited as a greater than 2- and 2.5-fold increase in Cmax and AUC0-t, respectively, compared to the suspension formulation. Overall, the present Ns are promising nanocarriers for the oral delivery of insoluble drugs, and the penetration of intact Ns across the GIT barrier into systemic circulation may be a new strategy for improved drug absorption with the use of nanocarriers.
Asunto(s)
Ácidos y Sales Biliares/administración & dosificación , Ácidos y Sales Biliares/química , Portadores de Fármacos/química , Fenofibrato/sangre , Fenofibrato/farmacocinética , Absorción Intestinal , Nanopartículas/administración & dosificación , Proteínas de Soja/química , Administración Oral , Animales , Ácidos y Sales Biliares/farmacocinética , Disponibilidad Biológica , Células CACO-2 , Supervivencia Celular/efectos de los fármacos , Química Farmacéutica , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/farmacocinética , Emulsiones/administración & dosificación , Emulsiones/efectos adversos , Emulsiones/química , Emulsiones/farmacocinética , Fenofibrato/administración & dosificación , Fenofibrato/química , Humanos , Nanopartículas/química , Nanopartículas/ultraestructura , Tamaño de la Partícula , Desnaturalización Proteica , Ratas , Solubilidad , Proteínas de Soja/administración & dosificación , Proteínas de Soja/farmacocinética , Suspensiones/farmacocinética , Distribución Tisular , Agua/químicaRESUMEN
Bilosomes represent an evolving vesicular carrier that have been explored for oral vaccines delivery based on its ability to resist enzymes and bile salts in the gastrointestinal tract (GIT). Bilosomes vesicles are formed of bilayer membrane of non-ionic surfactant molecules encompassing bile salts. Although, bilosomes have not been proposed for transdermal drug delivery, this carrier seems to have promising potential in this regard. Accordingly, the aim of this investigation was to assess the capability and safety of utilizing bilosomes for transdermal delivery of tenoxicam (TX) as a model drug. A 3(1)2(2) full factorial design was adopted to study the effects of different formulation parameters on bilosomes properties and select the optimal formulation using Design-Expert(®) software. The selected formulation displayed nano-sized spherical vesicles (242.5 ± 6.43nm) with reasonable entrapment efficiency percent (68.33 ± 2.33%). Confocal laser scanning microscopy confirmed the capability of the flourolabeled bilosomes to penetrate deep within the skin. Both, ex vivo permeation and in vivo skin deposition studies confirmed the superiority of bilosomes over drug solution in delivering TX transdermally. In addition, in vivo histopathological study proved the safety of topically applied bilosomes. In summary, the highlighted results confirmed that bilosomes can be further adopted for delivering drugs transdermally.
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Antiinflamatorios no Esteroideos/administración & dosificación , Ácidos y Sales Biliares/química , Portadores de Fármacos , Piroxicam/análogos & derivados , Absorción Cutánea , Piel/metabolismo , Tensoactivos/química , Administración Cutánea , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/metabolismo , Rastreo Diferencial de Calorimetría , Química Farmacéutica , Liposomas , Masculino , Microscopía Confocal , Microscopía Electrónica de Transmisión , Modelos Estadísticos , Nanopartículas , Nanotecnología , Tamaño de la Partícula , Permeabilidad , Piroxicam/administración & dosificación , Piroxicam/química , Piroxicam/metabolismo , Ratas Wistar , Propiedades de Superficie , Tecnología Farmacéutica/métodosRESUMEN
Hydroxysafflor yellow A (HSYA), a flavonoid derived and isolated from traditional Chinese medicine Carthamus tinctorius L., possesses anti-tumor activity. However, its effects on hepatocellular carcinoma (HCC) have not been investigated. The proliferation and metastasis of HCC are dependent on angiogenesis, which also strongly links with several signal transduction pathways associated with cell proliferation and apoptosis. This study aimed to explore the effect of HSYA on vasculogenesis and to determine its molecular mechanism by investigating the expression of ERK/MAPK (p-c-Raf, c-Raf, p-ERK1/2, ERK1/2) and NF-κB (p65, IκB and p-IκB) signaling pathway in H22 tumor-bearing mice. The results showed that HSYA could considerably suppress tumor growth by inhibiting secretion of angiogenesis factors (vascular endothelial growth factor A, basic fibroblast growth factor) and vascular endothelial growth factor receptor1. At the moleculcould block ERK1/2 phosphorylation and then restrain the activation of NF-κB and its nuclear translocation by down-regulating the expression of p65 in the nucleus, up-regulating p65 level in the cytoplasm, inhibiting IκB phosphorylation and cytoplasmic degradation of IκB-α. Finally, we demonstrate that HSYA could suppress mRNA expression levels of cell proliferation-related genes (cyclinD1, c-myc, c-Fos) compared with negative control group. And best of all, HSYA could improve spleen/thymus indexes, which was evaluated as the marker of protective effect on the immune system. Our findings support HSYA as a promising candidate for the prevention and treatment of HCC.