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1.
Eur J Drug Metab Pharmacokinet ; 49(3): 317-330, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38393637

RESUMEN

BACKGROUND AND OBJECTIVE: HY-088 injection is an ultrasmall superparamagnetic iron oxide nanoparticle (USPIOs) composed of iron oxide crystals coated with polyacrylic acid (PAA) on the surface. The purpose of this study was to investigate the pharmacokinetics, tissue distribution, and mass balance of HY-088 injection. METHODS: The pharmacokinetics of [55Fe]-HY-088 and [14C]-HY-088 were investigated in 48 SD rats by intravenous injection of 8.5 (low-dose group), 25.5 (medium-dose group), and 85 (high-dose group) mg/100 µCi/kg. Tissue distribution was studied by intravenous injection of 35 mg/100 µCi/kg in 48 SD rats, and its tissue distribution in vivo was obtained by ex vivo tissue assay. At the same time, [14C]-HY-088 was injected intravenously at a dose of 25.5 mg/100 µCi/kg into 16 SD rats, and its tissue distribution in vivo was studied by quantitative whole-body autoradiography. [14C]-HY-088 and [55Fe]-HY-088 were injected intravenously into 24 SD rats at a dose of 35 mg/100 µCi/kg, and their metabolism was observed. RESULTS: In the pharmacokinetic study, [55Fe]-HY-088 reached the maximum observed concentration (Cmax) at 0.08 h in the low- and medium-dose groups of SD rats. [14C]-HY-088 reached Cmax at 0.08 h in the three groups of SD rats. The area under the concentration-time curve (AUC) of [55Fe]-HY-088 and [14C]-HY-088 increased with increasing dose. In the tissue distribution study, [55Fe]-HY-088 and [14C]-HY-088 were primarily distributed in the liver, spleen, and lymph nodes of both female and male rats. In the mass balance study conducted over 57 days, the radioactive content of 55Fe from [55Fe]-HY-088 was primarily found in the carcass, accounting for 86.42 ± 4.18% in females and 95.46 ± 6.42% in males. The radioactive recovery rates of [14C]-HY-088 in the urine of female and male rats were 52.99 ± 5.48% and 60.66 ± 2.23%, respectively. CONCLUSIONS: Following single intravenous administration of [55Fe]-HY-088 and [14C]-HY-088 in SD rats, rapid absorption was observed. Both [55Fe]-HY-088 and [14C]-HY-088 were primarily distributed in the liver, spleen, and lymph nodes. During metabolism, the radioactivity of [55Fe]-HY-088 is mainly present in the carcass, whereas the 14C-labeled [14C]-HY-088 shell PAA is eliminated from the body mainly through the urine.


Asunto(s)
Nanopartículas Magnéticas de Óxido de Hierro , Ratas Sprague-Dawley , Animales , Distribución Tisular , Masculino , Ratas , Femenino , Nanopartículas Magnéticas de Óxido de Hierro/química , Inyecciones Intravenosas , Nanopartículas de Magnetita/química , Dextranos/farmacocinética , Resinas Acrílicas/química , Resinas Acrílicas/farmacocinética
2.
Sci Rep ; 11(1): 14565, 2021 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-34267273

RESUMEN

This study was aimed at establishing the subcorticals substrates of the cognitive and visceromotor circuits of the A32 and A25 cortices of the medial prefrontal cortex and their projections and interactions with subcortical complexes in the common marmoset monkey (Callithrix jacchus). The study was primarily restricted to the nuclei of the diencephalon and amygdala. The common marmoset is a neotropical primate of the new world, and the absence of telencephalic gyrus favors the mapping of neuronal fibers. The biotinylated dextran amine was employed as an anterograde tracer. There was an evident pattern of rostrocaudal distribution of fibers within the subcortical nuclei, with medial orientation. Considering this distribution, fibers originating from the A25 cortex were found to be more clustered in the diencephalon and amygdala than those originating in the A32 cortex. Most areas of the amygdala received fibers from both cortices. In the diencephalon, all regions received projections from the A32, while the A25 fibers were restricted to the thalamus, hypothalamus, and epithalamus at different densities. Precise deposits of neuronal tracers provided here may significantly contribute to expand our understanding of specific connectivity among the medial prefrontal cortex with limbic regions and diencephalic areas, key elements to the viscerocognitive process.


Asunto(s)
Callithrix , Corteza Prefrontal/fisiología , Amígdala del Cerebelo/fisiología , Animales , Biotina/análogos & derivados , Biotina/farmacocinética , Mapeo Encefálico , Dextranos/farmacocinética , Femenino , Hipotálamo/fisiología , Masculino , Vías Nerviosas/fisiología , Corteza Prefrontal/anatomía & histología , Técnicas Estereotáxicas , Tálamo/fisiología
3.
Eur J Pharm Biopharm ; 158: 313-322, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33259898

RESUMEN

Alginate can be gently crosslinked by calcium into hydrogels and microspheres for the encapsulation and release of proteins and drugs. However, the release is often over short periods unless alginate is also covalently modified or crosslinked. This research aims to sustain the release of encapsulated model drug FITC-dextran by covalently crosslinking alginate with short oligomers DNA because evidence suggests that DNA may also interact with alginate to further increase effective crosslinking. Furthermore, modulating the release of drugs from alginate in response to specific proteins could tailor release profiles to improve patient treatment. This research develops a DNA-crosslinked alginate hydrogel and layered alginate microspheres to encapsulate and then sustain the release FITC-dextran (model drug). An aptamer sequence to hen egg-white lysozyme is included in one DNA strand to allow for the disruption of the crosslinks by interactions with human lysozyme. Alginate was covalently modified with complementary strands of DNA to crosslink the alginate into hydrogels, which had increased crosslinking density when re-swollen (in comparison to controls crosslinked with PEG) and could sustained the release of encapsulated FITC-dextran. When an aptamer sequence for hen lysozyme was included in the DNA crosslinks, the hydrogels decrosslinked when incubated in human lysozyme for 60 days. In addition, calcium alginate microspheres were coated with 3 alternating layers of poly-Lysine, DNA-crosslinked alginate, and poly-L-lysine. FITC-dextran loaded into the microspheres released in a sustained manner past 30 days (into PBS at 37 °C) and would likely continue to release for far longer had the studies continued. When incubated with 3 µM of human lysozyme, a burst release of FITC-dextran occurred from both the hydrogels and microspheres, with no changes in the controls. The increased release was in bursts followed by similar sustained release rates suggesting that the human lysozyme temporarily disrupted the DNA crosslinks which were then re-established or were influenced by interactions between DNA and alginate. Importantly, covalently bound complementary strands of DNA could crosslink the alginate and additional interactions appeared to further sustain the release of encapsulated therapeutics.


Asunto(s)
Dextranos/farmacocinética , Portadores de Fármacos/química , Fluoresceína-5-Isotiocianato/análogos & derivados , Microesferas , Alginatos/química , Aptámeros de Nucleótidos/química , Reactivos de Enlaces Cruzados , ADN/química , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Dextranos/administración & dosificación , Composición de Medicamentos/métodos , Liberación de Fármacos , Fluoresceína-5-Isotiocianato/administración & dosificación , Fluoresceína-5-Isotiocianato/farmacocinética , Hidrogeles/química , Tamaño de la Partícula
4.
Carbohydr Polym ; 241: 116224, 2020 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-32507183

RESUMEN

Polypyrroles have shown great potential in photoacoustic imaging and photothermal therapy owing to its excellent photothermal conversion capabilities. However, the synthesis of polypyrrole-based nano-assemblies which have colloidal stability in biological buffers requires a number of steps, including the polymerization of pyrrole monomers, self-assembly of polypyrrole-based copolymers, and even an additional step to increase the biocompatibility of the nano-assemblies. Herein, a "polymerization/assembly" two-in-one synthesis is proposed for the first time to achieve the one-step synthesis of a new family of polypyrrole-based nano-assemblies, dextran-polypyrrole nano-assemblies (Dex-PPy NAs), under ambient conditions and in aqueous media. In addition, the approach employs tetravalent cerium ions as initiators which can initiate the polymerization of pyrrole monomers through the initiation of free radicals from dextran molecular chains. The resultant Dex-PPy NAs have a photothermal conversion efficiency reaching as high as 41 % and an excellent photostability. More importantly, the NAs with controllable nanoscale dimensions display no signs of cytotoxicity in both in vitro and in vivo studies owing to their biocompatible dextran "shell". An in vivo study further confirmed that the Dex-PPy NAs have excellent real-time photoacoustic imaging and photothermal therapy capabilities for malignant tumors. Therefore, this study represents an important step towards the scalable synthesis of polypyrrole-based nano-assemblies with photothermal/photoacoustic dual capabilities and enhanced biocompatibility.


Asunto(s)
Materiales Biocompatibles/administración & dosificación , Dextranos/administración & dosificación , Nanoestructuras/administración & dosificación , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Polímeros/administración & dosificación , Pirroles/administración & dosificación , Animales , Materiales Biocompatibles/farmacocinética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Dextranos/farmacocinética , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Ratones Endogámicos BALB C , Técnicas Fotoacústicas , Fototerapia , Polímeros/farmacocinética , Pirroles/farmacocinética
5.
Acta Neurobiol Exp (Wars) ; 77(1): 1-17, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28379212

RESUMEN

A number of neurological disorders such as epidural hematoma can cause compression of cerebral cortex. We here tested the hypothesis that sustained compression of primary somatosensory cortex may affect stellate neurons and thalamocortical afferent (TCA) fibers. A rat model with barrel cortex subjected to bead epidural compression was used. Golgi-Cox staining analyses showed the shrinkage of dendritic arbors and the stripping of dendritic spines of stellate neurons for at least 3 months post-lesion. Anterograde tracing analyses exhibited a progressive decline of TCA fiber density in barrel field for 6 months post-lesion. Due to the abrupt decrease of TCA fiber density at 3 days after compression, we further used electron microscopy to investigate the ultrastructure of TCA fibers at this time. Some TCA fiber terminal profiles with dissolved or darkened mitochondria and fewer synaptic vesicles were distorted and broken. Furthermore, the disruption of mitochondria and myelin sheath was observed in some myelinated TCA fibers. In addition, expressions of oxidative markers 3-nitrotyrosine and 4-hydroxynonenal were elevated in barrel field post-lesion. Treatment of antioxidant ascorbic acid or apocynin was able to reverse the increase of oxidative stress and the decline of TCA fiber density, rather than the shrinkage of dendrites and the stripping of dendritic spines of stellate neurons post-lesion. Together, these results indicate that sustained epidural compression of primary somatosensory cortex affects the TCA fibers and the dendrites of stellate neurons for a prolonged period. In addition, oxidative stress is responsible for the reduction of TCA fiber density in barrels rather than the shrinkage of dendrites and the stripping of dendritic spines of stellate neurons.


Asunto(s)
Vías Aferentes/patología , Lesiones Encefálicas/patología , Espacio Epidural , Neuronas/patología , Corteza Somatosensorial/patología , Tálamo/patología , Acetofenonas/uso terapéutico , Aldehídos/metabolismo , Animales , Antioxidantes/uso terapéutico , Ácido Ascórbico/uso terapéutico , Biotina/análogos & derivados , Biotina/farmacocinética , Lesiones Encefálicas/tratamiento farmacológico , Dendritas/patología , Dendritas/ultraestructura , Dextranos/farmacocinética , Modelos Animales de Enfermedad , Complejo IV de Transporte de Electrones/metabolismo , Espacio Epidural/fisiología , Lateralidad Funcional , Masculino , Neuronas/ultraestructura , Estrés Oxidativo/fisiología , Ratas , Corteza Somatosensorial/lesiones , Tálamo/ultraestructura , Factores de Tiempo , Tirosina/análogos & derivados , Tirosina/metabolismo
6.
Mar Drugs ; 12(11): 5677-97, 2014 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-25421323

RESUMEN

Bacterial-derived lipopolysaccharides (LPS) can cause defective intestinal barrier function and play an important role in the development of inflammatory bowel disease. In this study, a nanocarrier based on chitosan and fucoidan was developed for oral delivery of berberine (Ber). A sulfonated fucoidan, fucoidan-taurine (FD-Tau) conjugate, was synthesized and characterized by Fourier transform infrared (FTIR) spectroscopy. The FD-Tau conjugate was self-assembled with berberine and chitosan (CS) to form Ber-loaded CS/FD-Tau complex nanoparticles with high drug loading efficiency. Berberine release from the nanoparticles had fast release in simulated intestinal fluid (SIF, pH 7.4), while the release was slow in simulated gastric fluid (SGF, pH 2.0). The effect of the berberine-loaded nanoparticles in protecting intestinal tight-junction barrier function against nitric oxide and inflammatory cytokines released from LPS-stimulated macrophage was evaluated by determining the transepithelial electrical resistance (TEER) and paracellular permeability of a model macromolecule fluorescein isothiocyanate-dextran (FITC-dextran) in a Caco-2 cells/RAW264.7 cells co-culture system. Inhibition of redistribution of tight junction ZO-1 protein by the nanoparticles was visualized using confocal laser scanning microscopy (CLSM). The results suggest that the nanoparticles may be useful for local delivery of berberine to ameliorate LPS-induced intestinal epithelia tight junction disruption, and that the released berberine can restore barrier function in inflammatory and injured intestinal epithelial.


Asunto(s)
Berberina/administración & dosificación , Quitosano/química , Sistemas de Liberación de Medicamentos , Polisacáridos/química , Animales , Berberina/farmacología , Células CACO-2 , Línea Celular , Técnicas de Cocultivo , Citocinas/metabolismo , Dextranos/farmacocinética , Portadores de Fármacos/química , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/farmacocinética , Humanos , Concentración de Iones de Hidrógeno , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Lipopolisacáridos/toxicidad , Ratones , Nanopartículas , Óxido Nítrico/metabolismo , Permeabilidad , Taurina/química , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/metabolismo , Uniones Estrechas/patología
7.
J Biomed Mater Res B Appl Biomater ; 102(4): 860-8, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24458920

RESUMEN

In this research work, DEXTRAN- and polyethylene glycol (PEG)-coated iron-oxide superparamagnetic nanoparticles were synthetized and their cytotoxicity and biodistribution assessed. Well-crystalline hydrophobic Fe3 O4 SPIONs were formed by a thermal decomposition process with d = 18 nm and σ = 2 nm; finally, the character of SPIONs was changed to hydrophilic by a post-synthesis procedure with the functionalization of the SPIONs with PEG or DEXTRAN. The nanoparticles present high saturation magnetization and superparamagnetic behavior at room temperature, and the hydrodynamic diameters of DEXTRAN- and PEG-coated SPIONs were measured as 170 and 120 nm, respectively. PEG- and DEXTRAN-coated SPIONs have a Specific Power Absorption SPA of 320 and 400 W/g, respectively, in an ac magnetic field with amplitude of 13 kA/m and frequency of 256 kHz. In vitro studies using VERO and MDCK cell lineages were performed to study the cytotoxicity and cell uptake of the SPIONs. For both cell lineages, PEG- and DEXTRAN-coated nanoparticles presented high cell viability for concentrations as high as 200 µg/mL. In vivo studies were conducted using BALB/c mice inoculating the SPIONs intravenously and exposing them to the presence of an external magnet located over the tumour. It was observed that the amount of PEG-coated SPIONs in the tumor increased by up to 160% when using the external permanent magnetic as opposed to those animals that were not exposed to the external magnetic field.


Asunto(s)
Dextranos/farmacocinética , Compuestos Férricos/farmacocinética , Campos Magnéticos , Nanopartículas , Animales , Chlorocebus aethiops , Dextranos/administración & dosificación , Dextranos/toxicidad , Perros , Portadores de Fármacos , Evaluación Preclínica de Medicamentos , Femenino , Compuestos Férricos/administración & dosificación , Compuestos Férricos/toxicidad , Técnicas In Vitro , Inyecciones Intravenosas , Hígado/metabolismo , Pulmón/metabolismo , Células de Riñón Canino Madin Darby , Nanopartículas de Magnetita/administración & dosificación , Nanopartículas de Magnetita/toxicidad , Neoplasias Mamarias Experimentales/metabolismo , Ensayo de Materiales , Ratones , Ratones Endogámicos BALB C , Nanopartículas/administración & dosificación , Nanopartículas/toxicidad , Polietilenglicoles , Piel/metabolismo , Espectroscopía Infrarroja por Transformada de Fourier , Distribución Tisular , Células Vero
8.
Contrast Media Mol Imaging ; 8(3): 281-8, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23606432

RESUMEN

Tumor-associated macrophages (TAM) maintain a chronic inflammation in cancers, which is associated with tumor aggressiveness and poor prognosis. The purpose of this study was to: (1) evaluate the pharmacokinetics and tolerability of the novel ultrasmall superparamagnetic iron oxide nanoparticle (USPIO) compound GEH121333; (2) assess whether GEH121333 can serve as a MR imaging biomarker for TAM; and (3) compare tumor MR enhancement profiles between GEH121333 and ferumoxytol. Blood half-lives of GEH121333 and ferumoxytol were measured by relaxometry (n = 4 each). Tolerance was assessed in healthy rats injected with high dose GEH121333, vehicle or saline (n = 4 each). Animals were monitored for 7 days regarding body weight, complete blood counts and serum chemistry, followed by histological evaluation of visceral organs. MR imaging was performed on mice harboring MMTV-PyMT-derived breast adenocarcinomas using a 7 T scanner before and up to 72 h post-injection (p.i.) of GEH121333 (n = 10) or ferumoxytol (n = 9). Tumor R1, R2* relaxation rates were compared between different experimental groups and time points, using a linear mixed effects model with a random effect for each animal. MR data were correlated with histopathology. GEH121333 showed a longer circulation half-life than ferumoxytol. Intravenous GEH121333 did not produce significant adverse effects in rats. All tumors demonstrated significant enhancement on T1, T2 and T2*-weighted images at 1, 24, 48 and 72 h p.i. GEH121333 generated stronger tumor T2* enhancement than ferumoxytol. Histological analysis verified intracellular compartmentalization of GEH121333 by TAM at 24, 48 and 72 h p.i. MR imaging with GEH121333 nanoparticles represents a novel biomarker for TAM assessment. This new USPIO MR contrast agent provides a longer blood half-life and better TAM enhancement compared with the iron supplement ferumoxytol.


Asunto(s)
Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Medios de Contraste/síntesis química , Dextranos/farmacocinética , Macrófagos/inmunología , Imagen por Resonancia Magnética/métodos , Nanopartículas de Magnetita , Animales , Línea Celular Tumoral , Medios de Contraste/farmacocinética , Dextranos/síntesis química , Macrófagos/patología , Tasa de Depuración Metabólica , Ratones , Especificidad de Órganos , Ratas , Ratas Endogámicas Lew , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Distribución Tisular
9.
J Mater Sci Mater Med ; 24(5): 1125-9, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23371771

RESUMEN

Recently, organic-inorganic hybrids composed of derivatives of dextran, a polysaccharide, and magnetite nanoparticles have attracted much attention as novel thermoseeds. If they can be fabricated into microspheres of size 20-30 µm, they are expected to show not only hyperthermia effects but also embolization effects in human liver and kidney cancers. In this study, we examined the fabrication of carboxymethyldextran/magnetite microspheres using a water/oil emulsion as the reaction medium. Improvement of the chemical stability of the microcapsules by coating with silica using a sol-gel process was also investigated. The obtained hollow microspheres contained particles of size 20-30 µm. Silica coating using an appropriate catalyst for hydrolysis and polycondensation of alkoxysilanes was found to be effective for preventing dissolution and collapse in simulated body environments.


Asunto(s)
Dextranos/química , Óxido Ferrosoférrico/química , Hipertermia Inducida , Microesferas , Cápsulas , Materiales Biocompatibles Revestidos/síntesis química , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacocinética , Dextranos/síntesis química , Dextranos/farmacocinética , Composición de Medicamentos , Óxido Ferrosoférrico/síntesis química , Óxido Ferrosoférrico/farmacocinética , Humanos , Hipertermia Inducida/instrumentación , Hipertermia Inducida/métodos , Ensayo de Materiales , Nanocompuestos/química , Nanopartículas/química , Tamaño de la Partícula , Dióxido de Silicio/química , Dióxido de Silicio/farmacocinética
10.
J Pediatr Surg ; 47(6): 1135-42, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22703783

RESUMEN

BACKGROUND: Previously, we have shown that supplementation of intestinal alkaline phosphatase (IAP) decreased severity of necrotizing enterocolitis (NEC)-associated intestinal injury. We hypothesized that IAP administration is protective of intestinal epithelial barrier function in a dose-dependent manner. METHODS: Control rat pups were vaginally delivered and breast-fed. Premature rats were divided into 4 groups: formula fed with lipopolysaccharide and hypoxia (NEC) or additional daily bovine IAP 40, 4, or 0.4 U/kg (NEC + IAP 40 U, IAP 4 U, or IAP 0.4 U). RESULTS: Necrotizing enterocolitis is associated with decreased IAP protein expression and activity. Supplemental IAP increases IAP activity in intestinal homogenates and decreased NEC injury score in a dose-dependent manner. Intestinal injury as measured by fluorescein isothiocyanate-dextran flux from ileal loops showed increased permeability vs control, but supplemental IAP reversed this. Tight junction proteins claudin-1, claudin-3, occludin, and zonula occludin 1 were elevated in the NEC and IAP-treated groups with differences in expression patterns. No differences in messenger RNA levels were observed on postinjury day 3. Intestinal alkaline phosphatase administration decreases intestinal NEC injury in a dose-dependent manner. CONCLUSION: Early enteral supplemental IAP may reduce NEC-related injury and may be useful for preserving the intestinal epithelial barrier function.


Asunto(s)
Fosfatasa Alcalina/uso terapéutico , Enterocolitis Necrotizante/tratamiento farmacológico , Íleon/efectos de los fármacos , Absorción Intestinal/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Administración Oral , Fosfatasa Alcalina/administración & dosificación , Animales , Animales Recién Nacidos , Claudina-1 , Claudina-3 , Claudinas/biosíntesis , Claudinas/genética , Dextranos/farmacocinética , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Enterocolitis Necrotizante/etiología , Enterocolitis Necrotizante/fisiopatología , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/farmacocinética , Regulación de la Expresión Génica/efectos de los fármacos , Íleon/patología , Mucosa Intestinal/patología , Lipopolisacáridos/toxicidad , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Modelos Animales , Permeabilidad , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Uniones Estrechas/efectos de los fármacos
11.
J Drug Target ; 19(5): 336-43, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20615092

RESUMEN

Dextran-flufenamic acid ester (Dex-FFA) with varied degree of substitution (DS) was prepared by imidazolide method. Dex-FFA was stable in pH 1.2 or pH 6.8 buffer. The depolymerization degree of Dex-FFA by dextranase decreased as DS increased. Dex-FFA with DS of 13 or 20 released FFA up to 70% or 21% of the dose, respectively, on 24 h-incubation with the 10% cecal contents. FFA was liberated up to 29% of the dose on 24 h-incubation of dextranase pre-treated Dex-FFA with the homogenates of the upper intestine, whereas no FFA was detected devoid of dextranse-pretreatment. Upon oral administration of Dex-FFA (DS 13, 20 mg equivalent of FFA/kg) or FFA (10 mg/kg) to rats, t(max) for FFA with Dex-FFA administration delayed approximately 6 h compared with that of free FFA administration, while C(max) for FFA was similar. The plasma level for FFA became greater around 6 h after administration of Dex-FFA than free FFA and it was maintained throughout the period of 24 h-experiment. Dex-FFA markedly attenuated gastric ulcerogenicity of FFA. Taken together, Dex-FFA could be useful as a colon-specific prodrug which possesses anti-inflammatory properties and offers opportunities as a chronotherapeutic approach for the treatment of arthritis.


Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Colon/metabolismo , Dextranos/farmacología , Ácido Flufenámico/análogos & derivados , Profármacos/administración & dosificación , Profármacos/farmacología , Administración Oral , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/farmacocinética , Ciego/metabolismo , Cromatografía Líquida de Alta Presión , Preparaciones de Acción Retardada , Dextranos/administración & dosificación , Dextranos/efectos adversos , Dextranos/farmacocinética , Cronoterapia de Medicamentos , Composición de Medicamentos , Sistemas de Liberación de Medicamentos , Estabilidad de Medicamentos , Ácido Flufenámico/administración & dosificación , Ácido Flufenámico/efectos adversos , Ácido Flufenámico/farmacocinética , Ácido Flufenámico/farmacología , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Concentración de Iones de Hidrógeno , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Masculino , Estructura Molecular , Úlcera Péptica/inducido químicamente , Úlcera Péptica/patología , Profármacos/efectos adversos , Profármacos/farmacocinética , Ratas , Ratas Sprague-Dawley , Solubilidad , Espectrofotometría Ultravioleta , Distribución Tisular
12.
Neuroreport ; 19(16): 1623-6, 2008 Oct 29.
Artículo en Inglés | MEDLINE | ID: mdl-18845942

RESUMEN

The vomeronasal system is segregated from the epithelium to the bulb. Two classes of receptor neurons are apically and basally placed in the vomeronasal epithelium, express Gi2alpha and Goalpha proteins and V1R and V2R receptors and project to the anterior and posterior portions of the accessory olfactory bulb, respectively. Apart from common vomeronasal recipient structures in the amygdala, only the anterior accessory olfactory bulb projects to the bed nucleus of the stria terminalis and only the posterior accessory olfactory bulb projects to the dorsal anterior amygdala. The efferent projections from these two amygdaloid structures to the hypothalamus were investigated. These two vomeronasal subsystems mediated by V1R and V2R receptors were partially segregated, not only in amygdala, but also in the hypothalamus.


Asunto(s)
Vías Aferentes/fisiología , Vías Eferentes/fisiología , Hipotálamo/fisiología , Receptores de Vasopresinas/metabolismo , Órgano Vomeronasal/fisiología , Vías Aferentes/anatomía & histología , Vías Aferentes/metabolismo , Aminas/administración & dosificación , Aminas/farmacocinética , Amígdala del Cerebelo/anatomía & histología , Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/fisiología , Animales , Dextranos/administración & dosificación , Dextranos/farmacocinética , Vías Eferentes/anatomía & histología , Vías Eferentes/metabolismo , Femenino , Fluoresceína/administración & dosificación , Fluoresceína/farmacocinética , Colorantes Fluorescentes/administración & dosificación , Colorantes Fluorescentes/farmacocinética , Hipotálamo/anatomía & histología , Hipotálamo/metabolismo , Masculino , Microinyecciones , Bulbo Olfatorio/anatomía & histología , Bulbo Olfatorio/metabolismo , Bulbo Olfatorio/fisiología , Ratas , Ratas Sprague-Dawley , Rodaminas/administración & dosificación , Rodaminas/farmacocinética , Núcleos Septales/anatomía & histología , Núcleos Septales/metabolismo , Núcleos Septales/fisiología , Órgano Vomeronasal/anatomía & histología , Órgano Vomeronasal/metabolismo
13.
Pharm Dev Technol ; 13(6): 513-21, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18720244

RESUMEN

The aim of the present work was to investigate if chitosan salification with ascorbic acid could produce an increase in chitosan penetration enhancement properties towards buccal mucosa and intestinal Caco-2 cell monolayer. Three different chitosan grades were considered. Chitosan hydrochloride and lactate were used as references. Fluorescein isothiocyanate-dextran (FD4), a hydrophilic high MW molecule, was employed as model penetrant. Chitosan ascorbate showed better penetration enhancement properties towards both buccal porcine mucosa and Caco-2 cell monolayer with respect to hydrochloride and lactate salts. Cytotoxicity of chitosan ascorbate assessed on Caco-2 cells was comparable with those of chitosan hydrochloride and lactate.


Asunto(s)
Adyuvantes Farmacéuticos/química , Ácido Ascórbico/química , Quitosano/química , Absorción/efectos de los fármacos , Adhesividad , Adyuvantes Farmacéuticos/farmacología , Animales , Células CACO-2 , Supervivencia Celular/efectos de los fármacos , Quitosano/análogos & derivados , Quitosano/farmacología , Dextranos/química , Dextranos/farmacocinética , Elasticidad , Impedancia Eléctrica , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/química , Fluoresceína-5-Isotiocianato/farmacocinética , Humanos , Ácido Láctico/química , Mucosa Bucal/citología , Mucosa Bucal/efectos de los fármacos , Mucosa Bucal/metabolismo , Porcinos , Uniones Estrechas/efectos de los fármacos , Viscosidad
14.
Eur J Pharm Sci ; 33(2): 166-76, 2008 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-18248966

RESUMEN

In the present work the employment of chitosan citrate (Chs citrate) as multifunctional polymer in vaginal applications was evaluated. Potential properties of penetration enhancement and protease inhibition could be expected because of the capability of citrate to bind divalent cations such as calcium, that is involved in the regulation of gap and tight junctions, and zinc, that is essential co-factor for some proteases. A comparison was performed with chitosan HCl (Chs HCl). Ex vivo drug permeation experiments were performed on pig vaginal mucosa, by application of 3.0% (w/w) chitosan gels. Acyclovir (5.0%, w/w) and ciprofloxacin HCl (0.3%, w/w) were used as low molecular weight model drugs. Fluorescein isothiocyanate dextran MW 4400 (FD4) was used as hydrophilic high molecular weight fluorescent probe (0.2%, w/w). In the case of low MW drugs the amount penetrated into pig vaginal mucosa was measured by extraction from tissue slices and HPLC detection. From the samples maintained in contact with FD4, slices were cut perpendicularly to the surface and observed by means of confocal laser scanning microscopy (CLSM). FD4 permeation was also measured in in-vitro cell culture model (Caco-2). The penetration enhancing capacity of Chs citrate was comparable to that of Chs HCl. Both Chs citrate and Chs HCl were tested for the inhibition of the proteolytic enzymes carboxypeptidase A and leucine aminopeptidase. In both cases Chs citrate showed a significantly higher inhibition of enzymatic activity with respect to Chs HCl.


Asunto(s)
Adyuvantes Farmacéuticos/farmacología , Quitosano/farmacología , Membrana Mucosa/efectos de los fármacos , Inhibidores de Proteasas/farmacología , Cremas, Espumas y Geles Vaginales/farmacología , Aciclovir/administración & dosificación , Aciclovir/farmacocinética , Adyuvantes Farmacéuticos/administración & dosificación , Adyuvantes Farmacéuticos/química , Administración Intravaginal , Animales , Disponibilidad Biológica , Células CACO-2 , Carboxipeptidasas A/antagonistas & inhibidores , Carboxipeptidasas A/química , Supervivencia Celular/efectos de los fármacos , Quitosano/administración & dosificación , Quitosano/química , Ciprofloxacina/administración & dosificación , Ciprofloxacina/farmacocinética , Dextranos/administración & dosificación , Dextranos/farmacocinética , Fluoresceína-5-Isotiocianato/administración & dosificación , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/farmacocinética , Humanos , Absorción Intestinal/efectos de los fármacos , Leucil Aminopeptidasa/antagonistas & inhibidores , Leucil Aminopeptidasa/química , Membrana Mucosa/metabolismo , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/química , Sus scrofa , Cremas, Espumas y Geles Vaginales/administración & dosificación , Cremas, Espumas y Geles Vaginales/química , Viscosidad
15.
J Comp Neurol ; 502(2): 309-24, 2007 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-17348015

RESUMEN

The amygdala complex participates in multiple systems having to do with affective processes. It has been implicated in human disorders of social and emotional behavior, such as autism. Of the interconnected functional networks, considerable research in rodents and primates has focused on connections between the amygdala and orbitofrontal cortex (OFC). The amygdala projects to OFC by both a direct amygdalocortical (AC) pathway and an indirect pathway through mediodorsal thalamus. In the rat, retrograde tracer experiments indicate that the AC and amygdalothalamic (AT) pathways originate from separate populations, and may therefore convey distinctive information, although the characteristics of these pathways remain unclear. To investigate this issue in monkeys we made anterograde tracer injections in the basolateral amygdala complex (BLC; n = 3). Three distinctive features were found preferentially associated with the AT or AC pathways. First, AT terminations are large (average diameter = 3.5 microm; range = 1.2-7.0 microm) and cluster around proximal dendrites, in contrast with small-bouton AC terminations. Second, AT terminations form small arbors (diameter approximately 0.1 mm), while AC are widely divergent (often >1.0 mm long). The AT terminations features are reminiscent of large bouton, "driver" corticothalamic terminations. Finally, AC but not AT terminations are positive for zinc (Zn), a neuromodulator associated with synaptic plasticity. From these results we suggest that AC and AT terminations originate from distinct populations in monkey as well as in rodent. Further work is necessary to determine the degree and manner of their segregation and how these subsystems interact within a broader connectivity network.


Asunto(s)
Amígdala del Cerebelo/anatomía & histología , Corteza Cerebral/anatomía & histología , Macaca/anatomía & histología , Tálamo/anatomía & histología , Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/ultraestructura , Animales , Biotina/análogos & derivados , Biotina/farmacocinética , Corteza Cerebral/metabolismo , Corteza Cerebral/ultraestructura , Dextranos/farmacocinética , Inmunohistoquímica , Microscopía Electrónica de Transmisión/métodos , Vías Nerviosas/anatomía & histología , Vías Nerviosas/metabolismo , Vías Nerviosas/ultraestructura , Parvalbúminas/metabolismo , Terminales Presinápticos/ultraestructura , Tálamo/metabolismo , Tálamo/ultraestructura
16.
Oncol Rep ; 17(3): 653-9, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17273747

RESUMEN

A novel drug delivery system (DDS) compound was formed by binding doxorubicin hydrochloride (DXR) to the macromolecular carrier carboxymethyldextran polyalcohol (CM-Dex-PA) via the peptidyl spacer (GGFG: Gly-Gly-Phe-Gly). Its use in a murine tumor model confirmed that the DDS (CM-Dex-PA-GGFG-DXR) was retained in the blood and distributed in tumor tissue. The combined use of hyperthermia (HT: 41-42 degrees C for 40 min) and DXR-conjugate (5, 10 or 20 mg/kg i.v.) on tumor accumulation and efficacy was investigated in a murine model of non-small cell lung cancer. Tumor size was measured and the tumor inhibition rate (IR) was calculated. The mean tumor concentration of conjugated DXR in the DXR-conjugate group was 9.40 microg/g compared with 19.04 microg/g in the DXR-conjugate + HT group (p=0.0008). The antitumor efficacy of the DXR-conjugate was significantly enhanced in the groups receiving the combination therapy (p=0.0039, p=0.0250). Significant differences were found between the groups given DXR and those given DXR-conjugate (p=0.0492, p=0.0104). The results demonstrate that the antitumor efficacy of DXR-conjugate is significantly superior to that of DXR alone and the combined use of DXR-conjugate and HT increases the drug's concentration in the tumor, with significant enhancement of antitumor efficacy.


Asunto(s)
Antineoplásicos/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/terapia , Doxorrubicina/administración & dosificación , Portadores de Fármacos/administración & dosificación , Hipertermia Inducida , Neoplasias Pulmonares/terapia , Animales , Antineoplásicos/farmacocinética , Dextranos/administración & dosificación , Dextranos/farmacocinética , Doxorrubicina/farmacocinética , Portadores de Fármacos/farmacocinética , Ratones , Ratones Desnudos , Distribución Tisular
17.
J Comp Neurol ; 496(2): 202-13, 2006 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-16538675

RESUMEN

The axonal projections arising from the forelimb area of the primary motor cortex (M1) in cynomolgus monkeys (Macaca fascicularis) were studied following microiontophoretic injections of biotinylated dextran amine under electrophysiological guidance. The microinjections were centered on layer V, and 42 anterogradely labeled corticofugal axons were reconstructed from serial frontal or sagittal sections with a camera lucida. Our investigation shows that the primate striatum receives both direct and indirect projections from M1. The direct corticostriatal projection is formed by axons that remain uniformly thin and unbranched throughout their sinuous trajectory to the ipsilateral striatum. They divide as they enter the dorsolateral sector of the post-commissural putamen, the so-called sensorimotor striatal territory. The indirect corticostriatal projection derives from a thin collateral emitted within the corona radiata by thick, long-range fibers that descend toward the brainstem. The collateral enters the putamen dorsomedially and remains unbranched until it reaches the dorsolateral sector of the putamen, where it breaks out into two to four axonal branches displaying small and equally spaced varicosities. Both direct and indirect corticostriatal axons branch moderately but occupy vast rostrocaudal striatal territories, where they appear to contact en passant several widely distributed striatal neurons. These findings reveal that, in contrast to current beliefs, the primate motor corticostriatal system is not exclusively formed by axons dedicated solely to the striatum. It also comprises collaterals from long-range corticofugal axons, which can thus provide to the striatum a copy of the neural information that is being conveyed to the brainstem and/or spinal cord.


Asunto(s)
Vías Aferentes/anatomía & histología , Axones/fisiología , Cuerpo Estriado/citología , Complejo IV de Transporte de Electrones/metabolismo , Corteza Motora/citología , Neuronas/citología , Vías Aferentes/metabolismo , Animales , Axones/metabolismo , Biotina/análogos & derivados , Biotina/farmacocinética , Cuerpo Estriado/metabolismo , Dextranos/farmacocinética , Femenino , Macaca fascicularis , Masculino , Neuronas/fisiología
18.
J Comp Neurol ; 496(3): 335-48, 2006 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-16566003

RESUMEN

Physiological, anatomical, and clinical data have demonstrated interactions between somatosensory and auditory brainstem structures. Spinal nerve projections influence auditory responses, although the nature of the pathway(s) is not known. To address this issue, we injected biotinylated dextran amine into the cochlear nucleus or dorsal root ganglion (DRG) at the second cervical segment (C2). Cochlear nucleus injections retrogradely labeled small ganglion cells in C2 DRG. C2 DRG injections produced anterograde labeling in the external cuneate nucleus, cuneate nucleus, nucleus X, central cervical nucleus, dorsal horn of upper cervical spinal segments, and cochlear nucleus. The terminal field in the cochlear nucleus was concentrated in the subpeduncular corner and lamina of the granule cell domain, where endings of various size and shapes appeared. Examination under an electron microscope revealed that the C2 DRG terminals contained numerous round synaptic vesicles and formed asymmetric synapses, implying depolarizing influences on the target cell. Labeled endings synapsed with the stalk of the primary dendrite of unipolar brush cells, distal dendrites of presumptive granule cells, and endings containing pleomorphic synaptic vesicles. These primary somatosensory projections contribute to circuits that are hypothesized to mediate integrative functions of hearing.


Asunto(s)
Vías Auditivas/anatomía & histología , Núcleo Coclear/ultraestructura , Ganglios Espinales/ultraestructura , Estimulación Acústica/métodos , Animales , Vías Auditivas/fisiología , Biotina/análogos & derivados , Biotina/farmacocinética , Vértebras Cervicales , Núcleo Coclear/efectos de los fármacos , Núcleo Coclear/fisiología , Dendritas/ultraestructura , Dextranos/farmacocinética , Ganglios Espinales/efectos de los fármacos , Masculino , Microscopía Electrónica de Transmisión/métodos , Ratas , Ratas Sprague-Dawley , Sinapsis/ultraestructura , Factores de Tiempo
19.
Neuroscience ; 120(2): 485-98, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-12890518

RESUMEN

The ventrolateral medulla (VLM) modulates autonomic functions, motor reactions and pain responses. The lateralmost part of the caudal VLM (VLMlat) was recently shown to be the VLM area responsible for pain modulation. In the present study, the brain sources of VLMlat afferent fibers were determined by tract-tracing techniques. Following injection of cholera toxin subunit B into the VLMlat, retrogradely labeled neurons in the forebrain occurred at the somatosensory, insular, motor, limbic and infralimbic cortices, and at the central amygdaloid nucleus. Retrogradely labeled neurons in diencephalic regions were observed in the lateral hypothalamus, posterior hypothalamus and paraventricular nucleus. In the brainstem, retrograde labeling occurred at the periaqueductal gray, red nucleus, parabrachial area, nucleus raphe magnus, nucleus tractus solitarii, lateral reticular nucleus and dorsal and ventral medullary reticular formation. In the cerebellum, retrogradely labeled neurons occurred at the lateral nucleus. Following injections of the anterograde tracer biotinylated dextran amine (BDA) into the lateral hypothalamus or paraventricular nucleus, anterogradely labeled fibers were mainly observed in the VLMlat. Injections of BDA into the periaqueductal gray, red nucleus or lateral nucleus of the cerebellum resulted in anterograde labeling in the VLMlat and lateral reticular nucleus. The present study gives an account of the brain regions putatively involved in triggering the modulatory actions elicited from the VLMlat. These include areas committed to somatosensory processing, autonomic control, somatic and visceral motor activity and affective reactions. The findings suggest that the VLMlat may play a major homeostatic role in the integration of nociception with other brain functions.


Asunto(s)
Biotina/análogos & derivados , Bulbo Raquídeo/anatomía & histología , Vías Nerviosas/anatomía & histología , Neuronas/metabolismo , Adyuvantes Inmunológicos/farmacocinética , Animales , Biotina/farmacocinética , Cerebelo/anatomía & histología , Cerebelo/metabolismo , Toxina del Cólera/farmacocinética , Dextranos/farmacocinética , Diencéfalo/anatomía & histología , Diencéfalo/metabolismo , Colorantes Fluorescentes/farmacocinética , Masculino , Bulbo Raquídeo/metabolismo , Mesencéfalo/anatomía & histología , Mesencéfalo/metabolismo , Vías Nerviosas/metabolismo , Prosencéfalo/anatomía & histología , Prosencéfalo/metabolismo , Ratas , Ratas Wistar
20.
J Comp Neurol ; 464(1): 98-103, 2003 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-12866130

RESUMEN

In freely moving rats, whisking is associated with a slow modulation of neuronal excitability in the primary somatosensory cortex. Because it persists after the blockade of vibrissa input, it was suggested that the slow modulation might be mediated by motor-sensory corticocortical connections and perhaps result from the corollary discharges of corticofugal cells. In the present study, we identified motor cortical cells that project to the barrel field and reconstructed their axonal projections after juxtacellularly staining single cells with a biotinylated tracer. On the basis of the final destination of main axons, two groups of neurons contribute to motor-sensory projections: callosal cells (87.5%) and corticofugal cells (12.5%). Axon collaterals of callosal cells arborize in layers five to six of the granular and dysgranular zones and give off several branches that ascend between the barrels to ramify in the molecular layer. In contrast, the axon collaterals of corticofugal cells do not ramify in the infragranular layers but in layer 1. The origin of the majority of motor sensory projections from callosally projecting cells does not support the notion that the slow modulation results from the corollary discharges of corticofugal axons. It would rather originate from a separate population of cells, which could output the slow signal to the barrel field in parallel with the corticofugal commands to a brainstem pattern generator. As free whisking is characterized by bilateral concerted movements of the vibrissae, the transcallosal contribution of motor-sensory axons represents a substrate for synchronizing the slow modulation across both hemispheres.


Asunto(s)
Biotina/análogos & derivados , Corteza Motora/citología , Vías Nerviosas/citología , Neuronas/metabolismo , Vibrisas/inervación , Animales , Axones/metabolismo , Biotina/farmacocinética , Mapeo Encefálico , Dextranos/farmacocinética , Colorantes Fluorescentes/farmacocinética , Ratas , Ratas Sprague-Dawley , Corteza Somatosensorial/citología , Corteza Somatosensorial/fisiología , Vibrisas/citología , Vibrisas/fisiología
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