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1.
Mol Pharm ; 10(5): 1795-803, 2013 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-23510188

RESUMO

Mesoporous silica nanoparticles, MSNs, have emerged as an interesting carrier for drugs in vitro and in vivo. The particles are typically used in a surface functionalized form, where functional silanes or other covalently linked surface functions are used to provide anchoring sites for additional functionalities like targeting groups, imaging agents, and drugs. Here, we report results related to extra- and intracellular degradation of silica nanoparticles using multilabeled nonporous silica core-mesoporous silica shell-surface hyperbranched poly(ethylene imine) shell nanoparticles as model particles. Different fluorophores have been selectively covalently linked to different regions of the particles in order to study the particle degradation in detail under in vitro conditions in human SAOS-2 cells. A novel, quantitative method for nanoparticle degradation evaluation based on confocal fluorescence microscopy is applied. Our results suggest that the core-shell-shell MSNs degrade at a higher rate inside cells as compared to outside cells, which is of high importance for further application of this class of drug carriers.


Assuntos
Portadores de Fármacos/química , Iminas/química , Nanopartículas/química , Polietilenos/química , Dióxido de Silício/química , Linhagem Celular , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos , Corantes Fluorescentes/farmacocinética , Humanos , Iminas/farmacocinética , Teste de Materiais , Nanopartículas/ultraestrutura , Nanotecnologia , Polietilenos/farmacocinética , Dióxido de Silício/farmacocinética , Propriedades de Superfície
2.
Biomed Mater Eng ; 31(2): 119-129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32568171

RESUMO

BACKGROUND: Fourier-transform infrared spectroscopy (FTIR) is one of the standard methods to analyze ultra-high molecular weight polyethylene (UHMWPE) in orthopedic implants. For retrieved components, lipid extraction using an organic solvent prior to the measurement is necessary to eliminate the influence of lipids absorbed in vivo. However, its influence on the measurement has not been substantially investigated. OBJECTIVE: To investigate the influence of lipid extraction on the FTIR analysis of UHMWPE and to develop a novel method to obtain reliable results without inconvenient lipid extraction. METHODS: FTIR analysis was repeatedly performed on UHMWPE specimens from retrieved components before and after lipid extraction under various conditions. A method to calculate the extent of influence of the absorbed lipids from the FTIR spectra was developed using a peak separation technique. RESULTS: An elevated temperature was necessary for lipid extraction; however, it had the potential to influence the results if the conditions were not properly controlled. The results obtained using the peak separation technique coincided with those obtained after lipid extraction. CONCLUSION: The use of the peak separation technique enables the efficient acquisition of reliable results without the need for lipid extraction.


Assuntos
Análise de Falha de Equipamento/métodos , Lipídeos/farmacocinética , Polietilenos/química , Polietilenos/farmacocinética , Absorção Fisico-Química , Adulto , Tornozelo , Artroplastia de Substituição do Tornozelo/instrumentação , Artroplastia de Quadril/instrumentação , Fracionamento Químico , Remoção de Dispositivo , Feminino , Prótese de Quadril , Humanos , Lipídeos/isolamento & purificação , Lipídeos/farmacologia , Teste de Materiais , Oxirredução , Reoperação , Espectroscopia de Infravermelho com Transformada de Fourier , Propriedades de Superfície/efeitos dos fármacos
3.
Nanotechnology ; 20(27): 275101, 2009 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-19528681

RESUMO

The thermally responsive wall permeability of an empty core-shell structured Pluronic nanocapsule (together with its temperature dependent size and surface charge) was successfully utilized for encapsulation, intracellular delivery, and controlled release of trehalose, a highly hydrophilic small (M(W) = 342 D) molecule (a disaccharide of glucose) that is exceptional for long-term stabilization of biologicals (particularly at ambient temperatures). It was found that trehalose can be physically encapsulated in the nanocapsule using a soaking-freeze-drying-heating procedure. The nanocapsule is capable of physically withholding trehalose with negligible release in hours for cellular uptake at 37 degrees C when its wall permeability is low. A quick release of the encapsulated sugar can be achieved by thermally cycling the nanocapsule between 37 and 22 degrees C (or lower). A significant amount of trehalose (up to 0.3 M) can be delivered into NIH 3T3 fibroblasts by incubating the cells with the trehalose-encapsulated nanocapsules at 37 degrees C for 40 min. Moreover, cytotoxicity of the nanocapsule for the purpose of intracellular delivery of trehalose was found to be negligible. Altogether, the thermally responsive nanocapsule is effective for intracellular delivery of trehalose, which is critical for the long-term stabilization of mammalian cells at ambient temperatures and the eventual success of modern cell-based medicine.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Nanocápsulas/química , Trealose/química , Trealose/farmacocinética , Animais , Linhagem Celular , Permeabilidade da Membrana Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colágeno/metabolismo , Preparações de Ação Retardada , Iminas/administração & dosagem , Iminas/química , Iminas/farmacocinética , Camundongos , Microscopia Confocal , Células NIH 3T3 , Nanocápsulas/administração & dosagem , Poloxâmero/administração & dosagem , Poloxâmero/química , Poloxâmero/farmacocinética , Polietilenos/administração & dosagem , Polietilenos/química , Polietilenos/farmacocinética , Temperatura , Trealose/administração & dosagem
4.
ACS Appl Mater Interfaces ; 11(35): 31671-31680, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31397149

RESUMO

Hypoxia and overexpression of glutathione (GSH) are typical characteristics of the tumor microenvironment, which severely hinders cancer treatments. Here, we design a novel biodegradable therapeutic system, O2-Cu/ZIF-8@Ce6/ZIF-8@F127 (OCZCF), to simultaneously achieve GSH depletion and O2-enhanced combination therapy. Notably, the doped Cu2+ doubles the O2 storage capacity of the ZIF-8 matrix, which makes OCZCF an excellent pH-sensitive O2 reservoir for conquering tumor hypoxia, enhancing the photodynamic therapy (PDT) efficiency of chlorin e6 (Ce6) under 650 nm laser irradiation. Moreover, the released Cu2+ can act as a smart reactive oxygen species protector by consuming intracellular GSH. The byproduct Cu+ will undergo highly efficient Fenton-like reaction to achieve chemodynamic therapy (CDT) in the presence of abundant H2O2. The accompanying O2 will further alleviate hypoxia. The in vitro and in vivo experimental data indicate that OCZCF could cause remarkable tumor inhibition through enhanced synergetic PDT and CDT, which may open up a new path for cancer therapy.


Assuntos
Nanocompostos , Neoplasias Experimentais , Fotoquimioterapia , Polietilenos , Polipropilenos , Porfirinas , Microambiente Tumoral/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Clorofilídeos , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Nanocompostos/química , Nanocompostos/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Polietilenos/química , Polietilenos/farmacocinética , Polietilenos/farmacologia , Polipropilenos/química , Polipropilenos/farmacocinética , Polipropilenos/farmacologia , Porfirinas/química , Porfirinas/farmacocinética , Porfirinas/farmacologia
5.
Eur J Pharm Sci ; 112: 195-206, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-29196024

RESUMO

Raloxifene HCl (RH) has poor water solubility and due to its extensive first pass metabolism; its bioavailability is only 2%. The purpose of the present study was to enhance the aqueous solubility, oral bioavailability and anti-osteoporotic effects of RH by electro-sprayed nanoparticles (NPs) in ovariectomized rats. NPs containing RH and different ratio of poly(methyl vinyl ether-co-maleic acid) (PMVEMA) were electrosprayed. The voltage, distance of needle to the collector, flow rate of the solution and polymeric percentage were optimized according to the size of NPs and drug solubility. The optimized formulation was characterized by SEM, XRD, DSC, and FTIR. The pharmacokinetic parameters were studies by oral administration of a single dose of 15mg/kg in Wistar rats. The anti-osteoporotic effects were studied in female ovariectomized rats. Animals were treated with 6mg/kg/day for 2months then serum calcium, phosphorous and alkaline phosphatase levels were measured. RH loaded electrosprayed NPs showed 10-fold enhanced solubility compared to the free drug. Moreover, the XRD and SEM tests displayed an amorphous state of drug in the NPs. FTIR and DSC tests revealed no interaction between the polymer and the drug. Serum calcium, phosphorous and alkaline phosphatase levels were significantly decreased in ovariectomized rats receiving oral RH NPs (P<0.05). No significant difference was detected between RH NPs and estradiol groups (P>0.05). Oral bioavailability of NPs showed 7.5-fold increase compared to the pure drug. The electrosprayed PMVEMA nanoparticles can enhance solubility, bioavailability and antiosteoporotic effects of RH.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Maleatos/administração & dosagem , Nanopartículas/administração & dosagem , Osteoporose/tratamento farmacológico , Polietilenos/administração & dosagem , Cloridrato de Raloxifeno/administração & dosagem , Administração Oral , Fosfatase Alcalina/sangue , Animais , Disponibilidade Biológica , Conservadores da Densidade Óssea/sangue , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/farmacocinética , Cálcio/sangue , Feminino , Maleatos/química , Maleatos/farmacocinética , Microscopia Eletrônica de Varredura , Nanopartículas/química , Nanopartículas/ultraestrutura , Osteoporose/sangue , Ovariectomia , Fósforo/sangue , Polietilenos/química , Polietilenos/farmacocinética , Cloridrato de Raloxifeno/sangue , Cloridrato de Raloxifeno/química , Cloridrato de Raloxifeno/farmacocinética , Ratos Wistar , Solubilidade , Tecnologia Farmacêutica
6.
Acta Biomater ; 74: 312-325, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29777958

RESUMO

Topical nitric oxide (NO) delivery has been shown to accelerate wound healing. However, delivering NO to wounds at appropriate rates and doses requires new biomaterial-based strategies. Here, we describe the development of supramolecular interpolymer complex hydrogels comprising PEO-PPO-PEO (F127) micelles embedded in a poly(acrylic acid) (PAA) matrix, with S-nitrosoglutathione (GSNO) molecules dissolved in the hydrophilic domain. We show that PAA:F127/GSNO hydrogels start releasing NO upon hydration at rates controlled by their rates of water absorption. SAXS measurements indicate that the supramolecular structure of the hydrogels retains long-range order domains of F127 micelles. The PAA/F1227 hydrogels displayed dense morphologies and reduced rates of hydration. The NO release rates remain constant over the first 200 min, are directly correlated with the hydration rates of the PAA:F127/GSNO hydrogels, and can be modulated in the range of 40 nmol/g h to 1.5 µmol/g h by changing the PAA:F127 mass ratio. Long-term NO-release profiles over 5 days are governed by the first-order exponential decay of GSNO, with half-lives in the range of 0.5-3.4 days. A preliminary in vivo study on full-thickness excisional wounds in mice showed that topical NO release from the PAA:F127/GSNO hydrogels is triggered by exudate absorption and leads to increased angiogenesis and collagen fiber organization, as well as TGF-ß, IGF-1, SDF-1, and IL-10 gene expressions in the cicatricial tissue. In summary, these results suggest that hydration-controlled NO release from topical PAA:F127/GSNO hydrogels is a potential strategy for enhancing wound healing. STATEMENT OF SIGNIFICANCE: The topical delivery of nitric oxide (NO) to wounds may provide significant beneficial results and represent a promising strategy to treat chronic wounds. However, wound dressings capable of releasing NO after application and allowing the modulation of NO release rates, demand new platforms. Here, we describe a novel strategy to overcome these challenges, based on the use of supramolecular poly(acrylic acid) (PAA):F127 hydrogels charged with the NO donor S-nitrosoglutathione (GSNO) from whereby the NO release can be triggered by exudate absorption and delivered to the wound at rates controlled by the PAA:F127 mass ratio. Preliminary in vivo results offer a proof of concept for this strategy by demonstrating increased angiogenesis; collagen fibers organization; and TGF-ß, IGF-1, SDF-1, and IL-10 gene expressions in the cicatricial tissue after topical treatment with a PAA:F127/GSNO hydrogel.


Assuntos
Resinas Acrílicas , Hidrogéis , Óxido Nítrico , Polietilenos , Polipropilenos , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões , Resinas Acrílicas/farmacocinética , Resinas Acrílicas/farmacologia , Animais , Citocinas/biossíntese , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hidrogéis/química , Hidrogéis/farmacocinética , Hidrogéis/farmacologia , Camundongos , Micelas , Óxido Nítrico/química , Óxido Nítrico/farmacocinética , Óxido Nítrico/farmacologia , Polietilenos/química , Polietilenos/farmacocinética , Polietilenos/farmacologia , Polipropilenos/química , Polipropilenos/farmacocinética , Polipropilenos/farmacologia , S-Nitrosoglutationa/química , S-Nitrosoglutationa/farmacocinética , S-Nitrosoglutationa/farmacologia , Ferimentos e Lesões/tratamento farmacológico , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/patologia
7.
J Biomed Mater Res B Appl Biomater ; 105(1): 39-45, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-26404508

RESUMO

This study examined retrieved UHMWPE tibial bearings made from a remelted highly crosslinked (HXL) UHMWPE to determine whether the material is chemically stable in vivo. Retrieved tibial components were measured for changes in ketone oxidation and crosslink density. Oxidation increased with in vivo duration, and a significant decrease in crosslink density with increased mean ketone oxidation index was observed. These results suggest that in vivo oxidation is causing material degradation. Furthermore, a subsurface whitened damage region was found below the articular surface of one bearing, indicating the possibility of a clinically relevant decrease in mechanical properties of this component. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 39-45, 2017.


Assuntos
Polietilenos , Tíbia , Animais , Oxirredução , Polietilenos/química , Polietilenos/farmacocinética , Polietilenos/farmacologia , Tíbia/lesões , Tíbia/metabolismo , Tíbia/patologia , Suporte de Carga
8.
Int J Pharm ; 517(1-2): 67-79, 2017 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-27908629

RESUMO

The main concerns with drugs designed for oral administration are their inactivation or degradation in the harsh conditions of the gastrointestinal tract, their poor solubility through the gastrointestinal mucus gel layer, the poor intestinal epithelium permeability that limits their absorption, and their toxicity. In this context, poly(anhydride) nanoparticles are capable of protecting the drug from the harsh environment, reduce the drug's toxicity and, by virtue of surface modification, to enhance or reduce their mucus permeability and the bioadhesion to specific target cells. The copolymer between methyl vinyl ether and maleic anhydride (commercialized as Gantrez® AN 119) are part of the poly(anhydride) nanoparticles. These biocompatible and biodegradable nanoparticles (NPs) can be modified by using different ligands. Their usefulness as drug carriers and their bioadhesion with components of the intestinal mucosa have been described. However, their toxicity, genotoxicity and mucus permeation capacity has not been thoroughly studied. The aim of this work was to evaluate and compare the in vitro toxicity, cell viability and in vitro genotoxicity of the bioadhesive empty Gantrez® AN 119 NPs modified with dextran, aminodextran, 2-hydroxypropyl-ß-cyclodextrin, mannosamine and poly-ethylene glycol of different molecular weights. Results showed that, in general, coated NPs exhibit better mucus permeability than the bare ones, those coated with mannosamine being the most permeable ones. The NPs studied did not affect cell metabolism, membrane integrity or viability of Caco-2 cells at the different conditions tested. Moreover, they did not induce a relevant level of DNA strand breaks and FPG-sensitive sites (as detected with the comet assay).


Assuntos
Quebras de DNA/efeitos dos fármacos , Portadores de Fármacos/toxicidade , Mucosa Gástrica/metabolismo , Mucosa Intestinal/metabolismo , Maleatos/toxicidade , Nanopartículas/química , Polietilenos/toxicidade , Administração Oral , Animais , Células CACO-2 , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Células HT29 , Humanos , Maleatos/química , Maleatos/farmacocinética , Permeabilidade , Polietilenos/química , Polietilenos/farmacocinética , Propriedades de Superfície , Suínos
9.
Int J Pharm ; 523(1): 300-309, 2017 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-28336457

RESUMO

Metastasis impedes the successful chemotherapy for breast cancer. In this study, an Akt inhibitor (quercetin, Qu) was co-delivered with a chemotherapeutic agent (docetaxel, DTX) by using hyaluronic acid (HA)-modified nanoparticles (NPs) as vectors to block metastasis. Dual DTX/Qu-loaded HA/polylactic-co-glycolic acid-polyethyleneimine NPs (PP-HA/NPs) were prepared through a modified emulsion solvent evaporation technique. The particle size of PP-HA/NPs with narrow polydispersity was 209.8±10.8nm. Wound healing assay revealed that Qu co-delivery and HA modification elicited synergistic inhibitory effects on cell motility. The downregulation of p-Akt and matrix metalloproteinase-9 (MMP-9) expression contributed to the significant inhibition of cell migration and invasion with inhibition rates of 95.6% and 99.3%, respectively. Further studies indicated that PP-HA/NPs could be efficiently uptaken by 4T1 breast cancer cells and could further induce cytotoxicity, decrease colony formation and promote cell apoptosis. Biodistribution assay demonstrated PP-HA/NPs also enhanced drug accumulation in the tumor and lungs and predicted that PP-HA/NPs could be employed as an effective therapy for primary tumor and pulmonary metastasis. Therefore, PP-HA/NPs could be a promising delivery system to treat metastatic breast cancer effectively.


Assuntos
Antineoplásicos/administração & dosagem , Antioxidantes/administração & dosagem , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Nanopartículas/administração & dosagem , Quercetina/administração & dosagem , Taxoides/administração & dosagem , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antioxidantes/química , Antioxidantes/farmacocinética , Apoptose/efeitos dos fármacos , Neoplasias da Mama , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Docetaxel , Feminino , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/química , Ácido Hialurônico/farmacocinética , Iminas/administração & dosagem , Iminas/química , Iminas/farmacocinética , Ácido Láctico/administração & dosagem , Ácido Láctico/química , Ácido Láctico/farmacocinética , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/química , Inibidores de Metaloproteinases de Matriz/farmacocinética , Camundongos Endogâmicos BALB C , Nanopartículas/química , Polietilenos/administração & dosagem , Polietilenos/química , Polietilenos/farmacocinética , Ácido Poliglicólico/administração & dosagem , Ácido Poliglicólico/química , Ácido Poliglicólico/farmacocinética , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quercetina/química , Quercetina/farmacocinética , Taxoides/química , Taxoides/farmacocinética , Cicatrização/efeitos dos fármacos
10.
J Biomed Mater Res B Appl Biomater ; 73(2): 214-20, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15772963

RESUMO

To make stochastic (probabilistic) failure predictions of a conventional or highly crosslinked ultrahigh molecular weight polyethylene (UHMWPE) material, not only must a failure criterion be defined, but it is also necessary to specify a probability distribution of the failure strength. This study sought to evaluate both parametric and nonparametric statistical approaches to describing the failure properties of UHMWPE, based on the Normal and Weibull model distributions, respectively. Because fatigue and fracture properties of materials have historically been well described with the use of Weibull statistics, it was expected that a nonparametric approach would provide a better fit of the failure distributions than the parametric approach. The ultimate true stress, true strain, and ultimate chain stretch data at failure were analyzed from 60 tensile tests conducted previously. The ultimate load and ultimate displacement from 121 small punch tests conducted previously were also analyzed. It was found that both Normal and Weibull models provide a reasonable description of the central tendency of the failure distribution. The principal difference between the Normal and Weibull models can be appreciated in the predicted lower-bound response at the tail end of the distribution. The data support the use of both parametric and nonparametric methods to bracket the lower-bound failure prediction in order to simulate the failure threshold for UHMWPE.


Assuntos
Polietilenos/farmacocinética , Raios gama , Teste de Materiais , Polietilenos/química , Probabilidade , Processos Estocásticos , Estresse Mecânico
11.
J Burn Care Rehabil ; 26(5): 430-3, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16151289

RESUMO

Acticoat (Smith and Nephew, Istanbul, Turkey), chlorhexidine acetate 0.5%, and silver sulfadiazine 1% were compared to assess the antibacterial effect of their application on experimental burn wounds in contaminated with Pseudomonas aeruginosa in rats. All treatment modalities were effective against P. aeruginosa because there were significant differences between treatment groups and control groups. The mean eschar concentrations did not differ significantly between Acticoat and chlorhexidine acetate groups, but there were significant differences between the silver sulfadiazine group and the other treatment groups, indicating that silver sulfadiazine significantly eliminated P. aeruginosa more effectively in the tissues than did the other two agents. All treatment modalities were sufficient to prevent the P. aeruginosa from invading to the muscle and from causing systemic infection. In conclusion, silver sulfadiazine is the most effective agent in the treatment of the P. aeruginosa-contaminated burn wounds; Acticoat can be considered as a treatment choice because of its peculiar ability of limiting the frequency of replacing wound dressings.


Assuntos
Anti-Infecciosos Locais/uso terapêutico , Queimaduras/microbiologia , Clorexidina/uso terapêutico , Poliésteres/uso terapêutico , Polietilenos/uso terapêutico , Infecções por Pseudomonas/prevenção & controle , Sulfadiazina de Prata/uso terapêutico , Administração Tópica , Animais , Anti-Infecciosos Locais/administração & dosagem , Anti-Infecciosos Locais/farmacocinética , Bandagens , Queimaduras/complicações , Clorexidina/administração & dosagem , Clorexidina/farmacocinética , Masculino , Poliésteres/administração & dosagem , Poliésteres/farmacocinética , Polietilenos/administração & dosagem , Polietilenos/farmacocinética , Pseudomonas aeruginosa/patogenicidade , Ratos , Ratos Wistar , Sulfadiazina de Prata/administração & dosagem , Sulfadiazina de Prata/farmacocinética
12.
Clin Pharmacokinet ; 41(7): 517-23, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12083979

RESUMO

OBJECTIVE: To examine the absorption, distribution and excretion of sevelamer hydrochloride in rats and humans. PARTICIPANTS: Twelve male Sprague-Dawley rats were used in the animal study, and twenty human volunteers participated in the clinical trial. METHODS: In the animal study, six rats received a single oral dose of [(3)H]sevelamer and six rats were pretreated with unlabelled sevelamer in the diet for 28 days followed by a single dose of [(3)H]sevelamer on day 29. Total urine and faeces were collected at intervals up to 72 hours post dose, and tissues were obtained at the time of sacrifice. In the clinical trial, subjects received a single oral dose of [(14)C]sevelamer following 28 days of pretreatment with unlabelled sevelamer. Blood, urine and faeces samples were collected at intervals up to 96 hours. RESULTS: In the rat study, no significant urinary excretion of radioactivity was observed. The average recovery of radioactivity in the faeces was 98% in the single-dose group and greater than 100% in the group pretreated with unlabelled sevelamer for 28 days. A total of less than 0.1% of the dose was found in the tissues. In the human study, no detectable amount of (14)C was found in the blood of any subject at any time. The majority of subjects had no detectable amounts of (14)C recovered in the urine. In subjects where (14)C was recovered in the urine, less than 0.02% was detected, a level equivalent to the free (14)C detected in the [(14)C]sevelamer preparation. On average, greater than 99% of the administered dose was recovered in the faeces of the subjects. CONCLUSION: These studies demonstrate that sevelamer is a non-absorbed compound.


Assuntos
Compostos de Epóxi/farmacocinética , Fosfatos/metabolismo , Polietilenos/farmacocinética , Polímeros/farmacocinética , Absorção , Administração Oral , Animais , Radioisótopos de Carbono , Compostos de Epóxi/sangue , Compostos de Epóxi/urina , Fezes/química , Humanos , Masculino , Poliaminas , Ratos , Ratos Sprague-Dawley , Sevelamer , Especificidade da Espécie , Fatores de Tempo , Distribuição Tecidual , Trítio
13.
Am J Kidney Dis ; 42(6): 1253-9, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14655198

RESUMO

BACKGROUND: The oral bioavailability of ciprofloxacin is significantly decreased when administered with calcium carbonate. Sevelamer hydrochloride is a phosphate-binding cationic polymer that is devoid of calcium. The authors conducted a 3-way, randomized, crossover study to determine the effects of sevelamer hydrochloride and calcium acetate on the relative oral bioavailability of ciprofloxacin. METHODS: Fifteen healthy volunteers were assigned randomly to receive each of the following oral regimens: ciprofloxacin 750 mg, alone (Arm A); ciprofloxacin 750 mg plus 7 sevelamer hydrochloride 403 mg capsules (Arm B); ciprofloxacin 750 mg plus 4 calcium acetate 667 mg tablets (Arm C). Serial blood and urine samples were obtained over 24 hours, and ciprofloxacin concentrations were determined by high-performance liquid chromatography. Pharmacokinetic data were analyzed using noncompartmental methods, and maximum serum concentration (Cmax) and area under the serum concentration time curve from 0 to infinity (AUC(0- infinity )) were tested for bioequivalence after log transformation of the data. The relative oral bioavailability of ciprofloxacin was calculated as AUC(0- infinity ), Arm B or Arm C/AUC(0- infinity ), Arm A. RESULTS: The Cmax and AUC(0- infinity ) of ciprofloxacin were significantly decreased when administered concomitantly with sevelamer hydrochloride or calcium acetate (P < 0.05), and bioequivalence was not achieved for either parameter. The relative oral bioavailability of ciprofloxacin was decreased by 48% with sevelamer hydrochloride and 51% with calcium acetate (P < 0.05). CONCLUSION: The relative oral bioavailability of ciprofloxacin is significantly decreased when administered with sevelamer hydrochloride or calcium acetate. Concomitant administration of these drugs may decrease clinical efficacy and promote bacterial resistance to ciprofloxacin.


Assuntos
Acetatos/farmacologia , Anti-Infecciosos/farmacologia , Ciprofloxacina/farmacocinética , Compostos de Epóxi/farmacologia , Polietilenos/farmacologia , Acetatos/farmacocinética , Administração Oral , Adulto , Anti-Infecciosos/farmacocinética , Disponibilidade Biológica , Compostos de Cálcio , Cromatografia Líquida de Alta Pressão , Ciprofloxacina/sangue , Ciprofloxacina/urina , Estudos Cross-Over , Depressão Química , Interações Medicamentosas , Farmacorresistência Bacteriana , Compostos de Epóxi/farmacocinética , Feminino , Humanos , Absorção Intestinal/efeitos dos fármacos , Masculino , Poliaminas , Polietilenos/farmacocinética , Sevelamer
14.
Biomaterials ; 17(9): 873-8, 1996 May.
Artigo em Inglês | MEDLINE | ID: mdl-8718932

RESUMO

The chemical characterization of 19 retrieved ultra-high-molecular-weight polyethylene tibial plateaux, six new ones and one raw bar was performed by means of infrared spectroscopy. The surface and bulk oxidation and biodegradation indexes were calculated. The raw bar has a measurable oxidation, which increases on the bulk and on the surfaces of the new plateaux. In the retrieved plateaux, the average oxidation index increases further both on the bulk and on the surfaces; the worse values were present on the worn area. Similar results were found for the biodegradation index. The data show that the biotic in vivo degradation is promoted by the oxidation present on the new plateaux and that it occurs through a different mechanism, abiotic thermal-, photo-, gamma-radiation oxidation, evaluated by the oxidation index.


Assuntos
Materiais Biocompatíveis/efeitos adversos , Prótese do Joelho/efeitos adversos , Polietilenos/efeitos adversos , Idoso , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacocinética , Biodegradação Ambiental , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peso Molecular , Oxirredução , Polietilenos/química , Polietilenos/farmacocinética , Falha de Prótese , Espectroscopia de Infravermelho com Transformada de Fourier , Propriedades de Superfície
15.
Biomaterials ; 19(1-3): 61-7, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-9678851

RESUMO

Spherical reservoir-type microcapsules fabricated using a water/oil/water (W/O/W) double emulsion technique with solvent evaporation and composed of poly(ethylene adipate) (PEAD) blended with 20% poly-epsilon-caprolactone (PCL II) containing a range of bovine serum albumin (BSA) loadings were incubated in Hank's buffer, pH 7.4, newborn calf serum, 1.5% pancreatin and synthetic gastric juice containing 10% pepsin A over 30 days and their percentage weight loss (PWL) and changes in ultrastructural morphology monitored by gravimetry and stereoscan electron microscopy (SEM) respectively. The greatest PWL from microcapsules was observed after incubation in newborn calf serum (NCS) and pancreatin and decreased in the order NCS > pancreatin > synthetic gastric juice > Hank's buffer. Only microcapsules theoretically loaded with 5-20% BSA and incubated in synthetic gastric juice showed a significant increase in PWL with increasing percentage BSA loading. The structural biodegradation of PEAD microcapsules in both Hank's buffer and synthetic gastric juice was minimal whilst the morphological changes observed during incubation in NCS involved pitting of the membrane, some surface erosion and reduction in diameter, followed by microcapsule membrane disruption and loss of reservoir contents. Biodegradation in pancreatin was associated with surface flaking and loss of large fragments of the microcapsule membrane. Only in NCS and pancreatin, where one would expect to see the effects of enzyme activity in addition to simple ester hydrolysis, did biodegradation proceed to the stage where there was a loss of spherical shape and almost total disruption of the microcapsule structure within 30 days.


Assuntos
Adipatos/química , Adipatos/farmacocinética , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacocinética , Plastificantes/química , Plastificantes/farmacocinética , Polietilenos/química , Polietilenos/farmacocinética , Animais , Biotransformação , Cápsulas , Bovinos , Emulsões , Suco Gástrico/química , Suco Gástrico/metabolismo , Pancreatina/química , Pancreatina/metabolismo , Suínos
16.
Biomaterials ; 11(8): 585-9, 1990 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-2279060

RESUMO

A homogeneous glycidyl acrylate polymer (GAP) has been grafted on to polytetrafluoroethylene (PTFE) and polyethylene (PE) using a modified plasma glow discharge technique with glycidyl acrylate. The polymeric layer appears to be extremely stable to acidic media and to common organic solvents. The modified surface can be derivatized via epoxy groups with hydroxy and amino compounds including sugars and amino sugars. These derivatized surfaces have been characterized by Fourier transform infrared (FTIR) spectroscopy and contact angle measurements. The wide variety of compounds which can be attached provides flexibility in the design of surfaces for the study of a range of biological interactions.


Assuntos
Materiais Biocompatíveis , Compostos de Epóxi/química , Teste de Materiais , Metacrilatos/química , Plasma/metabolismo , Polietilenos/farmacocinética , Polímeros/farmacocinética , Politetrafluoretileno/farmacocinética , Adsorção , Materiais Biocompatíveis/farmacocinética , Microscopia Eletrônica de Varredura , Polietilenos/química , Polímeros/química , Politetrafluoretileno/química , Solventes/química , Análise Espectral/métodos , Propriedades de Superfície
17.
J Control Release ; 92(1-2): 39-48, 2003 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-14499184

RESUMO

Many biodegradable polymers have been developed for controlled drug delivery. The plethora of drug therapies and types of drugs demand different formulations, fabrications conditions and release kinetics. No one single polymer can satisfy all the requirements. To extend the properties of poly(D,L-lactide) (PLA), we synthesized copolymers of PLA and poly(ethylethylene phosphate) (PEEP) by ring-opening polymerization using Al(Oipr)3 as the initiator. The copolymers were structurally characterized by IR and 1H NMR. DSC data confirmed the formation of random microphase structure in all the copolymers, and showed a decrease of Tg from 43.2 to -22.6 degrees C when the molar content of ethylethylene phosphate (EEP) increased from 5 to 40%. The hydrophilicity of the copolymers increased with EEP content. In contrast to the degradation behavior of PLA, disc samples made of PLAEEP90 showed a linear weight loss profile in PBS (pH 7.4) at 37 degrees C. BSA microspheres using PLAEEP90 were prepared by double-emulsion method, yielding a loading level of 4.3% and a loading efficiency of 75%. The BSA release profile consisted of an initial burst (9%) on the first day, followed by a daily 4% release for the following 40 days, resulting in 91% of the BSA release in a near linear manner. The released BSA remained intact according to SDS-PAGE data. Cytotoxicity and histopathology studies showed low toxicity in HeLa cells and good tissue biocompatibility in mouse brain, respectively. PLAEEP is a promising biodegradable polymer for controlled drug delivery.


Assuntos
Poliésteres/administração & dosagem , Poliésteres/farmacocinética , Polietilenos/administração & dosagem , Polietilenos/farmacocinética , Animais , Bovinos , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Células HeLa , Humanos , Camundongos , Fosfatos/administração & dosagem , Fosfatos/química , Fosfatos/farmacocinética , Poliésteres/química
18.
J Control Release ; 89(1): 19-30, 2003 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-12695060

RESUMO

The aim of this work was to investigate the influence of the cross-linkage of poly(methylvinylether-co-maleic anhydride) (PVM/MA) nanoparticles with increasing amounts of 1,3-diaminopropane (DP) and, eventually, bovine serum albumin (BSA) on their gastrointestinal transit and bioadhesive properties. The fluorescently-labelled formulations were orally administered to rats and, at different times, the amount of nanoparticles in both the lumen content and adhered to the gut mucosa were quantified. The gut transit was evaluated by calculating the gastric (k(ge)) and intestinal (k(ie)) emptying rates. The adhered fraction of nanoparticles in the whole gut was plotted versus time and, from these curves, the intensity, capacity and extent of the adhesive interactions were estimated. The bioadhesive potential of PVM/MA was much higher when formulated as nanoparticles (NP) than in the solubilised form in water. However, k(ge) and k(ie) increased by increasing the extent of cross-linkage of nanoparticles with DP, while the capacity to develop adhesive interactions and the intensity of the adhesive phenomenon were significantly higher for non-hardened than for DP-cross-linked carriers. In contrast, the BSA-coating of cross-linked nanoparticles significantly decreased k(ge) and k(gi), whereas the intensity of the bioadhesive phenomenon was significantly higher than for NP. In summary, the adhesivity of the nanoparticles appears to modulate their gastrointestinal transit profile.


Assuntos
Adesividade/efeitos dos fármacos , Maleatos/metabolismo , Maleatos/farmacocinética , Tamanho da Partícula , Polietilenos/metabolismo , Polietilenos/farmacocinética , Propriedades de Superfície/efeitos dos fármacos , Administração Oral , Animais , Química Farmacêutica , Diaminas/química , Diaminas/farmacocinética , Estabilidade de Medicamentos , Trânsito Gastrointestinal/efeitos dos fármacos , Trânsito Gastrointestinal/fisiologia , Nanotecnologia/métodos , Soroalbumina Bovina/química , Soroalbumina Bovina/farmacocinética
19.
Eur J Pharm Biopharm ; 57(2): 189-97, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15018974

RESUMO

In order to treat malignant brain tumors by local delivery of antineoplastic agents, the feasibility of 5-fluorouracil (5-FU)-sustained release biodegradable microspheres with a novel material, poly(methylidene malonate 2.1.2), was investigated using an emulsion/extraction method. This polymer was expected to present a slow degradation rate, thus leading to a long term local delivery system. Microparticles were successfully obtained and characterized in terms of drug loading, size, morphology and release profile. The size of the particles was between 40 and 50 microm, which was compatible with a stereotactic injection through a needle. Sufficient drug loadings were obtained (i.e. compatible with the preparation of therapeutic 5-FU doses in a minimal volume of injection), and perfectly spherical microspheres were observed. The respective influences of the polymer molecular weight, the polymer concentration, and the emulsion time on the release profiles were studied using a 2(3) factorial design. In the same objective, the solvent extraction time was extended while keeping all the previous parameters fixed at their optimal values. The in vitro study of these different parameters allowed a reduction of the initial burst release, with a percentage of 5-FU released after 24 h that was lowered from 90 to 65%, and the achievement of a long term drug delivery system, since the release was still ongoing after 43 days. Moreover, the microparticles could be gamma-sterilized (25 kGy) without modification of the release kinetics. Thus, the requested specifications to perform animal experiments were attained.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Fluoruracila/farmacocinética , Malonatos/farmacocinética , Microesferas , Polietilenos/farmacocinética , Neoplasias Encefálicas/metabolismo , Fluoruracila/administração & dosagem , Fluoruracila/síntese química , Malonatos/administração & dosagem , Malonatos/síntese química , Polietilenos/administração & dosagem , Polietilenos/síntese química
20.
J Drug Target ; 9(2): 141-53, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11697108

RESUMO

The goal of this paper was to investigate the fate of novel poly(methylidene malonate 2.1.2) microparticles with different surface properties, i.e. prepared with or without polyvinylalcohol (PVA), after oral administration, using in vitro cell culture and an in vivo mice model. Incubation of particles with Caco-2 cells induced no cytotoxicity except for the microparticles prepared without PVA at high concentrations. At subtoxic concentrations, microparticles were highly associated to cells, independently of particles concentrations, particles surface properties (with or without PVA) or incubation time. Confocal microscopy analysis revealed that adsorption was the main phenomenon leading to the association of particles to cells. However, association was greater at 37 degrees C than at 4 degrees C, suggesting that an active process, such as endocytosis, could also occur. In vivo, radiolabeled particles were mainly found in luminal content and also adsorbed onto the epithelium. After 24 hours, more than 15% of PVA-free microparticles were still present in the gastrointestinal tract, compared to 5% for particles prepared with PVA. However, histological evaluation revealed low uptake of particles by Peyer's patches. As a conclusion, this study provided a good correlation between in vitro and in vivo evaluation. These particles could be useful for oral sustained release and delivery of drugs to intestinal and colon epithelium.


Assuntos
Malonatos/farmacocinética , Polietilenos/farmacocinética , Administração Oral , Animais , Células CACO-2 , Células Cultivadas , Portadores de Fármacos , Corantes Fluorescentes , Humanos , Absorção Intestinal , Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Malonatos/química , Camundongos , Camundongos Endogâmicos C3H , Microesferas , Tamanho da Partícula , Polietilenos/química , Álcool de Polivinil/química , Distribuição Tecidual
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