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1.
Acta Gastroenterol Belg ; 82(3): 407-415, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31566329

RESUMO

OBJECTIVE: To assess the efficacy adjunction of oral simethicone to polyethylene glycol as bowel preparation agent on cecal intubation rate. METHODS: We searched EMBASE, PubMed and Cochrane library for randomized controlled trials regarding simeticone plus polyethylene glycol as oral drinking agents before gastroscopy,we used the soft RevMan5.3 to perform statistical analysis and stata12.0 for publication bias. RESULTS: 12 randomized trials that met the inclusion criteria were therefore pooled into a meta-analysis, which included a total of 5,112 patients. There were no significant differences on cecal intubation rate in two groups(RR=1.0,95%CI : 0.99-1.01, P=0.93) with moderate level of evidence;Subgroups analysis of 2LPEG+ Simethicone VS 2LPEG(RR =1.0, 95% CI : 0.98,1.01), 2LPEG+ Simethicone VS 4L PEG (RR=1.00, 95% CI : 0.98,1.02), PEG+ Simethicone with bisacodyl vs PEG (RR =1.00, 95% CI : 0.99,1.02), PEG+Simethicone without bisacodyl vs PEG (RR =1.00, 95% CI : 0.98,1.02) showed no difference on cecal intubation rate.There was aslo no significant difference on cecal intubation time.Abdominal bloating incidence was lower in PEG+Simethicone group than that in PEG group (RR=0.53, 95%CI : 0.31, 0.91, P=0.02). The meta-analysis result also showed a better acceptability in PEG+Simethicone group (RR=1.28, 95% CI : 1.01, 1.49, P=0.001). CONCLUSION: Adjunction of oral simethicone to polyethylene glycol as bowel preparation agent dose not improve cecal intubation rate on colonoscopy,but with better gastrointestinal tolerability and acceptability.


Assuntos
Catárticos/administração & dosagem , Colonoscopia/métodos , Polietilenoglicóis/administração & dosagem , Simeticone/administração & dosagem , Catárticos/efeitos adversos , Humanos , Intubação Intratraqueal , Polietilenoglicóis/efeitos adversos , Simeticone/efeitos adversos
2.
J Appl Oral Sci ; 27: e20180663, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31596368

RESUMO

OBJECTIVE: To investigate the use of polymethyl methacrylate (PMMA) electrospun fiber mats containing different amounts of polyethylene oxide (PEO) as a doxycycline delivery system and to test antibacterial activity against an oral pathogen. METHODOLOGY: PMMA powders or PEO (mol wt 200 Kd) (10,20,30% w/w/) were dissolved in N, N-dimethylformamide (DMF) to obtain a final polymer concentration of 15% in DMF (w/v). 2% Doxycycline monohydrate was added to the solutions and submitted to vortex mixing. The solution was transferred to a plastic syringe and fit into a nanofiber electrospinning unit. The parameters applied were: voltage at 17.2 kV; distance of 20 cm between the needle tip and the collector plate; target speed at 2 m/min; and transverse speed at 1cm/min. Syringe pump speed was 0.15 mm/min. The drug release analysis was performed by removing aliquots of the drug-containing solution (in PBS) at specific periods. Doxycycline release was quantified using RP-HPLC. Fiber mats from all groups had their antibacterial action tested against S. mutans based on inhibition halos formed around the specimens. The experiments were performed in triplicate. Gravimetric analysis at specific periods was performed to determine any polymer loss. Morphological characterization of the electrospun fibers was completed under an optical microscope followed by SEM analysis. RESULTS: The addition of PEO to the PMMA fibers did not affect the appearance and diameter of fibers. However, increasing the %PEO caused higher doxycycline release in the first 24 h. Fibers containing 30% PEO showed statistically significant higher release when compared with the other groups. Doxycycline released from the fibers containing 20% or 30% of PEO showed effective against S. mutans. CONCLUSION: The incorporation of PEO at 20% and 30% into PMMA fiber mat resulted in effective drug release systems, with detected antibacterial activity against S. mutans.


Assuntos
Antibacterianos/farmacocinética , Doxiciclina/farmacocinética , Nanofibras/química , Polietilenoglicóis/farmacocinética , Polimetil Metacrilato/farmacocinética , Análise de Variância , Antibacterianos/química , Cromatografia Líquida de Alta Pressão/métodos , Doxiciclina/química , Imersão , Microscopia Eletrônica de Varredura , Peso Molecular , Polietilenoglicóis/química , Polimetil Metacrilato/química , Reprodutibilidade dos Testes , Streptococcus mutans/efeitos dos fármacos , Fatores de Tempo , Água/química
3.
Rinsho Ketsueki ; 60(9): 1176-1185, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31597841

RESUMO

Although the Janus kinase (JAK) inhibitor ruxolitinib has long been the only drug licensed for treatment of the classic Philadelphia chromosome negative (Ph-) myeloproliferative neoplasms, years of drug development efforts have begun to bear fruit with the recent approval of a novel monopegylated interferon alfa-2b, ropeginterferon alfa, for patients with polycythemia vera without symptomatic splenomegaly in Europe. Several newer JAK inhibitors (fedratinib, pacritinib, momelotinib) have shown activity in phase 3 trials in patients with myelofibrosis but have, for various reasons, not yet received regulatory approval; all these agents, however, remain in active clinical development. Many other agents with diverse mechanisms of action are being explored in clinical trials in patients with myelofibrosis, both as single agents and in combination with ruxolitinib. Besides splenomegaly and symptoms, improvement of anemia has become a new focus of drug development in myelofibrosis. Ruxolitinib appears promising also in chronic neutrophilic leukemia, where mutations in CSF3R are common. Pemigatinib, a potent and selective inhibitor of fibroblast growth factor receptor (FGFR), has shown impressive efficacy in a small registration-directed trial in patients with FGFR1-rearranged myeloid/lymphoid neoplasms. Finally, avapritinib, a highly potent and selective inhibitor of KITD816V, has demonstrated unprecedented response rates in patients with advanced systemic mastocytosis.


Assuntos
Transtornos Mieloproliferativos/terapia , Mielofibrose Primária/terapia , Ensaios Clínicos Fase III como Assunto , Europa (Continente) , Humanos , Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Policitemia Vera , Polietilenoglicóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Esplenomegalia
4.
Inorg Chem ; 58(18): 12302-12310, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31522510

RESUMO

Photochemistry is a rich source of inspiration for developing alternative methods to functionalize proteins with drug molecules, fluorophores, and radioactive probes. Here, we report the synthesis and photochemical reactivity of a modified diethylenediamine pentaacetic acid chelate that was derivatized with a light-responsive aryl azide group (DTPA-PEG3-ArN3, compound 1). The corresponding nonradioactive and radioactive nat/68Ga3+ and nat/111In3+ complexes of DTPA-PEG3-ArN3 were synthesized and their physical and photochemical properties were studied to evaluate the potential of employing this ligand system in the photochemical synthesis of radiolabeled antibodies. Photodegradation kinetics revealed that irradiation with ultraviolet light (365 nm) induced rapid photoactivation of compound 1 and the metal complexes nat/68Ga-1- and nat/111In-1-. Light-induced reactions were complete in <100 s, with measured first-order rate constants of 0.078 ± 0.045 s-1, 0.093 ± 0.009 s-1, and 0.117 ± 0.054 s-1 (n = 2, per species) for compound 1, natGa-1-, and natIn-1-, respectively. Photochemically induced bioconjugation reactions between DTPA-PEG3-ArN3 and the monoclonal antibody trastuzumab, as well as pre- and postconjugation 68Ga- and 111In-radiolabeling experiments, were performed using either a one-pot or two-step strategy. Both approaches yielded radiolabeled trastuzumab ([68Ga]GaDTPA-azepin-trastuzumab) with average radiochemical conversions of 3.9 ± 1.0% (n = 4, one-pot), and 10.0 ± 1.0% (n = 3, two-step). One-pot radiolabeling reactions with [111In]InCl3 produced the corresponding [111In]InDTPA-azepin-trastuzumab radiotracer in a similar radiochemical conversion of 5.4 ± 0.8% (n = 3). Radiochemical conversions for the desired bimolecular coupling between the chelate and the protein were comparatively low. This observation is likely caused by the high photoinduced reactivity of the compounds and subsequent competition with background reactions. Nevertheless, access to DTPA-PEG3-ArN3 increases the scope of photoradiochemical methods to include metal ions like In3+ that form complexes with higher coordination numbers.


Assuntos
Quelantes/química , Radioisótopos de Gálio/química , Imunoconjugados/química , Radioisótopos de Índio/química , Ácido Pentético/química , Polietilenoglicóis/química , Trastuzumab/química , Argônio/química , Quelantes/síntese química , Luz , Ácido Pentético/síntese química , Fotólise , Polietilenoglicóis/síntese química
5.
Chem Commun (Camb) ; 55(79): 11860-11863, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31528890

RESUMO

An easy to synthesize azobenzene based amphiphile spontaneously self-assembles into monodisperse nanoaggregates in water. The large difference in the critical aggregation concentration between the E and Z stereoisomeric forms enables photocontrol of its aggregation state over a wide concentration range: light-triggered release and uptake of lipophilic molecules is achieved in aqueous solution.


Assuntos
Compostos Azo/química , Nanocápsulas/química , Corantes Fluorescentes/química , Interações Hidrofóbicas e Hidrofílicas , Luz , Tamanho da Partícula , Processos Fotoquímicos , Polietilenoglicóis/química , Estereoisomerismo , Água/química
6.
Bone Joint J ; 101-B(9): 1115-1121, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31474138

RESUMO

AIMS: The aim of this study was to explore risk factors for complications associated with dural tear (DT), including the types of DT, and the intra- and postoperative management of DT. PATIENTS AND METHODS: Between 2012 and 2017, 12 171 patients with degenerative lumbar diseases underwent primary lumbar spine surgery. We investigated five categories of potential predictors: patient factors (sex, age, body mass index, and primary disease), surgical factors (surgical procedures, operative time, and estimated blood loss), types of DT (inaccessible for suturing/clipping and the presence of cauda equina/nerve root herniation), repair techniques (suturing, clipping, fibrin glue, polyethylene glycol (PEG) hydrogel, and polyglycolic acid sheet), and postoperative management (drainage duration). Postoperative complications were evaluated in terms of dural leak, prolonged bed rest, headache, nausea/vomiting, delayed wound healing, postoperative neurological deficit, surgical site infection (SSI), and reoperation for DT. We performed multivariable regression analyses to evaluate the predictors of postoperative complications associated with DT. RESULTS: In total, 429/12 171 patients (3.5%) had a DT. Multivariable analysis revealed that PEG hydrogel significantly reduced the incidence of dural leak and prolonged bed rest, and that patients treated with sealants (fibrin glue and PEG hydrogel) significantly less frequently suffered from headache. A longer drainage duration significantly increased the incidence of headache, nausea/vomiting, and delayed wound healing. Headache and nausea/vomiting were significantly more prevalent in younger female patients. Postoperative neurological deficit and reoperation for DT significantly depended on the presence of cauda equina/nerve root herniation. A longer operative time was the sole independent risk factor for SSI and was also a risk factor for dural leak, prolonged bed rest, and nausea/vomiting. CONCLUSION: Sealants, particularly PEG hydrogel, may be useful in reducing symptoms related to cerebrospinal fluid leakage, whereas prolonged drainage may be unnecessary. Younger female patients should be carefully treated when DT occurs. Cite this article: Bone Joint J 2019;101-B:1115-1121.


Assuntos
Vazamento de Líquido Cefalorraquidiano/terapia , Dura-Máter/lesões , Dura-Máter/cirurgia , Vértebras Lombares/cirurgia , Procedimentos Ortopédicos/efeitos adversos , Doenças da Coluna Vertebral/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Vazamento de Líquido Cefalorraquidiano/etiologia , Drenagem , Feminino , Adesivo Tecidual de Fibrina/administração & dosagem , Humanos , Hidrogel de Polietilenoglicol-Dimetacrilato/administração & dosagem , Complicações Intraoperatórias/etiologia , Complicações Intraoperatórias/terapia , Masculino , Pessoa de Meia-Idade , Procedimentos Ortopédicos/métodos , Polietilenoglicóis/administração & dosagem , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/terapia , Prognóstico , Reoperação , Estudos Retrospectivos , Fatores de Risco , Técnicas de Sutura , Adesivos Teciduais/administração & dosagem , Adulto Jovem
7.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 37(4): 384-388, 2019 Aug 01.
Artigo em Chinês | MEDLINE | ID: mdl-31512830

RESUMO

OBJECTIVE: To evaluate the effect of sandblasting or acid etching on the three-point bending strength to the modified polyetheretherketone (PEEK). METHODS: Forty-eight bars (15 mm×2 mm×1 mm) of specimens were fabricated from the modified PEEK (BioHPP). They were randomly divided into the following groups: A, B, C and D groups, which were blasted with alumina particles; E, F, and G groups, which were etched with 98% concentrated sulfuric acid; and control group H. The sand blast pressure of groups A, B and C was 0.2 MPa, and the grain sizes of the sand blasted were 120, 50, and 250 µm, respectively. Group D was blasted with 120 µm particle size at 0.7 MPa pressure. Groups E, F and G were acid etched for 60, 120, and 300 s, respectively. No surface treatment was conducted in group H. After all the specimens were processed, one sample was randomly selected from each group to observe its surface morphology under a scanning electron microscope (SEM), and the other specimens were tested for their three-point bending strength. SPSS 22.0 software was used to analyze the experimental data and to test whether the difference was statistically significant. RESULTS: SEM observation showed that the surface morphology of the specimen changed after the treatment and revealed different degrees of cracks, pits, or voids. The three-point bending test indicated that the strength of the specimens treated with sandblasting or concentrated sulfuric acid decreased compared with that of the control group (P<0.05). At the same pressure, no significant difference in flexural strength was observed among groups A, B, and C (P>0.05). The strength of group D was lower than that of group A at the same particle size (P<0.05), and no significant difference was found in the bending strength of the specimens etched with concentrated sulfuric acid (P>0.05). CONCLUSIONS: The bending strength of BioHPP could be significantly decreased by surface sand blasting or concentrated sulfate etching as the sandblasting pressure increased, but the bending strength did not decrease as sand particle size and acid etching time changed.


Assuntos
Colagem Dentária , Cimentos de Resina , Cetonas , Teste de Materiais , Microscopia Eletrônica de Varredura , Polietilenoglicóis , Resistência ao Cisalhamento , Propriedades de Superfície
8.
Chem Pharm Bull (Tokyo) ; 67(9): 929-934, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474731

RESUMO

We investigated the water contents in commercial semi-solid preparations used for pressure ulcer (PU) treatment using near-IR spectroscopy (NIRS) and compared the results with those measured using the Karl Fischer (KF) method. The aim of this study was to determine a standard method and select the appropriate topical preparation with the optimal moisture for PU treatment. The water absorption properties of bases and formulations were evaluated with a time-dependent factor using Transwell as the model membrane. KF and NIRS were applicable as measurement methods of the water content in semi-solid formulations. NIRS was shown to be a useful, simple, nondestructive tool that is more advantageous than the KF method. The water absorption characteristics tested using Transwell revealed that the rate of and capacity for water absorption are determined not only by the absorption ability of the polymer base but also by other factors, such as the osmotic pressure exerted by additives. KF and NIR measurements can be used to choose external skin preparations to control the amount of water in PU treatment.


Assuntos
Composição de Medicamentos/métodos , Água/química , Administração Tópica , Glicerol/química , Humanos , Pomadas/química , Pomadas/uso terapêutico , Polietilenoglicóis/química , Lesão por Pressão/tratamento farmacológico , Espectroscopia de Luz Próxima ao Infravermelho
9.
Int J Nanomedicine ; 14: 4541-4558, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31417257

RESUMO

Background: Tumor metastasis is responsible for most cancer death worldwide, which lacks curative treatment. Purpose: The objective of this study was to eliminate tumor and control the development of tumor metastasis. Methods: Herein, we demonstrated a smart nano-enabled platform, in which 2-[2-[2-chloro-3-[(1,3-dihydro-3,3-dimethyl-1-propyl-2h-indol-2-ylidene)ethylidene]-1-cyclohexen-1-yl]ethenyl]-3,3-dimethyl-1-propylindolium iodide (IR780) and tirapazamine (TPZ) were co-loaded in poly(ε-caprolactone)-poly(ethylene glycol) (PEG-PCL) to form versatile nanoparticles (PEG-PCL-IR780-TPZ NPs). Results: The intelligence of the system was reflected in the triggered and controlled engineering. Specially, PEG-PCL not only prolonged the circulation time of IR780 and TPZ but also promoted tumor accumulation of nanodrugs through enhanced permeability and retention (EPR) effect. Moreover, reactive oxygen species (ROS) generated by IR780 armed by an 808 nm laser irradiation evoked a cargo release. Meanwhile, IR780, as a mitochondria-targeting phototherapy agent exacerbated tumor hypoxic microenvironment and activated TPZ for accomplishing hypoxia-activated chemotherapy. Most significantly, IR780 was capable of triggering immunogenic cell death (ICD) during the synergic treatment. ICD biomarkers as a "danger signal" accelerated dendritic cells (DCs) maturation, and subsequently activated toxic T lymphocytes. Conclusion: Eventually, antitumor immune responses stimulated by combinational phototherapy and hypoxia-activated chemotherapy revolutionized the current landscape of cancer treatment, strikingly inhibiting tumor metastasis and providing a promising prospect in the clinical application.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Fototerapia , Animais , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Imunoterapia , Indóis/uso terapêutico , Lipossomos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/ultraestrutura , Fotoquimioterapia , Fototerapia/métodos , Polietilenoglicóis/química , Espécies Reativas de Oxigênio/metabolismo , Temperatura Ambiente , Tirapazamina/farmacologia , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
10.
AAPS PharmSciTech ; 20(7): 274, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31385095

RESUMO

With the increase concern of solubilization for insoluble drug, ternary solid dispersion (SD) formulations developed more rapidly than binary systems. However, rational formulation design of ternary systems and their dissolution molecular mechanism were still under development. Current research aimed to develop the effective ternary formulations and investigate their molecular mechanism by integrated experimental and modeling techniques. Glipizide (GLI) was selected as the model drug and PEG was used as the solubilizing polymer, while surfactants (e.g., SDS or Tween80) were the third components. SD samples were prepared at different weight ratio by melting method. In the dissolution tests, the solubilization effect of ternary system with very small amount of surfactant (drug/PEG/surfactant 1/1/0.02) was similar with that of binary systems with high polymer ratios (drug/PEG 1/3 and 1/9). The molecular structure of ternary systems was characterized by differential scanning calorimetry (DSC), infrared absorption spectroscopy (IR), X-ray diffraction (XRD), and scanning electron microscope (SEM). Moreover, molecular dynamic (MD) simulations mimicked the preparation process of SDs, and molecular motion in solvent revealed the dissolution mechanism of SD. As the Gordon-Taylor equation described, the experimental and calculated values of Tg were compared for ternary and binary systems, which confirmed good miscibility of GLI with other components. In summary, ternary SD systems could significantly decrease the usage of polymers than binary system. Molecular mechanism of dissolution for both binary and ternary solid dispersions was revealed by combined experiments and molecular modeling techniques. Our research provides a novel pathway for the further research of ternary solid dispersion formulations.


Assuntos
Glipizida/química , Modelos Moleculares , Polietilenoglicóis/química , Polissorbatos/química , Varredura Diferencial de Calorimetria/métodos , Glipizida/análise , Hipoglicemiantes/análise , Hipoglicemiantes/química , Polietilenoglicóis/análise , Polímeros/análise , Polímeros/química , Polissorbatos/análise , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Tensoativos/análise , Tensoativos/química , Difração de Raios X/métodos
11.
Int J Nanomedicine ; 14: 5109-5123, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371950

RESUMO

Background: Renal cell carcinoma (RCC) is notorious for its resistance towards chemotherapy and radiation therapy in general. Combination therapy is often helpful in alleviating the resistance mechanisms by targeting multiple signaling pathways but is usually more toxic than monotherapy. Co-encapsulation of multiple therapeutic agents in a tumor-targeted drug delivery platform is a promising strategy to mitigate these limitations. Methods: A tumor-targeted liposomal formulation was prepared using phospholipids, cholesterol, DSPE-(PEG)2000-OMe and a proprietary tumor-targeting-peptide (TTP)-conjugated lipopeptide. An efficient method was optimized to encapsulate everolimus and vinorelbine in this liposomal formulation. Single drug-loaded liposomes were also prepared for comparison. Finally, the drug-loaded liposomes were tested in vitro and in vivo in two different RCC cell lines. Results: The tumor-targeted liposomal formulation demonstrated excellent tumor-specific uptake. The dual drug-loaded liposomes exhibited significantly higher growth inhibition in vitro compared to the single drug-loaded liposomes in two different RCC cell lines. Similarly, the dual drug-loaded liposomes demonstrated significantly higher suppression of tumor growth compared to the single drug-loaded liposomes in two different subcutaneous RCC xenografts. In addition, the dual drug-loaded liposomes instigated significant reduction in lung metastasis in those experiments. Conclusion: Taken together, this study demonstrates that co-delivery of everolimus and vinorelbine with a tumor-targeted liposomal formulation is an effective approach to achieve improved therapeutic outcome in RCC.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Composição de Medicamentos , Sistemas de Liberação de Medicamentos/métodos , Everolimo/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Vinorelbina/administração & dosagem , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Antígeno Ki-67/metabolismo , Lipossomos , Neoplasias Pulmonares/secundário , Camundongos SCID , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Int J Nanomedicine ; 14: 4975-4989, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371942

RESUMO

The porous surface of a polyetheretherketone (PK)-nanoporous lithium-doped magnesium silicate (NLS) blend (PKNLS) was fabricated on a PK surface by layer-by-layer pressuring, sintering, and salt-leaching. As controls, porous surfaces of a PK/lithium-doped magnesium silicate blend (PKLS) and PK were fabricated using the same method. The results revealed that porosity, water absorption, and protein absorption of the porous surface of PKNLS containing macropores and nanopores were obviously enhanced compared to PKLS and PK containing macropores without nanopores. In addition, PKNLS, with both macroporostiy and nanoporosity, displayed the highest ability of apatite mineralization in simulated body liquid, indicating excellent bioactivity. In vitro responses (including adhesion, proliferation, and differentiation) of MC3T3E1 cells to PKNLS were significantly enhanced compared to PKLS and PK. In vivo implantation results showed that new bone grew into the macroporous surface of PKNLS, and the amount of new bone for PKNLS was the highest. In short, PKNLS integration with PK significantly promoted cells/bone-tissue responses and exhibited excellent osteogenesis in vivo, which might have great potential for bone repair.


Assuntos
Osso e Ossos/fisiologia , Cetonas/farmacologia , Lítio/farmacologia , Silicatos de Magnésio/farmacologia , Nanoporos , Osteoblastos/citologia , Polietilenoglicóis/farmacologia , Adsorção , Fosfatase Alcalina/metabolismo , Animais , Apatitas/química , Osso e Ossos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Imagem Tridimensional , Masculino , Camundongos , Nanoporos/ultraestrutura , Osteoblastos/efeitos dos fármacos , Osteoblastos/ultraestrutura , Osteogênese/efeitos dos fármacos , Porosidade , Coelhos , Água/química , Difração de Raios X
13.
Int J Nanomedicine ; 14: 5527-5540, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31413561

RESUMO

Background: Nonspecific tumor targeting, potential relapse and metastasis of tumor after treatment are the main barriers in clinical photodynamic therapy (PDT) for cancer, hence, inhibiting relapse and metastasis of tumor is significant issues in clinic. Purpose: In this work, chidamide as a histone deacetylases inhibitor (HADCi) was bound onto a pH-responsive block polymer folate polyethylene glycol-b-poly(aspartic acid) (PEG-b-PAsp) grafted folate (FA-PEG-b-PAsp) to obtain the block polymer folate polyethylene glycol-b-poly(asparaginyl-chidamide) (FA-PEG-b-PAsp-chidamide, FPPC) as multimodal tumor-targeting drug-delivery carrier to inhibiting tumor cell proliferation and tumor metastasis in mice. Methods: Model photosensitizer pyropheophorbide-a (Pha) was encapsulated by FPPC in PBS to form the polymer micelles Pha@FPPC [folate polyethylene glycol-b-poly(asparaginyl-chidamide) micelles encapsulating Pha]. Pha@FPPC was characterized by transmission electron microscope and dynamic light scattering; also, antitumor activity in vivo and in vitro were investigated by determination of cellular ROS level, detection of cell apoptosis and cell cycle arrest, PDT antitumor activity in vivo and histological analysis. Results: With favorable and stable sphere morphology under transmission electron microscope (TEM) (~93.0 nm), Pha@FPPC greatly enhanced the cellular uptake due to its folate-mediated effective endocytosis by mouse melanoma B16-F10 cells and the yield of ROS in tumor cells induced by PDT, and mainly caused necrocytosis and blocked cell growth cycle not only in G2 phase but also in G1/G0 phase after PDT. Pha@FPPC exhibited lower dark cytotoxicity in vitro and a better therapeutic index because of its higher dark cytotoxicity/photocytotoxicity ratio. Moreover, Pha@FPPC not only significantly inhibited the growth of implanted tumor and prolonged the survival time of melanoma-bearing mice due to both its folate-mediated tumor-targeting and selectively accumulation at tumor site by EPR (enhanced permeability and retention)effect as micelle nanoparticles but also remarkably prevented pulmonary metastasis of mice melanoma after PDT compared to free Pha, demonstrating its dual antitumor characteristics of PDT and HDACi. Conclusion: As a folate-mediated and acid-activated chidamide-grafted drug-delivery carrier, FPPC may have great potential to inhibit tumor metastasis in clinical photodynamic treatment for cancer because of its effective and multimodal tumor-targeting performance as photosensitizer vehicle.


Assuntos
Aminopiridinas/química , Benzamidas/química , Ácido Fólico/uso terapêutico , Micelas , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Clorofila/análogos & derivados , Clorofila/farmacologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Ácido Fólico/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Nanopartículas/química , Nanopartículas/ultraestrutura , Fármacos Fotossensibilizantes/farmacologia , Polietilenoglicóis/química , Espécies Reativas de Oxigênio/metabolismo
14.
Int J Nanomedicine ; 14: 5611-5622, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31413566

RESUMO

Background: Multimodal imaging probes have become a powerful tool for improving detection sensitivity and accuracy, which are important in disease diagnosis and treatment. Methods: In this study, novel bifunctional magnetic resonance imaging (MRI)/fluorescence probes were prepared by loading gadodiamide into fluorescent silica nanoparticles (NPs) (Gd@Cy5.5@SiO2-PEG-Ab NPs) for targeting of prostate cancer (PCa). The physicochemical characteristics, biosafety and PCa cell targeting ability of the Gd@Cy5.5@SiO2-PEG-Ab NPs were studied in vitro and in vivo. Results: The Gd@Cy5.5@SiO2-PEG-Ab NPs had a spherical morphology with a relatively uniform size distribution and demonstrated high efficiency for Gd loading. In vitro and in vivo cell-targeting experiments demonstrated a high potential for the synthesized NPs to target prostate-specific membrane antigen (PSMA) receptor-positive PCa cells, enabling MRI and fluorescence imaging. In vitro cytotoxicity assays and in vivo hematological and pathological assays showed that the prepared NPs exhibited good biological safety. Conclusion: Our study demonstrates that the synthesized Gd@Cy5.5@SiO2-PEG-Ab NPs have great potential as MRI/fluorescence contrast agents for specific identification of PSMA receptor-positive PCa cells.


Assuntos
Gadolínio DTPA/química , Imagem por Ressonância Magnética , Nanopartículas/química , Polietilenoglicóis/química , Neoplasias da Próstata/diagnóstico por imagem , Dióxido de Silício/química , Animais , Anticorpos/metabolismo , Linhagem Celular Tumoral , Meios de Contraste , Endocitose , Fluorescência , Glutamato Carboxipeptidase II/metabolismo , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/toxicidade , Nanopartículas/ultraestrutura , Especificidade de Órgãos , Polietilenoglicóis/síntese química , Padrões de Referência
15.
Int J Nanomedicine ; 14: 5713-5728, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31413571

RESUMO

Purpose: The levels of reactive oxygen species (ROS) in tumor cells are much higher than that in normal cells, and rise rapidly under the influence of exogenous or endogenous inducing factors, eventually leading to the apoptosis of tumor cells. Therefore, this study prepared a dual pH/reducing-responsive poly (N-isopropylacrylamide-co-Cinnamaldehyde-co-D-α-tocopheryl polyethylene glycol 1000 succinate, PssNCT) nanogels, which employed two exogenous ROS inducers, cinnamaldehyde (CA) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), to selectively induce apoptosis by regulating ROS levels in tumor cells. Methods: The PssNCT nanogels were prepared by the free radical precipitation polymerization under the crosslink between pH-sensitive hydrazone and reducing-sensitive disulfide bonds, followed by the physicochemical and morphological characteristics investigations. Plasma stability, dual pH/reducing responsive degradation and in vitro release were also assessed. In cell experiments, cytotoxicity in different cells were first detected. The intracellular ROS levels and mitochondrial functions of tumor cells were then evaluated. Moreover, the apoptosis and western-blot assays were employed to verify the association between ROS levels elevation and apoptosis in tumor cells. Results: The nanogels exhibited a round-like hollow structure with the diameter smaller than 200nm. The nanogels were stable in plasma, while showed rapid degradation in acidic and reducing environments, thus achieving significant release of CA and TPGS in these media. Furthermore, the sufficient amplification of ROS signals was induced by the synergistically function of CA and TPGS on mitochondria, which resulted in the opening of the mitochondrial apoptotic pathway and enhanced cytotoxicity on MCF-7 cells. However, nanogels barely affected L929 cells owing to their lower intracellular ROS basal levels. Conclusion: The specific ROS regulation method achieved by these nanogels could be explored to selectively kill tumor cells according to the difference of ROS signals in different kinds of cells.


Assuntos
Apoptose , Espaço Intracelular/química , Polietilenoglicóis/farmacologia , Polietilenoimina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Acroleína/análogos & derivados , Acroleína/farmacologia , Animais , Apoptose/efeitos dos fármacos , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Vitamina E/síntese química , Vitamina E/química
16.
Biomater Sci ; 7(9): 3729-3740, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31403142

RESUMO

Targeted delivery of immunosuppressants to allografts can increase the concentrations of drugs in pathological tissues, improve therapeutic effects and reduce unfavorable side effects. Therefore, we synthesized FK506-loaded microbubbles (FK506-MBs) for site-specific release of FK506 into transplanted hearts by the ultrasound-targeted microbubble destruction (UTMD) technique. The average particle size of FK506-MBs was 1.65 ± 0.32 µm and they had high drug loading and encapsulation efficiency. The in vivo drug concentration in transplanted hearts that were treated with FK506-MBs plus UTMD was about 1.64-fold higher than that in grafts that received free FK506 at the same dosage. The degree of graft rejection in the FK506-MB plus UTMD group was lower than those of other groups. Both infiltration of T cells and secretion of inflammatory cytokines were significantly reduced in the FK506-MB plus UTMD group. More importantly, the mean survival time of the grafts was significantly longer (16.00 ± 0.89 day) than those of the PBS group (6.66 ± 1.36 day) and the FK506 group (12.83 ± 1.17 day). In addition, we also found that the concentration of FK506 in whole blood was lower in the FK506-MB plus UTMD group than that in the FK506 group, which would be beneficial for reducing the side effects. Hence, our results showed that combining FK506-MBs with UTMD was an effective strategy to deliver FK506 to transplanted hearts, which can increase the local drug concentration and enhance its efficacy on rejection. Ultrasound-targeted drug release is safe and radiation-free, with great potential for clinical transformation, and could also be extended to the treatment of other graft rejection cases, such as liver transplantation, kidney transplantation and so on.


Assuntos
Portadores de Fármacos/química , Rejeição de Enxerto/tratamento farmacológico , Transplante de Coração , Imunossupressores/farmacocinética , Miocárdio/metabolismo , Tacrolimo/farmacocinética , Animais , Liberação Controlada de Fármacos , Estudos de Viabilidade , Imunossupressores/administração & dosagem , Masculino , Microbolhas , Fosfatidilcolinas/química , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Ratos , Tacrolimo/administração & dosagem , Ultrassonografia
17.
Lancet ; 394(10201): 840-848, 2019 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-31402112

RESUMO

BACKGROUND: Decreased surgical site infections (SSIs) and morbidity have been reported with mechanical and oral antibiotic bowel preparation (MOABP) compared with no bowel preparation (NBP) in colonic surgery. Several societies have recommended routine use of MOABP in patients undergoing colon resection on the basis of these data. Our aim was to investigate this recommendation in a prospective randomised context. METHODS: In this multicentre, parallel, single-blinded trial, patients undergoing colon resection were randomly assigned (1:1) to either MOABP or NBP in four hospitals in Finland, using a web-based randomisation technique. Randomly varying block sizes (four, six, and eight) were used for randomisation, and stratification was done according to centre. The recruiters, treating physicians, operating surgeons, data collectors, and analysts were masked to the allocated treatment. Key exclusion criteria were need for emergency surgery; bowel obstruction; colonoscopy planned during surgery; allergy to polyethylene glycol, neomycin, or metronidazole; and age younger than 18 years or older than 95 years. Study nurses opened numbered opaque envelopes containing the patient allocated group, and instructed the patients according to the allocation group to either prepare the bowel, or not prepare the bowel. Patients allocated to MOABP prepared their bowel by drinking 2 L of polyethylene glycol and 1 L of clear fluid before 6 pm on the day before surgery and took 2 g of neomycin orally at 7 pm and 2 g of metronidazole orally at 11 pm the day before surgery. The primary outcome was SSI within 30 days after surgery, analysed in the modified intention-to-treat population (all patients who were randomly allocated to and underwent elective colon resection with an anastomosis) along with safety analyses. The trial is registered with ClinicalTrials.gov, NCT02652637, and EudraCT, 2015-004559-38, and is closed to new participants. FINDINGS: Between March 17, 2016, and Aug 20, 2018, 738 patients were assessed for eligibility. Of the 417 patients who were randomised (209 to MOABP and 208 to NBP), 13 in the MOABP group and eight in the NBP were excluded before undergoing colonic resection; therefore, the modified intention-to-treat analysis included 396 patients (196 for MOABP and 200 for NBP). SSI was detected in 13 (7%) of 196 patients randomised to MOABP, and in 21 (11%) of 200 patients randomised to NBP (odds ratio 1·65, 95% CI 0·80-3·40; p=0·17). Anastomotic dehiscence was reported in 7 (4%) of 196 patients in the MOABP group and in 8 (4%) of 200 in the NBP group, and reoperations were necessary in 16 (8%) of 196 compared with 13 (7%) of 200 patients. Two patients died in the NBP group and none in the MOABP group within 30 days. INTERPRETATION: MOABP does not reduce SSIs or the overall morbidity of colon surgery compared with NBP. We therefore propose that the current recommendations of using MOABP for colectomies to reduce SSIs or morbidity should be reconsidered. FUNDING: Vatsatautien Tutkimussäätiö Foundation, Mary and Georg Ehrnrooth's Foundation, and Helsinki University Hospital research funds.


Assuntos
Antibacterianos/administração & dosagem , Cefuroxima/administração & dosagem , Colectomia/métodos , Metronidazol/administração & dosagem , Cuidados Pré-Operatórios/métodos , Infecção da Ferida Cirúrgica/prevenção & controle , Administração Intravenosa , Idoso , Catárticos/administração & dosagem , Procedimentos Cirúrgicos Eletivos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Estudos Prospectivos , Método Simples-Cego
18.
Rozhl Chir ; 98(7): 277-281, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31398987

RESUMO

INTRODUCTION: The aim of the study was to compare the efficacy and tolerability of polyethylene glycol/ascorbic acid (PEGA), sodium picosulfate/magnesium citrate (SPMC) and the oral sulfate formula (SIR) in a single- or split-dose regimen for bowel preparation prior to colonoscopy. METHODS: Randomised, multicentre, open-label study. The subjects received either PEGA, SPMC or SIR in the single- or split-dose regimen before the colonoscopy. Quality and tolerability of the preparation and complaints during preparation were recorded using a 5 point scale. RESULTS: 558 subject were analysed. Preparation quality was comparable in the single-dose regimen. The rate of satisfactory bowel cleansing (Aronchick score 1+2) was higher for split-dose SIR and PEGA compared to SPMC (95.6%, 86.2% vs. 72.5%, p.


Assuntos
Ácido Ascórbico , Catárticos , Colonoscopia , Polietilenoglicóis , Ácido Ascórbico/uso terapêutico , Catárticos/uso terapêutico , Humanos , Polietilenoglicóis/uso terapêutico , Estudos Prospectivos
19.
Anticancer Res ; 39(8): 4379-4383, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366533

RESUMO

BACKGROUND/AIM: Dose-dense doxorubicin and cyclophosphamide (ddAC) followed by dose-dense paclitaxel (ddP) (ddAC-P) has improved disease-free survival of patients with breast cancer. The aim of this study was to evaluate the safety and relative dose intensity (RDI) of ddAC-P administered together with pegfilgrastim. PATIENTS AND METHODS: Between May 2015 and Aug 2017, 44 patients were retrospectively reviewed; they were administered 4 cycles of ddAC, followed by 4 cycles of ddP. Pegfilgrastim (3.6 mg) was administered in every cycle. RESULTS: The mean RDIs for ddAC-P, ddAC, and ddP were 95.0%, 94.5%, and 93.3%, respectively. The prevalence of high RDIs (≥85%) for ddAC-P, ddAC, and ddP was 90.9%, 84.1%, and 88.6%, respectively. Seven of the 10 patients with low RDIs experienced grade 1 or 2 fever. CONCLUSION: DdAC-P administered together with pegfilgrastim (3.6 mg) appears to be feasible and maintains RDI in most of Japanese patients with breast cancer. Rapid evaluation and proper management of fever may prevent low RDI.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Paclitaxel/administração & dosagem , Adulto , Idoso , Neoplasias da Mama/patologia , Ciclofosfamida/efeitos adversos , Relação Dose-Resposta a Droga , Doxorrubicina/efeitos adversos , Feminino , Filgrastim/administração & dosagem , Humanos , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Polietilenoglicóis/administração & dosagem
20.
J Biomed Nanotechnol ; 15(10): 2025-2044, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31462369

RESUMO

In this study we employed self-designed PDLLA-PEG-PDLLA (PLEL) thermosensitive hydrogel to blend with norcantharidin (NCTD), a hydrophilic chemotherapeutic drug possessing curative effect on primary hepatocellular carcinoma (HCC) and adverse effects, then utilized the composite in HCC interstitial chemotherapy. PLEL copolymer was synthesized by ring-opening polymerization, NCTD-loaded PLEL hydrogel was prepared in a simple and reasonable way. The addition of NCTD had no significant effect on the temperature-dependent rheological properties of PLEL hydrogel. The pH values of NCTD-loaded gel solutions (13 wt%) and free NCTD solutions with three drug concentrations of 0.4 mg/mL, 0.8 mg/mL and 1.2 mg/mL under different storage conditions met the pH requirement of small-volume injection. There was no significant difference among the drug release behaviors of NCTD-loaded gels with drug concentrations of 0.4 mg/mL, 0.8 mg/mL and 1.2 mg/mL, they fitted first-order dynamics, exhibited significantly slower drug release than free drug solutions and the release was mainly based on drug diffusion. Drug-loaded gel solution (13 wt%) could evenly distribute throughout tumor tissue before converting into gel after being intratumorally injected and was able to significantly prolong retention time of the drug in tumor compared to free drug solution. The sustained-release performance of NCTD-loaded gel (13 wt%) was confirmed from the perspective of pharmacodynamics in vitro. The in vivo evaluation demonstrated that intratumoral injection of NCTD-loaded PLEL gel (13 wt%) was capable of improving curative effect of the drug and reducing its toxicity.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Compostos Bicíclicos Heterocíclicos com Pontes , Carcinoma Hepatocelular/terapia , Humanos , Hidrogéis , Injeções Intralesionais , Neoplasias Hepáticas/terapia , Poliésteres , Polietilenoglicóis
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