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1.
J Pharm Health Care Sci ; 7(1): 23, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34193299

RESUMO

BACKGROUND: A multicenter investigation of neonate exposure to potentially harmful excipients (PHEs) in neonatal intensive care units (NICUs) in Japan has not been conducted. METHODS: A multicenter nationwide observational study was conducted. Neonate patient demographic data and information on all medicines prescribed and administered during hospitalization on 1 day between November 2019 and March 2021 were extracted from the medical records. Nine PHEs, paraben, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol, benzalkonium chloride, and aspartame, were selected. PHEs were identified from the package insert and the Interview Form. The quantitative daily exposure was calculated if quantitative data were available for each product containing the PHE. RESULTS: Prescription data was collected from 22 NICUs in Japan. In total, 343 neonates received 2360 prescriptions for 426 products containing 228 active pharmaceutical ingredients. PHEs were found in 52 (12.2%) products in 646 (27.4%) prescriptions for 282 (82.2%) neonates. Benzyl alcohol, sodium benzoates, and parabens were the most common PHEs in parenteral, enteral, and topical formulations, respectively. Quantitative analysis showed that 10 (10%), 38 (42.2%), 37 (94.9%), and 9 (39.1%) neonates received doses exceeding the acceptable daily intake of benzyl alcohol, polysorbate 80, propylene glycol, and sorbitol, respectively. However, due to the lack of quantitative information for all enteral and topical products, accurate daily PHE exposure could not be quantified. CONCLUSIONS: Neonates admitted to NICUs in Japan were exposed to PHEs, and several of the most commonly prescribed medicines in daily clinical practice in NICUs contained PHEs. Neonate PHE exposure could be reduced by replacing these medicines with available PHE-free alternatives.

2.
Biochim Biophys Acta ; 1828(9): 2134-42, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23711826

RESUMO

Arginine-rich cell-penetrating peptides, including octaarginine (R8) and HIV-1 TAT peptides, have the ability to translocate through cell membranes and transport exogenous bioactive molecules into cells. Hydrophobic counteranions such as pyrenebutyrate (PyB) have been reported to markedly promote the membrane translocation of these peptides. In this study, using model membranes having liquid-ordered (Lo) and liquid-disordered (Ld) phases, we explored the effects of PyB on the promotion of R8 translocation. Confocal microscopic observations of giant unilamellar vesicles (GUVs) showed that PyB significantly accelerated the accumulation of R8 on membranes containing negatively charged lipids, leading to the internalization of R8 without collapse of the GUV structures. PyB displayed an alternative activity, increasing the fluidity of the negatively charged membranes, which diminished the distinct Lo/Ld phase separation on GUVs. This was supported by the decrease in fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPH). Additionally, PyB induced membrane curvature, which has been suggested as a possible mechanism of membrane translocation for R8. Taken together, our results indicate that PyB may have multiple effects that promote R8 translocation through cell membranes.


Assuntos
Peptídeos Penetradores de Células/química , Oligopeptídeos/química , Fosfatidilcolinas/química , Pirenos/química , Lipossomas Unilamelares/química , Animais , Difenilexatrieno , Polarização de Fluorescência , Corantes Fluorescentes , Interações Hidrofóbicas e Hidrofílicas , Fluidez de Membrana , Microscopia Confocal , Transporte Proteico , Eletricidade Estática , Suínos
4.
Mol Pharm ; 9(5): 1222-30, 2012 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-22486588

RESUMO

Arginine-rich cell-penetrating peptides (CPPs), including oligoarginine peptides, have been widely used as a tool for intracellular delivery of various molecules with low membrane permeability. We previously reported the enhanced cytosolic entry of arginine-rich CPPs by the attachment of a short peptide segment, the penetration accelerating sequence (Pas). In this study, the importance of hydrophobic sequences, especially phenylalanine residues, in the Pas segment was demonstrated for this enhanced translocation through cell membranes. The advantage of using Pas for intracellular delivery was particularly marked for delivering cargoes with a relatively small molecular weight, such as bioactive peptides. In addition, the results of this study indicate the important roles that the total hydrophobicity of the PasR8 conjugates play in cytosolic translocation and the eventual bioactivity thus attained.


Assuntos
Oligopeptídeos/química , Fragmentos de Peptídeos/química , Arginina/química , Linhagem Celular Tumoral , Sobrevivência Celular , Peptídeos Penetradores de Células/administração & dosagem , Peptídeos Penetradores de Células/química , Inibidor de Quinase Dependente de Ciclina p27/química , Inibidor de Quinase Dependente de Ciclina p27/farmacologia , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas
5.
Mol Ther ; 20(5): 984-93, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22334015

RESUMO

Endocytosis has been implicated in the cellular uptake of arginine-rich, cell-penetrating peptides (CPPs). However, accumulating evidence suggests that certain conditions allow the direct, non-endocytic penetration of arginine-rich peptides through the plasma membrane. We previously showed that Alexa Fluor 488-labeled dodeca-arginine (R12-Alexa488) directly enters cells at specific sites on the plasma membrane and subsequently diffuses throughout cells. In this study, we found that the peptide influx was accompanied by the formation of unique, "particle-like" multivesicular structures on the plasma membrane, together with topical inversion of the plasma membrane. Importantly, the conjugation of dodeca-arginine (R12) to Alexa Fluor 488 or a peptide tag derived from hemagglutinin (HAtag) significantly accelerated particle formation, suggesting that the chemical properties of the attached molecules (cargo molecules) may contribute to translocation of the R12 peptide. Coincubation with R12-HAtag allowed the membrane-impermeable R4-Alexa488 to permeate cells. These results suggest that R12 peptides attached to hydrophobic cargo molecules stimulate dynamic morphological alterations in the plasma membrane, and that these structural changes allow the peptides to permeate the plasma membrane. These findings may provide a novel mode of cell permeabilization by arginine-rich peptides as a means of drug delivery.


Assuntos
Arginina/química , Membrana Celular/ultraestrutura , Peptídeos Penetradores de Células/síntese química , Oligopeptídeos/síntese química , Arginina/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Permeabilidade da Membrana Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/metabolismo , Peptídeos Penetradores de Células/farmacologia , Difusão , Corantes Fluorescentes , Células HeLa , Hemaglutininas/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Maleimidas , Microscopia Confocal , Microscopia Eletrônica , Oligopeptídeos/metabolismo , Oligopeptídeos/farmacologia , Transporte Proteico
6.
J Control Release ; 149(1): 29-35, 2011 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-20144669

RESUMO

Cell-penetrating peptides (CPPs) have the ability to efficiently internalize into cells and thus have been used as a vector for the intracellular delivery of various bioactive molecules. The introduction of a hydrophobic core to CPPs may increase their interaction with membranes and facilitate their translocation into cells. While the usefulness of acylated oligoarginine to gene and siRNA delivery has been largely reported, little information is available about their use for the delivery of small molecular-weight compounds, peptides and proteins. In this report, we employed octaarginine (R8) as a typical arginine-rich CPP and evaluated the effect of acylation using butanoic, hexanoic and decanoic acids on its capacity as a delivery vector. Hexanoyl octaarginine (C6R8-Alexa) showed the highest efficiency of cellular uptake of the studied variants, ten times higher than R8-Alexa. C6R8-Alexa also produced a diffuse cytosolic distribution. On the other hand, a less significant effect of C6R8 over R8 was observed for the delivery of proteins, suggesting that the advantage of C6R8 may be obtained during the delivery of relatively small molecular-weight compounds. Although less prominent than at 37°C, a significant cytosolic distribution of C6R8-Alexa was observed at 4°C, and this suggested the potential ability of the C6R8 peptide for direct penetration through plasma membranes.


Assuntos
Peptídeos Penetradores de Células/química , Portadores de Fármacos/química , Endocitose/efeitos dos fármacos , Oligopeptídeos/química , Preparações Farmacêuticas/administração & dosagem , Bibliotecas de Moléculas Pequenas/administração & dosagem , Acilação , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/farmacologia , Portadores de Fármacos/farmacologia , Ácidos Graxos/química , Células HeLa , Humanos , Oligopeptídeos/farmacologia , Preparações Farmacêuticas/química , Bibliotecas de Moléculas Pequenas/química
7.
Biochim Biophys Acta ; 1798(12): 2249-57, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20170629

RESUMO

Expressed protein ligation (EPL) is a useful method for the native chemical ligation of proteins with other proteins or peptides. This study assessed the practicability of EPL in the preparation of fusion proteins of enhanced green fluorescent protein (EGFP) with chemically synthesized cell-penetrating peptides (CPPs) for intracellular delivery. Using intein-mediated purification with an affinity chitin-binding tag (IMPACT) system, the thioester of EGFP (EGFP-SR) was prepared. Optimization of the ligation of EGFP-SR with arginine 12-mer (R12) produced the fusion protein in high yield. The EPL procedure also allows the preparation of EGFP-R12 containing a low level of endotoxin (ET), via the satisfactory ET removal of EGFP-SR prior to ligation with the R12 peptide. Fusion proteins of EGFP with R12 and the d-isomer of R12 prepared by EPL showed similar levels of cellular uptake compared to the fusion protein directly expressed in Escherichiacoli.


Assuntos
Endotoxinas , Proteínas Recombinantes de Fusão , Animais , Peptídeos Penetradores de Células/biossíntese , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/genética , Peptídeos Penetradores de Células/isolamento & purificação , Peptídeos Penetradores de Células/farmacologia , Cromatografia de Afinidade/métodos , Escherichia coli , Expressão Gênica , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/farmacologia , Células HeLa , Humanos , Inteínas , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/farmacologia
8.
Biol Pharm Bull ; 31(5): 990-3, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18451532

RESUMO

Camptothecin (CPT) has anticancer activity. While only the lactone form of CPT is biologically active, this form exhibits poor aqueous solubility. Pharmaceutical formulation of CPT incorporated in liposomes is of significant importance to develop the therapeutic utilization of CPT. The aim of this study was to increase incorporation efficiency and stability of CPT in liposomes composed of hydrogenated soybean phosphatidylcholine, cholesterol, and oleic acid (7 : 3 : 1, molar ratio), by incorporating three kinds of artificial lipids (DBs) (DB-liposome); 4-n-(M12B), 3,5-bis(B12B) and 3,4,5-tris(dodecyloxy)benzoic acid (T12B). The interaction of CPT with DB in the state of liposomes, was examined. In DB-liposomes presenting mean diameters of 150 nm, incorporation efficiency of CPT up to 55% and final drug to lipid molar ratio up to 0.07 were obtained when the liposomes were prepared at a feeding ratio of 1/30 (w/w) CPT/total lipid. However, in the optimal formulations, incorporated DB mol% was different; T12B and D12B were incorporated about one third and half mol% of M12B, respectively. Moreover, we demonstrated that T12B stabilized CPT in liposomes significantly compared with other DBs as measured by CPT release, and by steady state fluorescence polarization degree of CPT using intrinsic fluorescence of CPT. These findings suggested that in addition of contribution of phenyl group of DB, dodecyloxy group may interact strongly with lactone ring of CPT. The capacity to contain CPT interacted with DBs may be limited in liposomes. T12B may be incorporated in the interior of the bilayers, resulting in increase of incorporation stability of CPT. This finding demonstrates a potential application of the novel liposome formulation of CPT in drug delivery.


Assuntos
Antineoplásicos Fitogênicos/química , Camptotecina/química , Lipídeos/química , Lipossomos/química , Algoritmos , Anisotropia , Portadores de Fármacos , Excipientes , Imunoensaio de Fluorescência por Polarização
9.
J Clin Gastroenterol ; 38(9): 823-6, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15365414

RESUMO

Primary hepatic mucosa-associated lymphoid tissue (MALT) lymphoma is an extremely rare disease. A 65-year-old female patient with chronic hepatitis B presented with multiple solid masses in segment (S) 4, S5, and S6 of the liver. The nodule in S5 was diagnosed preoperatively as hepatocellular carcinoma by computed tomography, magnetic resonance imaging, and angiography. The nodule in S4 was initially interpreted as lymphoid follicles by needle biopsy. Segmentectomy of S5 and partial resection of S6 were performed. Microscopic examination of the S5 nodule revealed moderately differentiated hepatocellular carcinoma. The nodule from S6 showed nodular proliferation of atypical intermediate to medium-sized lymphoid cells in the portal area and lymph epithelial lesions of bile ducts. The atypical lymphoid cells were positive for LCA, L-26 and bcl-2 and negative for UCHL-1. These features were consistent with the diagnosis of MALT lymphoma. This is the first case report of synchronous hepatic MALT lymphoma and hepatocellular carcinoma associated with chronic hepatitis B.


Assuntos
Carcinoma Hepatocelular/complicações , Hepatite B Crônica/complicações , Neoplasias Hepáticas/complicações , Linfoma de Zona Marginal Tipo Células B/complicações , Idoso , Feminino , Humanos , Fígado/patologia , Fígado/cirurgia , Imageamento por Ressonância Magnética , Mastectomia Segmentar , Tomografia Computadorizada por Raios X , Resultado do Tratamento
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