RESUMEN
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.
Asunto(s)
Antibacterianos/farmacocinética , Doxiciclina/farmacocinética , Nanofibras/química , Polietilenglicoles/farmacocinética , Polimetil Metacrilato/farmacocinética , Análisis de Varianza , Antibacterianos/química , Cromatografía Líquida de Alta Presión/métodos , Doxiciclina/química , Inmersión , Microscopía Electrónica de Rastreo , Peso Molecular , Polietilenglicoles/química , Polimetil Metacrilato/química , Reproducibilidad de los Resultados , Streptococcus mutans/efectos de los fármacos , Factores de Tiempo , Agua/químicaRESUMEN
Polymersomes are versatile nanostructures for protein delivery with hydrophilic core suitable for large biomolecule encapsulation and protective stable corona. Nonetheless, pharmaceutical products based on polymersomes are not available in the market, yet. Here, using commercially available copolymers, we investigated the encapsulation of the active pharmaceutical ingredient (API) L-asparaginase, an enzyme used to treat acute lymphoblastic leukemia, in polymersomes through a quality-by-design (QbD) approach. This allows for streamlining of processes required for improved bioavailability and pharmaceutical activity. Polymersomes were prepared by bottom-up (temperature switch) and top-down (film hydration) methods employing the diblock copolymers poly(ethylene oxide)-poly(lactic acid) (PEG45-PLA69, PEG114-PLA153, and PEG114-PLA180) and the triblock Pluronic® L-121 (poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), PEG5-PPO68-PEG5). Quality Target Product Profile (QTPP), Critical Quality Attributes (CQAs), Critical Process Parameters (CPPs), and the risk assessment were discussed for the early phase of polymersome development. An Ishikawa diagram was elaborated focusing on analytical methods, raw materials, and processes for polymersome preparation and L-asparaginase encapsulation. PEG-PLA resulted in diluted polymersomes systems. Nonetheless, a much higher yield of Pluronic® L-121 polymersomes of 200 nm were produced by temperature switch, reaching 5% encapsulation efficiency. Based on these results, a risk estimation matrix was created for an initial risk assessment, which can help in the future development of other polymersome systems with biological APIs nanoencapsulated.
Asunto(s)
Antineoplásicos/síntesis química , Asparaginasa/síntesis química , Nanoestructuras/química , Poloxámero/síntesis química , Polietilenglicoles/síntesis química , Antineoplásicos/farmacocinética , Asparaginasa/farmacocinética , Interacciones Hidrofóbicas e Hidrofílicas , Poloxámero/farmacocinética , Polietilenglicoles/farmacocinética , Glicoles de Propileno/síntesis química , Glicoles de Propileno/farmacocinéticaRESUMEN
In this work, several normal, oil-in-water (o/w) microemulsions (MEs) were prepared using peppermint essential oil, jojoba oil, trans-anethole, and vitamin E as oil phases to test their capacity to load paclitaxel (PTX). Initially, pseudo-ternary partial phase diagrams were constructed in order to find the normal microemulsion region using d-α-tocopherol polyethylene glycol 1000 succinate (TPGS-1000) as surfactant and isobutanol (iso-BuOH) as co-surfactant. Selected ME formulations were loaded with PTX reaching concentrations of 0.6 mg mL-1 for the peppermint oil and trans-anethole MEs, while for the vitamin E and jojoba oil MEs, the maximum concentration was 0.3 mg mL-1. The PTX-loaded MEs were stable according to the results of heating-cooling cycles and mechanical force (centrifugation) test. Particularly, drug release profile for the PTX-loaded peppermint oil ME (MEPP) showed that â¼ 90% of drug was released in the first 48 h. Also, MEPP formulation showed 70% and 90% viability reduction on human cervical cancer (HeLa) cells after 24 and 48 h of exposure, respectively. In addition, HeLa cell apoptosis was confirmed by measuring caspase activity and DNA fragmentation. Results showed that the MEPP sample presented a major pro-apoptotic capability by comparing with the unloaded PTX ME sample.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Apoptosis/efectos de los fármacos , Citotoxinas/síntesis química , Nanosferas/química , Paclitaxel/síntesis química , Aceites de Plantas/síntesis química , Antineoplásicos Fitogénicos/farmacocinética , Apoptosis/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Citotoxinas/farmacocinética , Relación Dosis-Respuesta a Droga , Liberación de Fármacos , Células HeLa , Humanos , Mentha piperita , Paclitaxel/farmacocinética , Aceites de Plantas/farmacocinética , Polietilenglicoles/síntesis química , Polietilenglicoles/farmacocinética , Tensoactivos/síntesis química , Tensoactivos/farmacocinética , Vitamina E/síntesis química , Vitamina E/farmacocinéticaRESUMEN
Liposomes are lipid vesicles widely used as nanocarriers in targeted drug delivery systems for therapeutic and/or diagnostic purposes. A strategy to prolong the blood circulation time of the liposomes includes the addition of a hydrophilic polymer polyethylene glycol (PEG) moiety onto the surface of the vesicle. Several studies claim that liposome PEGylation by a single chain length or a combination of PEG with different chain lengths may alter the liposomes' pharmacokinetic properties. Therefore, the purpose of this study was to evaluate the influence of PEG on the biodistribution of pH-sensitive liposomes in a tumor-bearing animal model. Three liposomal formulations (PEGylated or not) were prepared and validated to have a similar mean diameter, monodisperse distribution, and neutral zeta potential. The pharmacokinetic properties of each liposome were evaluated in healthy animals, while the biodistribution and scintigraphic images were evaluated in tumor-bearing mice. High tumor-to-muscle ratios were not statistically different between the PEGylated and non-PEGylated liposomes. While PEGylation is a well-established strategy for increasing the blood circulation of nanostructures, in our study, the use of polymer coating did not result in a better in vivo profile. Further studies must be carried out to confirm the feasibility of the non-PEGylated pH-sensitive liposomes for tumor treatment.
Asunto(s)
Neoplasias de la Mama/fisiopatología , Polietilenglicoles/farmacocinética , Tecnecio/química , Animales , Tiempo de Circulación Sanguínea , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Concentración de Iones de Hidrógeno , Liposomas , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Polietilenglicoles/administración & dosificación , Polietilenglicoles/química , Distribución TisularRESUMEN
Abstract 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.
Asunto(s)
Polietilenglicoles/farmacocinética , Doxiciclina/farmacocinética , Polimetil Metacrilato/farmacocinética , Nanofibras/química , Antibacterianos/farmacocinética , Polietilenglicoles/química , Streptococcus mutans/efectos de los fármacos , Factores de Tiempo , Agua/química , Microscopía Electrónica de Rastreo , Reproducibilidad de los Resultados , Análisis de Varianza , Cromatografía Líquida de Alta Presión/métodos , Doxiciclina/química , Polimetil Metacrilato/química , Inmersión , Antibacterianos/química , Peso MolecularRESUMEN
Marketed formulations of erythropoietin (EPO) ior®EPOCIM, MIRCERA® and two newly developed pegylated-EPO analogues (PEG-EPO 32 and 40â¯kDa) formulations were intravenously administered to New Zealand rabbits. A semi-mechanistic Pharmacokinetic/Pharmacodynamic (PK/PD) model describing in a simultaneous and integrated form the time course of reticulocytes, red blood cells and hemoglobin was built to account for the time course of hematopoiesis stimulation after erythropoietin administration. Data analysis was performed based on the population approach with the software NONMEM version 7.3. Erythropoietin disposition of each of the administered formulations was best described with a two compartment model and linear elimination. Different formulations show different clearance and apparent volume of distribution of the central compartment but share estimates of inter-compartmental clearance and apparent peripheral volume of distribution. A semi-mechanistic model including cell proliferation, maturation, and homeostatic regulation provided a good description of the data regardless the type of erythropoietin formulation administered. The system-, and drug-related parameters showed consistency and differed across formulations, respectively. A single IV administration of PEG-EPO 32 and 40â¯kDa formulations in New Zealand rabbits achieves a median change of 27% and 22% on RET levels, and of 47% and 63% on RBC and HGB levels, respectively compared to MIRCERA®. The administration of new branched PEG-chains formulations improves PK and PD properties of EPO, in terms of increasing elimination half-lives and pharmacological activity on RET, RBC and HGB compared to commercially available formulations (ior®EPOCIM and MIRCERA®).
Asunto(s)
Eritropoyetina/farmacocinética , Hematínicos/farmacocinética , Hematopoyesis/efectos de los fármacos , Modelos Biológicos , Polietilenglicoles/farmacocinética , Animales , Disponibilidad Biológica , Composición de Medicamentos , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Eritropoyetina/administración & dosificación , Eritropoyetina/sangre , Eritropoyetina/química , Hematínicos/administración & dosificación , Hematínicos/sangre , Hematínicos/química , Hemoglobinas/metabolismo , Inyecciones Intravenosas , Modelos Lineales , Masculino , Polietilenglicoles/administración & dosificación , Polietilenglicoles/química , Conejos , Proteínas Recombinantes/farmacocinética , Reticulocitos/efectos de los fármacos , Reticulocitos/metabolismoRESUMEN
BACKGROUND: Several countries have used pegylation technology to improve the pharmacokinetic properties of essential drugs. Recently, a novel interferon alfa-2b protein conjugated to four-branched 12 kDa polyethylene glycol molecules was developed jointly between Cuba and Brazil. The aim of this study was to compare the pharmacokinetic properties of BIP48 (pegylated interferon alfa-2b from Bio-Manguinhos/Fiocruz, Brazil) to those of PEGASYS® (commercially available pegylated interferon alfa-2a from Roche Pharmaceutical). METHODS: This phase I, single-centre, randomized, double-blind crossover trial enrolled 31 healthy male volunteers aged 19 to 35 who were allocated to two stages, either side of a 5-week wash-out period, with each arm lasting 14 consecutive days after subcutaneous administration of 180 µg of one formulation or the other (study or comparator). The main outcome variable was serum pegylated interferon concentrations in 15 samples collected during the course of the study and tested using an enzyme immunoassay. RESULTS: There were no differences between formulations in terms of magnitude or absorption parameters. Analysis of time parameters revealed that BIP48 remained in the body significantly longer than PEGASYS® (Tmax: 73 vs. 54 h [p = 0.0010]; MRT: 133 vs. 115 h [p = 0.0324]; ke: 0.011 vs. 0.013 h(-1) [p = 0.0153]; t1/2: 192 vs. 108 h [p = 0.0218]). CONCLUSION: BIP48 showed the expected pharmacokinetic profile for a pegylated product with a branched molecular structure. Compared to PEGASYS®, the magnitude absorption was similar, but time parameters were consistent with slower elimination. Further studies should be conducted to evaluate the clinical implications of these findings. A phase II-III repeated-dose clinical trial is ongoing to study these findings in patients with chronic hepatitis C virus infection. TRIAL REGISTRATION: This study is registered on the ClinicalTrials.gov platform (accession number NCT01889849 ). This trial was retrospectively registered in June 2013.
Asunto(s)
Interferón alfa-2/farmacocinética , Interferón-alfa/farmacocinética , Polietilenglicoles/farmacocinética , Adulto , Estudios Cruzados , Método Doble Ciego , Voluntarios Sanos , Humanos , Interferón alfa-2/sangre , Interferón-alfa/sangre , Masculino , Proteínas Recombinantes/sangre , Proteínas Recombinantes/farmacocinética , Adulto JovenRESUMEN
BACKGROUND: Curcumin (CUR) has properties that can be useful for the treatment of Alzheimer's disease. Such properties are the inhibition of amyloid-ß-protein (Aß) aggregation, Aß-induced inflammation, and activities of ß-secretase and acetylcholinesterase. However, previous studies have revealed that CUR exhibited low bioavailability and difficulties in reaching the brain. OBJECTIVE: To overcome such drawbacks, this study aims at developing nasal lipid nanocarriers loaded with CUR to effectively target the brain. METHODS: The lipid nanocarriers (NE) were prepared using the hot solvent diffusion associated with the phase inversion temperature methods. Physico-chemical and morphological characterizations and in vitro drug release of the nanocarriers were carried out. The CUR permeation/retention was analyzed in Franz-type diffusion cell using porcine nasal mucosa. Confocal laser scan and histopathological studies were also performed. RESULTS: The results showed that the NE sizes ranged between 18ânm and 44ânm with negative zeta potential. The CUR content ranged from 0.24 to 1.50âmg/mL with an encapsulation efficiency of 99%. The profiles of CUR release indicated a biphasic kinetics. CUR-NE permeation across the porcine nasal mucosa was higher when compared to free CUR. These results have also been validated through an analysis on a confocal microscopy. In addition, no toxicity on the nasal mucosa has been observed in a histopathological analysis. CONCLUSION: These results suggest that it is possible to develop NEs with a high content of CUR and small particle size. Such an encapsulation increases the potential of CUR permeation across the porcine nasal mucosa.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Curcumina/química , Curcumina/farmacocinética , Lípidos/administración & dosificación , Mucosa Nasal/efectos de los fármacos , Mucosa Nasal/metabolismo , Animales , Compuestos de Bifenilo/metabolismo , Relación Dosis-Respuesta a Droga , Composición de Medicamentos , Microscopía Confocal , Microscopía Electrónica de Transmisión , Nanopartículas/administración & dosificación , Nanopartículas/química , Nanopartículas/ultraestructura , Mucosa Nasal/ultraestructura , Picratos/metabolismo , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacocinética , Porcinos , Factores de TiempoRESUMEN
The purpose of this study was to evaluate the effect of generation and surface PEGylation of degradable polyester-based dendrimers nanocarriers on their interactions with an in vitro model of the pulmonary epithelium as well as to assess the ability to formulate such carriers in propellant-based, portable oral-inhalation devices to determine their potential for local and systemic delivery of drugs to and through the lungs. Hydroxyl (-OH) terminated polyester dendrimers of generation 3 and 4 (G3, and G4) were synthesized using a divergent approach. G4 was surface-modified with PEG (1,000Da). All dendrimers and their building blocks were determined to be highly compatible with the model pulmonary epithelium, with toxicity profiles much more favorable than non-degradable polyamidoamine dendrimers (PAMAM). The transport of the species from the apical to basolateral side across polarized Calu-3 monolayers showed to be generation and surface-chemistry (PEGylation) dependent. The extent of the transport is modulated by their interaction with the polarized epithelium and their transient opening of the tight junctions. G3 was the one most efficiently internalized by the epithelium, and had a small impact on the integrity of the monolayer. On the other hand, the PEGylated G4 was the one least internalized by the polarized epithelium, and at the same time had a more pronounced transient impact on the cellular junctions, resulting in more efficient transport across the cell monolayer. PEGylation of the dendrimer surface played other roles as well. PEGylation modulated the degradation profile of the dendrimer, slowing the process in a step-wise fashion - first the PEG layer is shed and then the dendrimer starts degrading. PEGylation also helped increase the solvation of the nanocarriers by the hydrofluoroalkane propellant used in pressurized metered-dose inhalers, resulting in formulations with excellent dispersibility and aerosol quality (deep lung deposition of 88.5%), despite their very small geometric diameter. The combined in vitro and formulation performance results shown here demonstrated that degradable, modified polyester dendrimers may serve as a valuable platform that can be tailored to target the lung tissue for treating local diseases, or the circulation, using the lungs as pathway to the bloodstream.
Asunto(s)
Dendrímeros/farmacocinética , Composición de Medicamentos/métodos , Epitelio/metabolismo , Pulmón/metabolismo , Inhaladores de Dosis Medida , Poliésteres/farmacocinética , Proteínas de Artrópodos , Plásticos Biodegradables/química , Plásticos Biodegradables/farmacocinética , Plásticos Biodegradables/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Dendrímeros/química , Dendrímeros/farmacología , Humanos , Poliésteres/química , Poliésteres/farmacología , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Presión , Venenos de ArañaRESUMEN
The development of delivery systems efficiently uptaken by cells is of due importance since sites of drug action are generally localized in subcellular compartments. Herein, naked and core-shell polymeric nanoparticles (NPs) have been produced from poly(lactic-co-glycolic acid)-PLGA, poly(ethylene oxide)-b-poly(ε-caprolactone)-PEO-b-PCL, and poly(ethylene oxide)-b-poly(lactic acid)-PEO-b-PLA. The nanostructures are characterized and the cellular uptake behavior is evaluated. The data evidence that cellular uptake is enhanced as the length of the hydrophilic PEO-stabilizing shell reduces and that high negative surface charge restricts cellular uptake. Furthermore, NPs of higher degree of hydrophobicity (PEO-b-PCL) are more efficiently internalized as compared to PEO-b-PLA NPs. Accordingly, taking into account our recent published results and the findings of the current investigation, there should be a compromise regarding protein fouling and cellular uptake as resistance to nonspecific protein adsorption and enhanced cellular uptake are respectively directly and inversely related to the length of the PEO-stabilizing shell.
Asunto(s)
Nanopartículas/química , Poliésteres , Línea Celular Tumoral , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ácido Láctico/química , Ácido Láctico/farmacocinética , Ácido Láctico/farmacología , Poliésteres/química , Poliésteres/farmacocinética , Poliésteres/farmacología , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Polietilenglicoles/farmacología , Ácido Poliglicólico/química , Ácido Poliglicólico/farmacocinética , Ácido Poliglicólico/farmacología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Relación Estructura-ActividadRESUMEN
Poly(lactic acid) (PLA) or poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) blend nanoparticles were developed loading 5-fluorouracil (5-FU), an antitumor agent broadly used in therapy. A 2(3) factorial experimental design was conducted to indicate an optimal formulation and demonstrate the influence of the interactions of components on the mean particle size and drug encapsulation efficiency. Optimized PLA nanoparticles presented 294nm and 51% of 5-FU encapsulation efficiency and PLA-PEG blend nanoparticles presented 283nm and 55% of 5-FU encapsulation efficiency. In vitro release assay demonstrated after 320h about 50% of 5-FU was released from PLA and PLA-PEG blend nanoparticles. Release kinetics of 5-FU from nanoparticles followed second order and the release mechanism calculated by Korsmeyer-Peppas model was diffusion and erosion. In the assessment of cytotoxicity over Hep-2 tumor cells, PLA or PLA-PEG blend nanoparticles presented similar IC50 value than free 5-FU. Pharmacokinetic parameters after oral administration of 5-FU were improved by nanoencapsulation. Bioavailability, Cmax, Tmax, t1/2 and distribution volume were significantly improved, while clearance were decreased. PEG presence in nanoparticles didn't influence physicochemical and biological parameters evaluated. PLA and PLA-PEG nanoparticles can be potential carriers for oral delivery of 5-FU.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Portadores de Fármacos/administración & dosificación , Fluorouracilo/administración & dosificación , Nanopartículas/administración & dosificación , Poliésteres/administración & dosificación , Polietilenglicoles/administración & dosificación , Animales , Antimetabolitos Antineoplásicos/sangre , Antimetabolitos Antineoplásicos/farmacocinética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Química Farmacéutica , Portadores de Fármacos/farmacocinética , Fluorouracilo/sangre , Fluorouracilo/farmacocinética , Humanos , Masculino , Poliésteres/farmacocinética , Polietilenglicoles/farmacocinética , Ratas WistarRESUMEN
Early and reliable diagnosis of melanoma, a skin tumor with a poor prognosis, is extremely important. Phage display peptide libraries are a convenient screening resource for identifying bioactive peptides that interact with cancer targets. The aim of this study was to evaluate two technetium-99m tracers for angiogenesis detection in a melanoma model, using cyclic pegylated pentapeptide with RGD and NGR motifs conjugated with the bifunctional chelator mercaptoacetyltriglycine (MAG(3)). The conjugated peptides (10 µl of a µg/µl solution) were labeled with technetium-99m using a sodium tartrate buffer. Radiochemical evaluation was carried out by instant thin-layer chromatography and confirmed by high-performance liquid chromatography. The partition coefficient was determined and internalization assays were performed in two melanoma cell lines (B16F10 and SKMEL28). Biodistribution evaluation of the tracers was carried out in healthy animals at different time points and also in tumor-bearing mice, 120 min post injection. Blocking studies were also conducted by coinjection of cold peptides. The conjugates displayed a rather similar pharmacokinetic profile. They were radiolabeled with high radiochemical purity (>97%) and both were hydrophilic with preferential renal excretion. Yet, tumor uptake was higher for human than for murine melanoma cells, especially for [(99m)Tc]-MAG(3)-PEG(8)-c(RGDyk) (7.85±2.34%injected dose/g 120 min post injection). The performance of [(99m)Tc]-MAG(3)-PEG(8)-c(RGDyk) was better than the NGR tracer with regard to human melanoma uptake. In this sense, it should be considered for future radiotracer studies of tumor diagnosis.
Asunto(s)
Melanoma/irrigación sanguínea , Melanoma/diagnóstico por imagen , Radiofármacos , Tecnecio , Animales , Modelos Animales de Enfermedad , Humanos , Melanoma/metabolismo , Melanoma/patología , Melanoma Experimental/irrigación sanguínea , Melanoma Experimental/diagnóstico por imagen , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Ratones , Neovascularización Patológica/diagnóstico por imagen , Oligopéptidos/química , Oligopéptidos/farmacocinética , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Polivinilos/química , Polivinilos/farmacocinética , Trazadores Radiactivos , Cintigrafía , Radiofármacos/química , Radiofármacos/farmacocinética , Tecnecio/química , Tecnecio/farmacocinética , Compuestos de Tecnecio/química , Compuestos de Tecnecio/farmacocinéticaRESUMEN
We examined the association between IL28B single-nucleotide polymorphism rs12979860, hepatitis C virus (HCV) kinetic, and pegylated interferon alpha-2a pharmacodynamic parameters in HIV/HCV-coinfected patients from South America. Twenty-six subjects received pegylated interferon alpha-2a + ribavirin. Serum HCV-RNA and interferon concentrations were measured frequently during the first 12 weeks of therapy and analyzed using mathematical models. African Americans and whites had a similar distribution of IL28B genotypes (P = 0.5). The IL28B CC genotype was overrepresented (P = 0.015) in patients infected with HCV genotype-3 compared with genotype-1. In both genotype-1 and genotype-3, the first-phase viral decline and the average pegylated interferon-alpha-2a effectiveness during the first week of therapy were larger (trend P <= 0.12) in genotype-CC compared with genotypes-TC/TT. In genotype-1 patients, the second slower phase of viral decline (days 2-29) and infected cells loss rate, [delta], were larger (P = 0.02 and 0.11, respectively) in genotype-CC than in genotypes-TC/TT. These associations were not observed in genotype-3 patients.
Asunto(s)
Antivirales/farmacocinética , Infecciones por VIH/complicaciones , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/farmacocinética , Interleucinas/genética , Polietilenglicoles/farmacocinética , Polimorfismo de Nucleótido Simple , Antivirales/administración & dosificación , Población Negra , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferones , Modelos Teóricos , Polietilenglicoles/administración & dosificación , ARN Viral/sangre , Proteínas Recombinantes , Ribavirina/administración & dosificación , Suero/química , Suero/virología , América del Sur , Carga Viral , Población BlancaRESUMEN
Papain is an enzyme used in topical formulations as a proteolytic debriding agent for the treatment of open, extensive wounds and burnings. It is also employed as an enhancer for cutaneous permeation of active compounds, chemical peeling and as a progressive depilatory agent. The stability of formulations containing enzymes is not easy. In this research, papain was modified with polyethylene glycol in order to increase the stability of the formulations. The comparative Normal Stability Testing of the topical formulations containing unmodified and modified papain showed that the modified variety presented with a differentiated profile under the adopted temperature conditions (5.0 ± 1.0 °C; 22.0 ± 2.0 °C; 40.0 ± 2.0 °C). The most suitable condition for non-modified papain were 5.0 ± 1.0 °C and, for modified papain, they were 22.0 ± 2.0 °C. These results confirmed the higher stability of modified papain compared to free papain, as well as its potential to be applied in topical formulations.
A papaína é uma enzima utilizada em formulações tópicas como agente proteolítico debridante no tratamento de lesões abertas de grande extensão e queimaduras. É, também, empregada na pele íntegra como agente promotor da permeação cutânea de princípios ativos, peeling químico e como agente depilatório progressivo. A estabilidade de formulações contendo enzimas não é facilmente alcançada. No presente trabalho realizou-se a modificação da enzima com polietilenoglicol, visando maior estabilidade das formulações. A realização do Teste Estabilidade Normal comparativo entre as formulações contendo as formas da enzima não modificada e modificada demonstrou que a última apresentou um perfil de estabilidade diferenciado, nas diferentes condições (5,0 ± 1,0 °C; 22,0 ± 2,0 °C; 40,0 ± 2,0 °C). A condição de 5,0 ± 1,0 °C foi a mais adequada para a formulação contendo papaína não modificada enquanto a 22,0 ± 2,0 °C foi indicada para aquela contendo a forma modificada. Estes resultados confirmaram o aumento da estabilidade da papaína modificada comparada com a livre e seu potencial de aplicação em formulações de uso tópico.
Asunto(s)
Estudio Comparativo , Papaína/análisis , Química Farmacéutica , Polietilenglicoles/farmacocinéticaRESUMEN
BACKGROUND: Interferon (IFN) alpha conjugation to polyethylene glycol (PEG) results in a better pharmacokinetic profile and efficacy. The aim of this study was to compare the pharmacokinetic, pharmacodynamic and safety properties of a new, locally developed, 40-kDa PEG-IFN alpha-2b preparation with a reference, commercially available PEG-IFN alpha-2a in healthy male volunteers. METHODS: A randomized, crossover, double-blind study with a 3-weeks washout period, was done. A single 180 micrograms PEG-IFN alpha-2 dose was administered subcutaneously in both groups. Sixteen apparently healthy male subjects were included. Serum PEG-IFN concentration was measured during 336 hours by an enzyme immunoassay (EIA). Other clinical and laboratory variables were used as pharmacodynamic and safety criteria. RESULTS: The pharmacokinetic comparison by EIA yielded a high similitude between the formulations. In spite of a high subject variability, the parameters' mean were very close (in all cases p > 0.05): AUC: 53623 vs. 44311 pg.h/mL; Cmax: 333 vs. 271 pg/mL; Tmax: 54 vs. 55 h; half-life (t1/2): 72.4 vs. 64.8 h; terminal elimination rate (lambda): 0.011 vs. 0.014 h(-1); mean residence time (MRT): 135 vs. 123 h for reference and study preparations, respectively. There were no significant differences with respect to the pharmacodynamic variables either: serum neopterin and beta-2 microglobulin levels, stimulation of 2'5' oligoadenylate synthetase expression, and serum IFN antiviral activity. A strong Spearman's rank order correlation (p < 0.01) between the pharmacokinetic and pharmacodynamic concentration-time curves was observed. Both products caused similar leukocyte counts diminution and had similar safety profiles. The most frequent adverse reactions were leukopenia, fever, thrombocytopenia, transaminases increase and asthenia, mostly mild. CONCLUSIONS: Both formulations are fully comparable from the pharmacokinetic, pharmacodynamic, and safety profiles. Efficacy trials can be carried out to confirm clinical similarity.
Asunto(s)
Antivirales/farmacología , Antivirales/farmacocinética , Interferón-alfa/farmacología , Interferón-alfa/farmacocinética , Polietilenglicoles/farmacología , Polietilenglicoles/farmacocinética , 2',5'-Oligoadenilato Sintetasa/sangre , 2',5'-Oligoadenilato Sintetasa/genética , Adulto , Antivirales/sangre , Antivirales/toxicidad , Biomarcadores/sangre , Química Farmacéutica , Estudios Cruzados , Método Doble Ciego , Semivida , Humanos , Interferón alfa-2 , Interferón-alfa/sangre , Interferón-alfa/toxicidad , Leucopenia/inducido químicamente , Masculino , Tasa de Depuración Metabólica , Pruebas de Sensibilidad Microbiana , Neopterin/sangre , Polietilenglicoles/toxicidad , ARN Mensajero/metabolismo , Proteínas Recombinantes , Adulto Joven , Microglobulina beta-2/sangreRESUMEN
The effect of interferon alfa against hepatitis C virus has been well documented. However, clinical efficacy is low due to the short interferon residence in the body. To prolong half-life, interferon molecules have been bound to the biologically inert polymer, polyethyleneglycol. Pegylated interferons exhibit a longer residence time with an improved clinical efficacy, although the rate of therapeutic failure is still important. Addition of ribavirin to interferon, either pegylated or not, significantly increases efficacy. Therefore, the combination of a pegylated interferon with ribavirin has become the standard treatment of chronic hepatitis C. As the efficacy and safety of such combinations are not yet optimal, different drugs, including other types of long-acting interferons and ribavirin analogs, are presently been investigated.
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Antivirales/uso terapéutico , Hepatitis C/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Antivirales/farmacocinética , Quimioterapia Combinada , Humanos , Interferón alfa-2 , Interferón-alfa/farmacocinética , Polietilenglicoles/farmacocinética , Proteínas Recombinantes , Resultado del TratamientoRESUMEN
Mononuclear (macrophages) and polymorphonuclear leucocytes cells play an important role in the immunopathogenesis of acquired immunodeficiency syndrome. Zidovudine is a broad-spectrum drug used in current antiretroviral therapy. The development of controlled drug delivery systems for the treatment of chronic diseases is of great interest since these systems can act as vectors, carrying the drug only to the target, and the adverse effects can be reduced. In this study, PLA and PLA/PEG blend nanoparticles containing zidovudine were developed and their uptake by polymorphonuclear leucocytes were studied in vitro. The influence of polymer type on particle size, Zeta potential and particle uptake by polymorphonuclear leucocytes was investigated. The cells were isolated from rat peritoneal exudate and their activation by nanoparticles was measured by luminol-dependent chemiluminescence and microscopical analysis. The PEG in the blend modified the Zeta potential suggested the formation of a PEG coat on the particle surface. The phagocytosis depended on the PEG and its ratio in the blend, the results showed that the PLA nanoparticles were more efficiently phagocytosed than PLA/PEG blends. The blend with the highest PEG proportion did not prevent phagocytosis, indicating that the steric effect of PEG was concentration dependent.
Asunto(s)
Nanopartículas , Neutrófilos/metabolismo , Fagocitos/metabolismo , Poliésteres/farmacocinética , Polietilenglicoles/farmacocinética , Zidovudina/farmacocinética , Animales , Nanopartículas/química , Neutrófilos/efectos de los fármacos , Tamaño de la Partícula , Fagocitos/efectos de los fármacos , Fagocitosis/fisiología , Poliésteres/química , Polietilenglicoles/química , Polímeros/química , Polímeros/farmacocinética , Ratas , Zidovudina/químicaRESUMEN
BACKGROUND/AIMS: To compare the pharmacokinetics, pharmacodynamics, and antiviral activity of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C virus genotype 1. METHODS: Thirty-six patients were randomised to peginterferon alfa-2b (1.5 microg/kg/week) or peginterferon alfa-2a (180 microg/week) for 4 weeks, then in combination with ribavirin (13 mg/kg/day) for a further 4 weeks. The pharmacokinetic profile of both peginterferons, mRNA expression of a selected group of interferon-induced gene transcripts, and serum HCV-RNA levels were assessed. RESULTS: Patients receiving peginterferon alfa-2b had significantly greater up-regulation of interferon-alfa response genes compared with those receiving peginterferon alfa-2a. Correspondingly, patients treated with peginterferon alfa-2b also had a significantly greater log10 maximum and log10 time-weighted average decrease in serum HCV-RNA. A greater proportion of peginterferon alfa-2b patients achieved a > or = 2.0 log10 reduction in serum HCV-RNA levels by week 8 (72% vs 44% of peginterferon alfa-2a patients, P = 0.09). There was an approximately 16-fold greater exposure to peginterferon in the serum of patients treated with peginterferon alfa-2a. CONCLUSIONS: These findings suggest that the biological activity, measured by early interferon-induced gene transcripts and early antiviral responsiveness, may have been greater in patients treated with peginterferon alfa-2b despite their lower exposure to the drug compared with patients treated with peginterferon alfa-2a.
Asunto(s)
Antivirales/farmacocinética , Hepatitis C Crónica/sangre , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/farmacocinética , Polietilenglicoles/farmacocinética , Adolescente , Adulto , Anciano , Antivirales/uso terapéutico , Método Doble Ciego , Portadores de Fármacos , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatitis C Crónica/virología , Humanos , Interferón alfa-2 , Interferón-alfa/uso terapéutico , Masculino , Persona de Mediana Edad , Polietilenglicoles/uso terapéutico , Reacción en Cadena de la Polimerasa , ARN Viral/análisis , Proteínas Recombinantes , Ribavirina/farmacocinética , Ribavirina/uso terapéutico , Resultado del Tratamiento , Carga ViralRESUMEN
The intracellular triphosphorylation and plasma pharmacokinetics of lamivudine (3TC), stavudine (d4T), and zidovudine (ZDV) were assessed in a pharmacokinetic substudy, in 56 human immunodeficiency virus-hepatitis C virus (HIV-HCV) coinfected patients receiving peginterferon alfa-2a (40KD) 180 microg/week plus either placebo or ribavirin (RBV) 800 mg/day in the AIDS PEGASYS Ribavirin International Coinfection Trial. There were no significant differences between patients treated with RBV and placebo in plasma pharmacokinetics parameters for the nucleoside reverse transcriptase inhibitors (NRTIs) at steady state (weeks 8 to 12): ratios of least squares mean of area under the plasma concentration-time curve (AUC(0-12 h)) were 1.17 (95% confidence interval, 0.91 to 1.51) for 3TC, 1.44 (95% confidence interval, 0.58 to 3.60) for d4T and 0.85 (95% confidence interval, 0.50 to 1.45) for ZDV, and ratios of least squares mean plasma C(max) were 1.33 (95% confidence interval, 0.99 to 1.78), 1.06 (95% confidence interval, 0.68 to 1.65), and 0.84 (95% confidence interval, 0.46 to 1.53), respectively. Concentrations of NRTI triphosphate (TP) metabolites in relation to those of the triphosphates of endogenous deoxythymidine-triphosphate (dTTP) and deoxcytidine-triphosphate (dCTP) were similar in the RBV and placebo groups. Differences (RBV to placebo) in least squares mean ratios of AUC(0-12 h) at steady state were 0.274 (95% confidence interval, -0.37 to 0.91) for 3TC-TP:dCTP, 0.009 (95% confidence interval, -0.06 to 0.08) for d4T-TP:dTTP, and -0.081 (95% confidence interval, -0.40 to 0.24) for ZDV-TP:dTTP. RBV did not adversely affect HIV-1 replication. In summary, RBV 800 mg/day administered in combination with peginterferon alfa-2a (40KD) does not significantly affect the intracellular phosphorylation or plasma pharmacokinetics of 3TC, d4T, and ZDV in HIV-HCV-coinfected patients.