RESUMEN
The accelerated blood clearance (ABC) phenomenon is induced upon repeated injections of poly(ethylene glycol) (PEG)-coated colloidal carriers. It is essential to suppress this phenomenon in a clinical setting because the pharmacokinetics must be reproducible. In this study, we evaluated the induction of the ABC phenomenon using nanoparticles coated with various hydrophilic polymers instead of PEG. Nanoparticles encapsulating prostaglandin E1 were prepared by the solvent diffusion method from a blend of poly(lactic acid) (PLA) and block copolymers consisting of various hydrophilic polymers and PLA. Coating of nanoparticles with poly(N-vinyl-2-pyrrolidone) (PVP), poly(4-acryloylmorpholine), or poly(N,N-dimethylacrylamide) led to extended residence of the nanoparticles in blood circulation in rats, although they had a shorter half-life than the PEG-coated nanoparticles. The ABC phenomenon was not induced upon repeated injection of PVP-coated nanoparticles at various time intervals, dosages, or frequencies, whereas it was elicited by PEG-coated nanoparticles. In addition, anti-PVP IgM antibody, which is estimated to be one of the crucial factors for induction of the ABC phenomenon, was not produced after injection of PVP-coated nanoparticles. These results suggest that the use of PVP, instead of PEG, as a coating material for colloidal carriers can evade the ABC phenomenon.
Asunto(s)
Portadores de Fármacos/farmacocinética , Nanopartículas/química , Polímeros/farmacocinética , Animales , Tiempo de Circulación Sanguínea , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/efectos adversos , Ensayo de Inmunoadsorción Enzimática , Interacciones Hidrofóbicas e Hidrofílicas , Inmunoglobulina M/sangre , Inyecciones Intravenosas , Masculino , Tasa de Depuración Metabólica , Nanopartículas/administración & dosificación , Nanopartículas/efectos adversos , Polímeros/administración & dosificación , Polímeros/efectos adversos , Polivinilos/administración & dosificación , Polivinilos/efectos adversos , Pirrolidinas/administración & dosificación , Pirrolidinas/efectos adversos , Pirrolidinas/sangre , Ratas , Ratas WistarRESUMEN
Idiopathic pulmonary fibrosis (IPF) is thought to involve inflammatory infiltration of leukocytes, lung injury induced by reactive oxygen species (ROS), in particular superoxide anion, and fibrosis (collagen deposition). No treatment has been shown to improve definitively the prognosis for IPF patients. Superoxide dismutase (SOD) catalyzes the dismutation of superoxide anion to hydrogen peroxide, which is subsequently detoxified by catalase. Lecithinized SOD (PC-SOD) has overcome clinical limitations of SOD, including low tissue affinity and low stability in plasma. In this study, we examined the effect of PC-SOD on bleomycin-induced pulmonary fibrosis. Severity of the bleomycin-induced fibrosis in mice was assessed by various methods, including determination of hydroxyproline levels in lung tissue. Intravenous administration of PC-SOD suppressed the bleomycin-induced increase in the number of leukocytes in bronchoalveolar lavage fluid. Bleomycin-induced collagen deposition and increased hydroxyproline levels in the lung were also suppressed in animals treated with PC-SOD, suggesting that PC-SOD suppresses bleomycin-induced pulmonary fibrosis. The dose-response profile of PC-SOD was bell-shaped, but concurrent administration of catalase restored the ameliorative effect at high doses of PC-SOD. Intratracheal administration or inhalation of PC-SOD also attenuated the bleomycin-induced inflammatory response and fibrosis. The bell-shaped dose-response profile of PC-SOD was not observed for these routes of administration. We consider that, compared with intravenous administration, inhalation of PC-SOD may be a more therapeutically beneficial route of administration due to the higher safety and quality of life of the patient treated with this drug.
Asunto(s)
Fosfatidilcolinas/uso terapéutico , Fibrosis Pulmonar/tratamiento farmacológico , Superóxido Dismutasa/uso terapéutico , Administración por Inhalación , Animales , Bleomicina , Catalasa/administración & dosificación , Muerte Celular/efectos de los fármacos , Colágeno/metabolismo , Epitelio/efectos de los fármacos , Epitelio/patología , Peróxido de Hidrógeno/metabolismo , Inyecciones Intravenosas , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Mesodermo/efectos de los fármacos , Mesodermo/patología , Ratones , Fosfatidilcolinas/administración & dosificación , Fosfatidilcolinas/sangre , Fosfatidilcolinas/farmacología , Neumonía/tratamiento farmacológico , Fibrosis Pulmonar/inducido químicamente , Superóxido Dismutasa/administración & dosificación , Superóxido Dismutasa/sangre , Superóxido Dismutasa/farmacologíaRESUMEN
We have prepared polymeric nanoparticles using a blend of poly(lactic acid) and monomethoxy-polyethyleneglycol(PEG)-polylactide block copolymer along with betamethasone disodium phosphate (BP). Nanoparticles have been screened for anti-inflammatory activity using experimental rat models of inflammation. In the present study, we examined the degradation of nanoparticles in vitro during incubation. We found that the nanoparticles lost the PEG chains present on their surfaces within a few days, and subsequently gradually released BP. Furthermore, we found that these nanoparticles preferentially accumulated in the inflammatory lesion in adjuvant arthritis rat models, and that the amount of BP gradually depleted from the lesion over 14 days. These results suggested the mechanism underlying the anti-inflammatory effect of the nanoparticles in vivo: the initial accumulation of BP in the lesion due to the enhanced permeability and retention effect, the subsequent internalization in inflammatory macrophages due to the loss of PEG, and the release of BP in cells during the hydrolysis of polymers. The nanoparticles were successfully prepared on a large-scale and stably stored in the form of a freeze-dried formulation for at least 69 weeks below 25 degrees C. These results suggest that the nanoparticles can be used as an anti-inflammatory pharmaceutical formulation in a clinical setting.
Asunto(s)
Antiinflamatorios/farmacología , Artritis Experimental/tratamiento farmacológico , Betametasona/análogos & derivados , Portadores de Fármacos , Lactatos/química , Nanopartículas , Polietilenglicoles/química , Animales , Antiinflamatorios/química , Antiinflamatorios/metabolismo , Artritis Experimental/inducido químicamente , Artritis Experimental/metabolismo , Artritis Experimental/microbiología , Betametasona/química , Betametasona/metabolismo , Betametasona/farmacología , Química Farmacéutica , Preparaciones de Acción Retardada , Estabilidad de Medicamentos , Almacenaje de Medicamentos , Liofilización , Adyuvante de Freund , Hidrólisis , Masculino , Mycobacterium , Nanotecnología , Permeabilidad , Ratas , Ratas Endogámicas Lew , Solubilidad , Tecnología Farmacéutica/métodos , Temperatura , Factores de TiempoRESUMEN
PURPOSE: We recently developed prostaglandin E(1) (PGE(1))-encapsulated nanoparticles, prepared with a poly(lactide) homopolymer (PLA, Mw = 17,500) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA) (NP-L20). In this study, we tested whether the accelerated blood clearance (ABC) phenomenon is observed with NP-L20 and other PEG-modified PLA-nanoparticles in rats. METHODS: The plasma levels of PGE(1) and anti-PEG IgM antibody were determined by EIA and ELISA, respectively. RESULTS: Second injections of NP-L20 were cleared much more rapidly from the circulation than first injections, showing that the ABC phenomenon was induced. This ABC phenomenon, and the accompanying induction of anti-PEG IgM antibody production, was optimal at a time interval of 7 days between the first and second injections. Compared to NP-L20, NP-L33s that were prepared with PLA (Mw = 28,100) and have a smaller particle size induced production of anti-PEG IgM antibody to a lesser extent. NP-L20 but not NP-L33s gave rise to the ABC phenomenon with a time interval of 14 days. NP-L33s showed a better sustained-release profile of PGE(1) than NP-L20. CONCLUSIONS: This study revealed that the ABC phenomenon is induced by PEG-modified PLA-nanoparticles. We consider that NP-L33s may be useful clinically for the sustained-release and targeted delivery of PGE(1).
Asunto(s)
Nanopartículas/administración & dosificación , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacocinética , Animales , Tiempo de Circulación Sanguínea/efectos de los fármacos , Tasa de Depuración Metabólica/efectos de los fármacos , Tasa de Depuración Metabólica/fisiología , Tamaño de la Partícula , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
To achieve the effective intracellular delivery of siRNA and silence specific genes, various types of conjugates between cell-penetrating peptides (CPPs; Transportan, Penetratin, Tat) and cationic peptides were developed. Uptake, intracellular localization, cytotoxicity, and biological activity of siRNA were significantly dependent on the kind of CPP used and the length of the cationic peptides in the conjugate. Transportan-based conjugates yielded both high internalization of siRNA and strong gene silencing activity, while Penetratin- and Tat-based conjugates did not. These different properties of CPPs emphasize the importance of careful peptide selection and design when attempting the application of CPP technology.
Asunto(s)
Proteínas Portadoras/química , Oligopéptidos/química , Péptidos/química , ARN Interferente Pequeño/administración & dosificación , Permeabilidad de la Membrana Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Péptidos de Penetración Celular , Sistemas de Liberación de Medicamentos , Galanina/química , Silenciador del Gen , Células HeLa , Humanos , Luciferasas/antagonistas & inhibidores , Luciferasas/genética , Microscopía Fluorescente , Oligopéptidos/síntesis química , Transporte de Proteínas/efectos de los fármacos , Proteínas Recombinantes de Fusión/química , Células Tumorales Cultivadas , Venenos de Avispas/químicaRESUMEN
PURPOSE: Prostaglandin E(1) (PGE(1)) is an effective treatment for peripheral vascular diseases. The encapsulation of PGE(1) in nanoparticles for its sustained-release would improve its therapeutic effect and quality of life (QOL) of patients. METHODS: In order to encapsulate PGE(1) in nanoparticles prepared with a poly(lactide) homopolymer (PLA) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA), we synthesized a series of PGE(1) phosphate derivatives and tested their efficacy. RESULTS: Among them, PGE(1) 2-(phosphonooxy)ethyl ester sodium salt (C2) showed the most efficient hydrolysis to yield PGE(1) in human serum. An in vitro platelet aggregation assay showed that C2 inhibited aggregation only after pre-incubation in serum, suggesting that C2 is a prodrug of PGE(1). In vivo, intravenous administration of C2 caused increase in cutaneous blood flow. In the presence of zinc ions, all of the synthesized PGE(1) phosphate derivatives could be encapsulated in PLA-nanoparticles. Use of L-PLA instead of D,L-PLA, and high molecular weight PLA resulted in a slower release of C2 from the nanoparticles. CONCLUSIONS: We consider that C2-encapsulated nanoparticles prepared with L-PLA and PEG-D,L-PLA have good sustained-release profile of PGE(1), which is useful clinically.
Asunto(s)
Alprostadil/administración & dosificación , Alprostadil/síntesis química , Portadores de Fármacos/química , Nanopartículas/química , Fosfatos/química , Alprostadil/metabolismo , Alprostadil/farmacología , Animales , Humanos , Hidrólisis , Ácido Láctico/química , Tamaño de la Partícula , Fosfatos/síntesis química , Agregación Plaquetaria/efectos de los fármacos , Poliésteres , Polietilenglicoles/química , Polímeros/química , Profármacos/metabolismo , Ratas , Ratas Wistar , Flujo Sanguíneo Regional/efectos de los fármacos , Suero/metabolismo , Piel/irrigación sanguínea , Zinc/químicaRESUMEN
Polymeric micelles consisting of amphiphilic block copolymers have emerged as a promising carrier of various drugs, but unfortunately show a limited potential for encapsulating (solubilizing) such drugs. In this study, hybrid nanoparticles consisting of monomethoxypolyethyleneglycol-polylactide block copolymer (PEG-PLA) and oleic acid calcium salt were prepared to enhance the solubilization of poorly water-soluble drugs. Micelles made of a mixture of sodium oleate and PEG-PLA at various ratios were used as the template for preparation of the nanoparticles. These mixed micelles could efficiently solubilize poorly water-soluble drugs in aqueous media, when compared with polymeric micelles made of PEG-PLA alone. Addition of calcium to the mixed micelles induced the formation of oleic acid calcium salt, resulting in hybrid nanoparticles. These hybrid nanoparticles had a high colloidal stability, neutral zeta potential, and high drug entrapment efficiency. Drugs entrapped in nanoparticles made at a high PEG-PLA ratio were protected from enzymatic degradation in serum, while drugs entrapped in the mixed micelles were not, indicating that the hybrid nanoparticles show good drug retention. These results suggested that such hybrid nanoparticles may be used to expand the availability of poorly water-soluble drugs for various therapeutic applications.
Asunto(s)
Nanopartículas/química , Ácido Oléico/química , Preparaciones Farmacéuticas/química , Polietilenglicoles/química , Animales , Calcio/química , Bovinos , Micelas , Preparaciones Farmacéuticas/metabolismo , Suero/enzimología , Solubilidad , Agua/químicaRESUMEN
Solid nanoparticles consisting of biodegradable polymers have emerged as a promising carrier for various drugs, but unfortunately the encapsulation of drugs remains challenging. In this study, a technique for encapsulation of water-soluble drugs in solid nanoparticles was developed. Nanoparticles were prepared from a blend of biodegradable polymers, including poly(lactic acid) (PLA) and poly(lactic/glycolic acid) (PLGA), and monomethoxypolyethyleneglycol-polylactide block copolymer by an oil-in-water solvent diffusion method. Betamethasone sodium phosphate (BP) was not encapsulated by the nanoparticles due to its hydrophilicity, but it was effectively encapsulated in the presence of appropriate amounts of zinc and diethanolamine. It was found that BP formed an ionic complex with zinc at a certain pH range obtained by addition of diethanolamine. Furthermore, a carboxyl group located at the end of PLA/PLGA was shown to be essential for encapsulation of BP in nanoparticles, and the molar ratio among BP, zinc, and carboxyl groups in various nanoparticles was almost constant. These results strongly suggested that the encapsulation was promoted by zinc creating an ionic bridge between a carboxyl group on PLA/PLGA and a phosphate group on BP. This technique for entrapment of water-soluble drugs in solid biodegradable nanoparticles may expand the use of nanoparticles for various therapeutic applications.
Asunto(s)
Betametasona/análogos & derivados , Portadores de Fármacos/química , Glucocorticoides/química , Polímeros/química , Betametasona/química , Química Farmacéutica , Cloruros/química , Etanolaminas/química , Concentración de Iones de Hidrógeno , Ácido Láctico/química , Nanopartículas , Poliésteres/química , Polietilenglicoles/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Solubilidad , Compuestos de Zinc/químicaRESUMEN
Ulcerative colitis (UC) involves intestinal mucosal damage induced by reactive oxygen species (ROS), in particular, superoxide anion. Superoxide dismutase (SOD) catalyzes dismutation of superoxide anion to hydrogen peroxide, which is subsequently detoxified by catalase. Lecithinized SOD (PC-SOD) is a new modified form of SOD that has overcome previous clinical limitations of SOD. In this study, we examined the action of PC-SOD using an animal model of UC, dextran sulfate sodium (DSS)-induced colitis. DSS-induced colitis was ameliorated by daily intravenous administration of PC-SOD. Unmodified SOD produced a similar effect but only at more than 30 times the concentration of PC-SOD. In vivo electron spin resonance analysis confirmed that the increase in the colonic level of ROS associated with development of colitis was suppressed by PC-SOD administration. The dose-response profile of PC-SOD was bell-shaped, but simultaneous administration of catalase restored the ameliorative effect at high doses of PC-SOD. Accumulation of hydrogen peroxide was observed with the administration of high doses of PC-SOD, an effect that was suppressed by the simultaneous administration of catalase. We also found that either a weekly intravenous administration or daily oral administration of PC-SOD conferred protection. These results suggest that PC-SOD achieves its ameliorative effect against colitis through decreasing the colonic level of ROS and that its ineffectiveness at higher doses is because of the accumulation of hydrogen peroxide. Furthermore, we consider that intermittent or oral administration of PC-SOD can be applied clinically to improve the quality of life of UC patients.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Fosfatidilcolinas/uso terapéutico , Superóxido Dismutasa/uso terapéutico , Animales , Catalasa/uso terapéutico , Colon/anatomía & histología , Colon/efectos de los fármacos , Colon/enzimología , Cartilla de ADN , ADN Complementario/genética , Humanos , Inmunohistoquímica , Interleucina-1/genética , Interleucina-23/genética , Interleucina-6/genética , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mucosa Intestinal/fisiopatología , Ratones , Neutrófilos/fisiología , Peroxidasa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
PURPOSE: Prostaglandins have potent and diverse biologic activities, but their clinical application is severely restricted, mainly due to rapid inactivation in vivo. In order to modulate the pharmacokinetics of prostaglandin E(1) (PGE(1)), we prepared biodegradable nanoparticles as a drug carrier. METHODS: Nanoparticles encapsulating PGE(1) were prepared from a blend of poly(lactic acid) homopolymer and poly(ethylene glycol)-poly(lactide) block copolymer by the solvent diffusion method in the presence of iron. RESULTS: PGE(1) was efficiently and stably embedded in the nanoparticles through interaction with iron, despite being relatively hydrophilic and having unstable chemical properties. Depending on the isomers and molecular weight of poly(lactic acid) selected, PGE(1) was gradually released from the nanoparticles at various rates into diluted serum in vitro. Both stable retention of PGE(1) in the nanoparticles and coating of the nanoparticles with poly(ethylene glycol) led to an extremely extended blood residence time of PGE(1), as well as preferential accumulation in vascular lesions. CONCLUSIONS: These results suggest that the present strategy is useful to advance the clinical application of PGE(1) as a therapeutic agent for vascular disorders.
Asunto(s)
Alprostadil/administración & dosificación , Alprostadil/farmacocinética , Vasodilatadores/administración & dosificación , Vasodilatadores/farmacocinética , Implantes Absorbibles , Animales , Área Bajo la Curva , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patología , Línea Celular , Fenómenos Químicos , Química Física , Preparaciones de Acción Retardada , Composición de Medicamentos , Semivida , Hierro/química , Macrófagos/metabolismo , Masculino , Ratones , Nanopartículas , Tamaño de la Partícula , Poliésteres , Polietilenglicoles , Ratas , Ratas Wistar , SolubilidadRESUMEN
To study the pharmacokinetics of single increasing intravenous doses (40-160 mg) and repeated doses (80 mg for 7 days) of lecithinized superoxide dismutase (PC-SOD) in Japanese volunteers and to compare the pharmacokinetics of PC-SOD between Caucasians and Japanese. The Japanese study consisted of 2 parts: a single-dose, open-label, dose-escalation part and a multiple-dose, single-blind, placebo-controlled part. The pharmacokinetics of PC-SOD were determined using noncompartmental and compartmental methods. Pharmacokinetic data from a study with PC-SOD in Caucasians were reanalyzed using the same methodology. The mean (SD) terminal half-life of PC-SOD in Japanese subjects was 25 (4) hours for the 40-mg and 80-mg doses and 31 (15) hours for the 160-mg dose. There was nonlinearity between dose-normalized C(max) and clearance (P values .002 and .022). After multiple dosing, steady state was reached after 5 days. The observed accumulation ratio was 2.6 (0.5). The pharmacokinetics of the single 80-mg dose were similar for Japanese and Caucasians. The pharmacokinetics of PC-SOD was shown to be nonlinear with dose, which may be attributable to a saturable clearing mechanism. The relatively long half-life of PC-SOD (>24 hours) suggests that it is worthwhile to study the compound as a protective agent in clinical conditions with free radical overload.
Asunto(s)
Pueblo Asiatico , Fosfatidilcolinas/farmacocinética , Superóxido Dismutasa/farmacocinética , Población Blanca , Área Bajo la Curva , Estudios de Cohortes , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Ensayo de Inmunoadsorción Enzimática , Femenino , Semivida , Humanos , Inyecciones Intravenosas , Masculino , Fosfatidilcolinas/administración & dosificación , Fosfatidilcolinas/sangre , Método Simple Ciego , Superóxido Dismutasa/administración & dosificación , Superóxido Dismutasa/sangre , Factores de TiempoRESUMEN
We present a case of thymic carcinoid, in which primary and metastatic lesions of lymph nodes and bones could be detected by [(18)F]fluoro-2-deoxy-D-glucose (FDG)-PET, but not by (123)I-meta-iodobenzylguanidine ((123)I-MIBG) SPECT, or by (99m)Tc-methylene diphosphonate ((99m)Tc-MDP) bone scintigraphy. FDG-PET may be a useful tool for managing thymic carcinoids in patients with negative results on (123)I-MIBG SPECT or (99m)Tc-MDP imaging.
Asunto(s)
Neoplasias Óseas/diagnóstico por imagen , Tumor Carcinoide/diagnóstico por imagen , Tomografía de Emisión de Positrones , Neoplasias del Timo/diagnóstico por imagen , 3-Yodobencilguanidina , Anciano , Neoplasias Óseas/secundario , Tumor Carcinoide/patología , Tumor Carcinoide/terapia , Fluorodesoxiglucosa F18 , Humanos , Radioisótopos de Yodo , Metástasis Linfática , Masculino , Radiofármacos , Medronato de Tecnecio Tc 99m , Neoplasias del Timo/patología , Neoplasias del Timo/terapiaRESUMEN
Drug-supported spherical microparticles with below 3 microm in diameter of calcium carbonate (CC) nanocrystals were precipitated by a complex decomposition method from Na2CO3 and CaCl2 solutions with hydrocortisone phosphate (HyC). The HyC was completely incorporated into the microparticles and was adsorbed on the surface of nanocrystals. The crystal phases of vaterite and calcite were controlled by the addition of magnesium ions. Spherical microparticles of calcite cores and petal-shaped hydroxyapatite (HAp) outer layers were fabricated by soaking calcite into the SBF, or a supersaturated solution of phosphate ions to enhance the crystal growth of HAp.
Asunto(s)
Carbonato de Calcio/química , Durapatita/química , Sistemas de Liberación de Medicamentos , Hidrocortisona/administración & dosificación , Microscopía Electrónica , Microscopía Electrónica de Rastreo , Nanopartículas/química , Nanopartículas/ultraestructura , Nanotecnología , Tamaño de la Partícula , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos XRESUMEN
We conducted a 28-week, randomized, double-blind, parallel-group study of iguratimod in 376 Japanese patients with active rheumatoid arthritis to compare the efficacy and safety of the drug with those of placebo and salazosulfapyridine. In the American College of Rheumatology (ACR) 20 response rate, iguratimod was superior to placebo (53.8% versus 17.2%; Fisher's exact test, P < 0.001) and was not inferior to salazosulfapyridine (63.1% versus 57.7%, 95% confidence interval for the rate difference, -7.9% to 18.7%). Iguratimod began exhibiting its therapeutic effect within 8 weeks after the initiation of treatment and was effective even in patients who had a poor response to previous treatment with disease-modifying antirheumatic drugs. No statistically significant difference was noted in the incidence of adverse reactions between iguratimod and salazosulfapyridine. The study results suggest that iguratimod could become a new option for the treatment of rheumatoid arthritis.
Asunto(s)
Antirreumáticos/farmacología , Artritis Reumatoide/tratamiento farmacológico , Cromonas/uso terapéutico , Inmunosupresores/uso terapéutico , Sulfasalazina/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Cromonas/efectos adversos , Cromonas/farmacología , Método Doble Ciego , Femenino , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/farmacología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Sulfasalazina/efectos adversos , Sulfasalazina/farmacología , Sulfonamidas/efectos adversos , Sulfonamidas/farmacologíaRESUMEN
We conducted a 52-week clinical study of iguratimod in 394 Japanese patients with rheumatoid arthritis to evaluate the long-term safety of the drug. Iguratimod was administered orally at a daily dose of 25 mg for the first 4 weeks and 50 mg for the subsequent 48 weeks. Some of the patients continued the treatment for 100 weeks for their benefit. The cumulative incidence of adverse events for 100 weeks was 97.6%. The cumulative incidence of adverse reactions was 65.3%; unfavorable symptoms and signs (excluding abnormal laboratory data changes) accounted for 33.2% of the reactions, and abnormal laboratory data changes accounted for 50.4%. The continued treatment rate was 66.8% at week 28 and 53.6% at week 52. For reference, the American College of Rheumatology (ACR) 20 response rate was calculated for the patients who had assessable disease activity, who did not violate the study protocol, and who continued the study treatment at weeks 28 and 52. The rate was 46.9% at week 28 and 41.0% at week 52. To use iguratimod safely for a long time, patients should be observed closely for adverse reactions such as increased hepatic enzymes.
Asunto(s)
Antirreumáticos/farmacología , Artritis Reumatoide/tratamiento farmacológico , Cromonas/efectos adversos , Citocinas/antagonistas & inhibidores , Inmunosupresores/efectos adversos , Hígado/efectos de los fármacos , Sulfonamidas/efectos adversos , Cromonas/uso terapéutico , Femenino , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Sulfonamidas/uso terapéutico , Resultado del TratamientoAsunto(s)
Anticuerpos Monoclonales/efectos adversos , Antirreumáticos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Polimiositis/inducido químicamente , Factor de Necrosis Tumoral alfa , Artritis Reumatoide/patología , Artritis Reumatoide/fisiopatología , Quimioterapia Combinada , Femenino , Humanos , Infliximab , Metotrexato/uso terapéutico , Persona de Mediana Edad , Polimiositis/patología , Polimiositis/fisiopatología , Prednisolona/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
Oxidative stress has long been linked to the pathogenesis of neurodegenerative diseases; however, whether it is a cause or merely a consequence of the degenerative process is still unknown. We show that mice deficient in Cu, Zn-superoxide dismutase (SOD1) have features typical of age-related macular degeneration in humans. Investigations of senescent Sod1(-/-) mice of different ages showed that the older animals had drusen, thickened Bruch's membrane, and choroidal neovascularization. The number of drusen increased with age, and exposure of young Sod1(-/-) mice to excess light induced drusen. The retinal pigment epithelial cells of Sod1(-/-) mice showed oxidative damage, and their beta-catenin-mediated cellular integrity was disrupted, suggesting that oxidative stress may affect the junctional proteins necessary for the barrier integrity of the retinal pigment epithelium. These observations strongly suggest that oxidative stress may play a causative role in age-related retinal degeneration, and our findings provide evidence for the free radical theory of aging. In addition, these results demonstrate that the Sod1(-/-) mouse is a valuable animal model to study human age-related macular degeneration.
Asunto(s)
Enfermedades de la Coroides/patología , Degeneración Macular/genética , Degeneración Macular/patología , Neovascularización Patológica , Drusas del Disco Óptico/patología , Epitelio Pigmentado Ocular/metabolismo , Superóxido Dismutasa/genética , Animales , Enfermedades de la Coroides/genética , Modelos Animales de Enfermedad , Luz , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Drusas del Disco Óptico/genética , Estrés Oxidativo , Superóxido Dismutasa-1 , beta Catenina/metabolismoRESUMEN
To detect dioxin using a quartz crystal microbalance (QCM) immunosensor, anti-2,3,7,8-tetrachloro-p-dibenzodioxin (TCDD) monoclonal antibodies (MAbs) were produced as types of IgG1 and IgM, with mono 6-(2,3,6,7-tetrachloroxanthene-9-ylidene) hexyl succinate (as a hapten) conjugated with bovine serum albumin (dioxin-BSA). Furthermore, ScFv was generated from hybridoma-producing IgG1 MAb. Among these antibodies, ScFv showed excellent capability for dioxin detection using QCM immunosensors.
Asunto(s)
Anticuerpos Monoclonales/química , Técnicas Biosensibles/instrumentación , Dioxinas/análisis , Inmunoensayo/instrumentación , Succinatos/química , Animales , Anticuerpos Monoclonales/inmunología , Técnicas Biosensibles/métodos , Dioxinas/química , Dioxinas/inmunología , Diseño de Equipo , Análisis de Falla de Equipo , Haptenos/química , Haptenos/inmunología , Inmunoensayo/métodos , Ratones , Ratones Endogámicos BALB C , Dibenzodioxinas Policloradas/química , Dibenzodioxinas Policloradas/inmunología , Succinatos/inmunología , Contaminantes Químicos del Agua/análisisRESUMEN
BACKGROUND: This study evaluates the pharmacokinetic and pharmacodynamic effects of a transdermally delivered insulin using novel CaCO(3)-nanoparticles in normal mice and those with diabetes. METHODS: CaCO3-nanoparticles encapsulating insulin (nanoinsulin) were transdermally applied to the back skin of normal ddY mice and dB/dB and kkAy mice with diabetes after fasting for 1 h. Serum insulin levels of ddY mice were analyzed by enzyme immunoassay, and blood glucose of normal mice and those with diabetes was monitored. RESULTS: Maximum serum insulin was 67.1 +/- 25.9 microIU/mL at 4 h with 200 microg of transdermal nanoinsulin in ddY mice, whereas that after subcutaneous injection of 3 microg of monomer insulin was 462 +/- 20.9 microIU/mL at 20 min. Transdermal nanoinsulin decreased glucose levels in a dose-dependent manner. A maximum decrease in blood glucose of 48.3 +/- 3.9% (ddY), 32.5 +/- 9.8% (dB/dB), and 26.2 +/- 7.6% (kkAy) after 6 h was observed with 200 microg of transdermal nanoinsulin, compared with 64.1+/-1.0% (ddY), 57.9 +/-3.4% (dB/dB), and 24.1 +/- 6.7% (kkAy) after 1 h with 3 microg of subcutaneous monomer insulin. Insulin bioavailability until 6 h with transdermal nanoinsulin in ddY mice was 0.9% based on serum insulin level and 2.0% on pharmacodynamic blood glucose-lowering effects. CONCLUSIONS: This CaCO(3)-nanoparticle system successfully delivered insulin transdermally, as evidenced by a significant sustained decrease in blood glucose in normal mice and those with diabetes. These results support the feasibility of developing transdermal nanoinsulin for human applications.
Asunto(s)
Carbonato de Calcio/administración & dosificación , Insulina/administración & dosificación , Insulina/sangre , Administración Cutánea , Animales , Insulina/farmacocinética , Ratones , Ratones Endogámicos , Nanoestructuras , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/sangreRESUMEN
We developed nanospheres for the intravenous injection that have had sustained release and targeting to the efficiently anti-inflammation effect. These nanospheres formed by poly(D,L-lactic/glycolic acid) (PLGA) or poly(D,L-lactic acid) (PLA), biodegradability and biocompatibility polymer, that were encapsulated betamethasone phosphate and zinc. Result of experimental inflammation models shown that there nanospheres increased effect by targeting to inflammatory sites and also promoted sustained release of betamethasone phosphate from the nanospheres. Moreover, the effect of nanospheres were stronger than clinical pharmaceutical preparation. We propose that these nanospheres are the pharmaceutical preparation to have efficient powerful inflammation action.