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1.
Clin Pharmacol Drug Dev ; 12(6): 579-587, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36583544

RESUMO

This study aimed to evaluate the safety, pharmacokinetics, and pharmacodynamics of PPMX-T003, a novel human monoclonal antibody for transferrin receptor 1 (TFR1), in healthy individuals. Forty participants were enrolled and randomized to PPMX-T003 dose groups (n = 6/group) and the placebo group (n = 10). The safety and pharmacokinetics profiles were assessed according to the sequential, ascending single-dose intravenous infusions of PPMX-T003 from 0.008 mg/kg to 0.25 mg/kg. Adverse events (AEs) after PPMX-T003 administration occurred in 16 of 30 participants. Any severe AE and AE incidence were not reported, but they tended to increase depending on the dose. Laboratory tests, vital signs, and standard 12-lead electrocardiogram showed no clinically relevant changes. Five participants experienced an infusion-related reaction but recovered on days 5-10. Regarding pharmacokinetics, PPMX-T003 has a nonlinear elimination pattern. PPMX-T003 in the 0.25 mg/kg group showed apparent (>50%) decreased serum levels of reticulocytes from day 3 and sustained moderate (<10%) fall of hematocrit and hemoglobin counts from day 7. In conclusion, the antibody-mediated blockade of TFR1 elicited the expected fall in blood cell levels and showed an acceptable safety profile, supporting the continuing development of PPMX-T003 as a new candidate for polycythemia vera treatment.


Assuntos
Anticorpos Monoclonais , Antígenos CD , Humanos , Infusões Intravenosas , Método Duplo-Cego , Receptores da Transferrina
2.
Pharmacology ; 101(3-4): 148-155, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29275416

RESUMO

When the Kampo medicine, Hochuekkito (Hochu), was administered to normal mice for 2 weeks, influenza virus titer was reduced. The mechanism of action of Hochu was examined using the plaque assay method. It was suggested that Hochu may either obstruct the first stage of the infection process (adsorption and entry) or may directly target viral particles. Using the plaque assay method, these 2 modes of action could not be differentiated. Virus RNA in the infected cell was verified by quantitative real-time polymerase chain reaction. An equal inhibition effect was obtained when Hochu was preprocessed for normal cells and when they were made to act simultaneously with virus adsorption. The viral load at the cell surface following UV irradiation was higher in the Hochu-administered group as compared with that of the control. Moreover, the affinity of Hochu for the influenza virus was hundred times higher than its affinity for the host cell. The effect of entry obstruction by Hochu was observed via image analysis, where the amount of virus nucleocapsid protein (NP) invading the cell was visualized with FITC-labeled NP antibody. Hochu does not seem to have an effect on nucleic acid synthesis, viral release from infected cells, and on the subsequent second round of infection. In conclusion, Hochu binds to viral particles and forms complexes that can obstruct the entry of influenza virus into cells.


Assuntos
Antivirais/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Vírus da Influenza A Subtipo H1N1 , Infecções por Orthomyxoviridae/tratamento farmacológico , Animais , Linhagem Celular , Cães , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/crescimento & desenvolvimento , Vírus da Influenza A Subtipo H1N1/fisiologia , Células Madin Darby de Rim Canino , Masculino , Medicina Kampo , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/virologia , Fitoterapia , RNA Viral/análise , Vesiculovirus/crescimento & desenvolvimento , Ensaio de Placa Viral , Internalização do Vírus/efeitos dos fármacos
3.
Pharmacology ; 91(5-6): 314-21, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23796966

RESUMO

A Kampo medicine, Hochuekkito (TJ-41), with an influenza virus-preventing effect had life-extending effectiveness, and immunological responses other than interferon (IFN)-α release were examined. TJ-41 (1 g/kg) was given to C57BL/6 male mice orally once a day for 2 weeks. Mice were then intranasally infected with influenza virus. After infection, virus titers and various parameters, mRNA levels and protein expression, for immunoresponses in the bronchoalveolar lavage fluid or removed lung homogenate, were measured by plaque assay, quantitative RT-PCR and ELISA. IFN-α and -ß levels of TJ-41-treated mice were higher than those of the control. Toll-like receptor TLR7 and TLR9 mRNAs were elevated after infection, but retinoic acid-inducible gene (RIG-1) family mRNA levels, RIG-1, melanoma differentiation-associated gene 5 and Leishmania G protein 2 showed no response in either TJ-41 or control groups. Interferon regulatory transcription factor (IRF)-3 mRNA levels to stimulate type I (α/ß) IFN were increased, but IRF-7 did not change. Only granulocyte-macrophage colony-stimulating factor (GM-CSF) after Hochuekkito treatment was significantly elevated 2 and 3 days after infection. The mRNA levels of 7 defensins after infection increased compared to preinfection values. The key roles of TJ-41 were not only stimulation of type I IFN release but also GM-CSF-derived anti-inflammation activity. Furthermore, defensin (antimicrobial peptide) mRNA levels increased by infection and were further enhanced by TJ-41 treatment. Defensin might prevent influenza virus replication.


Assuntos
Antivirais/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Infecções por Orthomyxoviridae/tratamento farmacológico , Animais , Antivirais/farmacologia , Líquido da Lavagem Broncoalveolar/imunologia , Linhagem Celular , Citocinas/imunologia , Defensinas/genética , Cães , Medicamentos de Ervas Chinesas/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Vírus da Influenza A Subtipo H1N1/fisiologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Masculino , Medicina Kampo , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/imunologia , RNA Mensageiro/metabolismo , Replicação Viral/efeitos dos fármacos
4.
J Biol Chem ; 279(32): 33984-91, 2004 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-15150263

RESUMO

Autoimmune regulator (AIRE) is responsible for the development of organ-specific autoimmune disease in a monogenic fashion. Rare and low levels of tissue expression together with the lack of AIRE-expressing cell lines have hampered a detailed analysis of the molecular dynamics of AIRE. Here we have established cell lines stably transfected with AIRE and studied the regulatory mechanisms for its subcellular expression. We found that nuclear body (NB) formation by AIRE was dependent on the cell cycle. Biochemical fractionation revealed that a significant proportion of AIRE is associated with the nuclear matrix, which directs the functional domains of chromatin to provide sites for gene regulation. Upon proteasome inhibition, AIRE NBs were increased with concomitant reduced expression in the cytoplasm, suggesting that subcellular targeting of AIRE is regulated by a ubiquitin-proteasome pathway. We also found that AIRE NBs compete for cAMP-response element-binding protein-binding protein/p300, a common coactivator of transcription, with the promyelocytic leukemia gene product. These results suggest that the transcriptional regulating activities of AIRE within a cell are controlled and organized in a spatiotemporal manner.


Assuntos
Regulação da Expressão Gênica , Frações Subcelulares/metabolismo , Fatores de Transcrição/genética , Animais , Ligação Competitiva , Núcleo Celular/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Cisteína Endopeptidases/metabolismo , DNA Complementar/genética , Proteína p300 Associada a E1A , Inibidores Enzimáticos/farmacologia , Proteínas de Fluorescência Verde , Células HeLa , Humanos , Imuno-Histoquímica , Proteínas Luminescentes/genética , Camundongos , Complexos Multienzimáticos/antagonistas & inibidores , Complexos Multienzimáticos/metabolismo , Células NIH 3T3 , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Reação em Cadeia da Polimerase , Proteína da Leucemia Promielocítica , Complexo de Endopeptidases do Proteassoma , Proteínas Recombinantes de Fusão , Frações Subcelulares/ultraestrutura , Fatores de Tempo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Transfecção , Proteínas Supressoras de Tumor , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteína AIRE
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