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1.
Hepatol Commun ; 6(12): 3379-3392, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36271849

RESUMO

Rencofilstat (RCF) demonstrated antifibrotic effects in preclinical models and was safe and well tolerated in Phase 1 studies. The aim of this Phase 2a study was safety, tolerability, pharmacokinetics, and exploration of efficacy biomarkers in subjects with nonalcoholic steatohepatitis (NASH). This Phase 2a, multicenter, single-blind, placebo-controlled study randomized 49 presumed F2/F3 subjects to RCF 75 mg once daily (QD), RCF 225 mg QD, or placebo for 28 days. Primary safety and tolerability endpoints were explored using descriptive statistics with post hoc analyses comparing active to placebo groups. Pharmacokinetics were evaluated using population pharmacokinetics methods. Efficacy was explored using biomarkers, transcriptomics, and lipidomics. RCF was safe and well tolerated, with no safety signals identified. The most frequently reported treatment-emergent adverse events were constipation, diarrhea, back pain, dizziness, and headache. No clinically significant changes in laboratory parameters were observed, and RCF pharmacokinetics were unchanged in subjects with NASH. Alanine transaminase (ALT) reduction was greater in active subjects than in placebo groups. Nonparametric analysis suggested that ALT reductions were statistically different in the 225-mg cohort compared with matching placebo: -16.3 ± 25.5% versus -0.7 ± 13.4%, respectively. ProC3 and C6M reduction was statistically significant in groups having baseline ProC3 > 15.0 ng/ml. RCF was safe and well tolerated after 28 days in subjects with presumed F2/F3 NASH. Presence of NASH did not alter its pharmacokinetics. Reductions in ALT, ProC3, and C6M suggest direct antifibrotic effects with longer treatment duration. Reductions in key collagen genes support a mechanism of action via suppression and/or regression of collagen deposition. Conclusion: These results support advancement of rencofilstat into a larger and longer Phase 2b study.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Método Simples-Cego , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ciclofilinas/uso terapêutico , Método Duplo-Cego , Alanina Transaminase/uso terapêutico , Biomarcadores
2.
Tohoku J Exp Med ; 258(3): 219-223, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36047131

RESUMO

Telitacicept is a novel humanized, recombinant transmembrane activator and calcium modulator and cyclophilin ligand interactor and the Fc portion (TACI-Fc) fusion protein, designed to neutralize the activity of both B-cell lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL). On March 9, 2021, telitacicept received its first approval in China for the treatment of adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE). Additionally, on April 15, 2020, the U.S. Food and Drug Administration (FDA) granted fast track designation to telitacicept for the treatment of SLE. Clinical studies of telitacicept in several other indications, including IgA nephropathy, multiple sclerosis, myasthenia gravis, neuromyelitis optica spectrum disorders, rheumatoid arthritis and Sjögren's syndrome are underway in China. This is the first case that reports telitacicept successfully treated a SLE patient with refractory cutaneous involvement, which provides a potential therapeutic option for recalcitrant cutaneous manifestations of SLE. Furthermore, we review reported studies of BLyS targeted treatments for mucocutaneous lupus. Telitacicept appears to have activity in refractory cutaneous involvement of SLE and clinical trials are warranted to further assess this potential therapy.


Assuntos
Lúpus Eritematoso Sistêmico , Dermatopatias , Estados Unidos , Adulto , Humanos , Ligantes , Cálcio , Ciclofilinas/uso terapêutico , Fator Ativador de Células B/uso terapêutico , Lúpus Eritematoso Sistêmico/complicações , Imunossupressores/uso terapêutico
3.
Nat Commun ; 9(1): 4381, 2018 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-30348973

RESUMO

Maintaining innate immune homeostasis is important for individual health. Npl4 zinc finger (NZF) domain-mediated ubiquitin chain sensing is reported to function in the nuclear factor-kappa B (NF-κB) signal pathway, but the regulatory mechanism remains elusive. Here we show that cyclophilin J (CYPJ), a member of the peptidylprolyl isomerase family, is induced by inflammation. CYPJ interacts with the NZF domain of transform growth factor-ß activated kinase 1 binding protein 2 and 3 as well as components of the linear ubiquitin chain assembly complex to block the binding of ubiquitin-chain and negatively regulates NF-κB signaling. Mice with Cypj deficiency are susceptible to lipopolysaccharide and heat-killed Listeria monocytogenes-induced sepsis and dextran sulfate sodium-induced colitis. These findings identify CYPJ as a negative feedback regulator of the NF-κB signaling pathway, and provide insights for understanding the homeostasis of innate immunity.


Assuntos
Colite/imunologia , Ciclofilinas/uso terapêutico , Sepse/imunologia , Ubiquitina/metabolismo , Animais , Chlorocebus aethiops , Colite/induzido quimicamente , Colite/tratamento farmacológico , Sulfato de Dextrana/toxicidade , Citometria de Fluxo , Células HEK293 , Células HeLa , Humanos , Lipopolissacarídeos/toxicidade , Listeria monocytogenes/patogenicidade , Camundongos , Microscopia Confocal , NF-kappa B , Poliubiquitina/metabolismo , Ligação Proteica , Interferência de RNA , Sepse/tratamento farmacológico , Sepse/microbiologia , Transdução de Sinais/efeitos dos fármacos , Células Vero
4.
Biomolecules ; 7(4)2017 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-28961224

RESUMO

Analyses of sequences and structures of the cyclosporine A (CsA)-binding proteins (cyclophilins) and the immunosuppressive macrolide FK506-binding proteins (FKBPs) have revealed that they exhibit peculiar spatial distributions of charges, their overall hydrophobicity indexes vary within a considerable level whereas their points isoelectric (pIs) are contained from 4 to 11. These two families of peptidylprolyl cis/trans isomerases (PPIases) have several distinct functional attributes such as: (1) high affinity binding to some pharmacologically-useful hydrophobic macrocyclic drugs; (2) diversified binding epitopes to proteins that may induce transient manifolds with altered flexibility and functional fitness; and (3) electrostatic interactions between positively charged segments of PPIases and negatively charged intracellular entities that support their spatial integration. These three attributes enhance binding of PPIase/pharmacophore complexes to diverse intracellular entities, some of which perturb signalization pathways causing immunosuppression and other system-altering phenomena in humans.


Assuntos
Ciclofilinas/química , Portadores de Fármacos/uso terapêutico , Peptidilprolil Isomerase/química , Proteínas de Ligação a Tacrolimo/química , Ciclofilinas/imunologia , Ciclofilinas/uso terapêutico , Portadores de Fármacos/química , Epitopos/química , Epitopos/imunologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Terapia de Imunossupressão , Compostos Macrocíclicos/imunologia , Compostos Macrocíclicos/uso terapêutico , Peptidilprolil Isomerase/imunologia , Peptidilprolil Isomerase/uso terapêutico , Eletricidade Estática , Proteínas de Ligação a Tacrolimo/imunologia , Proteínas de Ligação a Tacrolimo/uso terapêutico
5.
Curr Opin Virol ; 24: 1-8, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28411509

RESUMO

Enteroviruses (e.g., poliovirus, enterovirus-A71, coxsackievirus, enterovirus-D68, rhinovirus) include many human pathogens causative of various mild and more severe diseases, especially in young children. Unfortunately, antiviral drugs to treat enterovirus infections have not been approved yet. Over the past decades, several direct-acting inhibitors have been developed, including capsid binders, which block virus entry, and inhibitors of viral enzymes required for genome replication. Capsid binders and protease inhibitors have been clinically evaluated, but failed due to limited efficacy or toxicity issues. As an alternative approach, host-targeting inhibitors with potential broad-spectrum activity have been identified. Furthermore, drug repurposing screens have recently uncovered promising new inhibitors with disparate viral and host targets. Together, these findings raise hope for the development of (broad-range) anti-enteroviral drugs.


Assuntos
Antivirais/uso terapêutico , Infecções por Enterovirus/tratamento farmacológico , Enterovirus/efeitos dos fármacos , Animais , Antivirais/administração & dosagem , Capsídeo/efeitos dos fármacos , Ciclofilinas/uso terapêutico , Reposicionamento de Medicamentos , Humanos , Camundongos , Poliovirus/efeitos dos fármacos , Inibidores de Proteases/uso terapêutico , Rhinovirus/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
6.
J Immunother ; 25(5): 439-44, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12218782

RESUMO

Cyclophilin B (CypB) possesses two antigenic epitopes (CypB(84-92) and CypB(91-99) ) recognized by HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes (CTLs). To determine the safety of CypB-derived peptides and its ability to generate antitumor immune responses, patients with advanced lung cancer received subcutaneous vaccinations of these peptides or their modified peptides. All 16 patients were vaccinated with CypB(91-99) or its modified peptide, whereas only two patients were vaccinated with the modified CypB(84-92), as immediate-type hypersensitivity to CypB(84-92) or its modified peptide was observed in the remaining patients. No severe adverse events were associated with the vaccination. No significant increase in cellular responses to either peptides or tumor cells was observed in the postvaccination PBMCs by the conventional CTL assays in any patients tested. These results suggest that the vaccination of CypB(91-99) peptide was safe, but failed to induce objective immune responses at this regimen.


Assuntos
Vacinas Anticâncer/uso terapêutico , Ciclofilinas/uso terapêutico , Neoplasias Pulmonares/terapia , Adulto , Idoso , Vacinas Anticâncer/efeitos adversos , Ciclofilinas/efeitos adversos , Feminino , Humanos , Imunidade Celular , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade , Peptidilprolil Isomerase , Segurança , Linfócitos T Citotóxicos/imunologia , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/uso terapêutico
7.
Expert Opin Biol Ther ; 1(1): 67-77, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11727548

RESUMO

Heat shock proteins (Hsps), cyclophilins (Cyps) and FK binding proteins (FKBPs) form a family of intracellular chaperone molecules that facilitate protein folding and assembly. These stress proteins are selectively expressed in cells in response to a range of stimuli, including heat, lymphokine and microbial/viral infections. This review discusses the role of stress proteins in the HIV-1 viral life cycle, with regard to the development of specific Hsp-based therapeutic strategies against HIV-1 infection. Cumulative findings are cited implicating CypA, Hsp27, Hsp70 and FKBPs in host cell and viral activation, viral entry, assembly or formation of infectious virions. Biological response modifiers that show specific high-affinity interactions with Cyp, FKBPs and Hsps, including cyclosporins, FK-506 and cyclopentenone prostaglandins respectively, may block HIV-1 replication and infection, providing novel HIV-1 therapeutic strategies. Moreover, Hsp binding to viral complexes can enhance antiviral immunity, including natural killer (NK), antibody-dependent (ADCC), gamma delta T-cell and cytotoxic T-lymphocyte (CTL) activities against HIV-1 infected cells. The ability of Hsps to interact with HIV-1 viral proteins, combined with their inherent adjuvant and immunogenic properties indicates that Hsps may also serve as vehicles for antigen delivery and the design of AIDS vaccines.


Assuntos
Síndrome da Imunodeficiência Adquirida/prevenção & controle , Infecções por HIV/tratamento farmacológico , Proteínas de Choque Térmico/uso terapêutico , Vacinas , Animais , Ciclofilinas/uso terapêutico , Ciclosporinas/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Modelos Biológicos , Chaperonas Moleculares
8.
Nihon Rinsho ; 59(1): 81-4, 2001 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-11197867

RESUMO

The gene therapy or the immunotherapy targeting specific molecule(s) have just introduced into the clinical field in Japan. The first gene therapy for the human lung cancer is underway; an adenoviral vector harboring wild type p53 gene is intratumorally injected. A cancer immunotherapy using the Cyclophilin B derived peptide is in the phase I clinical trial. As the next generation cancer therapies, a variety of strategies are planned and investigated at the laboratory level. They range from the usage of a new viral vector to the introduction of genes with specific biological functions into the cells. In this article, by reviewing the possible approach, an ideal combination of the future remedies is discussed.


Assuntos
Terapia Genética , Neoplasias Pulmonares/terapia , Adenoviridae/genética , Terapia Combinada , Ciclofilinas/uso terapêutico , Genes p53 , Terapia Genética/métodos , Vetores Genéticos , Genoma Humano , Genômica , Projeto Genoma Humano , Humanos , Imunoterapia , Peptidilprolil Isomerase
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