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1.
Clin Transl Sci ; 17(5): e13789, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38761014

RESUMO

This first-in-human study evaluated the safety, tolerability, single- and multiple-dose pharmacokinetic profiles with dietary influence, and pharmacodynamics (PD) of DFV890, an oral NLRP3 inhibitor, in healthy participants. In total, 122 participants were enrolled into a three-part trial including single and 2-week multiple ascending oral doses (SAD and MAD, respectively) of DFV890, and were randomized (3:1) to DFV890 or placebo (SAD [3-600 mg] and MAD [fasted: 10-200 mg, once-daily or fed: 25 and 50 mg, twice-daily]). DFV890 was generally well-tolerated. Neither deaths nor serious adverse events were reported. A less than dose-proportional increase in exposure was observed with the initially used crystalline suspension (3-300 mg); however, an adjusted suspension formulation using spray-dried dispersion (SDD; 100-600 mg) confirmed dose-proportional increase in exposure. Relative bioavailability between crystalline suspension and tablets, and food effect were evaluated at 100 mg. Under fasting conditions, Cmax of the tablet yielded 78% compared with the crystalline suspension, and both formulations showed comparable AUC. The fed condition led to a 2.05- and 1.49-fold increase in Cmax and AUC0-last compared with the fasting condition. The median IC50 and IC90 for ex-vivo lipopolysaccharide-stimulated interleukin IL-1ß release inhibition (PD) were 61 (90% CI: 50, 70) and 1340 ng/mL (90% CI: 1190, 1490). Crystalline tablets of 100 mg once-daily or 25 mg twice-daily were sufficient to maintain ~90% of the IL-1ß release inhibition over 24 h at steady state. Data support dose and formulation selection for further development in diseases, in which an overactivated NLRP3 represents the underlying pathophysiology.


Assuntos
Relação Dose-Resposta a Droga , Interleucina-1beta , Proteína 3 que Contém Domínio de Pirina da Família NLR , Humanos , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Adulto , Feminino , Administração Oral , Pessoa de Meia-Idade , Adulto Jovem , Interleucina-1beta/metabolismo , Voluntários Saudáveis , Interações Alimento-Droga , Método Duplo-Cego , Disponibilidade Biológica , Adolescente , Esquema de Medicação
2.
Clin Ther ; 38(12): 2589-2597, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27823869

RESUMO

PURPOSE: The conduct of thorough QTc (TQT) studies is often challenging with compounds that are characterized by limited tolerability in healthy individuals. This is applicable to several central nervous system drugs, including mavoglurant acting as a selective allosteric modulator of metabotropic glutamate receptor 5. This TQT study describes the use of a single intravenous dosing regimen as an alternate approach allowing for sufficiently high Cmax values while controlling tolerability. METHODS: This study was a randomized, placebo- and active-controlled, 4-period, crossover, TQT study composed of 2 sequential phases. In the pilot phase, the safety and tolerability profile of 10-minute infusions of 25, 37.5, and 50 mg of mavoglurant was assessed in 36 healthy individuals. In the TQT phase, individuals received in random sequence single intravenous doses of mavoglurant (25 and 50 mg) and placebo and an oral dose of moxifloxacin (400 mg). FINDINGS: Mavoglurant was well tolerated up to a single intravenous dose of 50 mg, and supratherapeutic Cmax values were achieved that were approximately 2-fold higher than at the multiple maximum tolerated dose and more than 3-fold higher relative to therapeutic plasma concentrations. The upper bound of the 2-sided 90% CI of Fridericia-corrected placebo- and baseline-adjusted QTc intervals (QTcFs) did not exceed 10 milliseconds at any postdose time point for both mavoglurant doses. The pharmacokinetic and pharmacodynamic analysis confirmed the lack of an association between mavoglurant plasma concentrations and ΔΔQTcF data over the entire range of plasma concentration data at 25 and 50 mg of mavoglurant. An outlier analysis revealed no individuals with newly identified QTcF intervals >480 milliseconds or any QTcF prolongations >60 milliseconds compared with baseline in any of the treatment groups. Hence, the lack of any clinically relevant QTc prolongation was found for therapeutic and supratherapeutic single intravenous doses of 25 and 50 mg of mavoglurant. IMPLICATIONS: This TQT study describes the use of single intravenous dosing as an alternate approach to achieve supratherapeutic plasma concentrations as required per the International Council for Harmonisation E14 guideline with compounds characterized by exposure related tolerability limitations. The increased Cmax/AUC ratio compared with conventional oral dosing may contribute to a reduced incidence of adverse events that appear more related to overall exposure.


Assuntos
Coração/efeitos dos fármacos , Indóis/farmacologia , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Administração Intravenosa , Adulto , Regulação Alostérica , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia , Fluoroquinolonas/farmacologia , Coração/fisiologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Humanos , Indóis/farmacocinética , Masculino , Moxifloxacina , Projetos Piloto
3.
Mol Cancer Ther ; 10(9): 1611-23, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21697397

RESUMO

TNF-related apoptosis-inducing ligand (TRAIL) kills tumor cells selectively. We asked how emerging tumor cells escape elimination by TRAIL and how tumor-specific killing by TRAIL could then be restored. We found that TRAIL expression is consistently downregulated in HRAS(G12V)-transformed cells in stepwise tumorigenesis models derived from four different tissues due to DNA hypermethylation of CpG clusters within the TRAIL promoter. Decitabine de-silenced TRAIL, which remained inducible by interferon, while induction of TRAIL by blocking the HRAS(G12V)-activated mitogen-activated protein kinase pathway was subordinated to epigenetic silencing. Decitabine induced apoptosis through upregulation of endogenous TRAIL in cooperation with favorable regulation of key players acting in TRAIL-mediated apoptosis. Apoptosis induction by exogenously added TRAIL was largely increased by decitabine. In vivo treatment of xenografted human HRAS(G12V)-transformed human epithelial kidney or syngenic mice tumors by decitabine blocked tumor growth induced TRAIL expression and apoptosis. Our results emphasize the potential of decitabine to enhance TRAIL-induced apoptosis in tumors and thus provide a rationale for combination therapies with decitabine to increase tumor-selective apoptosis.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Azacitidina/análogos & derivados , Transformação Celular Neoplásica/genética , Metilação de DNA/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inativação Gênica , Ligante Indutor de Apoptose Relacionado a TNF/genética , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Linhagem Celular Transformada , Linhagem Celular Tumoral , Decitabina , Regulação para Baixo/genética , Inibidores Enzimáticos/uso terapêutico , Epigênese Genética , Regulação da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Interferons/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Int J Biochem Cell Biol ; 40(1): 1-8, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-17951100

RESUMO

The large majority of today's cancer therapies are based on the removal of solid tumor masses (for example by surgery when possible) and a plethora of chemical or physical treatments such as chemo- and radiotherapy which induce death of particularly sensitive or rapidly growing cells. These approaches are variously combined in order to optimize therapeutic indices. While in some cases, such as childhood leukemia, these treatments may cure patients, it is common knowledge that they are associated with serious side effects. The main conceptual reason for this is that neither cancer cells nor the cancer cause(s) are directly targeted. In addition to a high toxicity and a low quality of life, these traditional therapies can give rise to therapy-induced secondary cancers. Here we will neither discuss the various optimization possibilities nor arguments for and against established therapies. Rather we want to reflect about recent advances, challenges and perspectives of cancer therapeutic concepts which aim at increasing cancer-selectivity. More precisely, we will discuss two such concepts from a cell biological and molecular oncology perspective, namely to (i) target the cause of the cancer and (ii) to (re)activate specific endogenous pathways for cancer cell-selective apoptosis.


Assuntos
Neoplasias/terapia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/efeitos da radiação , Terapia Combinada/tendências , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Imunoterapia/tendências , Camundongos , Neoplasias/imunologia , Neoplasias/patologia , Radioterapia/tendências , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação
5.
Nat Med ; 11(1): 77-84, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15619633

RESUMO

Chromatin is a dynamic macromolecular structure epigenetically modified to regulate specific gene expression. Altered chromatin function can lead to aberrant expression of growth regulators and may, ultimately, cause cancer. That many human diseases have epigenetic etiology has stimulated the development of 'epigenetic' therapies. Inhibitors of histone deacetylases (HDACIs) induce proliferation arrest, maturation and apoptosis of cancer cells, but not normal cells, in vitro and in vivo, and are currently being tested in clinical trials. We investigated the mechanism(s) underlying this tumor selectivity. We report that HDACIs induce, in addition to p21, expression of TRAIL (Apo2L, TNFSF10) by directly activating the TNFSF10 promoter, thereby triggering tumor-selective death signaling in acute myeloid leukemia (AML) cells and the blasts of individuals with AML. RNA interference revealed that the induction of p21, TRAIL and differentiation are separable activities of HDACIs. HDACIs induced proliferation arrest, TRAIL-mediated apoptosis and suppression of AML blast clonogenicity irrespective of French-American-British (FAB) classification status, karyotype and immunophenotype. No apoptosis was seen in normal CD34(+) progenitor cells. Our results identify TRAIL as a mediator of the anticancer action of HDACIs.


Assuntos
Apoptose/efeitos dos fármacos , Inibidores de Histona Desacetilases , Leucemia Mieloide/tratamento farmacológico , Glicoproteínas de Membrana/metabolismo , Receptores de Superfície Celular/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Doença Aguda , Proteínas Reguladoras de Apoptose , Humanos , Ligante Indutor de Apoptose Relacionado a TNF , Proteína Supressora de Tumor p53/metabolismo
6.
EMBO J ; 23(15): 3051-60, 2004 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-15241475

RESUMO

Retinoids and interferons are signaling molecules with pronounced anticancer activity. We show that in both acute promyelocytic leukemia and breast cancer cells the retinoic acid (RA) and interferon signaling pathways converge on the promoter of the tumoricidal death ligand TRAIL. Promoter mapping, chromatin immunoprecipitation and RNA interference reveal that retinoid-induced interferon regulatory factor-1 (IRF-1), a tumor suppressor, is critically required for TRAIL induction by both RA and IFNgamma. Exposure of breast cancer cells to both antitumor agents results in enhanced TRAIL promoter occupancy by IRF-1 and coactivator recruitment, leading to strong histone acetylation and synergistic induction of TRAIL expression. In coculture experiments, pre-exposure of breast cancer cells to RA and IFNgamma induced a dramatic TRAIL-dependent apoptosis in heterologous cancer cells in a paracrine mode of action, while normal cells were not affected. Our results identify a novel TRAIL-mediated tumor suppressor activity of IRF-1 and suggest a mechanistic basis for the synergistic antitumor activities of certain retinoids and interferons. These data argue for combination therapies that activate the TRAIL pathway to eradicate tumor cells.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ligação a DNA/metabolismo , Interferon gama/farmacologia , Glicoproteínas de Membrana/metabolismo , Fosfoproteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tretinoína/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Reguladoras de Apoptose , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Fator Regulador 1 de Interferon , Leucemia/metabolismo , Leucemia/patologia , Glicoproteínas de Membrana/genética , Regiões Promotoras Genéticas/genética , Ligante Indutor de Apoptose Relacionado a TNF , Fator de Necrose Tumoral alfa/genética
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