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1.
Cancer Chemother Pharmacol ; 78(2): 405-17, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27349901

RESUMO

PURPOSE: This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and antitumor activity of the Aurora B kinase inhibitor BI 811283 in patients with advanced solid tumors. METHODS: BI 811283 was administered via 24-h infusion on Days 1 and 15 of a 4-week cycle (schedule A) or Day 1 of a 3-week cycle (schedule B) in a modified 3 + 3 dose-escalation design. Pharmacodynamic assessments included immunohistochemistry for phosphorylated histone H3 (pHH3) on skin biopsies to determine Aurora B kinase inhibition and plasma concentrations of caspase-cleaved CK-18 (apoptosis marker). RESULTS: A total of 121 patients were treated. The MTDs of BI 811283 were 125 mg (schedule A) and 230 mg (schedule B). Dose-limiting toxicities were primarily hematological (febrile neutropenia and grade 4 neutropenia); the most common drug-related adverse effects included neutropenia, fatigue, leukopenia, nausea, alopecia, diarrhea, and decreased appetite. A trend toward a decrease in pHH3 was observed, with increasing BI 811283 doses, indicating target engagement; there was no consistent trend regarding caspase-cleaved CK-18 levels. No objective response was observed although 19 patients in each schedule achieved clinical benefit (stable disease). CONCLUSIONS: BI 811283 demonstrated a generally manageable safety profile and disease stabilization in some patients. TRIAL REGISTRATION: EudraCT No: 2007-000191-17, ClinicalTrials.gov Identifier: NCT00701324.


Assuntos
Antineoplásicos/administração & dosagem , Aurora Quinase B/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Imuno-Histoquímica , Queratina-18/sangue , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Resultado do Tratamento , Adulto Jovem
2.
J Chem Ecol ; 28(7): 1315-27, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12199498

RESUMO

Gas chromatographic and mass spectroscopic analyses of extracts of cantharidin-containing meloid, clerid, and staphylinid beetles revealed the presence of minor to significant amounts of palasonin, previously only known from seeds and fruits of the Indian shrub Buteafrondosa (Leguminaceae). Unlike (S)-(-)-palasonin (> 99% ee) from B. frondosa, the insects produce palasonin of low ee with the (R)-(+)-enantiomer (0-50% ee) prevailing. The ee of palasonin from individual specimens of predatory insects (Trichodes apiarius), which acquire their chemical protection from cantharidin-producing insects, may vary considerably. The absolute configuration of (S)-(-)-palasonin, previously deduced from indirect chemical and spectroscopic methods, was confirmed by X-ray crystal structure analysis of a cyclic imide derived from (S)-(-)-palasonin and (S)-(-)- 1 -(4-nitrophenyl)-ethylamine.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , Cantaridina/química , Besouros/química , Compostos de Epóxi/química , Fabaceae/química , Irritantes/química , Animais , Hidrocarbonetos Aromáticos com Pontes/isolamento & purificação , Cantaridina/isolamento & purificação , Compostos de Epóxi/isolamento & purificação , Frutas/química , Cromatografia Gasosa-Espectrometria de Massas , Hemolinfa/química , Irritantes/isolamento & purificação , Plantas Comestíveis/química , Sementes/química
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