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1.
Ann Oncol ; 27(12): 2210-2215, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27681866

RESUMO

BACKGROUND: Treatment with sorafenib, although associated with inhibition of tumour growth and angiogenesis in in vivo studies, leads to up-regulation of pERK. The addition of MEK inhibition could potentially abrogate this effect and potentiate anti-tumour activity. This phase I study investigated the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK) and biomarker correlates of selumetinib combined with sorafenib in patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients with Child-Pugh (CP) score ≤7 were treated with 400 mg twice daily of sorafenib with escalating doses of selumetinib in a 3 + 3 study design. The dose-limiting toxicity (DLT) evaluation period was 28 days. PK of selumetinib was determined. Angiogenic effect was evaluated with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS: Twenty-seven patients of Asian ethnicity were enrolled. The MTD was selumetinib 75 mg daily with sorafenib 400 mg twice daily. DLT included grade 3 transaminitis, diarrhoea and fatigue. Most common treatment-related adverse events at MTD (all grades) were diarrhoea (85%), rash (59%), hypertension (44%), fatigue (30%), anorexia (22%) and hand-foot syndrome (22%). Four patients (15%) had PR and 13 (48%) had SD. PR or SD was observed for ≥6 months in seven patients. The median overall survival was 14.4 months. Selumetinib exposures in combination with sorafenib were comparable to other monotherapy studies. A reduction in permeability-surface area product noted in DCE-MRI with treatment correlated with worse survival outcomes. CONCLUSION: The MTD of selumetinib was 75 mg daily when combined with sorafenib 400 mg twice a day in CP ≤7 HCC. Acceptable adverse events and encouraging anti-tumour activity warrant further evaluation. DCE-MRI findings deserve prospective evaluation. CLINICALTRIALSGOV IDENTIFIER: NCT01029418.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzimidazóis/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/efeitos adversos , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Sorafenibe
3.
Neurosci Lett ; 398(1-2): 28-33, 2006 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-16443325

RESUMO

It has been well documented that oxidative stress is involved in stroke. Currently, many neuroprotective strategies have been targeted at molecules that are able to act as an oxidant to intervene with free-radical mediated apoptosis in the ischemic penumbra. In particular, natural products which contain antioxidant properties have undoubtedly efficacious for stroke treatment. In the current study, therapeutic effects of Ginkgo biloba extract (EGb) against cerebral protection in Wistar rats underwent middle cerebral artery occlusion (MCAO) was evaluated. A comparison study was conducted by using Losartan, an antihypertensive drug. Gene expression levels of pro-apoptotic genes (AT2 receptor, Fas, Bax and Bcl-xS) have shown to have significant reduction by EGb- and Losartan-treated groups as compared to vehicle group. Significant reduction of immunoreactivity of protein production of these genes, together with least nuclear green fluorescence observed in TUNEL, EGb, as an antioxidant drug, is concluded to have potent and promising therapeutic effect for stroke treatment.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Antioxidantes/uso terapêutico , Córtex Cerebral/efeitos dos fármacos , Ginkgo biloba , Losartan/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Animais , Apoptose , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/prevenção & controle , Masculino , Fitoterapia , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Receptor Tipo 2 de Angiotensina/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Proteína X Associada a bcl-2/biossíntese , Proteína bcl-X/biossíntese , Receptor fas/biossíntese
4.
J Mol Graph Model ; 22(6): 507-17, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15182810

RESUMO

Undesirable absorption, distribution, metabolism, excretion (ADME) properties are the cause of many drug development failures and this has led to the need to identify such problems earlier in the development process. This review highlights computational (in silico) approaches that have been used to identify the characteristics of ligands influencing molecular recognition and/or metabolism by the drug-metabolising enzyme UDP-gucuronosyltransferase (UGT). Current studies applying pharmacophore elucidation, 2D-quantitative structure metabolism relationships (2D-QSMR), 3D-quantitative structure metabolism relationships (3D-QSMR), and non-linear pattern recognition techniques such as artificial neural networks and support vector machines for modelling metabolism by UGT are reported. An assessment of the utility of in silico approaches for the qualitative and quantitative prediction of drug glucuronidation parameters highlights the benefit of using multiple pharmacophores and also non-linear techniques for classification. Some of the challenges facing the development of generalisable models for predicting metabolism by UGT, including the need for screening of more diverse structures, are also outlined.


Assuntos
Biologia Computacional , Desenho de Fármacos , Glucuronosiltransferase/farmacocinética , Simulação por Computador , Glucuronosiltransferase/metabolismo , Humanos , Estrutura Molecular , Preparações Farmacêuticas/química , Relação Quantitativa Estrutura-Atividade
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