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1.
Future Oncol ; 15(23): 2769-2777, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31401844

RESUMO

Dacomitinib is a second-generation EGFR tyrosine kinase inhibitor (TKI) that irreversibly binds to and inhibits EGFR/Her1, Her2 and Her4 subtypes with an efficacy comparable to other TKIs. In the ARCHER 1050 trial, progression-free survival was improved by dacomitinib compared with gefitinib, supporting dacomitinib as a first-line treatment option for advanced non-small-cell lung cancer with sensitive EGFR mutation. Regarding to the higher adverse events rate, dose reductions did not reduce the efficacy of dacomitinib and could effectively decreased the incidence and severity of adverse events. Considering the evolving landscape of EGFR-mutant non-small-cell lung cancer, future head to head comparison between dacomitinib and osimertinib could provide key information to determine the optimal TKI treatment schedule.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinonas/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Gefitinibe/uso terapêutico , Intervalo Livre de Progressão , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-4/antagonistas & inibidores
2.
Int J Mol Sci ; 20(16)2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31443187

RESUMO

Background: New treatments are needed to reduce myocardial infarct size (MI) and prevent heart failure (HF) following acute myocardial infarction (AMI), which are the leading causes of death and disability worldwide. Studies in rodent AMI models showed that genetic and pharmacological inhibition of mitochondrial fission, induced by acute ischemia and reperfusion, reduced MI size. Whether targeting mitochondrial fission at the onset of reperfusion is also cardioprotective in a clinically-relevant large animal AMI model remains to be determined. Methods: Adult pigs (30-40 kg) were subjected to closed-chest 90-min left anterior descending artery ischemia followed by 72 h of reperfusion and were randomized to receive an intracoronary bolus of either mdivi-1 (1.2 mg/kg, a small molecule inhibitor of the mitochondrial fission protein, Drp1) or vehicle control, 10-min prior to reperfusion. The left ventricular (LV) size and function were both assessed by transthoracic echocardiography prior to AMI and after 72 h of reperfusion. MI size and the area-at-risk (AAR) were determined using dual staining with Tetrazolium and Evans blue. Heart samples were collected for histological determination of fibrosis and for electron microscopic analysis of mitochondrial morphology. Results: A total of 14 pigs underwent the treatment protocols (eight control and six mdivi-1). Administration of mdivi-1 immediately prior to the onset of reperfusion did not reduce MI size (MI size as % of AAR: Control 49.2 ± 8.6 vs. mdivi-1 50.5 ± 11.4; p = 0.815) or preserve LV systolic function (LV ejection fraction %: Control 67.5 ± 0.4 vs. mdivi-1 59.6 ± 0.6; p = 0.420), when compared to vehicle control. Similarly, there were no differences in mitochondrial morphology or myocardial fibrosis between mdivi-1 and vehicle control groups. Conclusion: Our pilot study has shown that treatment with mdivi-1 (1.2 mg/kg) at the onset of reperfusion did not reduce MI size or preserve LV function in the clinically-relevant closed-chest pig AMI model. A larger study, testing different doses of mdivi-1 or using a more specific Drp1 inhibitor are required to confirm these findings.


Assuntos
Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Quinazolinonas/uso terapêutico , Animais , Modelos Animais de Doenças , Ecocardiografia , Feminino , Dinâmica Mitocondrial/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Projetos Piloto , Suínos , Função Ventricular Esquerda/efeitos dos fármacos
3.
Int J Mol Sci ; 20(13)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261724

RESUMO

Neurodegeneration caused with retinal ischemia or high intraocular pressure is irreversible in general. We have focused on the role of hypoxia-inducible factor (HIF) in retinal homeostasis and revealed that HIF inhibition may be effective against retinal neovascular and neurodegeneration. In this study, we performed in vitro screening of natural products and found halofuginone, which is a derivative of febrifugine extracted from hydrangea, as a novel HIF inhibitor. Administration of halofuginone showed a significant neuroprotective effect by inhibiting HIF-1α expression in a murine retinal ischemia-reperfusion model histologically and functionally. These results indicate that halofuginone can be a neuroprotective agent in ischemic retinal degenerative diseases.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Fármacos Neuroprotetores/uso terapêutico , Piperidinas/uso terapêutico , Quinazolinonas/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Degeneração Retiniana/tratamento farmacológico , Células 3T3 , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/complicações , Degeneração Retiniana/etiologia , Vasos Retinianos/patologia
4.
Mediators Inflamm ; 2019: 7329131, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31263382

RESUMO

Apoptosis of CD4+ T cells plays a central role in the progression of sepsis because it is associated with subsequent immunosuppression and the lack of specific treatment. Thus, developing therapeutic strategies to attenuate the apoptosis of CD4+ T cells in sepsis is critical. Several studies have demonstrated that Mdivi-1, which is a selective inhibitor of the dynamin-related protein 1 (Drp1), attenuates apoptosis of myocardial cells and neurons during various pathologic states. The present study revealed the impact of Mdivi-1 on the apoptosis of CD4+ T cells in sepsis and the potential underlying mechanisms. We used lipopolysaccharide (LPS) stimulation and cecal ligation and puncture (CLP) surgery as sepsis models in vitro and in vivo, respectively. Our results showed that Mdivi-1 attenuated the apoptosis of CD4+ T cells both in vitro and in vivo. The potential mechanism underlying the protective effect of Mdivi-1 involved Mdivi-1 reestablishing mitochondrial fusion-fission balance in sepsis, as reflected by the expression of the mitofusin 2 (MFN2) and optic atrophy 1 (OPA1) , Drp1 translocation, and mitochondrial morphology, as observed by electron microscopy. Moreover, Mdivi-1 treatment reduced reactive oxygen species (ROS) production and prevented the induction of endoplasmic reticulum stress (ERS) and associated apoptosis. After using tunicamycin to activate ER stress, the protective effect of Mdivi-1 on CD4+ T cells was reversed. Our results suggested that Mdivi-1 ameliorated apoptosis in CD4+ T cells by reestablishing mitochondrial fusion-fission balance and preventing the induction of endoplasmic reticulum stress in experimental sepsis.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Quinazolinonas/uso terapêutico , Sepse/tratamento farmacológico , Sepse/metabolismo , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , GTP Fosfo-Hidrolases/metabolismo , Humanos , Marcação In Situ das Extremidades Cortadas , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Transmissão , Dinâmica Mitocondrial/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Atrofia Óptica Autossômica Dominante/metabolismo , Espécies Reativas de Oxigênio/metabolismo
5.
Drugs Today (Barc) ; 55(4): 231-236, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31050691

RESUMO

Dacomitinib (PF-00299804, Vizimpro) was developed as a second-generation, oral, irreversible inhibitor of human epidermal growth factor receptor (EGFR)- 1, -2 and -4 tyrosine kinase. On September 27, 2018, the United States Food and Drug Administration (FDA) approved dacomitinib for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletion or exon 21 L858R substitution mutations. On January 8, 2019, the Ministry of Health, Labour and Welfare of Japan approved this second-generation EGFR tyrosine kinase inhibitor (TKI) for the treatment of EGFR mutation-positive inoperable or recurrent NSCLC. The European Commission also approved dacomitinib on April 3, 2019, as monotherapy for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR activating mutations. Approval of dacomitinib was based on a randomized, multicenter, open-label, active-controlled trial (ARCHER 1050; ClinicalTrials.gov Identifier NCT01774721) which demonstrated the safety and efficacy of dacomitinib compared to gefitinib in 452 patients with unresectable and metastatic NSCLC. Dacomitinib represents a powerful new treatment option compared with first-generation EGFR-TKIs. In this paper, we review the clinical and preclinical studies of dacomitinib and discuss the drug's clinical value.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinonas/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Humanos , Mutação , Recidiva Local de Neoplasia , Proteínas Tirosina Quinases/antagonistas & inibidores , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
Drugs ; 79(8): 823-831, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31069718

RESUMO

The use of targeted therapy in the management of epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer is an important milestone in the management of advanced lung cancer. There are several generations of EGFR tyrosine kinase inhibitors available for clinical use. Dacomitinib is a second-generation irreversible EGFR tyrosine kinase inhibitor with early-phase clinical studies showing efficacy in non-small-cell lung cancer. In the recently published ARCHER 1050 phase III study, dacomitinib given at 45 mg/day orally was superior to gefitinib, a first-generation reversible EGFR tyrosine kinase inhibitor, in improving both progression-free survival and overall survival when given as first-line therapy. There is no prospective evidence to support the use of dacomitinib as subsequent therapy in patients previously treated with chemotherapy or a first-generation EGFR tyrosine kinase inhibitor such as gefitinib and erlotinib. Dacomitinib has not demonstrated any benefit in unselected patients with non-small-cell lung cancer, and its use should be limited to those with known EGFR-sensitizing mutations. Dacomitinib is associated with increased toxicities of diarrhea, rash, stomatitis, and paronychia compared with first-generation EGFR inhibitors. Global quality of life was maintained when assessed in phase III studies. Overall, dacomitinib is an important first- line agent in EGFR-mutated non-small-cell lung cancer in otherwise fit patients whose toxicities can be well managed.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinonas/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Intervalo Livre de Doença , Cloridrato de Erlotinib/uso terapêutico , Gefitinibe/uso terapêutico , Humanos , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Qualidade de Vida , Quinazolinonas/administração & dosagem , Quinazolinonas/farmacologia
7.
Lancet Haematol ; 6(7): e366-e374, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31109827

RESUMO

BACKGROUND: Clinically validated prognostic models for overall survival do not exist for patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) who are on targeted therapies. We aimed to create a prognostic model to identify high-risk individuals who do not achieve a good outcome with available targeted therapies. METHODS: In this retrospective, pooled cohort study, 2475 patients with CLL treated between June 22, 2012, and Sept 23, 2015, in six randomised trials of ibrutinib, idelalisib, and venetoclax, or at the Mayo Clinic CLL Database (MCCD) were included. Eligible patients had CLL, were previously treated, were aged 18 years or older, had ECOG performance status 0-1, and required further treatment as per the international workshop on CLL 2008 criteria. There was heterogeneity in other eligibility criteria. We evaluated 28 candidate factors known to affect the overall survival of these patients and applied univariate and multivariate analyses to derive the risk score in a training dataset (n=727) of patients treated with ibrutinib or chemoimmunotherapy. We validated the score in an internal-validation dataset (n=242) of patients treated with ibrutinib or chemoimmunotherapy and three external-validation datasets (idelalisib or chemoimmunotherapy dataset, n=897; venetoclax or chemoimmunotherapy dataset, n=389; and the MCCD [including patients treated with heterogeneous therapies], n=220), applying C-statistics as a measure of discrimination. FINDINGS: The derived model consisted of four factors (one point each; serum ß2-microglobulin ≥5 mg/dL, lactate dehydrogenase >upper limit of normal, haemoglobin <110 g/L for women or <120 g/L for men, and time from initiation of last therapy <24 months), separating patients into low (score 0-1), intermediate (score 2-3), and high risk (score 4) groups. The risk score was prognostic for overall survival in the training dataset (CS=0·74, 95% CI 0·60-0·85, log-rank p<0·0001), and in the internal-validation (CS=0·79, 0·56-0·97, log-rank p=0·0003), and all three external-validation cohorts (idelalisib or chemoimmunotherapy: CS=0·71, 0·59-0·81, log-rank p<0·0001; venetoclax or chemoimmunotherapy: CS =0·76, 0·66-0·85, log-rank p=0·014; MCCD cohort: CS=0·61, 0·56-0·66), log-rank p<0·0001). The risk score is available on Calculate by QxMD. INTERPRETATION: We present the first validated risk score to predict overall survival in patients with relapsed or refractory CLL treated with targeted therapy. The model is applicable to patients treated with all currently approved targeted therapies (ibrutinib, idelalisib, and venetoclax) and chemoimmunotherapy. This tool allows the identification of a well defined cohort of previously treated patients with CLL who are at high risk of death, and could be used in future prospective trials to test therapeutic options for these patients with an unmet clinical need. FUNDING: Lymphoma Research Foundation, Lymphoma Research Fund (Andrew D Zelenetz), and National Institutes of Health/National Cancer Institute.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia , Leucemia Linfocítica Crônica de Células B/terapia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Bases de Dados Factuais , Feminino , Hemoglobinas/análise , Humanos , L-Lactato Desidrogenase/sangue , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Quinazolinonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Fatores de Risco , Sulfonamidas/uso terapêutico , Taxa de Sobrevida , Microglobulina beta-2/sangue
8.
Cell Oncol (Dordr) ; 42(4): 491-504, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31025257

RESUMO

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is the fourth most common cause of cancer-related death in the USA. Local progression, early tumor dissemination and low efficacy of current treatments are the major reasons for its high mortality rate. The ERBB family is over-expressed in PDAC and plays essential roles in its tumorigenesis; however, single-targeted ERBB inhibitors have shown limited activity in this disease. Here, we examined the anti-tumor activity of dacomitinib, a pan-ERBB receptor inhibitor, on PDAC cells. METHODS: Anti-proliferative effects of dacomitinib were determined using a cell proliferation assay and crystal violet staining. Annexin V/PI staining, radiation therapy and cell migration and invasion assays were carried out to examine the effects of dacomitinib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-tumor activity of dacomitinib. RESULTS: We found that dacomitinib diminished PDAC cell proliferation via inhibition of FOXM1 and its targets Aurora kinase B and cyclin B1. Moreover, we found that dacomitinib induced apoptosis and potentiated radio-sensitivity via inhibition of the anti-apoptotic proteins survivin and MCL1. Treatment with dacomitinib attenuated cell migration and invasion through inhibition of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, Snail and N-cadherin. In contrast, we found that the anti-tumor activity of single-targeted ERBB agents including cetuximab (anti-EGFR mAb), trastuzumab (anti-HER2 mAb), H3.105.5 (anti-HER3 mAb) and erlotinib (EGFR small molecule inhibitor) were marginal. CONCLUSIONS: Our findings indicate that dacomitinib-mediated blockade of the ERBB receptors yields advantages over single-targeted ERBB inhibition and provide a rationale for further investigation of the therapeutic potential of dacomitinib in the treatment of ERBB-driven PDAC.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Receptores ErbB/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Quinazolinonas/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Receptores ErbB/metabolismo , Humanos , Modelos Biológicos , Invasividade Neoplásica , Quinazolinonas/farmacologia , Tolerância a Radiação
9.
Oncol Rep ; 41(5): 3127-3136, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896840

RESUMO

The nitrostyrene scaffold was previously identified as a lead target structure for the development of effective compounds targeting Burkitt's lymphoma. The present study aimed to develop these compounds further in haematological malignancies, including chronic lymphocytic leukaemia (CLL). Cellular viability, flow cytometry and lactate dehydrogenase assays, amongst others, were used to examine the effects of nitrostyrene compounds on CLL cells, including a cell line representing disease with poor prognosis (HG­3) and in ex vivo CLL patient samples (n=14). The results demonstrated that two representative nitrostyrene compounds potently induced apoptosis in CLL cells. The pro­apoptotic effects of the compounds were found to be reactive oxygen species and caspase­dependent, and had minimal effects on the viability of normal donor peripheral blood mononuclear cells. Nitrostyrene compounds exhibited synergistic augmentation of apoptosis when combined with the phosphatidylinositol 3­kinase inhibitor idelalisib and demonstrated potent toxicity in ex vivo CLL cells, including those co­cultured with bone marrow stromal cells, making them more resistant to apoptosis (n=8). These compounds also demonstrated activity in samples from patients with poor prognostic indicators; unmutated immunoglobulin heavy chain genes, expression of CD38 and deletions in chromosomes 17p and 11q. These results suggest that this class of pharmaceutically active compounds offer potential in the treatment of CLL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Nitrocompostos/farmacologia , Estirenos/farmacologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Humanos , Concentração Inibidora 50 , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Nitrocompostos/química , Nitrocompostos/uso terapêutico , Cultura Primária de Células , Prognóstico , Purinas/farmacologia , Purinas/uso terapêutico , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico , Relação Estrutura-Atividade , Estirenos/química , Estirenos/uso terapêutico
10.
Eur J Med Chem ; 170: 157-172, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30884322

RESUMO

Emergence of drug resistance has created unmet medical need for the development of new classes of antibiotics. Discovery of new antibacterial agents with new mode of action remains a high priority universally. 4(3H)-quinazolinone, a fused nitrogen heterocyclic compound has emerged as a biologically privileged structure, possessing a wide range of biological properties viz. anticancer, antibacterial, antitubercular, antifungal, anti-HIV, anticonvulsant, anti-inflammatory and analgesic activities. Promising antibacterial properties of quinazolinones have enthused the medicinal chemists to explore and develop this fused heterocyclic system for new antibacterial agents. Utilization of quinazolinone core for the design and synthesis of new antibacterial agents has recently gained momentum. This review aims to provide an overview of the structures and antibacterial activity of various 4(3H)-quinazolinone derivatives covering various aspects of in vitro and in vivo pharmacological activities and structure activity relationships (SARs).


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Quinazolinonas/química , Quinazolinonas/farmacologia , Animais , Antibacterianos/uso terapêutico , Descoberta de Drogas/métodos , Humanos , Quinazolinonas/uso terapêutico , Relação Estrutura-Atividade
11.
Clin Transl Oncol ; 21(10): 1287-1301, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30864018

RESUMO

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) represents a paradigm shift in the treatment of non-small cell lung cancer (NSCLC) patients and has been the first-line therapy in clinical practice. While erlotinib, gefitinib and afatinib have achieved superior efficacy in terms of progression-free survival and overall survival compared with conventional chemotherapy in NSCLC patients, most people inevitably develop acquired resistance to them, which presents another challenge in the treatment of NSCLC. The mechanisms of acquired resistance can be classified as three types: target gene mutation, bypass signaling pathway activation and histological transformation. And the most common mechanism is T790M which accounts for approximately 50% of all subtypes. Many strategies have been explored to overcome the acquired resistance to EGFR TKI. Continuation of EGFR TKI beyond progressive disease is confined to patients in asymptomatic stage when the EGFR addiction is still preserved in some subclones. While the combination of EGFR TKI and chemotherapy or other targeted agents has improved the survival benefit in EGFR TKI resistant patients, there are controversies within them. The next-generation EGFR TKI and immunotherapy represent two novel directions for overcoming acquired resistance and have achieved promising efficacy. Liquid biopsy provides surveillance of the EGFR mutation by disclosing the entire genetic landscape but tissue biopsy is still indispensable because of the considerable rate of false-negative plasma.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Acrilamidas/uso terapêutico , Afatinib/uso terapêutico , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Transformação Celular Neoplásica , Classe I de Fosfatidilinositol 3-Quinases/genética , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Quimioterapia Combinada/métodos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Gefitinibe/uso terapêutico , Humanos , Imunoterapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-met/genética , Quinazolinonas/uso terapêutico , Receptores Proteína Tirosina Quinases/genética , Receptor IGF Tipo 1/genética , Transdução de Sinais
12.
Eur J Pharmacol ; 850: 97-108, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30753867

RESUMO

Accumulating evidence suggests that epidermal growth factor receptor (EGFR) plays a role in the progression of pulmonary arterial hypertension (PAH). Clinically-approved epidermal growth factor inhibitors such as gefitinib, erlotinib, and lapatinib have been explored for PAH. However, None of them were able to attenuate PAH. So, we explored the role of dacomitinib, a new pan-EGFR inhibitor, in PAH. Adult male Sprague-Dawley rats were used to study hypoxia- or monocrotaline-induced right ventricular remodeling as well as systolic function and hemodynamics using echocardiography and a pressure-volume admittance catheter. Morphometric analyses of lung vasculature and pressure-volume vessels were performed. Immunohistochemical staining, flow cytometry, and viability, as well as scratch-wound, and Boyden chamber migration assays were used to identify the roles of dacomitinib in pulmonary artery smooth muscle cells (PASMCs). The results revealed that dacomitinib has a significant inhibitory effect on the thickening of the media, adventitial collagen increased. Dacomitinib also has a significant role in attenuating pulmonary artery pressure and right ventricular hypertrophy. Additionally, dacomitinib inhibits hypoxia-induced proliferation, migration, autophagy and cell cycle progression through PI3K-AKT-mTOR signaling in PASMCs. Our study indicates that dacomitinib inhibited hypoxia-induced cell cycle progression, proliferation, migration, and autophagy of PASMCs, thereby attenuating pulmonary vascular remodeling and development of PAH via the PI3K-AKT-mTOR signaling pathway. Overall, dacomitinib may serve as new potential therapeutic for the treatment of PAH.


Assuntos
Receptores ErbB/antagonistas & inibidores , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/patologia , Pulmão/irrigação sanguínea , Quinazolinonas/farmacologia , Remodelação Vascular/efeitos dos fármacos , Animais , Autofagia/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinazolinonas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
13.
Am J Cardiovasc Drugs ; 19(2): 107-111, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30693439

RESUMO

Bromodomain and extra-terminal (BET) inhibitors, acting via epigenetic mechanisms, have been developed recently as potential new treatments for cancer, including prostate cancer, and inflammatory conditions. Some BET inhibitors, such as RVX-208, also raise high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1 levels. A recent meta-analysis of three small trials (n = 798) found that RVX-208 protected against major adverse cardiovascular events (MACE), raising the question as to whether this protective effect was an artefact, a chance finding, or mediated by HDL-C, anti-inflammatory pathways, or other factors. Notably, the effect of RVX-208 on MACE was largely driven by revascularizations, but fewer interventions in the treatment arm could have arisen accidently from favorable effects of RVX-208 on HDL-C and C-reactive protein influencing decisions about patient care. A larger (n = 2400) trial of RVX-208, BETonMACE (NCT02586155), with a more restricted definition of MACE, excluding hospitalizations, will shortly provide clarity. A successful BETonMACE trial would raise the question as to whether RVX-208 operates via lipids, inflammation, or other means, because several previous HDL-C modulators and anti-inflammatories have not provided effective means of treating cardiovascular disease and reducing overall mortality. Re-conceptualizing cardiovascular disease within the well-established evolutionary biology theory that growth and specifically reproduction trade-off against longevity might provide a more comprehensive explanation. Drivers of the gonadotropic axis, particularly androgens, suppress both HDL-C and the immune system while promoting ischemic heart disease and stroke. As such, any effects of RVX-208 on cardiovascular disease might be the result of reducing androgens, of which higher HDL-C and reduced inflammation are biomarkers. Notably, several other effective treatments for cardiovascular disease, such as statins and spironolactone, are known anti-androgens. Results of the BETonMACE trial, and corresponding insight about the mechanism of BET inhibitors in cardiovascular disease, are eagerly awaited.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Proteínas/antagonistas & inibidores , Quinazolinonas/uso terapêutico , Animais , Fármacos Cardiovasculares/farmacologia , Doenças Cardiovasculares/prevenção & controle , Humanos
14.
Drug Saf ; 42(2): 247-262, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30649751

RESUMO

Activation of phosphatidylinositol-3-kinase (PI3K) and downstream signalling by AKT/mammalian target of rapamycin (mTOR) modulates cellular processes such as increased cell growth, cell proliferation and increased cell migration as well as deregulated apoptosis and oncogenesis. The PI3K/AKT/mTOR pathway (particularly Class I PI3K isoforms) is frequently activated in a variety of solid tumours and haematological malignancies, making PI3K an attractive therapeutic target in oncology. Inhibitors of PI3K also have the potential to restore sensitivity to other modalities of treatments when administered as part of combination regimens. Although many PI3K inhibitors have reached different stages of clinical development, only two (idelalisib and copanlisib) have been currently approved for use in the treatment of B cell lymphoma and leukaemias. While these two agents are effective clinically, their use is associated with a number of serious class-related as well as drug-specific adverse effects. Some of these are immune-mediated and include cutaneous reactions, severe diarrhoea with or without colitis, hepatotoxicity and pneumonitis. They also induce various metabolic abnormalities such as hyperglycaemia and hypertriglyceridaemia. Not surprisingly, therefore, many new PI3K inhibitors with a varying degree of target selectivity have been synthesised in expectations of improved safety and efficacy, and are currently under clinical investigations for use in a variety of solid tumours as well as haematological malignancies. However, evidence from early clinical trials, reviewed herein, suggests that these newer agents are also associated not only with class-related but also other serious and unexpected adverse effects. Their risk/benefit evaluations have resulted in a number of them being discontinued from further development. Cumulative experience with the use of PI3K inhibitors under development suggests that, compared with their use as monotherapy, combining them with other anticancer therapies may be a more effective strategy in improving current standard-of-care and clinical outcomes in cancers beyond haematological cancers. For example, combination of alpelisib with fulvestrant has recently demonstrated unexpectedly superior efficacy compared to fulvestrant alone. Furthermore, the immunomodulatory activity of PI3Kδ and PI3Kγ inhibitors also provides unexpected opportunities for their use in cancer immunotherapy, as is currently being tested in several clinical trials.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Diarreia/induzido quimicamente , Diarreia/metabolismo , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacologia , Humanos , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Purinas/efeitos adversos , Purinas/farmacologia , Purinas/uso terapêutico , Quinazolinonas/efeitos adversos , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico
15.
Histol Histopathol ; 34(7): 791-801, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30628720

RESUMO

In Duchenne muscular dystrophy (DMD), the progressive loss of muscle and its ability to function is associated with significant fibrosis, representing the major disease complication in patients. Halofuginone, a halogenated analog of the naturally occurring febrifugine, has been shown to prevent fibrosis in various animal models, including those of muscular dystrophies. Here, two optically active enantiomers of deoxyhalofuginone - a halofuginone analogue in which the hydroxy group in position 3 was removed from the piperidinyl entity - were evaluated with respect to their effect on muscle histopathology in mdx mice. Male mdx mice were treated with either deoxyhalofuginone (as single enantiomers or in racemic form), or halofuginone, for 10 weeks, starting at the age of 4 weeks. Halofuginone caused a significant reduction in total collagen content, degenerative areas, as well as in utrophin and phosphorylated-Smad3 levels in the mdx diaphragms. However, neither the deoxyhalofuginone enantiomers, nor its racemic form had any effect on these parameters. A positive effect of the deoxyhalofuginone (+)-enantiomer was observed on myofiber diameters; however, it was lesser than that of halofuginone. It is concluded that the hydroxy group plays a key role in halofuginone's effects related to fibrosis in DMD, and points towards the transforming growth factor ß/Smad3 signaling pathway being involved in this inhibition. Elucidation of the structure-function relationship of halofuginone, in relation to inhibiting fibrosis in muscular dystrophies, is of the utmost importance for creating the next generation of anti-fibrotic therapies that will be more efficacious and less toxic, hence improving life quality of patients.


Assuntos
Músculo Esquelético/efeitos dos fármacos , Distrofia Muscular de Duchenne/tratamento farmacológico , Piperidinas/química , Piperidinas/uso terapêutico , Quinazolinonas/química , Quinazolinonas/uso terapêutico , Animais , Modelos Animais de Doenças , Colágenos Fibrilares/metabolismo , Fibrose , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/patologia , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/metabolismo , Utrofina/metabolismo
16.
Drug Dev Res ; 80(3): 368-385, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30609096

RESUMO

Hit, Lead & Candidate Discovery A variety of novel 2-(methyl/phenyl)-3-(4-(5-substituted-1,3,4-oxadiazol-2-yl)phenyl) quinazolin-4(3H)-ones have been synthesized by treating 3-(4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenyl)-2-(methyl/phenyl)-quinazolin-4(3H)-one with a variety of secondary amines. Graph theoretical analysis was used in identification of drug target that is, NMDAR (N-methyl-d-aspartate receptors). The observed reports of in silico modeling and ligand based toxicity, metabolism prediction studies were encouraging us to synthesize of title compounds and evaluate their antiepileptic effects. The title compounds were tested for its antiepileptic potency by MES and scPTZ model. Rotorod test is used to assess its neurotoxicity. In the preliminary test it was found that in MES test, analogs 6d, 6e, 6f, and 6l were potent; whereas in scPTZ test analogs 6d, 6e, 6f, and 6k displayed potent antiepileptic activity. Additionally these five derivatives were tested in rats orally at a dose of 30 mg/kg and found that compounds 2-methyl-3-(4-(5-morpholino-1,3,4-oxadiazol-2-yl)phenyl)quinazolin-4(3H)-one 6e and 2-methyl-3-(4-(5-(piperidin-1-yl)-1,3,4-oxadiazol-2-yl)phenyl)quinazolin-4(3H)-one 6f exhibited superior activity than reference Phenytoin. In MES test, these derivatives 6e and 6f showed activity at 30 mg/kg i.p. dose after 0.5 hr and 4.0 hr. In scPTZ test these derivatives 6e and 6f showed activity at 100 and 300 mg/kg i.p. dose after 0.5 hr and 4.0 hr, respectively.


Assuntos
Anticonvulsivantes , Modelos Teóricos , Quinazolinonas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/toxicidade , Simulação por Computador , Masculino , Camundongos , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Quinazolinonas/uso terapêutico , Quinazolinonas/toxicidade , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Teste de Desempenho do Rota-Rod , Convulsões/tratamento farmacológico
17.
World Neurosurg ; 122: e1090-e1101, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30439527

RESUMO

BACKGROUND: Increasing evidence has implicated dysfunctional mitochondria in the pathophysiology of neurodegenerative disorders. Selective degradation of dysfunctional mitochondria has been termed mitophagy and constitutes a pivotal component of mitochondrial quality control to maintain cellular homeostasis. Mitochondrial fission plays a prominent role in controlling mitochondrial shape and function. However, it is unclear whether mitochondrial fission in the context of eliminating damaged mitochondria is involved in traumatic brain injury (TBI). We examined the role of mitochondrial division inhibitor 1 (Mdivi1), a small-molecule inhibitor of dynamin-related protein (Drp1), in general autophagy and mitophagy after controlled cortical impact (CCI). METHODS: Mitophagy and the role of Drp1 in this process after CCI were examined using Western blotting, electron microscopy, double immunofluorescence staining, neurological severity scores, and hematoxylin and eosin staining. Statistical analysis was performed using 1-way analysis of variance, followed by the least significant difference test or the Games-Howell test. RESULTS: The rats exposed to CCI exhibited induction of mitophagy and fragmentation of mitochondria. When fission was blocked with Mdivi1, the mitochondria became excessively long and interconnected. Inhibition of Drp1 blocked the induction of mitophagy specifically, which aggravated neurological manifestations and neuronal apoptosis. Mdivi1 activated caspase-3 and caspase-9, implying that selective degradation of damaged mitochondria by autophagy markedly decreased cell apoptosis induced by TBI and, thus, promoted cell survival. CONCLUSIONS: The findings from the present study support the hypothesis that Drp1-dependent mitochondrial fission contributes to mitophagy in TBI, and further understanding of the regulatory mechanisms of Drp1 will provide opportunities to develop novel strategies against TBI.


Assuntos
Autofagia/efeitos dos fármacos , Lesões Encefálicas/metabolismo , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Quinazolinonas/uso terapêutico , Animais , Autofagia/fisiologia , Lesões Encefálicas/patologia , Lesões Encefálicas/prevenção & controle , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Dinaminas/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Quinazolinonas/farmacologia , Ratos , Ratos Sprague-Dawley
18.
Am J Cardiovasc Drugs ; 19(1): 49-57, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30155718

RESUMO

BACKGROUND: Apabetalone is a selective bromodomain and extra-terminal (BET) inhibitor which modulates lipid and inflammatory pathways implicated in atherosclerosis. The impact of apabetalone on attenuated coronary atherosclerotic plaque (AP), a measure of vulnerability, is unknown. METHODS: The ApoA-1 Synthesis Stimulation and intravascular Ultrasound for coronary atheroma Regression Evaluation (ASSURE; NCT01067820) study employed serial intravascular ultrasound (IVUS) measures of coronary atheroma in 281 patients treated with apabetalone or placebo for 26 weeks. AP was measured at baseline and follow-up. Factors associated with changes in AP were investigated. RESULTS: AP was observed in 31 patients (11%) [27 (13.0%) in the apabetalone group and four (5.5%) in the placebo group]. The apabetalone group demonstrated reductions in AP length by - 1 mm [interquartile range (IQR) - 4, 1] (p = 0.03), AP arc by - 37.0° (IQR - 59.2, 8.2) (p = 0.003) and the AP index by - 34.6 mm° (IQR - 52.6, 10.1) (p = 0.003) from baseline. The change in AP index correlated with on-treatment concentration of high-density lipoprotein (HDL) particles (r = - 0.52, p = 0.006), but not HDL cholesterol (r = - 0.11, p = 0.60) or apolipoprotein A-1 (r = - 0.16, p = 0.43). Multivariable analysis revealed that on-treatment concentrations of HDL particles (p = 0.03) and very low-density lipoprotein particles (p = 0.01) were independently associated with changes in AP index. CONCLUSIONS: Apabetalone favorably modulated ultrasonic measures of plaque vulnerability in the population studied, which may relate to an increase in HDL particle concentrations. The clinical implications are currently being investigated in the phase 3 major adverse cardiac event outcomes trial BETonMACE.


Assuntos
Aterosclerose/tratamento farmacológico , Doença da Artéria Coronariana/tratamento farmacológico , Placa Aterosclerótica/tratamento farmacológico , Quinazolinonas/uso terapêutico , Idoso , Apolipoproteína A-I/metabolismo , Aterosclerose/metabolismo , HDL-Colesterol/metabolismo , Angiografia Coronária/efeitos dos fármacos , Doença da Artéria Coronariana/metabolismo , Método Duplo-Cego , Feminino , Coração/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/metabolismo , Estudos Prospectivos
19.
Hematol Oncol ; 37(1): 3-14, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30187496

RESUMO

The introduction of new therapeutic agents in chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL), including the new kinase inhibitor idelalisib, has changed the therapeutic landscape of these diseases. However, the use of idelalisib is associated with a peculiar profile of side effects, which require an optimization of the current approach to prophylaxis and supportive treatment. Moving from the recognition that the abovementioned issue represents an unmet need in CLL and FL, a multidisciplinary panel of experts was convened to produce a consensus document aiming to provide practical recommendations for the management of the side effects during idelalisib therapy for CLL and FL. The present publication represents a consensus document from a series of meetings held during 2017. The Panel generated clinical key questions using the criterion of clinical relevance through a Delphi process and explored 4 domains, ie, diarrhea/colitis, transaminitis, pneumonitis, and infectious complications. Using the consensus method, the Panel was able to shape recommendations which may assist hematologist to minimize adverse events and guarantee adherence to treatment in patients with CLL and FL candidate to receive idelalisib.


Assuntos
Antineoplásicos/efeitos adversos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma Folicular/tratamento farmacológico , Purinas/efeitos adversos , Quinazolinonas/efeitos adversos , Aldeído Oxidase/metabolismo , Algoritmos , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Colite/diagnóstico , Colite/etiologia , Citocromo P-450 CYP3A/metabolismo , Diarreia/diagnóstico , Diarreia/etiologia , Gerenciamento Clínico , Interações de Medicamentos , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfoma Folicular/diagnóstico , Linfoma Folicular/metabolismo , Purinas/farmacocinética , Purinas/uso terapêutico , Quinazolinonas/farmacocinética , Quinazolinonas/uso terapêutico
20.
Drug Dev Res ; 80(3): 343-352, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30565722

RESUMO

In light of the pharmacophoric structural requirements for achieving anticonvulsant activity, a series of N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)benzamide (4a-g) and N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)-2-phenylacetamide (4h-n) derivatives were synthesized in two steps starting from the reaction of N-methyl isatoic anhydride with the appropriate hydrazide and followed by condensation with the appropriate aldehyde. The anticonvulsant activities of the synthesized compounds were evaluated according to the anticonvulsant drug development (ADD) programme protocol. Among the synthesized compounds, 4n showed promising activity in both the maximal electroshock (MES) and pentylenetetrazole (PTZ) tests with median effective dose (ED50 ) values of 40.7 and 6 mg/kg, respectively. The six most promising derivatives, 4b, 4a, 4c, 4f, 4j, and 4i, showed very low ED50 values in the PTZ test (3.1, 4.96, 8.68, 9.89, 12, and 13.53 mg/kg, respectively). All the tested compounds showed no to low neurotoxicity in the rotarod test with a wide therapeutic index. Docking studies of compound 4n suggested that GABAA binding could be the mechanism of action of these derivatives. The in silico drug likeliness parameters indicated that none of the designed compounds violate Lipinski's rule of five and that they are able to cross the blood-brain barrier. Hit, Lead & Candidate Discovery.


Assuntos
Anticonvulsivantes/uso terapêutico , Quinazolinonas/uso terapêutico , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Eletrochoque , Masculino , Camundongos , Simulação de Acoplamento Molecular , Pentilenotetrazol , Quinazolinonas/química , Quinazolinonas/farmacologia , Receptores de GABA-A/metabolismo , Teste de Desempenho do Rota-Rod , Convulsões/induzido quimicamente , Convulsões/metabolismo , Relação Estrutura-Atividade
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