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1.
Cancer Treat Rev ; 81: 101907, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31715422

RESUMO

The aberrant activation of RAS-derived mitogen-activated protein kinase (MAPK) signaling pathway plays a prominent role in tumorigenesis of an array of malignancies. The reasons are usually the upstream activated mutations including mitogen-activated protein kinase kinase 1/2 (MEK1/2). As oncogenic mutations, MEK1 mutations have been observed in a variety of malignancies including melanoma, histiocytic neoplasms, colorectal cancer and lung cancer. Presently, the use of trametinib, a highly selective MEK1/2 inhibitor, was limited to BRAF mutations, according to the approvals of FDA. Therefore, we consider that this is a question worth studying that whether malignancies with MEK1 mutations are sensitive to the treatment of trametinib. This review discussed the function of MEK1 mutations, retrieved the frequency and distribution of MEK1 mutations in various malignancies, and reviewed the basic experiments and clinical case reports on trametinib in the treatment of cell lines or patients with MEK1 mutations. Most studies have demonstrated that trametinib was effective to cells or tumor patients harboring MEK1 mutations, which suggest that the MEK1 mutations might be potential indications of trametinib therapy. In addition, it was also reported that resistance was observed in the treatment of trametinib, suggesting that different MEK1 mutations may have different response to trametinib, and further studies are necessary to distinguish that which MEK1 mutations are appropriate for the treatment with trametinib and which are not.


Assuntos
Antineoplásicos/uso terapêutico , MAP Quinase Quinase 1/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Animais , Antineoplásicos/farmacologia , Grupo com Ancestrais do Continente Asiático/genética , Histiocitose de Células de Langerhans/tratamento farmacológico , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/metabolismo , Camundongos , Células NIH 3T3 , Neoplasias/tratamento farmacológico , Neoplasias/genética , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Pirimidinonas/farmacologia
2.
World J Gastroenterol ; 25(33): 4835-4849, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31543677

RESUMO

Liver fibrosis is the common pathological basis of all chronic liver diseases, and is the necessary stage for the progression of chronic liver disease to cirrhosis. As one of pathogenic factors, inflammation plays a predominant role in liver fibrosis via communication and interaction between inflammatory cells, cytokines, and the related signaling pathways. Damaged hepatocytes induce an increase in pro-inflammatory factors, thereby inducing the development of inflammation. In addition, it has been reported that inflammatory response related signaling pathway is the main signal transduction pathway for the development of liver fibrosis. The crosstalk regulatory network leads to hepatic stellate cell activation and proinflammatory cytokine production, which in turn initiate the fibrotic response. Compared with the past, the research on the pathogenesis of liver fibrosis has been greatly developed. However, the liver fibrosis mechanism is complex and many pathways involved need to be further studied. This review mainly focuses on the crosstalk regulatory network among inflammatory cells, cytokines, and the related signaling pathways in the pathogenesis of chronic inflammatory liver diseases. Moreover, we also summarize the recent studies on the mechanisms underlying liver fibrosis and clinical efforts on the targeted therapies against the fibrotic response.


Assuntos
Mediadores da Inflamação/metabolismo , Inflamação/imunologia , Cirrose Hepática/imunologia , Fígado/patologia , Transdução de Sinais/imunologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Modelos Animais de Doenças , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/imunologia , Células Estreladas do Fígado/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/imunologia , Hepatócitos/metabolismo , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/patologia , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/imunologia , Fígado/citologia , Fígado/imunologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Terapia de Alvo Molecular/métodos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Ácido Ursodesoxicólico/análogos & derivados , Ácido Ursodesoxicólico/farmacologia , Ácido Ursodesoxicólico/uso terapêutico
3.
Expert Opin Investig Drugs ; 28(10): 827-833, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31474120

RESUMO

Introduction: A compound that simultaneously inhibits PDE3 and PDE4 should increase airway caliber by relaxing the smooth muscle and, simultaneously, suppress airway inflammatory responses. Ensifentrine (RPL554) is considered a PDE3/4 inhibitor, although its affinity for PDE3 is 3,440 times higher than that for PDE4, that is under clinical development for the treatment of asthma and COPD and, potentially, cystic fibrosis. Areas covered: We analyze the development of this molecule from its basic pharmacology to the present clinical Phase II studies. Expert opinion: Ensifentrine is an interesting drug but there is a lack of solid studies that still does not allow us to correctly allocate this molecule in the current COPD and even asthma therapeutic armamentarium. Furthermore, apparently ensifentrine has not yet entered Phase III clinical development and, in any case, there is no reliable evidence of its ability to elicit an anti-inflammatory activity in patients with COPD or asthma. Therefore, the real anti-inflammatory profile of ensifentrine must be clarified with new studies of basic pharmacology and adequate clinical studies specifically designed. However, at present the most intriguing perspective is linked to its possible use in the treatment of cystic fibrosis, also considering the lack of valid therapeutic options for this disease.


Assuntos
Asma/tratamento farmacológico , Isoquinolinas/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Pirimidinonas/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Asma/fisiopatologia , Fibrose Cística/tratamento farmacológico , Fibrose Cística/fisiopatologia , Desenvolvimento de Medicamentos/métodos , Humanos , Isoquinolinas/farmacologia , Inibidores da Fosfodiesterase 3/farmacologia , Inibidores da Fosfodiesterase 3/uso terapêutico , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Pirimidinonas/farmacologia
4.
Drugs Today (Barc) ; 55(8): 503-512, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31461087

RESUMO

Uterine leiomyomas represent the most common form of benign gynecological tumors affecting 20-40% of women during their life. Several therapeutic options are available for treating these patients. The use of medical treatment for myomas has largely grown in the last years, in particular for women who would refuse, postpone or are not candidates for surgery. In the last years, the clinical investigation of gonadotropin-releasing hormone (GnRH) antagonists (GnRH-ants) has emerged. This class of drugs exerts pure competitive antagonistic activity on the GnRH receptor at the pituitary gland, producing an immediate stop in the release of gonadotropins and sex steroids. Relugolix is an orally active nonpeptide GnRH-ant, recently licensed for marketing in Japan for the treatment of symptoms related to uterine myomas. Currently, several phase III clinical trials are ongoing to evaluate this molecule in this setting in the U.S. and Europe.


Assuntos
Leiomioma/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Pirimidinonas/uso terapêutico , Neoplasias Uterinas/tratamento farmacológico , Feminino , Humanos
5.
Nat Med ; 25(7): 1116-1122, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31263281

RESUMO

The treatment of lymphatic anomaly, a rare devastating disease spectrum of mostly unknown etiologies, depends on the patient manifestations1. Identifying the causal genes will allow for developing affordable therapies in keeping with precision medicine implementation2. Here we identified a recurrent gain-of-function ARAF mutation (c.640T>C:p.S214P) in a 12-year-old boy with advanced anomalous lymphatic disease unresponsive to conventional sirolimus therapy and in another, unrelated, adult patient. The mutation led to loss of a conserved phosphorylation site. Cells transduced with ARAF-S214P showed elevated ERK1/2 activity, enhanced lymphangiogenic capacity, and disassembly of actin skeleton and VE-cadherin junctions, which were rescued using the MEK inhibitor trametinib. The functional relevance of the mutation was also validated by recreating a lymphatic phenotype in a zebrafish model, with rescue of the anomalous phenotype using a MEK inhibitor. Subsequent therapy of the lead proband with a MEK inhibitor led to dramatic clinical improvement, with remodeling of the patient's lymphatic system with resolution of the lymphatic edema, marked improvement in his pulmonary function tests, cessation of supplemental oxygen requirements and near normalization of daily activities. Our results provide a representative demonstration of how knowledge of genetic classification and mechanistic understanding guides biologically based medical treatments, which in our instance was life-saving.


Assuntos
Anormalidades Linfáticas/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mutação , Proteínas Proto-Oncogênicas A-raf/genética , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Adulto , Animais , Criança , Feminino , Células HEK293 , Humanos , Anormalidades Linfáticas/tratamento farmacológico , Masculino , Sequenciamento Completo do Exoma , Peixe-Zebra
6.
Invest Ophthalmol Vis Sci ; 60(7): 2764-2772, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31247083

RESUMO

Purpose: To analyze the activity of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinases/mechanistic target of rapamycin (PI3K/mTOR) pathways in benign and malignant conjunctival melanocytic proliferations and explore whether specific inhibitors can suppress growth of conjunctival melanoma (CJM) cells. Methods: The presence of a BRAF V600E mutation and activation of ERK, MEK, S6, and AKT were assessed with immunohistochemistry in 35 conjunctival nevi and 31 melanomas. Three CJM cell lines were used: CRMM1, carrying the BRAF V600E mutation; CRMM2, harboring the NRAS Q61L mutation; and T1527A, with a BRAF G466E mutation. WST-1 assays were performed with a BRAF inhibitor (vemurafenib), two MEK inhibitors (trametinib, selumetinib), a PI3K inhibitor (pictilisib), and a dual PI3K/mTOR inhibitor (dactolisib). The phosphorylation of ERK, MEK, and S6 were tested with western blots and apoptosis with cleaved caspase-3 immunostaining. Results: A BRAF V600E mutation was detected in 42.6% of nevi and in 35.5% of CJM. MEK and ERK activation were higher in CJM, occurring in 62.9% and 45.7% of the nevi and 90.3% and 96.8% of the CJM, respectively. There was also a significant increase in S6 activation in CJM (90.3%) compared with the nevi (20%). CRMM1 was sensitive to trametinib and the PI3K inhibitors but only marginally to vemurafenib. CRMM2 was moderately sensitive to pictilisib, whereas T1527A was resistant to all drugs tested. Conclusions: The MAPK pathway activity in CJM is increased, not only as a consequence of the BRAF V600E mutation. Targeted therapy may be useful for patients with CJM, especially those with activating BRAF mutations, whereas NRAS-mutated melanomas are relatively resistant.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Túnica Conjuntiva/tratamento farmacológico , Melanoma/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Terapia de Alvo Molecular , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzimidazóis/uso terapêutico , Western Blotting , Neoplasias da Túnica Conjuntiva/enzimologia , Neoplasias da Túnica Conjuntiva/patologia , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Masculino , Melanoma/enzimologia , Melanoma/patologia , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Quinolinas/uso terapêutico , Sulfonamidas/uso terapêutico , Células Tumorais Cultivadas
7.
G3 (Bethesda) ; 9(7): 2267-2276, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31101653

RESUMO

Small aquarium fish models provide useful systems not only for a better understanding of the molecular basis of many human diseases, but also for first-line screening to identify new drug candidates. For testing new chemical substances, current strategies mostly rely on easy to perform and efficient embryonic screens. Cancer, however, is a disease that develops mainly during juvenile and adult stage. Long-term treatment and the challenge to monitor changes in tumor phenotype make testing of large chemical libraries in juvenile and adult animals cost prohibitive. We hypothesized that changes in the gene expression profile should occur early during anti-tumor treatment, and the disease-associated transcriptional change should provide a reliable readout that can be utilized to evaluate drug-induced effects. For the current study, we used a previously established medaka melanoma model. As proof of principle, we showed that exposure of melanoma developing fish to the drugs cisplatin or trametinib, known cancer therapies, for a period of seven days is sufficient to detect treatment-induced changes in gene expression. By examining whole body transcriptome responses we provide a novel route toward gene panels that recapitulate anti-tumor outcomes thus allowing a screening of thousands of drugs using a whole-body vertebrate model. Our results suggest that using disease-associated transcriptional change to screen therapeutic molecules in small fish model is viable and may be applied to pre-clinical research and development stages in new drug discovery.


Assuntos
Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Melanoma/tratamento farmacológico , Melanoma/genética , Transcriptoma , Animais , Animais Geneticamente Modificados , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Biologia Computacional/métodos , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Melanoma/patologia , Oryzias , Piridonas/farmacologia , Piridonas/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Life Sci ; 228: 198-207, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31039363

RESUMO

Oxidative stress and blood-retinal barrier (BRB) damage induced by hyperglycemia are the principal processes involved in the early stages of diabetic retinopathy (DR). CXC chemokine receptor 3 (CXCR3)-mediated inflammatory infiltration exists in many disease models. The main objective of the present study was to determine whether AMG487, a CXCR3 antagonist, can ameliorate BRB disruption and reactive oxygen species generation in the DR model. The retinal endothelial cell and ganglion cell ultrastructures were observed using a transmission electron microscope. The pericyte marker PDGFR-ß, tight junction occludin, and leaking albumin were evaluated. The oxidative stress level, CCAAT-enhancer-binding protein homologous protein (CHOP), and p-p38 expression were also investigated in vivo and in vitro. The results indicated that AMG487 application might alleviate PDGFR-ß and occludin loss, and decreased the residual content of retinal albumin in the streptozocin-induced DR mouse model via the inhibition of oxidative and endoplasmic reticulum stress, in which p38 activation was also involved. Thus, CXCR3 inhibition might be a target to prevent the early stage of DR injury.


Assuntos
Acetamidas/uso terapêutico , Antioxidantes/uso terapêutico , Barreira Hematorretiniana/efeitos dos fármacos , Retinopatia Diabética/tratamento farmacológico , Pirimidinonas/uso terapêutico , Receptores CXCR3/antagonistas & inibidores , Acetamidas/farmacologia , Animais , Antioxidantes/farmacologia , Barreira Hematorretiniana/metabolismo , Barreira Hematorretiniana/patologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Pirimidinonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Receptores CXCR3/metabolismo
9.
Drugs ; 79(6): 675-679, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30937733

RESUMO

The orally active nonpeptide gonadotropin-releasing hormone (GnRH)-receptor antagonist relugolix (Relumina) is being developed by Takeda and ASKA Pharmaceutical as a treatment for various sex hormone related disorders. Relugolix was recently approved for marketing in Japan as a treatment for symptoms associated with uterine fibroids, and studies evaluating the efficacy of the drug as treatment for endometriosis-associated pain and prostate cancer are currently underway. This article summarizes the milestones in the development of relugolix leading to this first approval for the treatment of symptoms associated with uterine fibroids.


Assuntos
Antagonistas de Hormônios/uso terapêutico , Leiomioma/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Pirimidinonas/uso terapêutico , Receptores LHRH/antagonistas & inibidores , Adolescente , Adulto , Idoso , Relação Dose-Resposta a Droga , Aprovação de Drogas , Endometriose/tratamento farmacológico , Feminino , Antagonistas de Hormônios/administração & dosagem , Antagonistas de Hormônios/efeitos adversos , Antagonistas de Hormônios/farmacocinética , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacocinética , Neoplasias da Próstata/tratamento farmacológico , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Pirimidinonas/farmacocinética , Resultado do Tratamento
10.
J Pharmacol Exp Ther ; 370(1): 84-91, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31010842

RESUMO

The illicit use of γ-hydroxybutyric acid (GHB), and its prodrug, γ-butyrolactone (GBL), results in severe adverse effects including sedation, coma, respiratory depression, and death. Current treatment of GHB/GBL overdose is limited to supportive care. Recent reports indicate that GHB-related deaths are on the rise; a specific treatment may reduce lethality associated with GHB/GBL. Pretreatment with inhibitors of monocarboxylate transporter 1 (MCT1), a transporter that mediates many of the processes involved in the absorption, distribution (including brain uptake), and elimination of GHB/GBL, has been shown to prevent GHB-induced respiratory depression by increasing the renal clearance of GHB. To identify whether MCT1 inhibition is an effective treatment of GHB overdose, the impact of two MCT1 inhibitors, (S)-5-(4-hydroxy-4-methylisoxazolidine-2-carbonyl)-1-isopropyl-3-methyl-6-((3-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thieno[2,3-day]pyrimidine-2,4(1H,3H)-dione (AZD3965) and 6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-[[(4S)-4-hydroxy-2-isoxazolidinyl]carbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-day]pyrimidine2,4(1H,3H)-dione (AR-C155858), on the toxicokinetics and toxicodynamics of GHB/GBL was assessed when the administration of the inhibitor was delayed 60 and 120 minutes (post-treatment) after administration of GHB/GBL. AR-C155858 and AZD3965 reduced the toxicodynamic effects of GHB when GHB was administered intravenously, orally, or orally as the prodrug GBL. The impact of these inhibitors on GHB toxicokinetics was dependent on the route of GHB administration and the delay between GHB/GBL administration and administration of the MCT1 inhibitor. The reduction in GHB plasma exposure did not explain the observed effect of MCT1 inhibition on GHB-induced respiratory depression. The efficacy of MCT1 inhibition on GHB toxicodynamics is likely driven by the pronounced reduction in GHB brain concentrations. Overall, this study indicates that inhibition of MCT1 is an effective treatment of GHB/GBL overdose.


Assuntos
4-Butirolactona/toxicidade , Overdose de Drogas/tratamento farmacológico , Hidroxibutiratos/toxicidade , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Pró-Fármacos/farmacologia , Pirimidinonas/farmacologia , Simportadores/antagonistas & inibidores , Tiofenos/farmacologia , Uracila/análogos & derivados , 4-Butirolactona/administração & dosagem , Administração Intravenosa , Administração Oral , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Overdose de Drogas/sangue , Overdose de Drogas/metabolismo , Hidroxibutiratos/administração & dosagem , Hidroxibutiratos/sangue , Hidroxibutiratos/farmacocinética , Masculino , Pirimidinonas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Tiofenos/uso terapêutico , Uracila/farmacologia , Uracila/uso terapêutico
11.
Pulm Pharmacol Ther ; 56: 86-93, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30917927

RESUMO

BACKGROUND: There are only limited treatment options for patients with non-cystic fibrosis bronchiectasis (non-CF BE). Human neutrophil elastase (HNE) is a mediator of tissue destruction in non-CF BE. BAY 85-8501, a selective and reversible HNE inhibitor, could represent a new treatment option for this disease. METHODS: This was a phase 2a, randomized, placebo-controlled, double-blind, parallel-group study. The primary objective was to assess the safety and tolerability of 1 mg BAY 85-8501 once daily (OD) for 28 days compared with placebo in patients with non-CF BE. Secondary objectives were to investigate the effects of 4 weeks of treatment with BAY 85-8501 on health-related quality of life, pulmonary function, and inflammatory and tissue damage biomarkers in sputum, blood and/or urine, and to evaluate the pharmacokinetics of BAY 85-8501. RESULTS: Overall, 94 patients (mean age, 66 years; 53% male) were randomized (n = 47 per group), and 82 completed the study (BAY 85-8501, n = 37; placebo, n = 45). Treatment-emergent adverse events (TEAEs) occurred in 31 patients (66%) taking BAY 85-8501 and in 36 patients (77%) taking placebo, and were mostly mild or moderate. The serious TEAEs (BAY 85-8501, n = 3; placebo, n = 1) were not considered to be study-drug related. There were no changes in pulmonary function parameters from baseline to end of treatment, and health-related quality of life did not improve in any group. HNE activity in blood after zymosan challenge decreased significantly with BAY 85-8501 treatment (P = 0.0250 versus placebo). There were no significant differences in other biomarkers between treatment groups, with the exception of a small increase in interleukin-8 levels in sputum in the BAY 85-8501 group. Trough plasma concentrations of BAY 85-8501 plateaued after 2 weeks. CONCLUSIONS: 1 mg BAY 85-8501 OD had a favourable safety and tolerability profile when administered for 28 days to patients with non-CF BE. Further studies with a longer treatment duration are needed to evaluate the potential clinical efficacy in this study population.


Assuntos
Bronquiectasia/tratamento farmacológico , Elastase de Leucócito/antagonistas & inibidores , Proteínas Secretadas Inibidoras de Proteinases/uso terapêutico , Pirimidinonas/uso terapêutico , Sulfonas/uso terapêutico , Idoso , Bronquiectasia/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Secretadas Inibidoras de Proteinases/efeitos adversos , Proteínas Secretadas Inibidoras de Proteinases/farmacocinética , Pirimidinonas/efeitos adversos , Pirimidinonas/farmacocinética , Qualidade de Vida , Escarro/metabolismo , Sulfonas/efeitos adversos , Sulfonas/farmacocinética , Resultado do Tratamento
12.
Obstet Gynecol ; 133(3): 423-433, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30741797

RESUMO

OBJECTIVE: To investigate the noninferiority of relugolix compared with leuprorelin acetate in reducing heavy menstrual bleeding associated with uterine leiomyomas. METHODS: In a double-blind, double-dummy trial, premenopausal women with uterine leiomyomas and heavy menstrual bleeding defined as a pictorial blood loss assessment chart score of at least 120 were randomized in a 1:1 ratio to relugolix (40 mg, oral, once daily) or leuprorelin acetate (1.88 mg or 3.75 mg, monthly injection) for 24 weeks. The primary endpoint was the proportion of patients with a total pictorial blood loss assessment chart score of less than 10 for weeks 6-12. Secondary endpoints included myoma and uterine volumes, and hemoglobin levels. A sample size of 144 patients per group (n=288) was estimated to provide at least 90% power to demonstrate noninferiority (prespecified noninferiority margin -15%; one-sided 0.025 level of significance). RESULTS: From March 2016 to September 2017, 281 patients were randomized (relugolix, n=139, leuprorelin n=142). Demographic and baseline characteristics were well balanced; mean pictorial blood loss assessment chart score was 254.3 in the relugolix group and 263.7 in the leuprorelin group. The proportion of patients with total pictorial blood loss assessment chart score of less than 10 for weeks 6-12 was 82.2% in the relugolix group and 83.1% in the leuprorelin group, demonstrating noninferiority of relugolix compared with leuprorelin (relugolix-leuprorelin difference -0.9%; 95% CI: -10.10 to 8.35; prespecified noninferiority margin -15%; P=.001). Reductions in myoma and uterine volumes and increases in hemoglobin levels were comparable in the two groups. Relugolix was associated with an earlier effect on menstrual bleeding than leuprorelin (pictorial blood loss assessment chart score of less than 10, 64.2% vs 31.7% [relugolix-leuprorelin difference 32.5%; 95% CI: 20.95-44.13%] for weeks 2-6 and pictorial blood loss assessment chart score of 0, 52.6% vs 21.8% [30.7%; 95% CI: 19.45-42.00%] for weeks 2-6) and faster recovery of menses after treatment discontinuation (relugolix median [Q1, Q3], 37 days [32.0, 46.0]; leuprorelin median, 65 days [54.0, 77.0]). Adverse events and bone mineral density loss were similar between relugolix and leuprorelin treatment groups. CONCLUSION: In women with uterine leiomyomas, once-daily treatment with relugolix, an oral gonadotropin-releasing hormone antagonist, demonstrated noninferiority to monthly leuprorelin for improvement of heavy menstrual bleeding at 6-12 weeks of treatment, had a more rapid effect on menstrual bleeding, and was generally well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02655237; JAPIC Clinical Trial Information, JapicCTI-163128. FUNDING SOURCE: Takeda Pharmaceutical Company Limited and an affiliate of NovaQuest Capital Management LLC.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Leiomioma/tratamento farmacológico , Leuprolida/uso terapêutico , Menorragia/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Pirimidinonas/uso terapêutico , Neoplasias Uterinas/tratamento farmacológico , Administração Oral , Adulto , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Método Duplo-Cego , Feminino , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Hemoglobinas/metabolismo , Humanos , Injeções , Leiomioma/complicações , Leiomioma/patologia , Leuprolida/administração & dosagem , Leuprolida/efeitos adversos , Menorragia/etiologia , Pessoa de Meia-Idade , Tamanho do Órgão , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Índice de Gravidade de Doença , Carga Tumoral , Neoplasias Uterinas/complicações , Neoplasias Uterinas/patologia , Útero/patologia
14.
Pediatrics ; 143(3)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30792255

RESUMO

Giant congenital nevi are melanocytic proliferations of the skin that may be complicated by melanoma, neurocutaneous melanocytosis, pain, pruritus, and disfigurement. Current treatment options include surgical resection and medical management of associated symptoms. There is limited efficacy in these modalities. No effective pharmacologic treatments are available for the treatment of these lesions. We present the case of a 7-year-old girl with a giant congenital melanocytic nevus that had an AKAP9-BRAF fusion and was treated with trametinib, which resulted in rapid resolution of the patient's lifelong, intractable pain and pruritus as well as dramatic improvement in the extent of her nevus.


Assuntos
Antineoplásicos/uso terapêutico , Nevo Pigmentado/diagnóstico por imagem , Nevo Pigmentado/tratamento farmacológico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/tratamento farmacológico , Criança , Feminino , Humanos , Nevo Pigmentado/cirurgia , Neoplasias Cutâneas/cirurgia , Resultado do Tratamento
15.
Clin Hemorheol Microcirc ; 72(2): 179-187, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30714951

RESUMO

BACKGROUND: Cardiac hypertrophy is an important risk factor for heart failure. The MEK-ERK axis has been reported as a major regulator in controlling cardiac hypertrophy. TAK733 is a potent and selective MEK inhibitor that suppresses cell growth in a broad range of cell lines. OBJECTIVE: Therefore, we aimed to investigate the anti-hypertrophic effect of TAK733 in cardiomyocytes. METHODS: Cardiomyocyte hypertrophy was induced with norepinephrine (NE) or phenylepinephrine (PE) using H9c2 cells. To confirm the cardiomyocyte hypertrophy, cell size and protein synthesis were measured and hypertrophy-related gene expression was estimated by reverse transcription polymerase chain reaction. To identify the signaling pathway involved, immunoblot analysis were performed. RESULTS: We observed that NE activated MEK-ERK signaling and increased ANP and BNP expression, resulting in cardiomyocyte hypertrophy. TAK733 significantly reduced cardiomyocyte hypertrophy by regulating NE-induced ERK1/2 and ERKThr188 activation, hypertrophy marker expression, and cardiomyocyte hypertrophy through depression of MEK activity. In addition, we examined that PE-induced cardiomyocyte hypertrophy was also attenuated by TAK733. CONCLUSIONS: Here, we report that TAK733 suppressed NE- or PE-induced cardiomyocyte hypertrophy by repressing a crucial component of cardiac hypertrophy-related pathways. These results suggest that TAK733 may be a useful therapeutics for cardiac hypertrophy and warrants further in vivo studies.


Assuntos
Cardiomegalia/tratamento farmacológico , Miócitos Cardíacos/patologia , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Receptores Adrenérgicos/uso terapêutico , Animais , Humanos , Fosforilação , Piridonas/farmacologia , Pirimidinonas/farmacologia , Ratos
16.
Support Care Cancer ; 27(10): 3869-3875, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30767130

RESUMO

The most common adverse event (AE) of dabrafenib and trametinib (DT) is pyrexia, which has been reported to occur in up to 71% of patients. Pyrexia resulted in therapy discontinuation in up to 26% of patients that otherwise were benefiting from the treatment. Little is known about the pathogenesis and optimal management of this common AE. We hypothesized that the etiology of pyrexia in patients treated with DT could be extrapolated from DT-related cutaneous adverse effects in which a paradoxical MAPK pathway activation has been identified. Based on preliminary data by our group suggesting an upregulation of the mitogen-activated protein kinases (MAPKs) in human lymphocytes exposed to dabrafenib and trametinib, specifically elevated expression of phosphorylated JNK (p-JNK), p38 MAPK (p-p38 MAPK), and ERK5 (p-ERK5), we hypothesized that the mechanism of MAPK pathway activation with DT therapy is similar to that reported in patients with familial Mediterranean fever (FMF), a rare, inherited condition characterized by episodes of fever and rash that responds exceedingly well to colchicine-based therapy in which the MAPK pathway is hyper-activated. Based on this association, our group explored the use of oral colchicine for the treatment of DT-associated pyrexia in five patients with metastatic melanoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Colchicina/uso terapêutico , Febre/induzido quimicamente , Febre/tratamento farmacológico , Imidazóis/efeitos adversos , Oximas/efeitos adversos , Piridonas/efeitos adversos , Pirimidinonas/efeitos adversos , Ativação Enzimática/efeitos dos fármacos , Humanos , Imidazóis/uso terapêutico , Masculino , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mutação , Oximas/uso terapêutico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico
17.
Nat Commun ; 10(1): 244, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30651561

RESUMO

FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzimidazóis/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Tirosina Quinase 3 Semelhante a fms/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/uso terapêutico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Epigênese Genética/efeitos dos fármacos , Feminino , GTP Fosfo-Hidrolases/genética , Células HEK293 , Humanos , Concentração Inibidora 50 , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Proteínas de Membrana/genética , Camundongos , Pessoa de Meia-Idade , Mutação/efeitos dos fármacos , Mutação/genética , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/farmacologia , Piridonas/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Sequências de Repetição em Tandem/genética , Resultado do Tratamento , Sequenciamento Completo do Exoma
18.
Platelets ; 30(6): 762-772, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30252580

RESUMO

The MEK inhibitors cobimetinib and trametinib are used in combination with BRAF inhibitors to treat metastatic melanoma but increase rates of hemorrhage relative to BRAF inhibitors alone. Platelets express several members of the MAPK signalling cascade including MEK1 and MEK2 and ERK1 and ERK2 but their role in platelet function and haemostasis is ambiguous as previous reports have been contradictory. It is therefore unclear if MEK inhibitors might be causing platelet dysfunction and contributing to increased hemorrhage. In the present study we performed pharmacological characterisation of cobimetinib and trametinib in vitro to investigate potential for MEK inhibitors to cause platelet dysfunction. We report that whilst both cobimetinib and trametinib are potent inhibitors of platelet MEK activity, treatment with trametinib did not alter platelet function. Treatment with cobimetinib results in inhibition of platelet aggregation, integrin activation, alpha-granule secretion and adhesion but only at suprapharmacological concentrations. We identified that the inhibitory effects of high concentrations of cobimetinib are associated with off-target inhibition on Akt and PKC. Neither inhibitor caused any alteration in thrombus formation on collagen under flow conditions in vitro. Our findings demonstrate that platelets are able to function normally when MEK activity is fully inhibited, indicating MEK activity is dispensable for normal platelet function. We conclude that the MEK inhibitors cobimetinib and trametinib do not induce platelet dysfunction and are therefore unlikely to contribute to increased incidence of bleeding reported during MEK inhibitor therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azetidinas/uso terapêutico , Plaquetas/efeitos dos fármacos , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Azetidinas/farmacologia , Humanos , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Pirimidinonas/farmacologia
19.
Int J Cancer ; 144(6): 1379-1390, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30144031

RESUMO

To determine the role of BRAFV600E mutation and MAPK signaling as well as the effects of BRAF and MEK directed therapy in gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN), with a focus on highly aggressive gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC). Using Sanger sequencing of BRAF exon 15 we determined the frequency of BRAFV600E mutations in 71 primary GEP-NENs. MEK phosphorylation was examined by immunohistochemistry in corresponding tissue samples. To evaluate the biological relevance of BRAFV600E mutation and MAPK signaling in GEP-NECs, effects of a pharmacological BRAF and MEK inhibition were analyzed in NEC cell lines both in vitro and in vivo. BRAFV600E mutation was detected in 9.9% of all GEP-NENs. Interestingly, only NECs of the colon harbored BRAFV600E mutations, leading to a mutation frequency of 46.7% in this subgroup of patients. In addition, a BRAFV600E mutation was significantly associated with high levels of MEK phosphorylation (pMEK) and advanced tumor stages. Pharmacological inhibition of BRAF and MEK abrogated NEC cell growth, inducing G1 cell cycle arrest and apoptosis only in BRAFV600E mutated cells. BRAF inhibitor dabrafenib and MEK inhibitor trametinib prevented growth of BRAFV600E positive NEC xenografts. High frequencies of BRAFV600E mutation and elevated expression levels of pMEK were detected in biologically aggressive and highly proliferative colorectal NECs. We provide evidence that targeting BRAF oncogene may represent a therapeutic strategy for patients with BRAF mutant colorectal NECs.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Neuroendócrino/genética , Neoplasias Colorretais/genética , Neoplasias Intestinais/genética , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Gástricas/genética , Idoso , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Éxons/genética , Feminino , Seguimentos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/mortalidade , Neoplasias Intestinais/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Mutação , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Oximas/farmacologia , Oximas/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Fosforilação/genética , Piridonas/farmacologia , Piridonas/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Análise Serial de Tecidos , Vemurafenib/farmacologia
20.
Future Oncol ; 15(2): 133-139, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30196713

RESUMO

AIM: A survival benefit was demonstrated by dabrafenib + trametinib for metastatic BRAF-mutated melanoma patients. Best response is a strong prognostic marker for survival. PATIENTS & METHODS: The specific features associated with complete response (CR) were evaluated. RESULTS: A total of 15/66 patients achieved CR. Median size of lesions was 3 cm (range: 0.5-10). Using that value as cut-off, the CR rate was 39.3% in patients with smaller lesions and 10.5% in patients with bigger size (p = 0.006). The clinical features associated with CR were the number of metastatic sites and the largest diameter of the biggest metastatic site. CONCLUSION: The number of the metastases and the diameter of the largest metastatic site are associated with a higher CR rate.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Feminino , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , MAP Quinase Quinase 1/antagonistas & inibidores , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Mutação , Oximas/farmacologia , Oximas/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/farmacologia , Piridonas/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Estudos Retrospectivos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Vemurafenib/farmacologia , Vemurafenib/uso terapêutico
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