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1.
Chemosphere ; 257: 127189, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32470540

RESUMO

The effects of chloridazon exposure at concentrations of 2.7 µg/L (maximal real environmental concentration in the Czech Republic), 27 µg/L, 135 µg/L and 270 µg/L on early life stages of marbled crayfish (Procambarus virginalis) were evaluated. Significantly higher glutathione S-transferase activity and reduced glutathione level was observed at all tested concentrations of chloridazon compared with the control. Chloridazon in concentrations 27, 135 and 270 µg/L caused delay ontogenetic development and slower growth. Histopathological changes in hepathopancreas were found in two highest tested concentrations (135 µg/L and 270 µg/L). Crayfish behaviour was not altered in control vs. exposed animals, while the activity parameters tend to decline with increasing chloridazon concentrations.


Assuntos
Astacoidea/fisiologia , Praguicidas/toxicidade , Piridazinas/toxicidade , Testes de Toxicidade , Animais , Astacoidea/efeitos dos fármacos , República Tcheca
2.
Oncology ; 98(7): 445-451, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348984

RESUMO

BACKGROUND: Target therapy can cause various cardiovascular complications. The aim of this study was to evaluate the burden of cardiovascular complications related to treatment with anti-BCR-ABL tyrosine kinase inhibitors (TKIs) and to determine if there are differences between the latest- and first-generation TKIs. METHODS: A retrospective observational study was carried out on 55 patients (39 men, 16 women; mean age ± SD: 58 ± 11 years) treated with TKIs targeting Bcr-Abl for a median period of 3.5 years. Patients were divided in two groups according to the type of treatment. Group A included patients treated with latest-generation TKI (nilotinib, dasatinib, and ponatinib), while group B included patients treated with first-generation TKI (imatinib). Cardiological evaluation included electrocardiogram, echocardiogram with global longitudinal strain of left ventricle (GLS), and carotid ultrasound scan with arterial stiffness measurement (pulse wave velocity, PWV). Adverse cardiovascular events were recorded in both groups. RESULTS: Statistical analysis showed that cardiovascular adverse events (myocardial ischemia, peripheral artery disease, deep vein thrombosis, and pleural effusion) were significantly more frequent in group A than group B (p value = 0.044). Moreover, there was a significant reduction in GLS and PWV in group A when compared to group B (respectively, p = 0.03 and p = 0.004). CONCLUSIONS: Our study confirms that imatinib is a relatively safe drug, while it reveals that the latest-generation TKIs may cause a burden of cardiovascular complications. GLS and PWV allow detection of early signs of cardiac and vascular toxicity in oncohematologic patients treated with TKI, and their use is advisable.


Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Doença da Artéria Coronariana/induzido quimicamente , Dasatinibe/efeitos adversos , Dasatinibe/uso terapêutico , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/uso terapêutico , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Análise de Onda de Pulso , Piridazinas/efeitos adversos , Piridazinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
3.
Int J Mol Sci ; 21(7)2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32276316

RESUMO

Neuroinflammation is considered to be one of the potential causes for the development of neurodegenerative diseases, including Alzheimer's disease. In this study, we evaluated the effect of four newly synthesized pyrrolo[3,4-d]pyridazinone derivatives on the neuron-like PC12 cells under simulated inflammation conditions by preincubation with lipopolysaccharide (LPS). Our novel derivatives are selective cyclooxygenase-2 (COX-2) inhibitors and have similar effects to nonsteroidal anti-inflammatory drugs (NSAIDs). We assessed viability (LDH assay), metabolic activity (MTT assay), DNA damage (number of double-strand breaks measured by fast halo assay), and the neuronal features of cells (average neurite length and neurite outgrowth measured spectrofluorimetrically). DCF-DA and Griess assays were also performed, which allowed determining the impact of the tested compounds on the level of oxygen free radicals and nitrites. LPS administration significantly negatively affected the results in all tests performed, and treatment with the tested derivatives in most cases significantly reduced this negative impact. Multiple-criteria decision analysis indicated that overall, the best results were observed for compounds 2a and 2b at a concentration of 10 µM. The new derivatives showed intense activity against free oxygen radicals and nitrites. Reduced reactive oxygen species level also correlated with a decrease in the number of DNA damage. The compounds improved neuronal features, such as neurite length and outgrowth, and they also increased cell viability and mitochondrial activity. Our results suggest that derivatives 2a and 2b may also act additionally on mechanisms other than 3a and 3b.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Inflamação/tratamento farmacológico , Neurônios/efeitos dos fármacos , Piridazinas/farmacologia , Doença de Alzheimer , Animais , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Inflamação/induzido quimicamente , Lipopolissacarídeos/toxicidade , Neurônios/patologia , Células PC12 , Piridazinas/uso terapêutico , Ratos
4.
Ann Rheum Dis ; 79(5): 626-634, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32161055

RESUMO

OBJECTIVES: To evaluate initial combination therapy with ambrisentan plus tadalafil (COMB) compared with monotherapy of either agent (MONO), and the utility of baseline characteristics and risk stratification in predicting outcomes, in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) and the systemic sclerosis (SSc)-pulmonary arterial hypertension (PAH) subpopulation. METHODS: This post hoc analysis of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) study included patients with CTD-PAH from the modified intention-to-treat population. Time to clinical failure (TtCF) was assessed by baseline characteristics, treatment assignment and risk group (low, intermediate and high) at baseline and week 16. TtCF was compared between groups using Kaplan-Meier curves and Cox proportional hazards regression modelling. RESULTS: The analysis included 216 patients (COMB, n=117; MONO, n=99). The risk of clinical failure was lower with COMB versus MONO (risk reduction: CTD-PAH 51.7%, SSc-PAH 53.7%), particularly in patients with haemodynamic parameters characteristic of typical PAH without features of left heart disease and/or restrictive lung disease at baseline. The risk of clinical failure was lower with COMB versus MONO in the baseline low-risk group (HR not calculated due to no events in COMB), baseline intermediate-risk group (HR 0.519, 95% CI 0.297 to 0.905) and in the week 16 low-risk group (HR 0.069, 95% CI 0.009 to 0.548). CONCLUSIONS: The benefit of COMB over MONO was demonstrated in patients with CTD-PAH, particularly in those with typical PAH haemodynamic characteristics at baseline. COMB is appropriate for patients categorised as low risk and intermediate risk at baseline and low risk at follow-up. TRIAL REGISTRATION NUMBER: NCT01178073.


Assuntos
Fenilpropionatos/administração & dosagem , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/epidemiologia , Piridazinas/administração & dosagem , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/epidemiologia , Tadalafila/administração & dosagem , Adulto , Comorbidade , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/tratamento farmacológico , Doenças do Tecido Conjuntivo/epidemiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Hipertensão Arterial Pulmonar/diagnóstico , Medição de Risco , Escleroderma Sistêmico/diagnóstico , Resultado do Tratamento , Vasodilatadores/administração & dosagem
5.
Ann Hematol ; 99(4): 829-834, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32107574

RESUMO

A single-center retrospective was performed with consecutive de novo BCR-ABL1-positive acute lymphoblastic leukemia (ALL) patients who received TKI-containing therapy between January 2010 and December 2018 to review the incidence, treatment, and outcome of the T315I mutation. A total of 38 (18%) patients harbored the T315I mutation in this period. According to the type of salvage therapy, patients were divided into subgroups of hematopoietic stem cell transplantation (HSCT) recipients (n = 9) and HSCT nonrecipients (n = 29). In the latter subgroup, there were 7 patients who newly acquired the T315I mutation after HSCT, and the median time was 10.8 months. In addition to these 7 cases, 5 out of 22 patients were managed with chimeric antigen receptor (CAR) T cells and ponatinib. There were 4 patients in the HSCT recipient subgroup who were treated with CAR-T cells or ponatinib before HSCT. The complete molecular remission (CMR) and recurrence rate of HSCT recipients were both 67%, and the median recurrence time was 3.6 months. A better overall survival (OS) was observed in the HSCT recipient subgroup than in the HSCT nonrecipient subgroup (median of 12.3 months vs 3.3 months, respectively; p = 0.004). Compared with patients who were not bridging to HSCT, the patients who were treated with CAR-T cells and/or ponatinib and bridged to HSCT tended to have a better OS (median of 3.3 months vs 13.3, respectively; p = 0.09). In conclusion, the outcomes in ALL patients with the T315I BCR-ABL1 mutation were poor. A better OS can be achieved through ponatinib, CAR-T cells, and bridging to HSCT, but it also has a higher risk of recurrence.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Genes abl , Imidazóis/uso terapêutico , Terapia de Alvo Molecular , Mutação de Sentido Incorreto , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/uso terapêutico , Adolescente , Adulto , Substituição de Aminoácidos , Terapia Combinada , Dasatinibe/uso terapêutico , Intervalo Livre de Doença , Feminino , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoterapia Adotiva , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Recidiva , Indução de Remissão , Risco , Terapia de Salvação , Adulto Jovem
7.
Mol Cell Biochem ; 464(1-2): 1-9, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31673920

RESUMO

Glioblastoma is the most common and deadly type of brain cancer. The poor prognosis may be largely attributed to inadequate disease response to current chemotherapeutic agents. Activation of p38 is associated with deleterious outcomes in glioblastoma patients, as its signaling mediates chemoresistance mechanisms. Antimicrobial peptide tilapia piscidin (TP) 4 was identified from Nile tilapia (Oreochromis niloticus) and exhibits strong bactericidal effects on Gram-positive and Gram-negative bacteria. TP4 also has anticancer activity toward human triple-negative breast cancer cells and glioblastoma cells. In the present study, we tested the cytotoxic effects of combined TP4 and p38 inhibitors on glioblastoma U251 cells. We found that the combination of TP4 and p38 inhibitors (SB202190 and VX-745) enhanced cytotoxicity in U251 glioblastoma cells but not noncancerous neural cells. Cytotoxicity from the combination treatments proceeded via necrosis and not apoptosis. Mechanistically, SB202190 potentiated TP4-induced mitochondrial dysfunction, reactive oxygen species generation and unbalanced antioxidant status, which resulted in necrotic cell death. Thus, we demonstrated for the first time that combinations of TP4 and p38 inhibitors have the potential to preferentially target glioblastoma cells, while sparing noncancerous neural cells.


Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Glioblastoma/tratamento farmacológico , Imidazóis/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Fragmentos de Peptídeos/farmacologia , Piridazinas/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Timopoietinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Glioblastoma/enzimologia , Glioblastoma/patologia , Humanos , Proteínas de Neoplasias/metabolismo , Tilápia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/enzimologia , Neoplasias de Mama Triplo Negativas/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Eur J Med Chem ; 187: 111912, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31812034

RESUMO

A family of 12 triazolo-pyridazine-6-yl-substituted piperazines (5a-l) was synthesized and evaluated for their Dipeptidyl peptidase-4 (DPP-4) inhibition potentials in order to develop them as anti-diabetic medications. In the two-step synthesis process, 6-chloro-3-(m-tolyl)-[1,2,4]triazolo[4,3-b]pyridazine was synthesized with one-pot mode using pyridine, 3,6-dichloropyridazine 5-(3-methyl-phenyl)tetrazole in toluene. Conjugating corresponding 2° amines with 6-chloro-3-(m-tolyl)-[1,2,4]triazolo[4,3-b]pyridazine afforded the target triazolo-pyridazine-6-yl-substituted piperazines (5a-l). DPP-4 inhibition potential of these compounds was testified in silico and in nitro along with their insulinotropic activities in 832/13 INS-1 cells. H2O2 radical scavenging assay and MTT assay were conducted to assess the antioxidant and cytotoxicity of these compounds respectively. Molecular docking and ELISA based enzyme inhibition assay results revealed the strong inhibition potential of the target compounds. MTT assay results indicated a maximum dose of 2.5 nM (IC50 1.25 nM) could be used and above this level vital for the cells. Compounds 5a, 5c, 5g and 5i were found with excellent antioxidant and insulinotropic activity up to 99%.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Piperazinas/farmacologia , Diabetes Mellitus/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Piridazinas/química , Piridazinas/farmacologia , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia
10.
J Med Chem ; 63(2): 756-783, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31846577

RESUMO

From a high-throughput screen of 42 444 known human kinases inhibitors, a pyrazolo[1,5-b]pyridazine scaffold was identified to begin optimization for the treatment of human African trypanosomiasis. Previously reported data for analogous compounds against human kinases GSK-3ß, CDK-2, and CDK-4 were leveraged to try to improve the selectivity of the series, resulting in 23a which showed selectivity for T. b. brucei over these three human enzymes. In parallel, properties known to influence the absorption, distribution, metabolism, and excretion (ADME) profile of the series were optimized resulting in 20g being progressed into an efficacy study in mice. Though 20g showed toxicity in mice, it also demonstrated CNS penetration in a PK study and significant reduction of parasitemia in four out of the six mice.


Assuntos
Piridazinas/síntese química , Piridazinas/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Tripanossomíase Africana/tratamento farmacológico , Animais , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Reposicionamento de Medicamentos , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Leishmania donovani/efeitos dos fármacos , Camundongos , Modelos Moleculares , Piridazinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Especificidade por Substrato , Distribuição Tecidual , Tripanossomicidas/farmacocinética , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/parasitologia
11.
Biomed Chromatogr ; 34(3): e4787, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31875652

RESUMO

Endothelin receptor antagonists (ERAs) such as, ambrisentan, macitentan and sitaxentan are primarily used for the treatment of pulmonary arterial hypertension. Considering the rise in endothelin in pre-eclampsia, ERAs may also be useful in its treatment. To evaluate the pharmacokinetics of ERAs, a rapid ultra-performance liquid chromatography tandem mass spectrometry method was developed and validated to determine the concentration of ambrisentan, macitentan and sitaxentan in human plasma. Plasma samples were treated with methanol to induce protein precipitation. A chromatographic separation was performed on a C18 column using a gradient of methanol-water containing 0.1% formic acid and 0.013% ammonium acetate and a flow rate of 0.5 ml/min. Multiple reaction monitoring was used for quantification. This method was validated in a linear range of 20.28-2028 µg/l for ambrisentan, 4.052-405.2 µg/l for macitentan and 205.4-10 270 µg/l for sitaxentan. The method was successfully validated according to US Food and Drug Administration guidelines to determine the concentrations of macitentan, ambrisentan and sitaxentan in human plasma. This method is now being used for study samples and clinical patient samples.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Isoxazóis/sangue , Fenilpropionatos/sangue , Piridazinas/sangue , Pirimidinas/sangue , Sulfonamidas/sangue , Espectrometria de Massas em Tandem/métodos , Tiofenos/sangue , Anti-Hipertensivos/sangue , Anti-Hipertensivos/química , Humanos , Isoxazóis/química , Modelos Lineares , Fenilpropionatos/química , Piridazinas/química , Pirimidinas/química , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sulfonamidas/química , Tiofenos/química
12.
Chemotherapy ; 64(4): 205-209, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31825920

RESUMO

Cardiovascular (CV) adverse events are considered common complications of ponatinib treatment. Recently, it has been demonstrated that ponatinib dose reductions in definite settings can obtain optimal responses and lower ponatinib-related CV events. In this study, we describe the management of 5 patients with chronic myeloid leukemia treated with ponatinib, from second to fourth line of tyrosine kinase inhibitor therapy, carrying high pre-ponatinib CV risk, who obtained optimal molecular response and developed no CV adverse event during follow-up. Among these 5 patients, 2 had diagnosis of ischemic heart disease and underwent percutaneous angioplasty, 2 had type 2 diabetes and arterial hypertension, and 1 had only arterial hypertension. Median follow-up for ponatinib therapy is 1,039 days (34.6 months). Median dosage administered is 30 mg a day. SCORE charts were used to estimate risk of CV death in 10 years and Charlson Comorbidity Index was applied to estimate age-adjusted risk of death related to comorbidities. Strict cardiologic follow-up (complete evaluation every 3 to 6 months) and maximum effort in the control of CV modifiable risk factors are strongly recommended in the management of ponatinib treatment in patients at high risk for CV events and may allow the use of ponatinib in patients belonging to CV risk category.


Assuntos
Imidazóis/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/uso terapêutico , Idoso , Doenças Cardiovasculares/etiologia , Comorbidade , Feminino , Humanos , Imidazóis/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Piridazinas/efeitos adversos , Fatores de Risco , Resultado do Tratamento
13.
Anticancer Res ; 39(12): 6965-6971, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810968

RESUMO

BACKGROUND/AIM: The Philadelphia chromosome is the most frequent cytogenetic abnormality in chronic myelogenous (CML). More than 95% of CML patients are diagnosed with the e13a2 or e14a2 BCR-ABL1 fusion transcripts while, in about 1% of these individuals, the break generates the e1a2 rearrangement. Furthermore, about 5% of CML patients are diagnosed with rare BCR-ABL1 fusion transcripts, such as e19a2, e8a2, e13a3, e14a3, e1a3 and e6a2. However, there is limited evidence concerning the clinical and prognostic implications of these infrequent oncogenic variants for CML patients receiving tyrosine kinase inhibitors (TKIs). CASE REPORT: We describe a novel atypical e12a2 insertion/deletion (Ins/Del) BCR-ABL1 fusion identified in a CML 59-year-old man diagnosed with a common e13a2 BCR-ABL1 isoform. The use of primers recognizing more distant exons from the common BCR-ABL1 breakpoint region correctly identified and monitored in time the atypical e12a2 Ins/Del BCR-ABL1 fusion. CONCLUSION: Treatment with second- (nilotinib) and third-generation (ponatinib) TKIs was effective in suppressing leukemic clones exhibiting the atypical e12a2 Ins/Del BCR-ABL1.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Humanos , Mutação INDEL , Imidazóis/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Isoformas de Proteínas/genética , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Resultado do Tratamento
14.
J Enzyme Inhib Med Chem ; 34(1): 1573-1589, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852269

RESUMO

Pyridazine scaffolds are considered privileged structures pertaining to its novelty, chemical stability, and synthetic feasibility. In our quest towards the development of novel scaffolds for effective vascular endothelial growth 2 (VEGFR-2) inhibition with antiangiogenic activity, four novel series of pyridazines were designed and synthesised. Five of the synthesised compounds; namely (8c, 8f, 15, 18b, and 18c) exhibited potent VEGFR-2 inhibitory potency (>80%); with IC50 values ranging from low micromolar to nanomolar range; namely compounds 8c, 8f, 15, 18c with (1.8 µM, 1.3 µM, 1.4 µM, 107 nM), respectively. Moreover, 3-[4-{(6-oxo-1,6-dihydropyridazin-3-yl)oxy}phenyl]urea derivative (18b) exhibited nanomolar potency towards VEGFR-2 (60.7 nM). In cellular assay, the above compounds showed excellent inhibition of VEGF-stimulated proliferation of human umbilical vein endothelial cells at 10 µM concentration. Finally, an extensive molecular simulation study was performed to investigate the probable interaction with VEGFR-2.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridazinas/síntese química , Piridazinas/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
15.
Lancet ; 394(10213): 2012-2024, 2019 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-31727409

RESUMO

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, hepatocellular injury, and progressive liver fibrosis. Resmetirom (MGL-3196) is a liver-directed, orally active, selective thyroid hormone receptor-ß agonist designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity. We aimed to assess the safety and efficacy of resmetirom in patients with NASH. METHODS: MGL-3196-05 was a 36-week randomised, double-blind, placebo-controlled study at 25 centres in the USA. Adults with biopsy confirmed NASH (fibrosis stages 1-3) and hepatic fat fraction of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned 2:1 by a computer-based system to receive resmetirom 80 mg or matching placebo, orally once a day. Serial hepatic fat measurements were obtained at weeks 12 and 36, and a second liver biopsy was obtained at week 36. The primary endpoint was relative change in MRI-PDFF assessed hepatic fat compared with placebo at week 12 in patients who had both a baseline and week 12 MRI-PDFF. This trial is registered with ClinicalTrials.gov, number NCT02912260. FINDINGS: 348 patients were screened and 84 were randomly assigned to resmetirom and 41 to placebo at 18 sites in the USA. Resmetirom-treated patients (n=78) showed a relative reduction of hepatic fat compared with placebo (n=38) at week 12 (-32·9% resmetirom vs -10·4% placebo; least squares mean difference -22·5%, 95% CI -32·9 to -12·2; p<0·0001) and week 36 (-37·3% resmetirom [n=74] vs -8·5 placebo [n=34]; -28·8%, -42·0 to -15·7; p<0·0001). Adverse events were mostly mild or moderate and were balanced between groups, except for a higher incidence of transient mild diarrhoea and nausea with resmetirom. INTERPRETATION: Resmetirom treatment resulted in significant reduction in hepatic fat after 12 weeks and 36 weeks of treatment in patients with NASH. Further studies of resmetirom will allow assessment of safety and effectiveness of resmetirom in a larger number of patients with NASH with the possibility of documenting associations between histological effects and changes in non-invasive markers and imaging. FUNDING: Madrigal Pharmaceuticals.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Piridazinas/uso terapêutico , Receptores beta dos Hormônios Tireóideos/agonistas , Uracila/análogos & derivados , Adulto , Alanina Transaminase/sangue , Biomarcadores/sangue , Diarreia/induzido quimicamente , Método Duplo-Cego , Feminino , Humanos , Inflamação/patologia , Lipídeos/sangue , Fígado/diagnóstico por imagem , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/patologia , Piridazinas/efeitos adversos , Uracila/efeitos adversos , Uracila/uso terapêutico
16.
Drug Res (Stuttg) ; 69(12): 671-682, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31698495

RESUMO

In this study, amino-oxy-diarylquinolines were designed using structure-guided molecular hybridization strategy and fusing of the pharmacophore templates of nevirapine (NVP), efavirenz (EFV), etravirine (ETV, TMC125) and rilpivirine (RPV, TMC278). The anti-HIV-1 reverse transcriptase (RT) activity was evaluated using standard ELISA method, and the cytotoxic activity was performed using MTT and XTT assays. The primary bioassay results indicated that 2-amino-4-oxy-diarylquinolines possess moderate inhibitory properties against HIV-1 RT. Molecular docking results showed that 2-amino-4-oxy-diarylquinolines 8(A-D): interacted with the Lys101 and His235 residue though hydrogen bonding and interacted with Tyr318 residue though π-π stacking in HIV-1 RT. Furthermore, 8A: and 8D: were the most potent anti-HIV agents among the designed and synthesized compounds, and their inhibition rates were 34.0% and 39.7% at 1 µM concentration. Interestingly, 8A: was highly cytotoxicity against MOLT-3 (acute lymphoblastic leukemia), with an IC50 of 4.63±0.62 µg/mL, which was similar with that in EFV and TMC278 (IC50 7.76±0.37 and 1.57±0.20 µg/ml, respectively). Therefore, these analogs of the synthesized compounds can serve as excellent bases for the development of new anti-HIV-1 agents in the near future.


Assuntos
Diarilquinolinas/química , Diarilquinolinas/farmacologia , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Benzoxazinas/química , Benzoxazinas/farmacologia , Linhagem Celular Tumoral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Humanos , Simulação de Acoplamento Molecular , Nevirapina/química , Nevirapina/farmacologia , Piridazinas/química , Piridazinas/farmacologia , Rilpivirina/química , Rilpivirina/farmacologia
17.
Gan To Kagaku Ryoho ; 46(11): 1795-1797, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31748496

RESUMO

A man in his late 50s had lumbago and thrombocytopenia. He was diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia(Ph plus ALL). Remission induction chemotherapy was initiated with JALSG Ph plus ALL 208 protocol, but cerebral infarction in the right occipital lobe developed on day 2 and, to make matters worse, was accompanied by hemorrhagic cerebral infarction in the left occipital lobe on day 9. We decided that chemotherapy with multiple drugs was difficult to continue, and it was stopped. After improvement of the general condition, dasatinib therapy was started on day 52. After about 5 months, Ph plus ALL relapsed. Although mild disorientation and visual field defects remained due to old cerebral infarction, organ function was maintained, and patient performance status(PS)was classified as 1. Introduction of ponatinib was considered feasible, and ponatinib was started from a dose of 15mg/day to prevent the occurrence of vaso- occlusive adverse events. It was gradually increased to 30mg /day and continued about 4 months without recurrence of cerebral infarction. Complete molecular response was achieved with ponatinib therapy. It was suggested that, in patients with Ph plus ALL with a history of cerebral infarction, ponatinib could be a treatment option under careful risk management.


Assuntos
Imidazóis/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras , Piridazinas/uso terapêutico , Acidente Vascular Cerebral , Humanos , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Indução de Remissão
18.
EBioMedicine ; 50: 111-121, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31761618

RESUMO

PURPOSE: Ponatinib is the only approved tyrosine kinase inhibitor (TKI) suppressing BCR-ABL1T315I-mutated cells in chronic myeloid leukemia (CML). However, due to side effects and resistance, BCR-ABL1T315I-mutated CML remains a clinical challenge. Hydroxyurea (HU) has been used for cytoreduction in CML for decades. We found that HU suppresses or even eliminates BCR-ABL1T315I+ sub-clones in heavily pretreated CML patients. Based on this observation, we investigated the effects of HU on TKI-resistant CML cells in vitro. METHODS: Viability, apoptosis and proliferation of drug-exposed primary CML cells and BCR-ABL1+ cell lines were examined by flow cytometry and 3H-thymidine-uptake. Expression of drug targets was analyzed by qPCR and Western blotting. FINDINGS: HU was more effective in inhibiting the proliferation of leukemic cells harboring BCR-ABL1T315I or T315I-including compound-mutations compared to cells expressing wildtype BCR-ABL1. Moreover, HU synergized with ponatinib and ABL001 in inducing growth inhibition in CML cells. Furthermore, HU blocked cell cycle progression in leukemic cells, which was accompanied by decreased expression of CDK4 and CDK6. Palbociclib, a more specific CDK4/CDK6-inhibitor, was also found to suppress proliferation in primary CML cells and to synergize with ponatinib in producing growth inhibition in BCR-ABL1T315I+ cells, suggesting that suppression of CDK4/CDK6 may be a promising concept to overcome BCR-ABL1T315I-associated TKI resistance. INTERPRETATION: HU and the CDK4/CDK6-blocker palbociclib inhibit growth of CML clones expressing BCR-ABL1T315I or complex T315I-including compound-mutations. Clinical studies are required to confirm single drug effects and the efficacy of `ponatinib+HU´ and ´ponatinib+palbociclib´ combinations in advanced CML. FUNDING: This project was supported by the Austrian Science Funds (FWF) projects F4701-B20, F4704-B20 and P30625.


Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Mutação , Inibidores de Proteínas Quinases/farmacologia , Adulto , Idoso , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Humanos , Hidroxiureia/farmacologia , Hidroxiureia/uso terapêutico , Imidazóis/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/farmacologia
20.
PLoS One ; 14(10): e0223164, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31581204

RESUMO

Pimobendan has gained enormous importance in the treatment of mitral valve disease in dogs. The current consensus statement of the American College of Veterinary Internal Medicine (ACVIM) recommends a treatment for dogs with symptomatic disease and dogs with asymptomatic disease with radiographic and echocardiographic signs of cardiomegaly. To investigate whether these dogs also benefit from a therapy with pimobendan, 21 dogs with mitral valve disease ACVIM B1 underwent a standardized submaximal exercise test on a treadmill. In this double-blinded and randomized study, the animals were divided into two groups, one receiving pimobendan and the other a placebo. At the first visit and at every follow-up appointment (at days 90 and 180), heart rate during the complete exercise test and lactate before and after running were measured. In addition to this, a questionnaire was completed by the dogs' owners and all dogs were given an echocardiographic examination to detect any changes and to observe if the disease had progressed. Due to the diagnosis of leishmaniosis, one dog in the pimobendan group was retrospectively removed from the study so that 20 dogs were included for statistical analysis. No differences were observed at any time between the pimobendan-group and the placebo-group regarding heart rate. At day 180, the increase in lactate after exercise was significantly lower than in the placebo-group. The increase in the pimobendan-group at day 180 was lower than at day 90. Most of the dog owners from the pimobendan-group declared that their dogs were more active at day 90 (6/10) and at day 180 (8/10), while most dog owners from the placebo-group observed no changes regarding activity at day 90 (8/10) and day 180 (6/10). It can be concluded that the results of this study indicate that some dogs with mitral valve disease ACVIM B1 might benefit from a therapy with pimobendan.


Assuntos
Cardiomegalia/complicações , Ecocardiografia , Doenças das Valvas Cardíacas/tratamento farmacológico , Doenças das Valvas Cardíacas/veterinária , Ácido Láctico/sangue , Valva Mitral/patologia , Aptidão Física/fisiologia , Piridazinas/farmacologia , Animais , Cardiomegalia/fisiopatologia , Doenças do Cão/tratamento farmacológico , Cães , Teste de Esforço , Feminino , Sopros Cardíacos/complicações , Sopros Cardíacos/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Doenças das Valvas Cardíacas/diagnóstico por imagem , Doenças das Valvas Cardíacas/fisiopatologia , Masculino , Valva Mitral/diagnóstico por imagem , Valva Mitral/fisiopatologia , Corrida
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