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2.
Lancet Haematol ; 7(2): e112-e121, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31866281

RESUMO

BACKGROUND: Chemoimmunotherapy is typically the standard of care for patients with Waldenström macroglobulinemia; however, infectious and hematologic toxic effects are problematic. Acalabrutinib is a selective, potent Bruton tyrosine-kinase inhibitor. The aim of this trial was to evaluate the activity and safety of acalabrutinib in patients with Waldenström macroglobulinemia. METHODS: This single-arm, multicentre, phase 2 trial was done in 19 European academic centres in France, Italy, Greece, the Netherlands, and the UK, and eight academic centres in the USA. Eligible patients were 18 years or older and had treatment naive (declined or not eligible for chemoimmunotherapy) or relapsed or refractory (at least one previous therapy) Waldenström macroglobulinemia that required treatment, an Eastern Cooperative Oncology Group performance status of 2 or less, and received no previous Bruton tyrosine-kinase inhibitor therapy. Patients received 100 mg oral acalabrutinib twice per day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response (at least a minor response) according to the 6th International Workshop for Waldenström Macroglobulinemia (IWWM) and the modified 3rd IWWM workshop criteria. The primary outcome and safety were assessed in all patients who received at least one dose of treatment. This study is registered with ClinicalTrials.gov, number NCT02180724, and is ongoing, but no longer enrolling. FINDINGS: Between Sept 8, 2014, and Dec 24, 2015, 122 patients were assessed for eligibility, of which 106 (87%) patients were given acalabrutinib (14 were treatment naive and 92 had relapsed or refractory disease). With a median follow-up of 27·4 months (IQR 26·0-29·7), 13 (93% [95% CI 66-100]) of 14 treatment naive patients achieved an overall response and 86 (93% [86-98]) of 92 relapsed or refractory patients per both the modified 3rd and 6th IWWM criteria. Seven (50%) of 14 treatment naive patients and 23 (25%) of 92 relapsed or refractory patients discontinued treatment on study. Grade 3-4 adverse events occurring in more than 5% of patients were neutropenia (17 [16%] of 106 patients) and pneumonia (7 [7%]). Grade 3-4 atrial fibrillation occurred in one (1%) patient and grade 3-4 bleeding occurred in three (3%) patients. The most common serious adverse events were lower respiratory tract infection (n=7 [7%]), pneumonia (n=7 [7%]), pyrexia (n=4 [4%]), cellulitis (n=3 [3%]), fall (n=3 [3%]), and sepsis (n=3 [3%]). Pneumonia (n=5 [5%]) and lower respiratory tract infection (n=4 [4%]) were considered treatment related. One treatment-related death was reported (intracranial hematoma). INTERPRETATION: This study provides evidence that acalabrutinib is active as single-agent therapy with a manageable safety profile in patients with treatment-naive, or relapse or refractory Waldenström macroglobulinemia. Further studies are needed to establish its efficacy against current standard treatments and to investigate whether outcomes can be improved with combination therapies. FUNDING: Acerta Pharma.


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Benzamidas/efeitos adversos , Benzamidas/farmacologia , Feminino , Gastroenteropatias/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/genética , Proteínas de Neoplasias/antagonistas & inibidores , Neutropenia/induzido quimicamente , Dor/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/efeitos adversos , Pirazinas/farmacologia , Qualidade de Vida , Recidiva , Infecções Respiratórias/etiologia , Terapia de Salvação , Resultado do Tratamento , Macroglobulinemia de Waldenstrom/enzimologia , Macroglobulinemia de Waldenstrom/genética
3.
Life Sci ; 239: 117016, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678281

RESUMO

The current study aimed to investigate the effects of tetramethylprazine (TMP) on myocardial ischemia/reperfusion (MI/R) injury and its underlying mechanisms. MI/R rat model and hypoxia/reoxygenation (H/R) cardiomyocytes model were established. CK level and LDH activity were detected to evaluate MI/R and H/R injury. Cell viability was determined by cell counting kit-8 (CCK-8) assay. Cell apoptosis were identified by flow cytometry and autophagy were detected by western blot. Treatment with TMP significantly reduced CK level and LDH activity and decreased myocardial infarct size in MI/R rats. TMP reduced autophagy dysfunction induced by MI/R. Moreover, TMP treatment decreased H/R-induced injury and attenuated autophagy dysfunction in cardiomyocytes. Inhibiting autophagic flux with chloroquine (CQ) decreased the cardioprotection exerted by TMP in vivo and in vitro. Additionally, the effects of TMP on the modulation of autophagy were inhibited by LY294002 (a PI3K inhibitor) in H/R cardiomyocytes. Our findings suggested TMP exerted cardioprotection against MI/R injury by decreasing Beclin-1 associated autophagy dysfunction through PI3K pathway.


Assuntos
Autofagia/efeitos dos fármacos , Cardiotônicos/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Pirazinas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cromonas/farmacologia , Creatina Quinase/metabolismo , L-Lactato Desidrogenase/metabolismo , Masculino , Morfolinas/farmacologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Cultura Primária de Células , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/antagonistas & inibidores , Pirazinas/farmacologia , Ratos , Ratos Sprague-Dawley
4.
Niger J Clin Pract ; 22(10): 1324-1327, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31607719

RESUMO

Background: Acute cerebral infarction threats human health and life safety. The edaravone is a new antioxidant and hydroxyl radical scavenger, which is the novel scavenger for clinical use, mainly for nervous system diseases. Objective: The purpose of this study is to observe the clinical treatment effects of edaravone on the degree of improvement of neurological impairment and functional movement impairment in patients with acute cerebral infarction. Method: A total of 130 patients admitted to our hospital because of acute cerebral infarction from December 2015 to May 2017 were selected for group analysis. These patients were divided into a control group (n = 65) and a treatment group (n = 65) with a random odd-even method. The control group accepted conventional treatment, while the treatment group received edaravone treatment on top of the conventional treatment of the control group. After treatment, the differences in functional movement, living ability score, neurological score, treatment effect, and adverse reaction of these two groups were tested and compared. Results: The total treatment efficiency of conventional treatment in the control group was significantly lower than the combination treatment in the treatment group (P < 0.05). The inter-group differences in the National Institutes of Health Stroke Scale, activities of daily living, and Fugl-Meyer assessment scores after the treatment were significant between these two groups (P < 0.05). The posttreatment effect on the treatment group was superior to that on the control group (P < 0.05). The adverse reaction rate of the treatment group did not significantly vary from that of the control group (P > 0.05). Conclusion: Edaravone can significantly improve the degree of neurological impairment during acute cerebral infarction, functional movement, and living quality with a definite effect and high safety. Thus, this drug has a good prospect in clinical treatment.


Assuntos
Infarto Cerebral/tratamento farmacológico , Edaravone/uso terapêutico , Depuradores de Radicais Livres/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Pirazinas/uso terapêutico , Vasodilatadores/uso terapêutico , Atividades Cotidianas , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
5.
N Engl J Med ; 381(18): 1728-1740, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31665578

RESUMO

BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML. METHODS: In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3-mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission. RESULTS: Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%). CONCLUSIONS: Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML. (Funded by Astellas Pharma; ADMIRAL ClinicalTrials.gov number, NCT02421939.).


Assuntos
Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação , Pirazinas/uso terapêutico , Terapia de Salvação , Tirosina Quinase 3 Semelhante a fms/genética , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Pirazinas/efeitos adversos , Recidiva , Indução de Remissão , Análise de Sobrevida
6.
Int J Mol Sci ; 20(16)2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31434286

RESUMO

There is a need for an efficient and low-cost leading compound discovery mode. However, drug development remains slow, expensive, and risky. Here, this manuscript proposes a leading compound discovery strategy based on a combination of traditional Chinese medicine (TCM) formulae and pharmacochemistry, using a ligustrazine-betulinic acid derivative (BA-12) in the treatment of angiogenesis as an example. Blocking angiogenesis to inhibit the growth and metastasis of solid tumors is currently one recognized therapy for cancer in the clinic. Firstly, based on a traditional Prunella vulgaris plaster, BA-12 was synthesized according to our previous study, as it exhibited better antitumor activities than other derivatives on human bladder carcinoma cells (T24); it was then uploaded for target prediction. Secondly, the efficacy and biotoxicity of BA-12 on angiogenesis were evaluated using human umbilical vein endothelial cells (HUVECs), a quail chick chorioallantoic membrane, and Caenorhabditis elegans. According to the prediction results, the main mechanisms of BA-12 were metabolic pathways. Thus, multiple metabolomics approaches were applied to reveal the mechanisms of BA-12. Finally, the predictive mechanisms of BA-12 on glutathione metabolism and glycerophospholipid metabolism activation were validated using targeted metabolomics and pharmacological assays. This strategy may provide a reference for highly efficient drug discovery, with the aim of sharing TCM wisdom for unmet clinical needs.


Assuntos
Neovascularização Patológica/tratamento farmacológico , Pirazinas/química , Pirazinas/uso terapêutico , Triterpenos/química , Triterpenos/uso terapêutico , Animais , Caenorhabditis elegans/efeitos dos fármacos , Membrana Corioalantoide/efeitos dos fármacos , Descoberta de Drogas , Células Endoteliais da Veia Umbilical Humana , Humanos , Metabolômica/métodos
7.
Chem Asian J ; 14(22): 3962-3968, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31389664

RESUMO

Eight different compounds, all nucleoside analogues, could presently be considered as potential drug candidates for the treatment of Ebola virus (EBOV) and/or other hemorrhagic fever virus (HFV) infections. They can be considered as either (i) adenine analogues (3-deazaneplanocin A, galidesivir, GS-6620 and remdesivir) or (ii) guanine analogues containing the carboxamide entity (ribavirin, EICAR, pyrazofurin and favipiravir). All eight owe their mechanism of action to hydrogen bonded base pairing with either (i) uracil or (ii) cytosine. Four out of the eight compounds (galidesivir, GS-6620, remdesivir and pyrazofurin) are C-nucleosides, and two of them (GS-6620, remdesivir) also contain a phosphoramidate part. The C-nucleoside and phosphoramidate (and for the adenine analogues the 1'-cyano group as well) may be considered as essential attributes for their antiviral activity.


Assuntos
Adenina/análogos & derivados , Antivirais/química , Guanina/análogos & derivados , Febres Hemorrágicas Virais/tratamento farmacológico , Adenina/farmacologia , Adenina/uso terapêutico , Amidas/química , Amidas/metabolismo , Amidas/farmacologia , Amidas/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Pareamento de Bases , Ebolavirus/efeitos dos fármacos , Guanina/farmacologia , Guanina/uso terapêutico , Humanos , Nucleotídeos/química , Nucleotídeos/uso terapêutico , Ácidos Fosfóricos/química , Ácidos Fosfóricos/uso terapêutico , Pirazinas/química , Pirazinas/metabolismo , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Triazinas/química , Triazinas/uso terapêutico
8.
Crit Rev Oncol Hematol ; 141: 125-138, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31279288

RESUMO

Internal tandem duplications and tyrosine kinase mutations in the fms-like tyrosine kinase 3 (FLT3) receptor can occur in acute myeloid leukemia (AML) and portend a poor prognosis. Midostaurin, a multikinase inhibitor that targets FLT3, demonstrated a survival benefit in FLT3-mutated AML in combination with front-line chemotherapy. Despite this advancement, the use of FLT3 inhibitors in clinical practice is complicated by significant drug-drug interactions and uncertainty about optimal timing, duration, and sequencing of therapy. As monotherapy, the utility of FLT3 inhibitors was initially limited by incomplete and transient clinical responses and the development of acquired resistance. This led to the development of more potent and selective FLT3 inhibitors designed to overcome common resistance mechanisms. One of these second generation FLT3 inhibitors, gilteritinib, is now FDA-approved for the treatment of relapsed or refractory AML. Now that multiple FLT3 inhibitors are commercially available, it is important to further delineate the role of these agents in the AML population. This review aims to provide a comprehensive overview of the role of FLT3 inhibitors in AML and apply the current literature to clinical practice.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Compostos de Anilina/uso terapêutico , Humanos , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/genética , Mutação , Pirazinas/uso terapêutico , Estaurosporina/análogos & derivados , Estaurosporina/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genética
9.
Blood ; 134(9): 741-745, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31243041

RESUMO

The natural history of FLT3-mutated AML is changing after the approval of midostaurin for frontline therapy and gilteritinib for relapsed or refractory patients. Recently reported, positive randomized trials of the drugs gilteritinib, quizartinib, and sorafenib predict even wider use of FLT3 inhibitors going forward. FLT3 inhibitors now emerge as an important, if not indispensable, part of therapy for a large subset of high-risk patients.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Animais , Antineoplásicos/farmacologia , Benzotiazóis/farmacologia , Benzotiazóis/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Estaurosporina/análogos & derivados , Estaurosporina/farmacologia , Estaurosporina/uso terapêutico
10.
Oxid Med Cell Longev ; 2019: 7096912, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223426

RESUMO

Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired acute kidney injury (AKI), but detailed pathogenesis and effectual remedy remain elusive. Here, we tested the hypothesis that contrast media (CM) impaired mitochondrial quality control (MQC) in tubules, including mitochondrial fragmentation and mitophagy, induced systemic inflammation, and intestinal injury. Since we previously demonstrated that the natural antioxidant 2,3,5,6-tetramethylpyrazine (TMP) can be a protectant against CIN, we moreover investigated the involved renoprotective mechanisms of TMP. In a well-established CIN rat model, renal functions, urinary AKI biomarkers, and renal reactive oxygen species (ROS) production were measured. Mitochondrial damage and mitophagy were detected by transmission electron microscopy (TEM) and western blot. The abundance of Drp1 and Mfn2 by western blot and immunohistochemistry (IHC) was used to evaluate mitochondrial fragmentation. TUNEL staining, TEM, and the abundance of cleaved-caspase 3 and procaspase 9 were used to assay apoptosis. We demonstrated that increased mitophagy, mitochondrial fragmentation, ROS generation, autophagy, and apoptosis occurred in renal tubular cells. These phenomena were accompanied by renal dysfunction and an increased excretion of urinary AKI biomarkers. Meanwhile, CM exposure resulted in concurrent small intestinal injury and villous capillary endothelial apoptosis. The abundance of the inflammatory cytokines CCL2 and CCR2 markedly increased in the renal tubules of CIN rats, accompanied by increased concentrations of IL-6 and TNF-α in the kidneys and the serum. Interestingly, TMP efficiently prevented CM-induced kidney injury in vivo by reversing these pathological processes. Mechanistically, TMP inhibited the CM-induced activation of the CCL2/CCR2 pathway, ameliorated renal oxidative stress and aberrant mitochondrial dynamics, and modulated mitophagy in tubular cells. In summary, this study demonstrated novel pathological mechanisms of CIN, that is, impairing MQC, inducing CCL2/CCR2-mediated inflammation and small intestinal injury, and provided novel renoprotective mechanisms of TMP; thus, TMP may be a promising therapeutic agent for CIN.


Assuntos
Glomerulonefrite por IGA/induzido quimicamente , Mediadores da Inflamação/metabolismo , Intestinos/lesões , Mitocôndrias/genética , Pirazinas/uso terapêutico , Animais , Masculino , Pirazinas/farmacologia , Ratos , Ratos Sprague-Dawley
11.
Clin Adv Hematol Oncol ; 17(4): 223-233, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31188814

RESUMO

Mantle cell lymphoma (MCL) is a heterogeneous and uncommon non-Hodgkin lymphoma that affects predominantly older patients and often is associated with an aggressive clinical course. MCL relies upon B-cell receptor signaling through Bruton tyrosine kinase (BTK); therefore, the development of the BTK inhibitors ibrutinib and acalabrutinib represents a therapeutic breakthrough. In this review, we provide a summary of the efficacy and safety data from the landmark trials of single-agent ibrutinib and acalabrutinib that led to US Food and Drug Administration approval of these agents for patients with relapsed or refractory MCL. Toxicities of interest observed with ibrutinib include bleeding, atrial fibrillation, and increased risk for infection. The selectivity of acalabrutinib for BTK is greater than that of ibrutinib, which mitigates the risk for certain off-target toxicities, including atrial fibrillation; however, these toxicities, along with frequent headaches, still occur. Ongoing clinical trials are investigating both alternate BTK inhibitors and BTK inhibitors in combination with chemo-immunotherapy or other targeted agents in an effort to enhance the depth and duration of response. Trials to evaluate the use of these agents in the frontline setting are emerging and are likely to build upon the success of BTK inhibitors in patients with MCL.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Antígenos CD20/efeitos dos fármacos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/efeitos adversos , Benzamidas/uso terapêutico , Doenças Cardiovasculares/induzido quimicamente , Ensaios Clínicos como Assunto , Previsões , Neoplasias Gastrointestinais/induzido quimicamente , Hemorragia/induzido quimicamente , Humanos , Fatores Imunológicos/administração & dosagem , Linfocitose/induzido quimicamente , Linfoma de Célula do Manto/enzimologia , Terapia de Alvo Molecular/efeitos adversos , Infecções Oportunistas/induzido quimicamente , Pirazinas/efeitos adversos , Pirazinas/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Terapia de Salvação
12.
Oxid Med Cell Longev ; 2019: 6791457, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31191802

RESUMO

Background/Aims: Coronary microembolization- (CME-) induced myocardial injury and progressive cardiac dysfunction are mainly caused due to CME-induced myocardial local inflammatory response and myocardial apoptosis. Ligustrazine plays an important protective role in multiple cardiovascular diseases, but its role and the protection mechanism in CME is unclear. This study hypothesized that ligustrazine attenuates CME-induced myocardial injury in rats. This study also explored the mechanism underlying this attenuation. Methods: Forty SD rats were randomly divided into CME group, ligustrazine group, ligustrazine+LY294002 (ligustrazine+LY) group, and sham group (ten rats in each). In each group, the cardiac function, apoptotic index, serum c-troponin I (cTnI) level, inflammation [interleukin-1ß (IL-1ß) and tumor necrosis factor-alpha (TNF-α)], and oxidative stress [nitric oxide (NO), superoxide dismutase (SOD), and malondialdehyde (MDA)] were determined. Western blotting was used to detect the proteins which are present in the PI3K/Akt pathway. Results: Ligustrazine improved cardiac dysfunction induced by CME, increased serum NO and SOD activities, and decreased the serum level in IL-1ß, MDA, cTnI, and TNF-α. Moreover, ligustrazine inhibited myocardial apoptosis, which is perhaps caused by the upregulated Bcl-2, the downregulated cleaved caspase-3 and Bax, and the increased protein level in endothelial nitric oxide synthase and phosphorylated Akt. These effects, however, were reduced if ligustrazine was coadministered with LY294002. Conclusions: Ligustrazine attenuates CME-induced myocardial injury. The effects associated with this attenuation may be achieved by activating the myocardium PI3K/Akt signaling pathway.


Assuntos
Traumatismos Cardíacos/tratamento farmacológico , Traumatismos Cardíacos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazinas/uso terapêutico , Animais , Malondialdeído/metabolismo , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
13.
Int J Mol Sci ; 20(10)2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31121826

RESUMO

OBJECTIVE: Heme oxygenase (HO-1) plays a critical role in adipogenesis and it is important to understand its function in obesity. Many studies have shown that upregulation of HO-1 can affect the biologic parameters in obesity-mediated diabetes, hypertension and vascular endothelial cell function. Thus, we aimed to explore the hypothesis that upregulation of HO-1, using a pharmacologic approach as well as gene targeting, would improve both adiposity and endothelial cell dysfunction by direct targeting of endothelial cells. Our second aim was to compare the short-term effect of a HO-1 inducer, cobalt-protoporphrin IX (CoPP), with the long-term effects of gene targeted therapy on vascular and adipocyte stem cells in obese mice. METHOD: We examined the effect of CoPP on fat pre-adipocytes and mesenchymal stem cells (MSC) in mice fed a high-fat diet (HFD). We also used a lentiviral construct that expressed heme oxygenase (HO-1) that was under the control of an endothelium specific promoter, vascular endothelium cadherin (VECAD) heme oxygenase (VECAD-HO-1). We targeted endothelial cells using vascular endothelium cadherin/green fluorescent protein fusion construct (VECAD-GFP) as the control. Conditioned media (CM) from endothelial cells (EC) was added to fat derived adipocytes. Additionally, we treated renal interlobar arteries with phenylephrine and dosed cumulative increments of acetylcholine both with and without exposure to CoPP. We did the same vascular reactivity experiments with VECAD-HO-1 lentiviral construct compared to the control. RESULTS: CoPP improved vascular reactivity and decreased adipogenesis compared to the control. MSCs exposed to CM from EC transfected with VECAD-HO-1 showed decreased adipogenesis, smaller lipid droplet size and decreased PPAR-γ, C/EBP and increased Wnt 10b compared to the control. HO-1 upregulation had a direct effect on reducing adipogenesis. This effect was blocked by tin mesoporphrin (SnMP). EC treated with VECAD-HO-1 expressed lower levels of ICAM and VCAM compared to the control, suggesting improved EC function. This also improved ACH induced vascular reactivity. These effects were also reversed by SnMP. The effect of viral transfection was much more specific and sustained than the effects of pharmacologic therapy, CoPP. CONCLUSION: This study demonstrates that a pharmacological inducer of HO-1 such as CoPP improves endothelial cell function while dampening adipogenesis, but long-term HO-1 expression by direct targeting of endothelial cells by gene transfer therapy may offer a more specific and ideal solution. This was evidenced by smaller healthier adipocytes that had improved insulin sensitivity, suggesting increased adiponectin levels. HO-1 upregulation reestablished the "crosstalk" between perivascular adipose tissue and the vascular system that was lost in the chronic inflammatory state of obesity. This study demonstrates that gene targeting of EC may well be the future direction in treating obesity induced EC dysfunction, with the finding that targeting the vasculature had a direct and sustained effect on adipogenesis.


Assuntos
Adiposidade , Heme Oxigenase-1/genética , Obesidade/genética , Obesidade/terapia , Adiposidade/efeitos dos fármacos , Animais , Linhagem Celular , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Ativadores de Enzimas/uso terapêutico , Marcação de Genes , Terapia Genética , Masculino , Camundongos Endogâmicos C57BL , Obesidade/patologia , Obesidade/fisiopatologia , Pirazinas/uso terapêutico , Pirróis/uso terapêutico , Regulação para Cima/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
14.
BMC Infect Dis ; 19(1): 376, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31046707

RESUMO

BACKGROUND: Management of Ebola virus disease (EVD) has historically focused on infection prevention, case detection and supportive care. Several specific anti-Ebola therapies have been investigated, including during the 2014-2016 West African outbreak. Our objective was to conduct a systematic review of the effect of anti-Ebola virus therapies on clinical outcomes to guide their potential use and future evaluation. METHODS: We searched PubMed, EMBASE, Global Health, Cochrane Library, African Index Medicus, WHOLIS (inception-9 April 2018), and trial registries for observational studies or clinical trials, in any language, that enrolled patients with confirmed EVD who received therapy targeting Ebola virus and reported on mortality, symptom duration, or adverse effects. RESULTS: From 11,257 citations and registered trials, we reviewed 55 full-text citations, of which 35 met eligibility criteria (1 randomized clinical trial (RCT), 8 non-randomized comparative studies, 9 case series and 17 case reports) and collectively examined 21 anti-Ebola virus agents. The 31 studies performed during the West African outbreak reported on 4.8% (1377/28616) of all patients with Ebola. The only RCT enrolled 72 patients (0.25% of all patients with Ebola) and compared the monoclonal antibody ZMapp vs. standard care (mortality, 22% vs. 37%; 95% confidence interval for risk difference, - 36 to 7%). Studies of convalescent plasma, interferon-ß-1a, favipiravir, brincidofovir, artesunate-amodiaquine and TKM-130803 were associated with at least moderate risk of bias. CONCLUSIONS: Research evaluating anti-Ebola virus agents has reached very few patients with EVD, and inferences are limited by non-randomized study designs. ZMapp has the most promising treatment signal.


Assuntos
Antivirais/uso terapêutico , Doença pelo Vírus Ebola/tratamento farmacológico , Amidas/uso terapêutico , Amodiaquina/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Artemisininas/uso terapêutico , Bases de Dados Factuais , Combinação de Medicamentos , Ebolavirus/isolamento & purificação , Doença pelo Vírus Ebola/epidemiologia , Doença pelo Vírus Ebola/virologia , Humanos , Pirazinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
15.
Ther Adv Respir Dis ; 13: 1753466619843774, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30983530

RESUMO

INTRODUCTION: Since its introduction to the market in 2016, selexipag has been an alternative oral therapy among both treatment-naïve patients and those with mono or dual therapy failure; however, limited information is available regarding the presentation and management of patients with pulmonary arterial hypertension (PAH) prior to selexipag initiation. This study examined treatment patterns, healthcare utilization, and costs in the 12 months prior to and the 6 months following selexipag initiation. METHODS: This was a retrospective study of adult commercial and Medicare Advantage with Part D (MAPD) health plan members with a medical or pharmacy claim for selexipag from 1 January 2016 through 31 May 2017, a diagnosis of pulmonary hypertension, and continuous health plan enrollment for 12 months prior to selexipag initiation (baseline period). Treatment patterns, healthcare utilization, and costs were measured over the baseline period and the 6 months following selexipag initiation (among patients with ⩾6 months of follow up). RESULTS: After inclusion and exclusion criteria were applied, 95 patients were included in the analysis. At study start, 57.9% of patients were prescribed combination therapy, increasing to 69.5% immediately prior to selexipag initiation. Approximately 60% of patients had one baseline regimen. Emergency visits and inpatient admissions during the baseline period occurred in 63.2% and 48.4% of patients, respectively. Baseline medical costs rose steadily, increasing 266.8% in commercial and 26.7% in MAPD enrollees from the beginning to the end of the 12-month baseline period. PAH-related healthcare costs accounted for more than 80% of total costs. Mean medical costs in the 6 months following selexipag initiation were US$17,215 in commercial and US$23,976 in MAPD enrollees. CONCLUSIONS: The majority of patients with PAH remained on the same therapy in the 12 months prior to selexipag initiation despite high rates of healthcare utilization and increasing costs. Mean medical costs appeared to decrease after adding or switching to selexipag.


Assuntos
Acetamidas/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Custos de Cuidados de Saúde/estatística & dados numéricos , Hipertensão Pulmonar/tratamento farmacológico , Pirazinas/uso terapêutico , Acetamidas/economia , Idoso , Anti-Hipertensivos/economia , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Seguimentos , Hospitalização/estatística & dados numéricos , Humanos , Hipertensão Pulmonar/economia , Masculino , Medicare Part C , Medicare Part D , Pessoa de Meia-Idade , Pirazinas/economia , Estudos Retrospectivos , Fatores de Tempo , Estados Unidos
16.
Bioengineered ; 10(1): 172-181, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31034353

RESUMO

Acute pancreatitis (AP) is a digestive disease characterized by pancreatic inflammation. Tetramethylpyrazine (TMP) has been effectively used to ameliorate the damage on intestinal mucosa injury in rats with acute necrotizing pancreatitis (ANP). We aim to study the protective effect of TMP on caerulein-induced AP and to explore the possible mechanism. The mice randomized into control and different experimental groups. AP was induced in mice by 6-hourly intraperitoneal (i.p) injections of caerulein (50 µg/kg at 1 h interval). TMP (i.p, 10 mg/kg, 1 h interval) was administered 3 h before caerulein injection. Administration of TMP attenuated the severity of AP as shown by the histopathology, reduced serum amylase activity and pro-inflammatory cytokines TNF-α and IL-6. Further, TMP enhances the beneficial effect by reducing caerulein-induced NF-κB activation and inducing cell apoptosis in pancreas. Therefore, inhibition of nuclear factor-kappa B(NF-κB) signals by TMP represents a potential therapeutic strategy for the treatment of acute pancreatitis.


Assuntos
NF-kappa B/metabolismo , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Pirazinas/uso terapêutico , Doença Aguda , Animais , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Ratos , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/metabolismo
17.
Eur J Pharmacol ; 854: 101-108, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-30954565

RESUMO

Management of chronic pain is restricted by the lack of effective tools. This study evaluated the efficacies of sinomenine combined gabapentin or ligustrazine hydrochloride in treating peripheral and central chronic neuropathic pain. The study was conducted in mice with photochemically induced sciatic nerve injury, and in rats with photochemically induced spinal cord injury. For assessing the effectiveness of combined therapy, sinomenine, gabapentin or ligustrazine hydrochloride was injected intraperitoneally (i.p.), and pain behavioral tests were performed. At sub-effective dosages, pre-administration of sinomenine (for 60 min) plus gabapentin or ligustrazine hydrochloride, generated significant anti-allodynic effects in mice or rats with peripheral or central neuropathic pain. However, these effects were abolished when gabapentin or ligustrazine hydrochloride was pre-administered, and then sinomenine was given 60 min later. The combined efficacies of sinomenine and gabapentin or ligustrazine hydrochloride, cannot be blocked or reversed by the naloxone, suggesting the underlying mechanism is not mediated by opioid receptors. Moreover, following repeated treatments, sinomenine and gabapentin combination increased the baseline mechanical threshold, while generating prolonged analgesia, without introducing notable side effects. Sinomenine can enhance the efficacy of gabapentin or ligustrazine hydrochloride in rodent models of peripheral or central neuropathic pain, without introducing tolerance or other notable side effects. Findings of current study suggest that combing sinomenine and gabapentin or ligustrazine hydrochloride could be highly beneficial in neuropathic pain therapies.


Assuntos
Gabapentina/farmacologia , Morfinanos/farmacologia , Neuralgia/tratamento farmacológico , Pirazinas/farmacologia , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Modelos Animais de Doenças , Sinergismo Farmacológico , Gabapentina/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Pirazinas/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico
18.
Blood ; 133(24): 2570-2574, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-30967367

RESUMO

Mantle cell lymphoma (MCL) is a unique type of non-Hodgkin lymphoma characterized by the overexpression of cyclin D1. MCL patients typically live for years but experience multiple relapses. Acalabrutinib is a novel second-generation oral Bruton tyrosine kinase inhibitor approved by the US Food and Drug Administration for relapsed MCL based on a clinical trial demonstrating an overall response rate of 81%. It provides a valuable new treatment option for MCL patients and is now being tested upfront.


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Pirazinas/uso terapêutico , Humanos , Inibidores de Proteínas Quinases/uso terapêutico
19.
Mol Cancer Ther ; 18(4): 762-770, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30872379

RESUMO

Small cell lung cancer (SCLC) is generally regarded as very difficult to treat, mostly due to the development of metastases early in the disease and a quick relapse with resistant disease. SCLC patients initially show a good response to treatment with the DNA damaging agents cisplatin and etoposide. This is, however, quickly followed by the development of resistant disease, which urges the development of novel therapies for this type of cancer. In this study, we set out to compile a comprehensive overview of the vulnerabilities of SCLC. A functional genome-wide screen where all individual genes were knocked out was performed to identify novel vulnerabilities of SCLC. By analysis of the knockouts that were lethal to these cancer cells, we identified several processes to be synthetic vulnerabilities in SCLC. We were able to validate the vulnerability to inhibition of the replication stress response machinery by use of Chk1 and ATR inhibitors. Strikingly, SCLC cells were more sensitive to these inhibitors than nontransformed cells. In addition, these inhibitors work synergistically with either etoposide and cisplatin, where the interaction is largest with the latter. ATR inhibition by VE-822 treatment in combination with cisplatin also outperforms the combination of cisplatin with etoposide in vivo Altogether, our study uncovered a critical dependence of SCLC on the replication stress response and urges the validation of ATR inhibitors in combination with cisplatin in a clinical setting.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Isoxazóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Células A549 , Animais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteína 9 Associada à CRISPR/genética , Sobrevivência Celular/efeitos dos fármacos , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Cisplatino/administração & dosagem , Dano ao DNA/efeitos dos fármacos , Sinergismo Farmacológico , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêutico , Humanos , Isoxazóis/administração & dosagem , Isoxazóis/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/administração & dosagem , Pirazinas/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Psychopharmacology (Berl) ; 236(7): 2173-2185, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30847567

RESUMO

Depression is a common but serious mental illness; meanwhile, it is also an inflammatory disorder. Toll-like receptor 4 (TLR4), as the pattern recognition receptor, has been shown to play a vital role in neuroinflammation. The nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome acts as an important signaling molecule downstream of TLR4 and can promote the maturation of inflammatory cytokines, such as interleukin-1ß (IL-1ß). Tetramethylpyrazine (TMP) is a natural compound with neuroprotective effects but with unknown mechanisms on its antidepressant-like effect. In this study, we hypothesized that TMP ameliorates depression may be through the inhibition of the TLR4-NF-κB-NLRP3 signal pathway. Our results have shown that chronic unpredictable mild stress (CUMS) that induced the decreased sucrose preference and increased immobile time was prominently reversed by TMP and fluoxetine. Additionally, we also found that CUMS induced the upregulation of proinflammatory cytokines; TLR4 and NLRP3-associated proteins were significantly suppressed by TMP in the prefrontal cortex and hippocampus. TMP also exhibited potent antioxidant effects and increased the monoamine levels in the serum and brain, such as increasing the activity of SOD and GSH-Px, and reducing the activity of MDA in the serum, and elevating the 5-HT and NE concentration in the serum and brain. Moreover, treatment with Cli-095 (TLR4 inhibitor) also markedly inhibited CUMS-induced depression-like behaviors. Taken together, our findings suggested that TMP exerted a potential antidepressant-like effect in CUMS mice, and the molecular mechanisms may relate to inhibit the TLR4-NF-κB-NLRP3 signaling pathway in the brain.


Assuntos
Depressão/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Pirazinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Depressão/metabolismo , Depressão/psicologia , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Pirazinas/farmacologia , Transdução de Sinais/fisiologia , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Receptor 4 Toll-Like/metabolismo , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico
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