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1.
Zhongguo Zhen Jiu ; 40(2): 137-41, 2020 Feb 12.
Artigo em Chinês | MEDLINE | ID: mdl-32100497

RESUMO

OBJECTIVE: To verify the clinical effect of laryngopharyngeal reflux (LPR) treated with acupuncture at the acupoints composed on the base of theory of the ascending and the descending of qi. METHODS: A total of 84 patients of LPR were randomized into an observation group and a control group, 42 cases in each one. The conventional treatment was provided in the two groups. Additionally, in the control group, the medication was administered, i.e. esomeprazole tablets (20 mg, twice a day) and mosapride tablets (5 mg, three times a day), consecutively for 14 days. In the observation group, the oral medication was the same as the control group. Besides, acupuncture at the acupoints composed on the base of theory of the ascending and the descending of qi was supplemented. The acupoints were Tiantu (CV 22), Danzhong (CV 17), Zhongwan (CV 12), Zusanli (ST 36), Taichong (LR 3) and Neiguan (PC 6). The acupuncture treatment was given once a day, 5 times a week, consecutively for 10 times in 2 weeks (14 days in total). Before and after treatment, the reflux symptom index (RSI) score, the reflux finding score (RFS) and the time proportion of esophageal pH < 4 in 24 h were compared, and the therapeutic effect was evaluated in the two groups. RESULTS: After treatment, RSI score, RFS, 24 h esophageal pH<4 time proportion were all reduced as compared with those before treatment in the two groups (P<0.05). After treatment, RSI score, RFS, 24 h esophageal pH<4 time proportion in the observation group were lower than those in the control group (P<0.05). The total effective rate was 92.9% (39/42) in the observation group, better than 71.4% (30/42) in the control group (P<0.05). CONCLUSION: On the base of the conventional treatment, acupuncture at the acupoints composed in compliance with the theory of the ascending and the descending of qi combined with western medication contribute to the recovery of gastrointestinal function, effectively control the laryngopharyngeal symptoms and physical signs. The therapeutic effect of this comprehensive therapy is better than the simple treatment with western medication.


Assuntos
Terapia por Acupuntura , Refluxo Laringofaríngeo/terapia , Qi , Pontos de Acupuntura , Benzamidas/uso terapêutico , Esomeprazol/uso terapêutico , Humanos , Morfolinas/uso terapêutico , Resultado do Tratamento
2.
Zhonghua Nei Ke Za Zhi ; 59(2): 117-123, 2020 Feb 01.
Artigo em Chinês | MEDLINE | ID: mdl-32074684

RESUMO

Objective: To evaluate the efficacy and safety of Oryz-Aspergillus enzyme and pancreatin tablets (Combizym(®)) in the treatment of postprandial distress syndrome (PDS) in the elderly, compared with gastrointestinal motility drugs. Methods: A prospective randomized controlled trial was designed and registered in the China Clinical Trials Registry (ChiCTR-IPR-16008185). The elderly patients with PDS were randomly divided into three groups, including Mosapride group with Mosapride citrate tablets 5 mg 3 times per day for 2 weeks; Combizym(®) group with Combizym tablets 244 mg 3 times per day for 2 weeks; combined treatment group with both drugs and same doses for 2 weeks. The modified Nepean dyspepsia index (NDSI) score, discomfort intensity score and PDS score were calculated on patients before treatment, at the end of first and second week of treatment, as well as 4 weeks after treatment finished, respectively. Adverse effects were evaluated. Results: A total of 323 patients from 16 tertiary hospitals in China were enrolled in this study. Among them, 105 patients were in Mosapride group, 109 in Combizym(®) group and 109 in combined treatment group. There were 148 males (45.8%) and 175 females (54.2%) with median age 71.4±9.0 years (60-100 years). Baseline characteristics of three groups were comparable. After treatment, the NDSI scores in three groups all decreased significantly (P<0.001), while they were similar between groups (P>0.05). The discomfort intensity score and PDS score in three groups showed a significant reduction after treatment (P<0.001), especially in the combined treatment group. Compared with Mosapride group, the scores in Combizym(®) group decreased significantly after one or two weeks [discomfort intensity score: after one week, 4.0(2.5, 8.0) vs. 6.0(3.0, 10.0); after two weeks, 3.0(0.0, 5.0) vs. 4.0(2.0, 6.0); all P<0.05. PDS score: after one week, 6.0(3.0, 9.0) vs. 7.0(3.5, 10.5); after two weeks, 3.0(0.0, 5.0) vs. 4.0(2.0, 7.0); all P<0.05]. The efficacy rate in all patients after first week of treatment was over 15.0%. The efficacy rates after two weeks were 55.2%, 68.8% and 73.4% in Mosapride group, Combizym(®) group and combined treatment group, respectively. After two week treatment, the efficacy rates in Combizym(®) group (P=0.041) and combined group (P=0.006) were higher than that of Mosapride group. The recurrence rate of Mosapride group was 9.5%, which was significantly higher than that of Combizym(®) group (1.8%, P<0.05) and combined treatment group (1.8%, P<0.05). There were no serious adverse effects in the three groups. Conclusions: The efficacy of Oryz-Aspergillus enzyme and pancreatin tablets is comparable with that of Mosapride in elderly PDS patients, with fewer adverse effects and low recurrence rate. Combination regimen indicates better efficacy than that of Oryz-Aspergillus enzyme and pancreatin tablets or Mosapride alone.


Assuntos
Benzamidas/uso terapêutico , Dispepsia/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Motilidade Gastrointestinal/efeitos dos fármacos , Glicosídeo Hidrolases/uso terapêutico , Morfolinas/uso terapêutico , Pancreatina/uso terapêutico , Peptídeo Hidrolases/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Benzamidas/efeitos adversos , China , Combinação de Medicamentos , Dispepsia/diagnóstico , Dispepsia/patologia , Feminino , Fármacos Gastrointestinais/efeitos adversos , Glicosídeo Hidrolases/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Pancreatina/efeitos adversos , Peptídeo Hidrolases/efeitos adversos , Período Pós-Prandial , Estudos Prospectivos , Resultado do Tratamento
3.
Nature ; 579(7798): 284-290, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32103175

RESUMO

Cancer recurrence after surgery remains an unresolved clinical problem1-3. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites4-6. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment6,7. Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant epigenetic therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy.


Assuntos
Epigênese Genética , Terapia Genética , Células Supressoras Mieloides/fisiologia , Neoplasias/terapia , Microambiente Tumoral , Animais , Azacitidina/farmacologia , Benzamidas/farmacologia , Diferenciação Celular , Movimento Celular/efeitos dos fármacos , Quimioterapia Adjuvante , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Camundongos , Células Supressoras Mieloides/citologia , Metástase Neoplásica/terapia , Neoplasias/cirurgia , Piridinas/farmacologia , Receptores CCR2/genética , Receptores de Interleucina-8B/genética , Microambiente Tumoral/efeitos dos fármacos
4.
Medicine (Baltimore) ; 99(2): e18702, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914075

RESUMO

BACKGROUND/AIMS: Old age is a risk factor of suboptimal bowel preparation. This study aimed to evaluate the efficacy of mosapride citrate with a split dose of polyethylene glycol (PEG) plus ascorbic acid for bowel preparation in elderly patients (aged ≥65 years) before they underwent a colonoscopy. MATERIALS AND METHODS: This prospective investigator-blinded randomized study was conducted from November 2017 to October 2018. The patients were randomly divided into 2 groups, a mosapride group (mosapride citrate with a split-dose of PEG plus ascorbic acid) or a non-mosapride group (a split-dose of PEG plus ascorbic acid alone). Mosapride citrate 15 mg (Gastin CR) was administered once with each split-dose of the bowel preparation. The bowel preparation quality was assessed using the Boston Bowel Preparation Scale (BBPS). RESULTS: A total of 257 patients were finally included and analyzed in our study. The total BBPS score was significantly higher in the mosapride group than in the non-mosapride group (8.53 vs 8.24, P = .033). The BBPS scores of the right colon and mid-colon were 2.75 vs 2.61 (P = .044) and 2.89 vs 2.79 (P = .030), respectively. The rate of adequate bowel preparation (BBPS ≥ 6) was similar in both groups (98.4% vs 98.5%, P = .968), while the rate of excellent bowel preparation (BBPS = 9) was higher in the mosapride group than in the non-mosapride group (73.8% vs 61.1%, P = .029). The total incidence of adverse events during the administration of the bowel cleansing agent, particularly abdominal fullness, was lower in the mosapride group (11.9% vs 30.5%, P < .001). CONCLUSION: The administration of mosapride citrate with a split-dose of PEG plus ascorbic acid in elderly patients showed an increase in bowel preparation efficacy and reduced adverse events, particularly abdominal fullness, during the administration of a bowel cleansing agent.


Assuntos
Ácido Ascórbico/uso terapêutico , Benzamidas/uso terapêutico , Catárticos/uso terapêutico , Colonoscopia/métodos , Morfolinas/uso terapêutico , Polietilenoglicóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Ácido Ascórbico/administração & dosagem , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Catárticos/administração & dosagem , Catárticos/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Cooperação do Paciente , Satisfação do Paciente , Polietilenoglicóis/administração & dosagem , Cuidados Pré-Operatórios , Estudos Prospectivos , Método Simples-Cego
5.
Expert Opin Pharmacother ; 21(3): 365-376, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31899982

RESUMO

Introduction: Functional Dyspepsia (FD), defined as chronic symptoms originating from the gastroduodenal region in absence of readily identifiable organic disease, is one of the most common gastrointestinal disorders. FD is divided into two subgroups: Post-Prandial Distress Syndrome (PDS) or meal-related FD, characterized by postprandial fullness and early satiation, and Epigastric Pain Syndrome (EPS) or meal-unrelated FD, characterized by epigastric pain and burning.Areas covered: This review summarizes the existing and off-label therapeutic options for FD.Expert opinion: The identification of mechanisms, the Rome IV classification, the reduction of PDS/EPS overlap and pictograms for symptom identification allow a better diagnosis and a more targeted treatment choice. Acotiamide, a first-in-class prokinetic agent available only in Japan and India, is the only agent of proven efficacy for FD, but clinicians use acid-suppressive therapy, prokinetics, neuromodulators and herbal therapies for treating FD symptoms. New emerging targets are duodenal low-grade inflammation with eosinophils and duodenal or other modified luminal microbiota.


Assuntos
Benzamidas/uso terapêutico , Dispepsia/tratamento farmacológico , Tiazóis/uso terapêutico , Dor Abdominal/fisiopatologia , Humanos , Período Pós-Prandial , Síndrome
6.
Life Sci ; 245: 117348, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31981633

RESUMO

AIMS: Haloperidol is a neuroleptic drug with high affinity towards the σ1 receptor (σ1R), acting as antagonist that decreases neuropathic pain, but has CNS side effects. This work describes the design and synthesis of a novel analog N­(1­benzylpiperidin­4-yl)­4­fluorobenzamide (LMH-2), which produced antihyperalgesic and antiallodynic effects in rats with neuropathy induced by chronic constriction injury of the sciatic nerve (CCI), being more active than gabapentin (The most widely used drug for the treatment of neuropathic pain). MAIN METHODS: LMH-2 was designed as haloperidol analog. Its structure was characterized by spectroscopic (1H and 13C NMR) and spectrometric mass (electronic impact) techniques. Additionally, in silico predictions of pharmacokinetic, pharmacodynamic and toxicological properties were obtained, with promising results. A competitive binding assay using radioligands was employed to evaluate the in vitro affinity for σ1R, whereas in vivo antihyperalgesic and antiallodynic activities were investigated using Wistar rats with CCI. KEY FINDINGS: LMH-2 showed high affinity for σ1R in an in vitro binding assay, with a Ki = 6.0 nM and a high σ1R/σ2R selectivity ratio. Molecular docking studies were carried out to determine the binding energy and to analyze LMH-2-protein interactions. Through an in silico pharmacological consensus analysis, LMH-2 was considered safe for in vivo evaluation. Thus, LMH-2 had dose-dependent antiallodynic and antihyperalgesic activities; its efficacy was comparable to that of gabapentin, but its potency was 2-times higher than this drug. SIGNIFICANCE: LMH-2 administration produced antihyperalgesic and antiallodynic effects by the antagonism of σ1R, suggesting its potential use as an analgesic drug for neuropathic pain.


Assuntos
Analgésicos/síntese química , Benzamidas/síntese química , Haloperidol/análogos & derivados , Nociceptividade/efeitos dos fármacos , Receptores sigma/antagonistas & inibidores , Analgésicos/farmacologia , Animais , Benzamidas/farmacologia , Relação Dose-Resposta a Droga , Hiperalgesia/induzido quimicamente , Masculino , Simulação de Acoplamento Molecular , Ratos , Ratos Wistar
7.
J Cancer Res Clin Oncol ; 146(2): 343-356, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31932908

RESUMO

PURPOSE: We set out to determine whether clinically tested epigenetic drugs against class I histone deacetylases (HDACs) affect hallmarks of the metastatic process. METHODS: We treated permanent and primary renal, lung, and breast cancer cells with the class I histone deacetylase inhibitors (HDACi) entinostat (MS-275) and valproic acid (VPA), the replicative stress inducer hydroxyurea (HU), the DNA-damaging agent cis-platinum (L-OHP), and the cytokine transforming growth factor-ß (TGFß). We used proteomics, quantitative PCR, immunoblot, single cell DNA damage assays, and flow cytometry to analyze cell fate after drug exposure. RESULTS: We show that HDACi interfere with DNA repair protein expression and trigger DNA damage and apoptosis alone and in combination with established chemotherapeutics. Furthermore, HDACi disrupt the balance of cell adhesion protein expression and abrogate TGFß-induced cellular plasticity of transformed cells. CONCLUSION: HDACi suppress the epithelial-mesenchymal transition (EMT) and compromise the DNA integrity of cancer cells. These data encourage further testing of HDACi against tumor cells.


Assuntos
Reparo do DNA/fisiologia , Proteínas de Ligação a DNA/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Neoplasias/tratamento farmacológico , Animais , Benzamidas/farmacologia , Plasticidade Celular/efeitos dos fármacos , Cisplatino/farmacologia , Enzimas Reparadoras do DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Humanos , Hidroxiureia/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Piridinas/farmacologia , Fator de Crescimento Transformador beta/farmacologia , Ácido Valproico/farmacologia
8.
Nat Commun ; 11(1): 583, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996670

RESUMO

Medulloblastoma (MB) is the most common malignant brain tumor in children and among the subtypes, Group 3 MB has the worst outcome. Here, we perform an in vivo, patient-specific screen leading to the identification of Otx2 and c-MYC as strong Group 3 MB inducers. We validated our findings in human cerebellar organoids where Otx2/c-MYC give rise to MB-like organoids harboring a DNA methylation signature that clusters with human Group 3 tumors. Furthermore, we show that SMARCA4 is able to reduce Otx2/c-MYC tumorigenic activity in vivo and in human cerebellar organoids while SMARCA4 T910M, a mutant form found in human MB patients, inhibits the wild-type protein function. Finally, treatment with Tazemetostat, a EZH2-specific inhibitor, reduces Otx2/c-MYC tumorigenesis in ex vivo culture and human cerebellar organoids. In conclusion, human cerebellar organoids can be efficiently used to understand the role of genes found altered in cancer patients and represent a reliable tool for developing personalized therapies.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Organoides/metabolismo , Organoides/patologia , Benzamidas/antagonistas & inibidores , Carcinogênese , Linhagem Celular Tumoral , Neoplasias Cerebelares/genética , DNA Helicases/genética , DNA Helicases/metabolismo , Metilação de DNA , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Humanos , Meduloblastoma/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fatores de Transcrição Otx/genética , Fatores de Transcrição Otx/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Piridonas/antagonistas & inibidores , Células-Tronco , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
9.
Exp Parasitol ; 208: 107793, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31711973

RESUMO

Praziquantel (PZQ) is the sole drug used to treat schistosomiasis, and the probability of developing resistance is growing the longer it is relied upon, justifying the search for alternatives. Phosphodiesterases (PDEs), particularly the PDE4 family, have attracted considerable attention as drug targets, including in Schistosoma mansoni, and especially SmPDE4A. This study investigates the potential antischistosomal activity of human PDE4 and potent SmPDE4A inhibitor roflumilast, either alone or combined with PZQ. In vitro, roflumilast resulted in a significant, concentration-dependent reduction in egg production but not of worm viability. In vitro exposure to roflumilast in combination with a low concentration of PZQ was less effective than PZQ alone, pointing to antagonism. S. mansoni-infected mice treated with roflumilast showed significant reductions in worm burden (27%) as well as hepatic and intestinal egg burdens (~28%) two weeks post treatment. Scanning EM of worms isolated from roflumilast-treated and untreated mice did not reveal noticeable changes to their tegument. S. mansoni-infected mice treated with a fixed dosage of roflumilast and a variable dosage of PZQ resulted in a higher reduction in worm burden, reduced hepatic egg counts, absence of immature eggs and a marked increase in dead eggs, compared to PZQ alone. However, the combination resulted in increased animal mortality, probably attributable to pharmacodynamic interactions between the two drugs. Although this study marks the first report of in vivo antischistosomal potential by a PDE inhibitor, an important proof of concept, we conclude that the antischistosomal effects of roflumilast are insufficient to warrant further development.


Assuntos
Aminopiridinas/farmacologia , Anti-Helmínticos/farmacologia , Benzamidas/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/efeitos dos fármacos , Ciclopropanos/farmacologia , Relação Dose-Resposta a Droga , Feminino , Concentração Inibidora 50 , Masculino , Camundongos , Microscopia Eletrônica de Varredura , Oviposição/efeitos dos fármacos , Praziquantel/farmacologia , Schistosoma mansoni/enzimologia , Schistosoma mansoni/fisiologia , Schistosoma mansoni/ultraestrutura
10.
Expert Opin Pharmacother ; 21(1): 29-38, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31738609

RESUMO

Introduction: Regimens involving intensive immuno-chemotherapy, followed by high-dose therapy and autologous stem cell transplant represent the standard treatment for younger fit patients with mantle cell lymphoma (MCL). Targeted approaches (i.e. ibrutinib, bortezomib, and lenalidomide) represent the backbone of therapy for relapsed cases.Areas covered: Acalabrutinib is a novel small molecule with a butynamide moiety specifically designed to irreversibly inhibit Bruton tyrosine kinase (BTK), which is more potent and selective than ibrutinib. Relevant publications have been identified through literature searches using the terms 'mantle cell lymphoma' and 'acalabrutinib'.Expert opinion: Acalabrutinib has been approved for the treatment of relapsed/refractory (RR) MCL patients. To date, clinical trials have reported some adverse effects such as cardiac toxicity or atrial fibrillation. Acalabrutinib in combination with other drugs, either in chemo-containing or chemo-free schedules, represent a valid option for MCL. However, none of the treatment schedules containing BTK inhibitors have been shown to be curative in MCL. Acalabrutinib may ultimately represent an option for patients who are 'fit' and exhibit well-controlled disease, which often characterizes only a limited 'niche' among MCL patients.


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/administração & dosagem , Linfoma de Célula do Manto/tratamento farmacológico , Pirazinas/administração & dosagem , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Inibidores de Proteínas Quinases/uso terapêutico
11.
Ecotoxicol Environ Saf ; 188: 109947, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31744624

RESUMO

Fluopyram, as a reasonably good fungicide and nematicide, is widely used to control agricultural pests worldwide. However, its effects on soil microbial communities and plant growth remain controversial. Therefore, in this study, we investigated the effects of three concentrations (0.5, 1.5, and 5.0 mg/kg) of the fluopyram (Lufuda 41.7% a.i., suspension concentrate, SC) on the pepper rhizosphere microorganisms and pepper seedlings growth in a plant growth room. Moreover, we also investigated the dissipation of fluopyram in the soil, pepper roots, and leaves across a time interval of 45 days. The results showed that fluopyram application increased the number of pepper rhizosphere phosphate (P)-solubilizing bacteria, the abundance of nitrogen (N)-fixing nifH genes, and the pepper seedling growth. The results of terminal restriction fragment length polymorphism (T-RFLP) analysis demonstrated that fluopyram did not alter rhizosphere bacterial community structure and diversity. However, fluopyram did increase the relative abundances of 138 bp and 400 bp T-RFs closely representing Bacillus and Rhizobium genera that were known as efficient plant growth promoting bacteria with P-solubilization and N-fixation properties. Corresponding to the increase of plant growth and beneficial microbes, the half-lives of fluopyram in soil and plant tissues also decreased that nevertheless suggested the role of plant-microbe interactions in the faster removal of fluopyram after application. Our results suggest that short-lived and easily degradable pesticides may have less toxicological effects on soil health while their judicious use may reshape plant-microbe interactions in favor of the plant growth.


Assuntos
Benzamidas/farmacologia , Capsicum/efeitos dos fármacos , Fungicidas Industriais/farmacologia , Bactérias Fixadoras de Nitrogênio/crescimento & desenvolvimento , Fosfatos/química , Piridinas/farmacologia , Microbiologia do Solo , Agricultura , Capsicum/crescimento & desenvolvimento , Fixação de Nitrogênio , Raízes de Plantas/química , Rizosfera , Solo/química
13.
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
14.
Nat Genet ; 51(12): 1714-1722, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31784732

RESUMO

Core regulatory transcription factors (CR TFs) orchestrate the placement of super-enhancers (SEs) to activate transcription of cell-identity specifying gene networks, and are critical in promoting cancer. Here, we define the core regulatory circuitry of rhabdomyosarcoma and identify critical CR TF dependencies. These CR TFs build SEs that have the highest levels of histone acetylation, yet paradoxically the same SEs also harbor the greatest amounts of histone deacetylases. We find that hyperacetylation selectively halts CR TF transcription. To investigate the architectural determinants of this phenotype, we used absolute quantification of architecture (AQuA) HiChIP, which revealed erosion of native SE contacts, and aberrant spreading of contacts that involved histone acetylation. Hyperacetylation removes RNA polymerase II (RNA Pol II) from core regulatory genetic elements, and eliminates RNA Pol II but not BRD4 phase condensates. This study identifies an SE-specific requirement for balancing histone modification states to maintain SE architecture and CR TF transcription.


Assuntos
Histonas/metabolismo , Rabdomiossarcoma/genética , Fatores de Transcrição/genética , Acetilação , Benzamidas/farmacologia , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Elementos Facilitadores Genéticos , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Histonas/genética , Humanos , Piridinas/farmacologia , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Estabilidade de RNA , Fatores de Transcrição SOXE/genética , Análise de Célula Única
15.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1134-1135: 121877, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31785533

RESUMO

PH-797804 is a selective p38 MAPK inhibitor currently evaluated in clinical trials. This study described a validated UPLC-MS/MS combined with one-step protein precipitation extraction method for determination of PH-797804 in rat plasma. After protein precipitation with acetonitrile, the plasma sample was analyzed by a Waters Acquity UPLC BEH C18 column, with acetonitrile/0.1% formic acid (70:30) as the mobile phase. Mass spectrometric detection was conducted with a Waters TQ-S mass spectrometer via electrospray, positive-mode ionization, with target quantitative ion pairs of m/z 476.895 → 126.860 for PH-797804, and 482.726 → 269.707 for regorafenib (internal standard). The assay showed a good linearity over the range of 1.0-1600 ng/mL, with acceptable accuracy (RE from -7.8% to 8.5%) and precision (RSD within 8.4%) values. Recovery from plasma was 81.4-90.2% and matrix effect was negligible (93.3-95.4%). The validated method presented a quantification method of PH-797804 in detail for the first time and utilized for a pharmacokinetic study at three dose concentrations after oral administration in Wistar rats. The pharmacokinetic profiles of PH-797804 showed a linear relationship between drug concentration and dose, which provided dosage and safety information on further clinical studies.


Assuntos
Benzamidas/sangue , Benzamidas/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Piridonas/sangue , Piridonas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Benzamidas/química , Modelos Lineares , Masculino , Piridonas/química , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
16.
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi ; 37(11): 801-805, 2019 Nov 20.
Artigo em Chinês | MEDLINE | ID: mdl-31826541

RESUMO

Objective: To investigate the intervention effect of SB431542, which inhibits the TGF-ß/Smad3 signaling pathway, on silicotic fibrosis in rats. Methods: A total of 40 specific pathogen-free Sprague-Dawley rats were divided into normal saline control group, model group, SB431542 inhibitor group, and SB431542 inhibitor control group using a random number table, with 10 rats in each group. All rats except those in the normal saline control group were given non-exposed single intratracheal instillation of free silicon dioxide dust suspension 1 mL (50 mg/mL) ; the rats in the SB431542 inhibitor group were given intraperitoneal injection of SB431542 (5 mg/kg) on days 7 and 30 after dust exposure, those in the SB431542 inhibitor control group were given intraperitoneal injection of SB431542 cosolvent (5 mg/kg) on days 7 and 30 after dust exposure, and those in the normal saline control group were given intratracheal instillation of an equal volume of normal saline (5 mg/kg). On day 60 after dust exposure, the paraffin-embedded section of the right upper lobe of lung was collected for HE staining; the left upper lobe of lung was collected to measure the mRNA levels of fibronectin (FN) , collagen type I (COL-I) , and collagen type III (COL-III) by quantitative real-time PCR; the right inferior lobe of lung was collected to measure the protein levels of FN, COL-I, COL-III, phosphorylated Smad3 (p-Smad3) , and Smad3. Results: Compared with the normal saline control group, the model group had nodules with various sizes in lung tissue, with rupture of some alveolar septa, emphysema changes, and pulmonary interstitial fibrosis, as well as significant increases in the mRNA expression of FN, COL-I, and COL-III and the protein expression of FN, COL-I, COL-III, p-Smad3, and Smad3 in lung tissue (P<0.05) . Compared with the SB431542 inhibitor control group, the SB431542 inhibitor group had a relatively complete structure of lung tissue without marked nodules and with a small amount of exudate in alveolar space and the lumen of bronchioles, as well as significant reductions in the mRNA expression of FN, COL-I, and COL-III and the protein expression of FN, COL-I, COL-III, p-Smad3, and Smad3 in lung tissue (P<0.05) . There were no significant differences in the mRNA expression of FN, COL-I, and COL-III and the protein expression of FN, COL-I, COL-III, p-Smad3, and Smad3 between the model group and the SB431542 inhibitor control group (P>0.05) . Conclusion: SB431542 exerts an intervention effect on silicotic fibrosis by blocking the TGF-ß/Smad3 signaling pathway and reducing the expression of the downstream fibrosis factors FN, COL-I, and COL-III.


Assuntos
Benzamidas/uso terapêutico , Dioxóis/uso terapêutico , Fibrose/tratamento farmacológico , Transdução de Sinais , Fator de Crescimento Transformador beta , Animais , Benzamidas/farmacologia , Dioxóis/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/genética , Fator de Crescimento Transformador beta/genética
17.
J Stroke Cerebrovasc Dis ; 28(12): 104470, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31680031

RESUMO

BACKGROUND: The nitric oxide (NO)-producing activity of endothelial nitric oxide synthase (eNOS) plays a significant role in maintaining endothelial function and protecting against the stroke injury. However, the activity of the eNOS enzyme and the metabolism of major NO metabolite S-nitrosoglutathione (GSNO) are dysregulated after stroke, causing endothelial dysfunction. We investigated whether an administration of exogenous of GSNO or enhancing the level of endogenous GSNO protects against neurovascular injury in wild-type (WT) and eNOS-null (endothelial dysfunction) mouse models of cerebral ischemia-reperfusion (IR). METHODS: Transient cerebral ischemic injury was induced by middle cerebral artery occlusion (MCAO) for 60 minutes in male adult WT and eNOS null mice. GSNO (0.1 mg/kg body weight, intravenously) or N6022 (GSNO reductase inhibitor, 5.0 mg/kg body weight, intravenously) was administered 30 minutes before MCAO in preinjury and at the reperfusion in postinjury studies. Brain infarctions, edema, and neurobehavioral functions were evaluated at 24 hours after the reperfusion. RESULTS: eNOS-null mice had a higher degree (P< .05) of injury than WT. Pre- or postinjury treatment with either GSNO or N6022 significantly reduced infarct volume, improved neurological and sensorimotor function in both WT and eNOS-null mice. CONCLUSION: Reduced brain infarctions and edema, and improved neurobehavioral functions by pre- or postinjury GSNO treatment of eNOS knock out mice indicate that GSNO can attenuate IR injury, likely by mimicking the eNOS-derived NO-dependent anti-ischemic and anti-inflammatory functions. Neurovascular protection by GSNO/N6022 in both pre- and postischemic injury groups support GSNO as a promising drug candidate for the prevention and treatment of stroke injury.


Assuntos
Álcool Desidrogenase/antagonistas & inibidores , Benzamidas/farmacologia , Encéfalo/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Pirróis/farmacologia , S-Nitrosoglutationa/farmacologia , Álcool Desidrogenase/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/embriologia , Encéfalo/patologia , Edema Encefálico/enzimologia , Edema Encefálico/patologia , Edema Encefálico/prevenção & controle , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/enzimologia , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo III/deficiência , Óxido Nítrico Sintase Tipo III/genética
18.
Anticancer Res ; 39(11): 5933-5942, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704818

RESUMO

BACKGROUND/AIM: Perineural invasion (PNI) is a significant pathological feature in head and neck cancer. The molecular mechanisms of PNI are poorly understood. Contrary to the previous belief that cancer cells invade nerves, recent studies have shown that Schwann cells (SC) can dedifferentiate, intercalate between cancer cells, and promote cancer dispersion. Communication between cells through brain-derived neurotrophic factor (BDNF) activation of its receptor tropomyosin receptor kinase B (TRKB) may contribute to these cellular events. We aimed to determine the effect of TRKB inhibitor ANA-12 on the direction of cell migration and degree of SC-induced oral cancer cell dispersion. MATERIALS AND METHODS: Cell migration and dispersion assays were performed in vitro using murine SC and oral carcinoma cell lines. Assays were performed with and without ANA-12. RESULTS: Although SCs preferentially migrated towards cancer cells in control medium, there was minimal SC-associated cancer cell dispersion. In contrast, treatment with ANA-12 reduced migration of SCs and cancer cells towards each other and initiated more SC-associated cancer cell dispersion. CONCLUSION: This pilot study shows that BDNF-TRKB signaling may have a role in regulating interactions between SC and oral cancer cells that affect cell migration, intercalation, and cancer cell dispersion. Further research into these interactions may provide important clues about the molecular and cellular mechanisms of PNI.


Assuntos
Azepinas/farmacologia , Benzamidas/farmacologia , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Carcinoma de Células Escamosas/patologia , Glicoproteínas de Membrana/antagonistas & inibidores , Neoplasias Bucais/patologia , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Receptor trkB/antagonistas & inibidores , Células de Schwann/patologia , Animais , Apoptose , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Movimento Celular , Proliferação de Células , Técnicas de Cocultura , Humanos , Técnicas In Vitro , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Projetos Piloto , Receptor trkB/metabolismo , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Células Tumorais Cultivadas
19.
Cancer Immunol Immunother ; 68(12): 2081-2094, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31720815

RESUMO

Histone deacetylase (HDAC) inhibitors impair tumor cell proliferation and alter gene expression. However, the impact of these changes on anti-tumor immunity is poorly understood. Here, we showed that the class I HDAC inhibitor, entinostat (ENT), promoted the expression of immune-modulatory molecules, including MHCII, costimulatory ligands, and chemokines on murine breast tumor cells in vitro and in vivo. ENT also impaired tumor growth in vivo-an effect that was dependent on both CD8+ T cells and IFNγ. Moreover, ENT promoted intratumoral T-cell clonal expansion and enhanced their functional activity. Importantly, ENT sensitized normally unresponsive tumors to the effects of PD1 blockade, predominantly through increases in T-cell proliferation. Our findings suggest that class I HDAC inhibitors impair tumor growth by enhancing the proliferative and functional capacity of CD8+ T cells and by sensitizing tumor cells to T-cell recognition.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Benzamidas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linfócitos T CD8-Positivos/imunologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Histona Desacetilases/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Piridinas/uso terapêutico , Animais , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Imunidade Celular , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo
20.
Life Sci ; 239: 117075, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31751587

RESUMO

AIMS: Arrhythmogenesis of chronic myocardial infarction (MI) is associated with the prolongation of action potential, reduction of inward rectifier potassium (IK1, Kir) channels and hyper-activity of Calcium/calmodulin-dependent kinase II (CaMKII) in cardiomyocytes. Zacopride, a selective IK1 agonist, was applied to clarify the cardioprotection of IK1 agonism via a CaMKII signaling on arrhythmias post-MI. METHODS: Male SD rats were implanted wireless transmitter in the abdominal cavity and subjected to left main coronary artery ligation or sham operation. The telemetric ECGs were monitored per day throughout 4 weeks. At the endpoint, isoproterenol (1.28 mg/kg, i.v.) was administered for provocation test. The expressions of Kir2.1 (dominant subunit of IK1 in ventricle) and CaMKII were detected by Western-blotting. KEY FINDINGS: In the telemetric rats post-MI, zacopride significantly reduced the episodes of atrioventricular conduction block (AVB), premature ventricular contraction (PVC), ventricular tachycardia (VT) and ventricular fibrillation (VF), without significant effect on superventricular premature contraction (SPVC). In provocation test, zacopride suppressed the onset of ventricular arrhythmias in conscious PMI or sham rats. The expression of Kir2.1 was significantly downregulated and p-CaMKII was upregulated post-MI, whereas both were restored by zacopride treatment. SIGNIFICANCE: IK1/Kir2.1 might be an attractive target for pharmacological controlling of lethal arrhythmias post MI.


Assuntos
Benzamidas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Infarto do Miocárdio/fisiopatologia , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Potenciais de Ação , Animais , Arritmias Cardíacas/tratamento farmacológico , Benzamidas/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Eletrocardiografia/métodos , Ventrículos do Coração/metabolismo , Isoproterenol/farmacologia , Masculino , Miócitos Cardíacos/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Ratos , Ratos Sprague-Dawley , Taquicardia Ventricular/metabolismo
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