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1.
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
2.
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
3.
Int J Mol Sci ; 20(18)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514437

RESUMO

There is robust evidence indicating that enhancing the endocannabinoid (eCB) tone has therapeutic potential in several brain disorders. The inhibition of eCBs degradation by fatty acid amide hydrolase (FAAH) blockade, is the best-known option to increase N-acyl-ethanolamines-(NAEs)-mediated signaling. Here, we investigated the hypothesis that intranasal delivery is an effective route for different FAAH inhibitors, such as URB597 and PF-04457845. URB597 and PF-04457845 were subchronically administered in C57BL/6 male mice every other day for 20 days for overall 10 drug treatment, and compared for their ability to inhibit FAAH activity by the way of three different routes of administration: intranasal (i.n.), intraperitoneal (i.p.) and oral (p.o.). Lastly, we compared the efficacy of the three routes in terms of URB597-induced increase of NAEs levels in liver and in different brain areas. Results: We show that PF-04457845 potently inhibits FAAH regardless the route selected, and that URB597 was less effective in the brain after p.o. administration while reached similar effects by i.n. and i.p. routes. Intranasal URB597 delivery always increased NAEs levels in brain areas, whereas a parallel increase was not observed in the liver. By showing the efficacy of intranasal FAAH inhibition, we provide evidence that nose-to-brain delivery is a suitable alternative to enhance brain eCB tone for the treatment of neurodegenerative disorders and improve patients' compliance.


Assuntos
Amidoidrolases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Amidoidrolases/metabolismo , Animais , Benzamidas/administração & dosagem , Benzamidas/farmacologia , Carbamatos/administração & dosagem , Carbamatos/farmacologia , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Endocanabinoides/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Piridazinas/administração & dosagem , Piridazinas/farmacologia , Ureia/administração & dosagem , Ureia/análogos & derivados , Ureia/farmacologia
4.
BMC Neurol ; 19(1): 191, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409292

RESUMO

BACKGROUND: We studied the efficacy and safety of a second dose of lasmiditan for acute treatment of migraine. METHODS: SAMURAI and SPARTAN were double-blind, placebo-controlled Phase 3 studies in which individuals with migraine were randomized to oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Study drug was to be taken within 4 h (h) of onset of a migraine attack (moderate or severe pain). A second dose of study drug was provided for rescue (patient not pain-free at 2 h and took a second dose 2-24 h post-first dose) or recurrence (patient pain-free at 2 h, but experienced recurrence of mild, moderate, or severe migraine pain and took a second dose 2-24 h after first dose). Randomization to second dose occurred at baseline; patients originally assigned lasmiditan were randomized to the same lasmiditan dose or placebo (2:1 ratio), and those originally assigned placebo received placebo. Data from SAMURAI and SPARTAN were pooled for efficacy and safety assessment of a second dose of lasmiditan. RESULTS: The proportion of patients taking a second dose was lower with lasmiditan versus placebo, and decreased with increasing lasmiditan dose; the majority who took a second dose did so for rescue. In patients taking lasmiditan as first dose, outcomes (pain free, most bothersome symptom [MBS] free) at 2 h after a second dose for rescue were similar whether the second dose was lasmiditan or placebo (p > 0.05 in all cases). In patients taking lasmiditan for first dose, outcomes at 2 h after a second dose for recurrence were as follows: lasmiditan pooled versus placebo - pain free, 50% vs 32% (p > 0.05); MBS free, 71% vs 41% (p = 0.02); pain relief, 77% vs 52% (p = 0.03). In patients whose first dose was lasmiditan, the incidence of treatment emergent adverse events (TEAEs) reported after the second dose was similar whether second dose was lasmiditan or placebo. CONCLUSIONS: A second dose of lasmiditan showed some evidence of efficacy when taken for headache recurrence. There was no clear benefit of a second dose of lasmiditan for rescue treatment. The incidences of TEAEs were similar whether the second dose was lasmiditan or placebo. TRIAL REGISTRATION: SAMURAI ( NCT02439320 ) [April 2015]. SPARTAN ( NCT02605174 ) [May 2016].


Assuntos
Benzamidas/administração & dosagem , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Agonistas do Receptor de Serotonina/administração & dosagem , Adulto , Benzamidas/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Piridinas/efeitos adversos , Recidiva , Agonistas do Receptor de Serotonina/efeitos adversos
5.
Nat Med ; 25(9): 1422-1427, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31406350

RESUMO

TRK fusions are found in a variety of cancer types, lead to oncogenic addiction, and strongly predict tumor-agnostic efficacy of TRK inhibition1-8. With the recent approval of the first selective TRK inhibitor, larotrectinib, for patients with any TRK-fusion-positive adult or pediatric solid tumor, to identify mechanisms of treatment failure after initial response has become of immediate therapeutic relevance. So far, the only known resistance mechanism is the acquisition of on-target TRK kinase domain mutations, which interfere with drug binding and can potentially be addressable through second-generation TRK inhibitors9-11. Here, we report off-target resistance in patients treated with TRK inhibitors and in patient-derived models, mediated by genomic alterations that converge to activate the mitogen-activated protein kinase (MAPK) pathway. MAPK pathway-directed targeted therapy, administered alone or in combination with TRK inhibition, re-established disease control. Experimental modeling further suggests that upfront dual inhibition of TRK and MEK may delay time to progression in cancer types prone to the genomic acquisition of MAPK pathway-activating alterations. Collectively, these data suggest that a subset of patients will develop off-target mechanisms of resistance to TRK inhibition with potential implications for clinical management and future clinical trial design.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Receptor trkA/genética , Adolescente , Adulto , Animais , Benzamidas/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Ácidos Nucleicos Livres/efeitos dos fármacos , Ácidos Nucleicos Livres/genética , Criança , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Xenoenxertos , Humanos , Imidazóis/administração & dosagem , Indazóis/administração & dosagem , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Terapia de Alvo Molecular , Neoplasias/genética , Neoplasias/patologia , Oximas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Pirimidinas/administração & dosagem , Pirimidinonas/administração & dosagem , Adulto Jovem
6.
BMC Cancer ; 19(1): 849, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462241

RESUMO

BACKGROUND: Recent years have witnessed the rapid evolution of therapies in chronic-phase chronic myeloid leukemia (CP-CML). To assess the efficacy and tolerability of all reported front-line treatments for patients with newly diagnosed CML, a multiple-treatments meta-analysis was performed, which accounted for both direct and indirect comparisons among those treatments. METHODS: Primary outcomes were the percentage of patients achieving major molecular response (MMR) and complete cytogenetic response (CCyR) within 12 months. Secondary outcomes included the percentage of progression to accelerated phase (AP), serious adverse effects (AEs), overall discontinuation and discontinuation for drug-related AEs. Direct pairwise meta-analysis and indirect multi-comparison meta-analysis among those treatments in each outcome were both conducted. The surface under the cumulative ranking curve (SUCRA) was calculated for all treatments in each outcome. Cluster analysis demonstrated the division of treatments into distinct groupings according to efficacy and tolerability profiles. RESULTS: A total of 21 randomized controlled trials (RCTs, including 10,187 patients) comparing 15 different interventions for CP-CML patients were included in this study. SUCRA analysis suggested that all tyrosine kinase inhibitors (TKIs) are highly effective in newly diagnosed CP-CML when compared to traditional drugs. Newer TKIs and higher-dose imatinib generally resulted in faster cytogenetic and molecular responses when compared with standard-dose imatinib and traditional drugs. Furthermore, traditional drugs, higher-dose imatinib and newer TKIs demonstrated lower acceptability than standard-dose imatinib. One cluster of interventions, which included nilotinib (300/400 mg BID), dasatinib (100 mg QD) and radotinib (300 mg BID), demonstrated higher efficacy and tolerability than other treatments. CONCLUSIONS: Nilotinib (300/400 mg BID), dasatinib (100 mg QD) and radotinib (300 mg BID) prove to be the most recommended front-line treatments of the greatest efficacy and tolerability for CP-CML patients. High-dose therapies are recommended only for patients in accelerated phase/blast phase or with suboptimal CML-CP response, and management of adverse events should be carried out to avoid compromising the clinical efficacy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Dasatinibe/administração & dosagem , Dasatinibe/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/efeitos adversos , Masculino , Meta-Análise em Rede , Inibidores de Proteínas Quinases/efeitos adversos , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento
7.
Clin Drug Investig ; 39(10): 967-978, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31321631

RESUMO

BACKGROUND: Non-clinical study data suggest that DS-8500a, a G protein-coupled receptor 119 agonist, exhibits antidiabetic activity, inhibition of some transporters and induction of cytochrome P450 (CYP) 3A. Statins are substrates for some transporters and CYP3A that may be coadministered with DS-8500a in clinical practice. OBJECTIVE: To determine the potential effects of DS-8500a on the pharmacokinetics of statins, we evaluated the effects of repeated oral administration of DS-8500a 75 mg on the pharmacokinetics of rosuvastatin and atorvastatin in healthy adults. METHODS: We performed two single-center, open-label, single-sequence studies. In Study I, subjects received single-dose rosuvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose rosuvastatin 10 mg (Period B). In Study II, subjects received single-dose atorvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose atorvastatin 10 mg (Period B). Primary pharmacokinetic endpoints were maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of rosuvastatin and atorvastatin. Safety was evaluated. RESULTS: In Study I, the Cmax and AUC of rosuvastatin increased by 66% and 33%, respectively, when coadministered with DS-8500a, versus rosuvastatin alone. In Study II, the Cmax of atorvastatin increased by 28%, but AUC remained unchanged following coadministration with DS-8500a, versus atorvastatin alone. Treatment-emergent adverse events were mild to moderate and mostly unrelated to the study drugs. CONCLUSIONS: Multiple doses of DS-8500a increased exposure to rosuvastatin and atorvastatin. This short-term study suggests that the impact of DS-8500a coadministration on atorvastatin exposure is limited and may not be clinically relevant. Nevertheless, caution may be necessary when patients are coadministered rosuvastatin with DS-8500a. CLINICALTRIALS. GOV IDENTIFIER: NCT03699774. JAPAN PHARMACEUTICAL INFORMATION CENTER IDENTIFIER: JapicCTI-152878.


Assuntos
Atorvastatina/farmacocinética , Benzamidas/farmacocinética , Ciclopropanos/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Hipoglicemiantes/farmacocinética , Oxidiazóis/farmacocinética , Receptores Acoplados a Proteínas-G/agonistas , Rosuvastatina Cálcica/farmacocinética , Adulto , Atorvastatina/administração & dosagem , Benzamidas/administração & dosagem , Estudos Cross-Over , Ciclopropanos/administração & dosagem , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Interações de Medicamentos/fisiologia , Feminino , Voluntários Saudáveis , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipoglicemiantes/administração & dosagem , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Oxidiazóis/administração & dosagem , Rosuvastatina Cálcica/administração & dosagem
8.
Artigo em Inglês | MEDLINE | ID: mdl-31354255

RESUMO

Background: Frequent development of adverse events and consequent low adherence are major barriers in the wide use of roflumilast. Asian patients may be more susceptible to adverse events due to low BMI. In this study, we aimed to determine if a dose-escalation strategy is useful to improve the drug adherence rate. Methods: This was a randomized, prospective, open-label, single-blind study to compare the adherence rate to roflumilast according to a dose-escalation or conventional dose strategy in patients with COPD in South Korea. Patients were randomized into two groups (1:1), either roflumilast 500 µg once daily for 12 weeks or roflumilast 250 µg once daily for 4 weeks, and then 500 µg for 12 weeks. The primary outcome was the percentage of patients prematurely discontinuing roflumilast due to adverse events. Results: A total of 55 patients were randomly assigned to either a conventional-dose group (n=28) or a dose-escalation group (n=27). Discontinuation rates of roflumilast due to adverse events were 46.4% for the conventional-dose group and 59.3% for the dose-escalation group. The median time to discontinuation was not different between groups (58 days for the conventional-dose group, 56 days for the dose-escalation group, p=0.629). In a multivariate analysis, older age was a significant risk factor for drug discontinuation. Conclusion: High discontinuation rates of roflumilast were observed in both groups regardless of the dose-escalation strategy. The frequent discontinuation suggests that the dose-escalation strategy may not be useful in Asian patients. Clinical trial: This study is registered at www.ClinicalTrials.gov with identifier number NCT02018432.


Assuntos
Aminopiridinas/administração & dosagem , Benzamidas/administração & dosagem , Adesão à Medicação , Inibidores da Fosfodiesterase 4/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Fatores Etários , Idoso , Aminopiridinas/efeitos adversos , Benzamidas/efeitos adversos , Ciclopropanos/administração & dosagem , Ciclopropanos/efeitos adversos , Feminino , Humanos , Masculino , Inibidores da Fosfodiesterase 4/efeitos adversos , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fatores de Risco , Seul , Método Simples-Cego , Fatores de Tempo , Resultado do Tratamento
9.
Life Sci ; 232: 116583, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31226417

RESUMO

TP53 mutation is an indicator of poor prognostic in chronic lymphocytic leukemia (CLL). Worse still, CLL patients with TP53 mutation are associated with poor efficacy to current chemotherapeutic, such as Fludarabine. Here, we confirmed that high expression of HDAC1 in CLL patients with TP53 mutation, which is closely related to poor prognosis and drug-resistance. Subsequently, we demonstrated Entinostat (HDAC1 inhibitor) combination with Fludarabine significantly induced apoptosis in TP53 mutations CLL cells. Its mechanism was associated with up-regulation of the pro-apoptotic protein Bax and the down-regulation of HDAC1, HO-1 and BCL-2 proteins. More importantly, we also confirmed that upregulation of HDAC1 could resistant Entinostat-induced apoptosis in TP53 mutations CLL cells by activating the HDAC1/P38/HO-1 pathway. In vivo, we found that Entinostat combination with Fludarabine significantly induced tumor cells apoptosis and prolong survival time in xenograft mouse model. Finally, combining vitro and vivo experiments, we presented the first demonstration that Entinostat combination with Fludarabine had a synergistic effect on the induction of apoptosis in TP53 mutations CLL cells. In conclusion, we provide valuable pre-clinical experimental evidence for the treatment of CLL patients with poor prognosis, especially for TP53 mutations.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzamidas/farmacologia , Heme Oxigenase-1/metabolismo , Histona Desacetilase 1/metabolismo , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piridinas/farmacologia , Proteína Supressora de Tumor p53/genética , Vidarabina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/efeitos dos fármacos , Benzamidas/administração & dosagem , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Histona Desacetilase 1/biossíntese , Histona Desacetilase 1/genética , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Piridinas/administração & dosagem , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Vidarabina/administração & dosagem , Vidarabina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/biossíntese , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
10.
Breast Cancer Res Treat ; 177(2): 383-393, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31172407

RESUMO

PURPOSE: Metastatic triple-negative breast cancer (TNBC) is a phenotypic breast cancer subgroup with a very poor prognosis, despite standard treatments. Combined twice-weekly iniparib and gemcitabine/carboplatin (GC+tw-iniparib) showed benefit over gemcitabine/carboplatin in a randomized phase II trial, and a phase III was initiated comparing these regimens. The present phase II study was initiated to compare GC+tw-iniparib with a more practical once-weekly schedule (GC+w-iniparib) in TNBC. METHODS: Metastatic TNBC patients were randomized to receive iniparib weekly (11.2 mg/kg on days 1 and 8) or twice-weekly (5.6 mg/kg on days 1, 4, 8, and 11) with gemcitabine (1000 mg/m2) and carboplatin (area under the curve 2 on days 1 and 8), every 3 weeks. The primary endpoint was the overall response rate (ORR). Pharmacokinetics of iniparib and its two metabolites were analyzed. RESULTS: A total of 163 patients were randomized, 82 GC+w-iniparib and 81 GC+tw-iniparib. Demographic and baseline characteristics were well balanced. ORR was 34.1% (95% CI 23.9-44.4%) vs. 29.6% (95% CI 19.7-39.6%) and median progression-free survival was 5.5 months (95% CI 4.2-5.7) vs. 4.3 months (95% CI 3.0-5.8) for GC+w-iniparib and GC+tw-iniparib, respectively. Safety was similar across treatment arms in terms of event severity and type. Iniparib plasma concentrations and exposure were two-fold higher with w-iniparib compared to tw-iniparib. Iniparib and its metabolites were cleared rapidly with a terminal half-life of < 1 h, without accumulation. CONCLUSIONS: Despite a doubled maximum concentration with weekly iniparib, no detectable differences in safety or efficacy were observed between the weekly and twice-weekly administration schedules in this population. TRIAL REGISTRATION: ClinicalTrial.gov Identifier NCT01045304.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/administração & dosagem , Benzamidas/farmacocinética , Biomarcadores Tumorais , Carboplatina/administração & dosagem , Carboplatina/farmacocinética , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Retratamento , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade
11.
Drugs Aging ; 36(8): 733-745, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31172422

RESUMO

Chronic obstructive pulmonary disease (COPD) can be a disabling disease, and the impact on older adults is particularly evident in the nursing home setting. Chronic obstructive pulmonary disease is present in about 20% of nursing home residents, most often in women, and accounts for significant healthcare utilization including acute care visits for exacerbations and pneumonia, as well as worsening heart disease and diabetes mellitus. The emphasis on hospital readmissions is particularly important in nursing homes where institutions have quality measures that have financial implications. Optimizing drug therapies in individuals with COPD involves choosing medications that not only improve symptoms, but also decrease the risk of exacerbations. Optimizing the treatment of comorbidities such as heart disease, infections, and diabetes that may affect COPD outcomes is also an important consideration. Depending on the nursing home setting and the patient, the options for optimizing COPD drug therapies may be limited owing to patient-related factors such as cognition and physical impairment or available resources, primarily reimbursement-related issues. Choosing the best drug therapy for COPD in older adults is limited by the difficulty in assessing respiratory symptoms using standardized assessment tools and potentially decreased inspiratory ability of frail individuals. Because of cognitive and physical impediments, ensuring optimal delivery of inhaled medications into the lungs has significant challenges. Long-acting bronchodilators, inhaled corticosteroids, and roflumilast decrease the risk of exacerbations, although inhaled corticosteroids should be used judiciously in this population because of the risk of pneumonia and oropharyngeal side effects. Treatment of COPD exacerbations should occur early and consideration should be made to the benefits and risks of systemic corticosteroids and antibiotics. Clinical research in the COPD population in nursing homes is clearly lacking, and ripe for discovery of effective management strategies.


Assuntos
Corticosteroides/uso terapêutico , Aminopiridinas/uso terapêutico , Benzamidas/uso terapêutico , Broncodilatadores/uso terapêutico , Casas de Saúde , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Corticosteroides/administração & dosagem , Idoso , Aminopiridinas/administração & dosagem , Benzamidas/administração & dosagem , Broncodilatadores/administração & dosagem , Ciclopropanos/administração & dosagem , Ciclopropanos/uso terapêutico , Feminino , Humanos , Casas de Saúde/estatística & dados numéricos , Guias de Prática Clínica como Assunto , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Estados Unidos/epidemiologia
12.
Crit Care Nurse ; 39(3): e1-e8, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31154337

RESUMO

Intracerebral hemorrhage is a major source of morbidity and mortality, accounting for 10% of all strokes. Oral anticoagulation therapy, while necessary to prevent thromboembolic complications, increases the risk of intracerebral hemorrhage and can potentially worsen bleeding in cases of acute hemorrhage. Before the introduction of direct oral anticoagulant agents in 2010, warfarin was the only option for oral anticoagulation. These new agents have an improved safety profile compared with warfarin but require different reversal strategies. Anticoagulation reversal in the setting of acute intracerebral hemorrhage is an evolving field. This article covers the most common direct oral anticoagulant medications, various available anticoagulant reversal strategies, and the latest guidelines for anticoagulation reversal in patients with acute intracranial hemorrhage.


Assuntos
Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Hemorragias Intracranianas/induzido quimicamente , Tromboembolia/prevenção & controle , Administração Oral , Anticoagulantes/farmacocinética , Antitrombinas/administração & dosagem , Antitrombinas/efeitos adversos , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Dabigatrana/administração & dosagem , Dabigatrana/efeitos adversos , Humanos , Hemorragias Intracranianas/prevenção & controle , Guias de Prática Clínica como Assunto , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Medição de Risco , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Resultado do Tratamento
13.
J Vet Med Sci ; 81(7): 1017-1020, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31155551

RESUMO

This study aimed to assess the effects of mosapride at various dosages on ruminal motility in cattle and the absorption kinetics of mosapride in cattle. Mosapride was rapidly absorbed after oral administration in cattle. Oral administration at dosages of 1, 3, and 10 mg/kg resulted in a dose-dependent increase in the detection time. At the 1 mg/kg dose, the motility index of rumen in cattle significantly increased at 60, 70, and 80 min (134 ± 20, 168 ± 37, 173 ± 45%, respectively), compared with that of the control. The administration of mosapride in cattle did not cause any subsequent adverse clinical signs or blood test abnormalities. It was suggested that mosapride enhanced ruminal motility without adverse effects in cattle.


Assuntos
Benzamidas/administração & dosagem , Benzamidas/farmacologia , Bovinos , Fármacos Gastrointestinais/farmacologia , Motilidade Gastrointestinal/efeitos dos fármacos , Morfolinas/administração & dosagem , Morfolinas/farmacologia , Administração Oral , Animais , Feminino , Fármacos Gastrointestinais/administração & dosagem , Rúmen/efeitos dos fármacos
14.
Int J Mol Sci ; 20(11)2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31174329

RESUMO

Negative and cognitive symptoms of schizophrenia contribute to an impaired social and professional life for schizophrenic patients, and in most cases, these symptoms are treatment resistant. Therefore, identification of new treatment strategies is sorely needed. Metabotropic glutamate receptors (mGlu) and muscarinic (M) receptors for acetylcholine have been considered promising targets for novel antipsychotics. Among them, mGlu2 and M4 subtypes seem to be of particular importance. In the present study, the effect of mutual activation of mGlu2 and M4 receptors was assessed in MK-801-based animal models of negative and cognitive symptoms of schizophrenia, that is, social interaction and novel object recognition tests. Low sub-effective doses of LY487379 (0.5 mg/kg), a positive allosteric activator of the mGlu2 receptor, and VU152100 (0.25-0.5 mg/kg), a positive allosteric modulator of the M4 receptor, were simultaneously administered in the aforementioned tests. Combined administration of these compounds prevented MK-801-induced disturbances in social interactions and object recognition when acutely administered 30 min before MK-801. Prolonged (7 days) administration of these compounds resulted in the loss of effectiveness in preventing MK-801-induced disruptions in the novel object recognition test but not in the social interaction test. In the next set of experiments, MK-801 (0.3 mg/kg) was administered for seven consecutive days, and the activity of the compounds was investigated on day eight, during which time MK-801 was not administered. In this model, based on prolonged MK-801 administration, the effectiveness of the compounds to treat MK-801-induced disruptions was evident at low doses which were ineffective in preventing the behavioural disturbances induced by an acute MK-801 injection. Combined administration of the compounds did not exert better efficacy than each compound given alone. Pharmacokinetic analysis confirmed a lack of possible drug-drug interactions after combined administration of LY487379 and VU152100. Our data show that modulation of M4 and mGlu2 receptors may potentially be beneficial in the treatment of negative and cognitive symptoms of schizophrenia.


Assuntos
Antipsicóticos/uso terapêutico , Benzamidas/uso terapêutico , Memória de Curto Prazo/efeitos dos fármacos , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Comportamento Social , Sulfonamidas/uso terapêutico , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacologia , Benzamidas/administração & dosagem , Benzamidas/farmacologia , Maleato de Dizocilpina/toxicidade , Quimioterapia Combinada , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Agonistas de Aminoácidos Excitatórios/farmacologia , Agonistas de Aminoácidos Excitatórios/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/toxicidade , Masculino , Camundongos , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Piridinas/administração & dosagem , Piridinas/farmacologia , Receptor Muscarínico M4/efeitos dos fármacos , Receptores de Glutamato , Esquizofrenia/etiologia , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia
15.
Pak J Pharm Sci ; 32(2 (Supplementary)): 793-798, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31103974

RESUMO

Cinitapride has been widely given in gastro-esophageal reflux disease (GERD) and dysphagia due to irregularities of GI motilities. Mouth dissolving tablets were prepared for rapid availability and action of drug. Multi-point dissolution studies were conducted in 0.1 N HCl solution of pH 1.2 and phosphate buffer of pH 4.5 and 6.8. Drug release profile showed higher liberation of cinitapride at lower pH then basic medium (<80%). Formulation containing crospovidone (10%) was found to be optimized trial having excellent quality pharmaceutical attributes. The lowest AIC, highest MSC and regression (> 0.9) values were observed for Weibull kinetics in all dissolution medium reflecting the excellent model fitting for the present study. Accelerated stability testing data showed excellent results of drug assay (>99%) along with physical characteristics indicating the absence of drug degradation as well excipient interaction. The estimated shelf life period of various optimized trial formulations was found in between 33 to 41 months.


Assuntos
Benzamidas/química , Benzamidas/farmacocinética , Comprimidos/química , Comprimidos/farmacocinética , Administração Oral , Benzamidas/administração & dosagem , Tampões (Química) , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Cinética , Comprimidos/administração & dosagem
16.
Pest Manag Sci ; 75(12): 3363-3370, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31074102

RESUMO

BACKGROUND: Two field experiments were conducted to determine the efficacy and field performance of three new non-fumigant chemical nematicides (fluensulfone, fluopyram, and fluazaindolizine) and two biological nematicides (Burkholderia rinojensis strain A396 and Purpureocillium lilacinus strain 251) for management of root-knot nematodes (Meloidogyne javanica) on tomato and associated double-crops in Florida. RESULTS: In experiment 1, soil fumigation with metam potassium increased plant growth and reduced root galling on tomato by 77% relative to that of the untreated soil. All non-fumigant chemical nematicides reduced root galling on tomato (47-85% reduction); however, only fluensulfone showed a trend towards yield enhancement. In experiment 2, soil fumigation with chloropicrin increased plant growth and reduced root galling on tomato by 35% relative to that of the untreated soil; however, end-of-season populations of M. javanica in soil were larger than that of the non-fumigated soil. Fluensulfone showed a trend towards reduced root galling and enhanced fruit yield, whereas other non-fumigant nematicides did not. Double-cropped cucumber was 69% more galled when planted into soil previously fumigated with chloropicrin relative to that of untreated soil, and also showed reduced plant vigor and fruit yield. CONCLUSION: Fluensulfone shows significant potential to be a component of an integrated pest management strategy for tomato in Florida. © 2019 Society of Chemical Industry.


Assuntos
Antinematódeos/administração & dosagem , Ascomicetos/fisiologia , Burkholderia/fisiologia , Lycopersicon esculentum/crescimento & desenvolvimento , Controle Biológico de Vetores/métodos , Doenças das Plantas/prevenção & controle , Tylenchoidea , Animais , Benzamidas/administração & dosagem , Produção Agrícola/métodos , Proteção de Cultivos/métodos , Cucumis sativus/crescimento & desenvolvimento , Florida , Compostos Heterocíclicos com 2 Anéis/administração & dosagem , Lycopersicon esculentum/parasitologia , Doenças das Plantas/parasitologia , Piridinas/administração & dosagem , Sulfonamidas/administração & dosagem , Sulfonas/administração & dosagem , Tiazóis/administração & dosagem
17.
Pediatr Blood Cancer ; 66(8): e27820, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31099166

RESUMO

BACKGROUND: Entinostat, a selective class I histone deacetylase inhibitor, has been reported to enhance the activity of cytotoxic agents and suppress expression of PAX3-FOXO1 in alveolar rhabdomyosarcoma (ARMS). PROCEDURES: Entinostat was tested against three rhabdomyosarcoma cell lines using 96-hour drug exposure. Entinostat alone or in binary combination with vincristine, actinomycin D or cyclophosphamide was tested in ARMS and two embryonal rhabdomyosarcoma (ERMS) xenograft models. Tumor growth was measured at weekly intervals. Drug-induced changes in acetylated histone H3(K9) and entinostat pharmacokinetics were determined. RESULTS: In vitro, the IC50 concentration of entinostat ranged from 280 to 1300 nM. In vivo, entinostat significantly inhibited the growth of only Rh10 xenografts. For most studies, entinostat did not potentiate the activity of the cytotoxic agent. Exceptions included the vincristine and entinostat combination for Rh10 and the entinostat and actinomycin D combination for Rh10 and Rh18, although the effects were modest. For Rh18, the combination of entinostat with vincristine showed evidence of an antagonistic interaction compared with single-agent vincristine. Pharmacokinetic studies showed the average Cmax was 569.4 ng/mL (1.51 µM) with Tmax at 15 minutes, and total exposure (AUC0-12 h ) was 435.6 h × ng/mL. Entinostat treatment increased acetylated histone H3. CONCLUSIONS: Entinostat demonstrated modest antitumor activity in only one of four models at dose and shedule that gave drug exposures relevant to human treatment. The addition of entinostat to standard-of-care cytotoxic agents was in most instances no more effective than the cytotoxic agents used alone. Entinostat demonstrated target inhibition with increased histone 2A acetylation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Padrão de Cuidado , Animais , Benzamidas/administração & dosagem , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Dactinomicina/administração & dosagem , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Piridinas/administração & dosagem , Células Tumorais Cultivadas , Vincristina/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
18.
BMC Cancer ; 19(1): 415, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31046743

RESUMO

BACKGROUND: While recent years have seen a revolution in the treatment of metastatic cutaneous melanoma, no treatment has yet been able to demonstrate any prolonged survival in metastatic uveal melanoma. Thus, metastatic uveal melanoma remains a disease with an urgent unmet medical need. Reports of treatment with immune checkpoint inhibitors have thus far been disappointing. Based on animal experiments, it is reasonable to hypothesize that the effect of immunotherapy may be augmented by epigenetic therapy. Proposed mechanisms include enhanced expression of HLA class I and cancer antigens on cancer cells, as well as suppression of myeloid suppressor cells. METHODS: The PEMDAC study is a multicenter, open label phase II study assessing the efficacy of concomitant use of the PD1 inhibitor pembrolizumab and the class I HDAC inhibitor entinostat in adult patients with metastatic uveal melanoma. Primary endpoint is objective response rate. Eligible patients have histologically confirmed metastatic uveal melanoma, ECOG performance status 0-1, measurable disease as per RECIST 1.1 and may have received any number of prior therapies, with the exception of anticancer immunotherapy. Twenty nine patients will be enrolled. Patients receive pembrolizumab 200 mg intravenously every third week in combination with entinostat 5 mg orally once weekly. Treatment will continue until progression of disease or intolerable toxicity or for a maximum of 24 months. DISCUSSION: The PEMDAC study is the first trial to assess whether the addition of an HDAC inhibitor to anti-PD1 therapy can yield objective anti-tumoral responses in metastatic UM. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT02697630 . (Registered 3 March 2016). EudraCT registration number: 2016-002114-50.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzamidas/administração & dosagem , Melanoma/tratamento farmacológico , Piridinas/administração & dosagem , Neoplasias Uveais/tratamento farmacológico , Administração Intravenosa , Administração Oral , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Masculino , Estudos Prospectivos , Piridinas/uso terapêutico , Projetos de Pesquisa , Resultado do Tratamento
19.
BMC Cancer ; 19(1): 471, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31109313

RESUMO

BACKGROUND: Transformation of chronic lymphocytic leukaemia (CLL) to diffuse large B-cell lymphoma (DLCBL) type Richter's syndrome (RS) carries a dismal prognosis. Standard-of-care chemoimmunotherapy for de novo RS is inadequate with median survival of less than one year. Patients are frequently elderly or have co-morbidities limiting dose-intense chemotherapy. Treatment of relapsed/refractory (R/R) RS and RS emerging after CLL-directed therapy represent urgent unmet clinical needs. Agents targeting Bruton's tyrosine kinase (BTK) deliver improved outcomes for patients with high-risk CLL and expand effective treatments to frailer patients. Acalabrutinib is an oral, second-generation BTK inhibitor with a favourable toxicity profile and demonstrated activity in CLL and B-cell lymphomas. Combination of acalabrutinib with standard-of-care CHOP-R chemoimmunotherapy offers a sound rationale to test in a prospective trial for de novo RS. METHODS: The prospective multicentre STELLAR study is designed in two elements, consisting of a randomised study to evaluate the safety and activity of CHOP-R chemoimmunotherapy in combination with acalabrutinib in newly diagnosed RS and single-arm studies of novel agents for other RS patient cohorts. Eligible patients with newly diagnosed DLBCL-type RS are randomised between six cycles of CHOP-R therapy and six cycles CHOP-R plus acalabrutinib, followed by acalabrutinib maintenance. The primary endpoint of the randomised component is progression free survival (PFS). Cohort 1 enrols RS patients with progressive disease following chemoimmunotherapy for acalabrutinib monotherapy. Patients with RS diagnosed while on ibrutinib may enrol in Cohort 2, a single-arm study of CHOP-R plus acalabrutinib. The primary endpoint for the single-arm studies is overall response rate (ORR). Secondary endpoints for all cohorts are overall survival (OS), quality of life and proportion of patients proceeding to stem cell transplantation. The study will be accompanied by exploratory analysis of the mutational landscape of RS and the relationship between dynamic changes in sequential circulating tumour DNA samples and clinical outcomes. DISCUSSION: The STELLAR randomised trial evaluates the role of CHOP-R plus acalabrutinib in newly diagnosed RS patients. The single-arm platform studies enable the incorporation of promising novel therapies into the protocol. The STELLAR study has potential to identify novel biomarkers of treatment response in this high-risk malignancy. TRIAL REGISTRATION: EudraCT: 2017-004401-40 , registered on the 31-Oct-2017. IRSCTN: https://www.isrctn.com/ISRCTN52839057 , registered on the 04-Mar-2019. ClinicalTrials.gov : NCT03899337 , registered on 02-April-2019.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzamidas/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Pirazinas/administração & dosagem , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Estudos Prospectivos , Pirazinas/efeitos adversos , Recidiva , Projetos de Pesquisa , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Adulto Jovem
20.
Psychopharmacology (Berl) ; 236(9): 2797-2810, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31049607

RESUMO

RATIONALE: Previous studies have demonstrated that repeated social defeat (RSD) stress only induces cognitive deficits when experienced during adulthood. However, RSD increases cocaine-rewarding effects in adult and adolescent mice, inducing different expressions of proBDNF in the ventral tegmental area. OBJECTIVE: The aim of the present study was to evaluate the effect of cocaine administration in socially defeated adult or adolescent mice on learning, memory, and anxiety. Additionally, the role of BDNF was also studied. METHODS: Adolescent and young adult mice were exposed to four episodes of social defeat or exploration (control), being treated with a daily injection of four doses of saline or 1 mg/kg of cocaine 3 weeks after the last social defeat. Other groups were treated with the TrkB receptor antagonist ANA-12 during this 21-day period. After this treatment, their cognitive and anxiogenic profiles were evaluated, along with the expression of BDNF, pCREB, and pERK1/2 in the dentate gyrus (DG) and basolateral amygdala (BLA). RESULTS: Cocaine induced an increased expression of pCREB and BDNF in the DG and BLA only in defeated animals. Although RSD did not affect memory, the administration of cocaine induced memory impairments only in defeated animals. Defeated adult mice needed more time to complete the mazes, and this effect was counteracted by cocaine administration. RSD induced anxiogenic effects only when experienced during adulthood and cocaine induced a general anxiolytic effect. Blockade of Trkb decreased memory retention without affecting spatial learning and modified anxiety on non-stressed mice depending on their age. CONCLUSION: Our results demonstrate that the long-lasting effects of social defeat on anxiety and cognition are modulated by cocaine administration. Our results highlight that the BDNF signaling pathway could be a target to counteract the effects of cocaine on socially stressed subjects.


Assuntos
Azepinas/administração & dosagem , Benzamidas/administração & dosagem , Cocaína/administração & dosagem , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Comportamento Social , Estresse Psicológico/psicologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Inibidores da Captação de Dopamina/administração & dosagem , Masculino , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Camundongos , Camundongos Endogâmicos , Receptor trkB/antagonistas & inibidores , Estresse Psicológico/tratamento farmacológico
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