Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.621
Filtrar
1.
ACS Appl Mater Interfaces ; 13(2): 2256-2268, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33423468

RESUMO

The aggressive progression of breast cancer is impacted significantly by the tumor microenvironment (TME). The current chemotherapy normally causes cytotoxicity to tumor cells, while does not effectively modulate the TME. Thus, the chemotherapy effect of breast cancer is usually dissatisfactory. In this study, a kind of hierarchically releasing bio-responsive nanoparticles (R(D)/H(S) NPs), constructed by ß-cyclodextrin-grafted heparin and pH-sensitive pseudorotaxane, were investigated to enhance the breast cancer chemotherapeutic efficacy through TME modulation. Doxorubicin (DOX) and transforming growth factor-ß (TGF-ß) receptor inhibitor (SB431542) loaded onto R(D)/H(S) NPs were released rapidly for the respective response to low pH in endosomes/lysosomes and heparanase (HPSE) in TME. Our results showed that R(D)/H(S) NPs effectively inhibited the formation of tumor-associated fibroblasts (TAFs) and reduced TGF-ß and collagen I secretion. Besides, the immunosuppressive microenvironment was effectively reversed into immunogenic, characterized by increased CD8+ and CD4+ T cell infiltration, which distinctly inhibited breast cancer metastasis. Therefore, R(D)/H(S) NPs remodeled the TME by downregulating TAFs, TGF-ß, and collagen I; activating the immune microenvironment; and then amplifying the chemotherapeutic efficacy of DOX.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Benzamidas/administração & dosagem , Preparações de Ação Retardada/química , Dioxóis/administração & dosagem , Doxorrubicina/administração & dosagem , Fator de Crescimento Transformador beta/antagonistas & inibidores , Microambiente Tumoral/efeitos dos fármacos , Células 3T3 , Animais , Antibióticos Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Fibroblastos Associados a Câncer/efeitos dos fármacos , Linhagem Celular Tumoral , Dioxóis/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Rotaxanos/química , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo
2.
Cancer Sci ; 112(3): 1123-1131, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33492746

RESUMO

BACKGROUND: Tazemetostat is a selective and orally available inhibitor of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and epigenetic regulator of cellular differentiation programs. We carried out a phase I study of tazemetostat in Japanese patients with relapsed or refractory B-cell non-Hodgkin-type lymphoma (B-NHL) to evaluate its tolerability, safety, pharmacokinetics, and preliminary antitumor activity. METHODS: Tazemetostat was given orally at a single dose of 800 mg on the first day and 800 mg twice daily (BID: total 1600 mg/d) on following days in a 28-day/cycle manner. Tazemetostat dose-limiting toxicity (DLT) was evaluated up to the end of the first treatment cycle. Archival tumor tissues were analyzed for hotspot EZH2 mutations. RESULTS: As of 15 January 2018, seven patients (four follicular lymphoma [FL] and three diffuse large B-cell lymphoma [DLBCL]) were enrolled. The median age was 73 (range, 59-85) years, and the median number of prior chemotherapy regimens was three (range, one to five). No DLT was observed (one patient was not evaluable due to early disease progression). The common treatment-related adverse events (AEs) were thrombocytopenia and dysgeusia (three patients each; 42.9%). No treatment-related serious AEs were observed. The objective response rate was 57% (4/7 patients), including responses in three of four patients with FL and one of three patients with DLBCL. An EZH2 mutation was detected in one patient with FL responding to treatment. CONCLUSIONS: Tazemetostat at 800 mg BID showed an acceptable safety profile and promising antitumor activity in Japanese patients with relapsed or refractory B-NHL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzamidas/efeitos adversos , Compostos de Bifenilo/efeitos adversos , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Linfoma de Células B/tratamento farmacológico , Morfolinas/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Piridonas/efeitos adversos , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/administração & dosagem , Benzamidas/farmacocinética , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/farmacocinética , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Humanos , Japão , Linfoma de Células B/genética , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/farmacocinética , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Piridonas/administração & dosagem , Piridonas/farmacocinética , Resultado do Tratamento
3.
Int J Mol Sci ; 22(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33375170

RESUMO

Sarcopenia has a significant negative impact on healthspan in the elderly and effective pharmacologic interventions remain elusive. We have previously demonstrated that sarcopenia is associated with reduced activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump. We asked whether restoring SERCA activity using pharmacologic activation in aging mice could mitigate the sarcopenia phenotype. We treated 16-month male C57BL/6J mice with vehicle or CDN1163, an allosteric SERCA activator, for 10 months. At 26 months, maximal SERCA activity was reduced 41% in gastrocnemius muscle in vehicle-treated mice but maintained in old CDN1163 treated mice. Reductions in gastrocnemius mass (9%) and in vitro specific force generation in extensor digitorum longus muscle (11%) in 26 versus 16-month-old wild-type mice were also reversed by CDN1163. CDN1163 administered by intra-peritoneal injection also prevented the increase in mitochondrial ROS production in gastrocnemius muscles of aged mice. Transcriptomic analysis revealed that these effects are at least in part mediated by enhanced cellular energetics by activation of PGC1-α, UCP1, HSF1, and APMK and increased regenerative capacity by suppression of MEF2C and p38 MAPK signaling. Together, these exciting findings are the first to support that pharmacological targeting of SERCA can be an effective therapy to counter age-related muscle dysfunction.


Assuntos
Aminoquinolinas/farmacologia , Benzamidas/farmacologia , Debilidade Muscular/prevenção & controle , Atrofia Muscular/prevenção & controle , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Fatores Etários , Aminoquinolinas/administração & dosagem , Animais , Benzamidas/administração & dosagem , Ativação Enzimática/efeitos dos fármacos , Injeções Intraperitoneais , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Debilidade Muscular/fisiopatologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/fisiopatologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Espécies Reativas de Oxigênio/metabolismo , Proteína Desacopladora 1/metabolismo
4.
Lancet Oncol ; 21(11): 1433-1442, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33035457

RESUMO

BACKGROUND: Activating mutations of EZH2, an epigenetic regulator, are present in approximately 20% of patients with follicular lymphoma. We investigated the activity and safety of tazemetostat, a first-in-class, oral EZH2 inhibitor, in patients with follicular lymphoma. METHODS: This study was an open-label, single-arm, phase 2 trial done at 38 clinics or hospitals in France, the UK, Australia, Canada, Poland, Italy, Ukraine, Germany, and the USA. Eligible patients were adults (≥18 years) with histologically confirmed follicular lymphoma (grade 1, 2, 3a, or 3b) that had relapsed or was refractory to two or more systemic therapies, had an Eastern Cooperative Oncology Group performance status of 0-2, and had sufficient tumour tissue for central testing of EZH2 mutation status. Patients were categorised by EZH2 status: mutant (EZH2mut) or wild-type (EZH2WT). Patients received 800 mg of tazemetostat orally twice per day in continuous 28-day cycles. The primary endpoint was objective response rate based on the 2007 International Working Group criteria for non-Hodgkin lymphoma, assessed by an independent radiology committee. Activity and safety analyses were done in patients who received one dose or more of tazemetostat. This study is registered with ClinicalTrials.gov, NCT01897571, and follow-up is ongoing. FINDINGS: Between July 9, 2015, and May 24, 2019, 99 patients (45 in the EZH2mut cohort and 54 in the EZH2WT cohort) were enrolled in the study. At data cutoff for the analysis (Aug 9, 2019), the median follow-up was 22·0 months (IQR 12·0-26·7) for the EZH2mut cohort and 35·9 months (24·9-40·5) for the EZH2WT cohort. The objective response rate was 69% (95% CI 53-82; 31 of 45 patients) in the EZH2mut cohort and 35% (23-49; 19 of 54 patients) in the EZH2WT cohort. Median duration of response was 10·9 months (95% CI 7·2-not estimable [NE]) in the EZH2mut cohort and 13·0 months (5·6-NE) in the EZH2WT cohort; median progression-free survival was 13·8 months (10·7-22·0) and 11·1 months (3·7-14·6). Among all 99 patients, treatment-related grade 3 or worse adverse events included thrombocytopenia (three [3%]), neutropenia (three [3%]), and anaemia (two [2%]). Serious treatment-related adverse events were reported in four (4%) of 99 patients. There were no treatment-related deaths. INTERPRETATION: Tazemetostat monotherapy showed clinically meaningful, durable responses and was generally well tolerated in heavily pretreated patients with relapsed or refractory follicular lymphoma. Tazemetostat is a novel treatment for patients with follicular lymphoma. FUNDING: Epizyme.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Benzamidas/administração & dosagem , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Linfoma Folicular/tratamento farmacológico , Piridonas/administração & dosagem , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/efeitos adversos , Feminino , Humanos , Linfoma Folicular/genética , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão , Piridonas/efeitos adversos , Resultado do Tratamento
5.
Lancet Oncol ; 21(11): 1423-1432, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33035459

RESUMO

BACKGROUND: Epithelioid sarcoma is a rare and aggressive soft-tissue sarcoma subtype. Over 90% of tumours have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2. In this study, we report the clinical activity and safety of tazemetostat, an oral selective EZH2 inhibitor, in patients with epithelioid sarcoma. METHODS: In this open-label, phase 2 basket study, patients were enrolled from 32 hospitals and clinics in Australia, Belgium, Canada, France, Germany, Italy, Taiwan, the USA, and the UK into seven cohorts of patients with different INI1-negative solid tumours or synovial sarcoma. Patients eligible for the epithelioid sarcoma cohort (cohort 5) were aged 16 years or older with histologically confirmed, locally advanced or metastatic epithelioid sarcoma; documented loss of INI1 expression by immunohistochemical analysis or biallelic SMARCB1 (the gene that encodes INI1) alterations, or both; and an Eastern Cooperative Oncology Group performance status score of 0-2. Patients received 800 mg tazemetostat orally twice per day in continuous 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed objective response rate measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints were duration of response, disease control rate at 32 weeks, progression-free survival, overall survival, and pharmacokinetic and pharmacodynamic analyses (primary results reported elsewhere). Time to response was also assessed as an exploratory endpoint. Activity and safety were assessed in the modified intention-to-treat population (ie, patients who received one or more doses of tazemetostat). This trial is registered with ClinicalTrials.gov, NCT02601950, and is ongoing. FINDINGS: Between Dec 22, 2015, and July 7, 2017, 62 patients with epithelioid sarcoma were enrolled in the study and deemed eligible for inclusion in this cohort. All 62 patients were included in the modified intention-to-treat analysis. Nine (15% [95% CI 7-26]) of 62 patients had an objective response at data cutoff (Sept 17, 2018). At a median follow-up of 13·8 months (IQR 7·8-19·0), median duration of response was not reached (95% CI 9·2-not estimable). 16 (26% [95% CI 16-39]) patients had disease control at 32 weeks. Median time to response was 3·9 months (IQR 1·9-7·4). Median progression-free survival was 5·5 months (95% CI 3·4-5·9), and median overall survival was 19·0 months (11·0-not estimable). Grade 3 or worse treatment-related adverse events included anaemia (four [6%]) and weight loss (two [3%]). Treatment-related serious adverse events occurred in two patients (one seizure and one haemoptysis). There were no treatment-related deaths. INTERPRETATION: Tazemetostat was well tolerated and showed clinical activity in this cohort of patients with advanced epithelioid sarcoma characterised by loss of INI1/SMARCB1. Tazemetostat has the potential to improve outcomes in patients with advanced epithelioid sarcoma. A phase 1b/3 trial of tazemetostat plus doxorubicin in the front-line setting is currently underway (NCT04204941). FUNDING: Epizyme.


Assuntos
Benzamidas/administração & dosagem , Piridonas/administração & dosagem , Proteína SMARCB1/genética , Sarcoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Piridonas/efeitos adversos , Piridonas/farmacocinética , Sarcoma/genética , Sarcoma/patologia , Resultado do Tratamento , Adulto Jovem
6.
Medicine (Baltimore) ; 99(43): e22788, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33120793

RESUMO

RATIONALE: The prognosis of patients with aggressive relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) remains poor. Both immunomodulatory drugs and histone deacetylase inhibitors have demonstrated activity against R/R NHL; yet, the combination of these 2 targeted therapies has rarely been explored. PATIENT CONCERNS: Here, we report 3 cases. Case 1 was a 68-year-old woman who presented to our hospital with dyspnea. Case 2 was a 75-year-old man with massive upper gastrointestinal bleeding. Case 3 was a 62-year-old woman with cough, dyspnea, and lymphadenopathy. DIAGNOSIS: The biopsy results revealed diffuse large B cell lymphoma (DLBCL), DLBCL, and angioimmunoblastic T-cell lymphoma, for Case 1, 2, and 3 respectively. INTERVENTION: All 3 patients experienced relapse after first-line therapy and multiple lines of salvage therapy. Finally, they all received lenalidomide combined with chidamide. OUTCOMES: All 3 patients achieved complete and durable remission. Case 1 relapsed again after 3 months, while the other 2 cases remained in complete remission. LESSONS: To our knowledge, this is the first report of lenalidomide combined with chidamide for the treatment of R/R NHL. Our findings warrant further evaluation of this novel chemo-free therapy in future prospective clinical trials.


Assuntos
Aminopiridinas/uso terapêutico , Benzamidas/uso terapêutico , Lenalidomida/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Idoso , Aminopiridinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/administração & dosagem , Feminino , Humanos , Lenalidomida/administração & dosagem , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Terapia de Salvação
7.
PLoS One ; 15(7): e0235423, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32628699

RESUMO

The root-knot nematode (Meloidogyne spp.) is one of the major challenges in eggplant (Solanum melongena L.) production. Fluopyram, known to be an effective fungicide, is also used for controlling root-knot nematode. However, in China, little information is currently available regarding the efficacy of fluopyram via chemigation against root-knot nematode and its effects on soil properties. For this, the objective of this work was to test mortality of root-knot nematode, functional diversity of soil microbial community, activity of soil enzyme after fluopyram applicated by chemigation. The results of two field experiments revealed that concentration of 60 g·ha-1 fluopyram applied with 200 L·ha-1 irrigation water at 2 L·h-1 flow velocity was the most effective chemigation parameters for controlling eggplant against root-knot nematode. The functional diversity of the soil microbial community was significantly affected by fluopyram. The activities of soil urease and ß-glucosidase decreased during the initial stages but recovered at later stages. In brief, fluopyram has advantageous for the efficient control of root-knot nematode with no deleterious effects on soil properties as well as chemigation is positive for application in karst landscape in Guangxi.


Assuntos
Benzamidas/toxicidade , Piridinas/toxicidade , Microbiologia do Solo , Solo/química , Solanum melongena/parasitologia , Tylenchoidea/isolamento & purificação , Irrigação Agrícola/métodos , Fosfatase Alcalina/análise , Animais , Benzamidas/administração & dosagem , China , Microbiota/efeitos dos fármacos , Raízes de Plantas/parasitologia , Piridinas/administração & dosagem , Urease/análise , beta-Glucosidase/análise
8.
N Engl J Med ; 383(3): 229-239, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32668113

RESUMO

BACKGROUND: Systemic oral phosphodiesterase type 4 (PDE-4) inhibitors have been effective in the treatment of psoriasis. Roflumilast cream contains a PDE-4 inhibitor that is being investigated for the topical treatment of psoriasis. METHODS: In this phase 2b, double-blind trial, we randomly assigned adults with plaque psoriasis in a 1:1:1 ratio to use roflumilast 0.3% cream, roflumilast 0.15% cream, or vehicle (placebo) cream once daily for 12 weeks. The primary efficacy outcome was the investigator's global assessment (IGA) of a status of clear or almost clear at week 6 (assessed on a 5-point scale of plaque thickening, scaling, and erythema; a score of 0 indicates clear, 1 almost clear, and 4 severe). Secondary outcomes included an IGA score indicating clear or almost clear plus a 2-grade improvement in the IGA score for the intertriginous area and the change in the Psoriasis Area and Severity Index (PASI) score (range, 0 to 72, with higher scores indicating worse disease). Safety was also assessed. RESULTS: Among 331 patients who underwent randomization, 109 were assigned to roflumilast 0.3% cream, 113 to roflumilast 0.15% cream, and 109 to vehicle cream. An IGA score indicating clear or almost clear at week 6 was observed in 28% of the patients in the roflumilast 0.3% group, in 23% in the roflumilast 0.15% group, and in 8% in the vehicle group (P<0.001 and P = 0.004 vs. vehicle for roflumilast 0.3% and 0.15%, respectively). Among the approximately 15% of patients overall who had baseline intertriginous psoriasis of at least mild severity, an IGA score at week 6 indicating clear or almost clear plus a 2-grade improvement in the intertriginous-area IGA score occurred in 73% of the patients in the roflumilast 0.3% group, 44% of those in the roflumilast 0.15% group, and 29% of those in the vehicle group. The mean baseline PASI scores were 7.7 in the roflumilast 0.3% group, 8.0 in the roflumilast 0.15% group, and 7.6 in the vehicle group; the mean change from baseline at week 6 was -50.0%, -49.0%, and -17.8%, respectively. Application-site reactions occurred with similar frequency in the roflumilast groups and the vehicle group. CONCLUSIONS: Roflumilast cream administered once daily to affected areas of psoriasis was superior to vehicle cream in leading to a state of clear or almost clear at 6 weeks. Longer and larger trials are needed to determine the durability and safety of roflumilast in psoriasis. (Funded by Arcutis Biotherapeutics; ARQ-151 201 ClinicalTrials.gov number, NCT03638258.).


Assuntos
Aminopiridinas/administração & dosagem , Benzamidas/administração & dosagem , Inibidores da Fosfodiesterase 4/administração & dosagem , Psoríase/tratamento farmacológico , Creme para a Pele/administração & dosagem , Administração Tópica , Adulto , Aminopiridinas/efeitos adversos , Benzamidas/efeitos adversos , Ciclopropanos/administração & dosagem , Ciclopropanos/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Inibidores da Fosfodiesterase 4/efeitos adversos , Índice de Gravidade de Doença
10.
Cochrane Database Syst Rev ; 5: CD002309, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32356609

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with cough, sputum production or dyspnoea, and a reduction in lung function, quality of life, and life expectancy. Apart from smoking cessation, no other treatments that slow lung function decline are available. Roflumilast and cilomilast are oral phosphodiesterase-4 (PDE4) inhibitors proposed to reduce the airway inflammation and bronchoconstriction seen in COPD. This Cochrane Review was first published in 2011, and was updated in 2017 and 2020. OBJECTIVES: To evaluate the efficacy and safety of oral PDE4 inhibitors for management of stable COPD. SEARCH METHODS: We identified randomised controlled trials (RCTs) from the Cochrane Airways Trials Register (date of last search 9 March 2020). We found other trials at web-based clinical trials registers. SELECTION CRITERIA: We included RCTs if they compared oral PDE4 inhibitors with placebo in people with COPD. We allowed co-administration of standard COPD therapy. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Two independent review authors selected trials for inclusion, extracted data, and assessed risk of bias. We resolved discrepancies by involving a third review author. We assessed our confidence in the evidence by using GRADE recommendations. Primary outcomes were change in lung function (minimally important difference (MID) = 100 mL) and quality of life (scale 0 to 100; higher score indicates more limitations). MAIN RESULTS: We found 42 RCTs that met the inclusion criteria and were included in the analyses for roflumilast (28 trials with 18,046 participants) or cilomilast (14 trials with 6457 participants) or tetomilast (1 trial with 84 participants), with a duration between six weeks and one year or longer. These trials included people across international study centres with moderate to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades II to IV), with mean age of 64 years. We judged risks of selection bias, performance bias, and attrition bias as low overall amongst the 39 published and unpublished trials. Lung function Treatment with a PDE4 inhibitor was associated with a small, clinically insignificant improvement in forced expiratory volume in one second (FEV1) over a mean of 40 weeks compared with placebo (mean difference (MD) 49.33 mL, 95% confidence interval (CI) 44.17 to 54.49; participants = 20,815; studies = 29; moderate-certainty evidence). Forced vital capacity (FVC) and peak expiratory flow (PEF) were also improved over 40 weeks (FVC: MD 86.98 mL, 95% CI 74.65 to 99.31; participants = 22,108; studies = 17; high-certainty evidence; PEF: MD 6.54 L/min, 95% CI 3.95 to 9.13; participants = 4245; studies = 6; low-certainty evidence). Quality of life Trials reported improvements in quality of life over a mean of 33 weeks (St George's Respiratory Questionnaire (SGRQ) MD -1.06 units, 95% CI -1.68 to -0.43; participants = 7645 ; moderate-certainty evidence). Incidence of exacerbations Treatment with a PDE4 inhibitor was associated with a reduced likelihood of COPD exacerbation over a mean of 40 weeks (odds ratio (OR) 0.78, 95% CI 0.73 to 0.84; participants = 20,382; studies = 27; high-certainty evidence), that is, for every 100 people treated with PDE4 inhibitors, five more remained exacerbation-free during the study period compared with those given placebo (number needed to treat for an additional beneficial outcome (NNTB) 20, 95% CI 16 to 27). No change in COPD-related symptoms nor in exercise tolerance was found. Adverse events More participants in the treatment groups experienced an adverse effect compared with control participants over a mean of 39 weeks (OR 1.30, 95% CI 1.22 to 1.38; participants = 21,310; studies = 30; low-certainty evidence). Participants experienced a range of gastrointestinal symptoms such as diarrhoea, nausea, vomiting, or dyspepsia. Diarrhoea was more commonly reported with PDE4 inhibitor treatment (OR 3.20, 95% CI 2.74 to 3.50; participants = 20,623; studies = 29; high-certainty evidence), that is, for every 100 people treated with PDE4 inhibitors, seven more suffered from diarrhoea during the study period compared with those given placebo (number needed to treat for an additional harmful outcome (NNTH) 15, 95% CI 13 to 17). The likelihood of psychiatric adverse events was higher with roflumilast 500 µg than with placebo (OR 2.13, 95% CI 1.79 to 2.54; participants = 11,168; studies = 15 (COPD pool data); moderate-certainty evidence). Roflumilast in particular was associated with weight loss during the trial period and with an increase in insomnia and depressive mood symptoms. Participants treated with PDE4 inhibitors were more likely to withdraw from trial participation; on average, 14% in the treatment groups withdrew compared with 8% in the control groups. Mortality No effect on mortality was found (OR 0.98, 95% CI 0.77 to 1.24; participants = 19,786; studies = 27; moderate-certainty evidence), although mortality was a rare event during these trials. AUTHORS' CONCLUSIONS: For this current update, five new studies from the 2020 search contributed to existing findings but made little impact on outcomes described in earlier versions of this review. PDE4 inhibitors offered a small benefit over placebo in improving lung function and reducing the likelihood of exacerbations in people with COPD; however, they had little impact on quality of life or on symptoms. Gastrointestinal adverse effects and weight loss were common, and the likelihood of psychiatric symptoms was higher, with roflumilast 500 µg. The findings of this review provide cautious support for the use of PDE4 inhibitors in COPD. In accordance with GOLD 2020 guidelines, they may have a place as add-on therapy for a subgroup of people with persistent symptoms or exacerbations despite optimal COPD management (e.g. people whose condition is not controlled by fixed-dose long-acting beta2-agonist (LABA) and inhaled corticosteroid (ICS) combinations). More longer-term trials are needed to determine whether or not PDE4 inhibitors modify FEV1 decline, hospitalisation, or mortality in COPD.


Assuntos
Aminopiridinas/administração & dosagem , Benzamidas/administração & dosagem , Ácidos Cicloexanocarboxílicos/administração & dosagem , Nitrilos/administração & dosagem , Inibidores da Fosfodiesterase 4/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tiazóis/administração & dosagem , Administração Oral , Aminopiridinas/efeitos adversos , Benzamidas/efeitos adversos , Ácidos Cicloexanocarboxílicos/efeitos adversos , Ciclopropanos/administração & dosagem , Ciclopropanos/efeitos adversos , Diarreia/induzido quimicamente , Progressão da Doença , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Nitrilos/efeitos adversos , Pico do Fluxo Expiratório/efeitos dos fármacos , Inibidores da Fosfodiesterase 4/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/mortalidade , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Tiazóis/efeitos adversos , Capacidade Vital/efeitos dos fármacos
11.
Lancet ; 395(10232): 1278-1291, 2020 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-32305093

RESUMO

BACKGROUND: Acalabrutinib is a selective, covalent Bruton tyrosine-kinase inhibitor with activity in chronic lymphocytic leukaemia. We compare the efficacy of acalabrutinib with or without obinutuzumab against chlorambucil with obinutuzumab in patients with treatment-naive chronic lymphocytic leukaemia. METHODS: ELEVATE TN is a global, phase 3, multicentre, open-label study in patients with treatment-naive chronic lymphocytic leukaemia done at 142 academic and community hospitals in 18 countries. Eligible patients had untreated chronic lymphocytic leukaemia and were aged 65 years or older, or older than 18 years and younger than 65 years with creatinine clearance of 30-69 mL/min (calculated by use of the Cockcroft-Gault equation) or Cumulative Illness Rating Scale for Geriatrics score greater than 6. Additional criteria included an Eastern Cooperative Oncology Group performance status score of 2 or less and adequate haematologic, hepatic, and renal function. Patients with significant cardiovascular disease were excluded, and concomitant treatment with warfarin or equivalent vitamin K antagonists was prohibited. Patients were randomly assigned (1:1:1) centrally via an interactive voice or web response system to receive acalabrutinib and obinutuzumab, acalabrutinib monotherapy, or obinutuzumab and oral chlorambucil. Treatments were administered in 28-day cycles. To reduce infusion-related reactions, acalabrutinib was administered for one cycle before obinutuzumab administration. Oral acalabrutinib was administered (100 mg) twice a day until progressive disease or unacceptable toxic effects occurred. In the acalabrutinib-obinutuzumab group, intravenous obinutuzumab was given on days 1 (100 mg), 2 (900 mg), 8 (1000 mg), and 15 (1000 mg) of cycle 2 and on day 1 (1000 mg) of cycles 3-7. In the obinutuzumab-chlorambucil group, intravenous obinutuzumab was given on days 1 (100 mg), 2 (900 mg), 8 (1000 mg), and 15 (1000 mg) of cycle 1 and on day 1 (1000 mg) of cycles 2-6. Oral chlorambucil was given (0·5 mg/kg) on days 1 and 15 of each cycle, for six cycles. The primary endpoint was progression-free survival between the two combination-therapy groups, assessed by independent review committee. Crossover to acalabrutinib was allowed in patients who progressed on obinutuzumab-chlorambucil. Safety was assessed in all patients who received at least one dose of treatment. Enrolment for this trial is complete, and the study is registered at ClinicalTrials.gov, NCT02475681. FINDINGS: Between Sept 14, 2015, and Feb 8, 2017, we recruited 675 patients for assessment. 140 patients did not meet eligibility criteria, and 535 patients were randomly assigned to treatment. 179 patients were assigned to receive acalabrutinib-obinutuzumab, 179 patients were assigned to receive acalabrutinib monotherapy, and 177 patients were assigned to receive obinutuzumab-chlorambucil. At median follow-up of 28·3 months (IQR 25·6-33·1), median progression-free survival was longer with acalabrutinib-obinutuzumab and acalabrutinib monotherapy, compared with obinutuzumab-chlorambucil (median not reached with acalabrutinib and obinutuzumab vs 22·6 months with obinutuzumab, hazard ratio [HR] 0·1; 95% CI 0·06-0·17, p<0·0001; and not reached with acalabrutinib monotherapy vs 22·6 months with obinutuzumab, 0·20; 0·13-0·3, p<0·0001). Estimated progression-free survival at 24 months was 93% with acalabrutinib-obinutuzumab (95% CI 87-96%), 87% with acalabrutinib monotherapy (81-92%), and 47% with obinutuzumab-chlorambucil (39-55%). The most common grade 3 or higher adverse event across groups was neutropenia (53 [30%] of 178 patients in the acalabrutinib-obinutuzumab group, 17 [9%] of 179 patients in the acalabrutinib group, and 70 [41%] of 169 patients in the obinutuzumab-chlorambucil group). All-grade infusion reactions were less frequent with acalabrutinib-obinutuzumab (24 [13%] of 178 patients) than obinutuzumab-chlorambucil (67 [40%] of 169 patients). Grade 3 or higher infections occurred in 37 (21%) patients given acalabrutinib-obinutuzumab, 25 (14%) patients given acalabrutinib monotherapy, and 14 (8%) patients given obinutuzumab-chlorambucil. Deaths occurred in eight (4%) patients given acalabrutinib-obinutuzumab, 12 (7%) patients given acalabrutinib, and 15 (9%) patients given obinutuzumab-chlorambucil. INTERPRETATION: Acalabrutinib with or without obinutuzumab significantly improved progression-free survival over obinutuzumab-chlorambucil chemoimmunotherapy, providing a chemotherapy-free treatment option with an acceptable side-effect profile that was consistent with previous studies. These data support the use of acalabrutinib in combination with obinutuzumab or alone as a new treatment option for patients with treatment-naive symptomatic chronic lymphocytic leukaemia. FUNDING: Acerta Pharma, a member of the AstraZeneca Group, and R35 CA198183 (to JCB).


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/administração & dosagem , Benzamidas/administração & dosagem , Clorambucila/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazinas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/efeitos adversos , Clorambucila/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Pirazinas/efeitos adversos
12.
Clin Drug Investig ; 40(6): 555-566, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32277364

RESUMO

BACKGROUND AND OBJECTIVE: Bentysrepinine (Y101), a derivative of repensine (a compound isolated from Dichondra repens Forst), is a novel phenylalanine dipeptide currently under development for the treatment of hepatitis B virus (HBV). The objectives of these studies were to assess the safety, tolerability and pharmacokinetics of bentysrepinine in healthy Chinese subjects. METHODS: Two randomised, double-blind, placebo-controlled trials evaluated a single oral dose (50-900 mg, study 01) and multiple doses (300 mg and 600 mg, study 02), and a randomised, open, crossover food-effect study (600 mg, study 03) of bentysrepinine was established. Safety and tolerability were assessed by adverse event (AE) reporting, clinical laboratory tests, physical examinations, vital sign monitoring and electrocardiogram (ECG). Plasma, urine and faecal samples were analysed using validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methods to investigate the pharmacokinetics of bentysrepinine. RESULTS: Ninety-four subjects were enrolled, and bentysrepinine was well tolerated. Mild and reversible AEs occurred for single and multiple oral doses between 50 and 900 mg. The most common adverse effects were increased alanine aminotransferase (ALT) and aspartate transaminase (AST). Other clinically significant AEs included nausea and elevated urine leukocytes, urine red blood cells, transaminase, creatine kinase, total cholesterol, triglycerides, and low-density cholesterol. There were no clinically significant changes in the ECG, vital signs or laboratory assessments during the studies. The maximum tolerated dose (MTD) was not reached in the dose escalation study. Bentysrepinine was rapidly absorbed and metabolised with a mean time to reach maximum concentration (Tmax) between 1-2 h and a mean terminal elimination half-life (t1/2) of approximately 1-3 h. In the single ascending dose study, the exposure including the area under the concentration-time curve (AUC) and the maximum plasma concentration (Cmax) of bentysrepinine generally increased in a dose-dependent but not dose-proportional manner in the 50-900 mg dose range. The urinary excretion and faecal excretion of unchanged bentysrepinine were 2.98% and 4.58% of the total dose, respectively. In the multiple-dose study, no accumulation was found after repeated administration at the 300 mg and 600 mg dose levels. The food-effect study using a 600 mg single dose showed that food intake has an obvious effect on the absorption of bentysrepinine from tablets. No experimental differences were found based on sex. CONCLUSION: Bentysrepinine exhibited acceptable safety and tolerability in healthy subjects in the dose range of 50-900 mg in both single- and multiple-dose studies. The drug did not exhibit linear pharmacokinetic characteristics. No accumulation was observed after the administration of multiple 300 and 600 mg doses. Bentysrepinine is extensively metabolised in the body. Food may increase its bioavailability. TRIALS REGISTRATION: CFDA registration numbers CTR20160096, CTR20160094, and CTR20140543 (www.chinadrugtrials.org.cn).


Assuntos
Antivirais/efeitos adversos , Benzamidas/administração & dosagem , Dipeptídeos/administração & dosagem , Adulto , Antivirais/administração & dosagem , Antivirais/farmacocinética , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Cromatografia Líquida , Estudos Cross-Over , Dipeptídeos/efeitos adversos , Dipeptídeos/farmacocinética , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Vírus da Hepatite B , Humanos , Masculino , Placebos , Espectrometria de Massas em Tandem
13.
J Oncol Pharm Pract ; 26(5): 1190-1199, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32279595

RESUMO

Mantle cell lymphoma is a rare subtype of B-cell non-Hodgkin's lymphomas that is generally classified as an aggressive lymphoma requiring front-line chemo-immunotherapy with stem cell rescue. Despite effective treatment, many patients relapse or are refractory to front-line therapy. In addition, these patients may also develop drug resistance requiring novel modalities for subsequent lines. Bruton's tyrosine kinase inhibitors have demonstrated a well-tolerated safety and efficacy profile across several B-cell malignancies. Ibrutinib, acalabrutinib, and zanubrutinib are FDA-approved as treatment options for patients with Mantle cell lymphoma following one prior line of therapy. Various factors should be considered which include the adverse event profile of these agents and ability to adhere to therapy. In this article, we review the role of Bruton's tyrosine kinase inhibitors for the management of Mantle cell lymphoma and review the clinical pharmacology, pharmacokinetics, safety and efficacy, and future directions.


Assuntos
Antineoplásicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Benzamidas/administração & dosagem , Humanos , Imunoterapia , Piperidinas/administração & dosagem , Pirazinas/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem
14.
Expert Opin Pharmacother ; 21(5): 567-580, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32286097

RESUMO

Introduction: Though many unanswered questions about the pathophysiology of Tourette Syndrome remain, several pharmacotherapies for tics have been studied, with varying results in terms of efficacy and the strength of evidence.Areas covered: This literature review encompasses pharmacotherapies for tics. The pharmacotherapies discussed in this review include: alpha agonists, antipsychotics, topiramate, botulinum toxin, and dopamine depleters.Expert opinion: Once the presence of tics is confirmed and psychoeducation and support are provided to patients and caregivers, one must examine the degree of tic-related impairment and the presence of psychiatric comorbidities. These factors influence treatment decisions as the presence of comorbidity and related impairment may shift the treatment target. When selecting a medication for tics, the presence of ADHD (the most frequent comorbidity) strengthens the case for choosing an alpha agonist. The case for antipsychotic medications is strongest when tic-related impairment is severe and/or the tics are refractory to more conservative measures. All medications require drug safety monitoring procedures and reevaluation over time.


Assuntos
Agonistas alfa-Adrenérgicos/uso terapêutico , Antipsicóticos/uso terapêutico , Transtornos de Tique/tratamento farmacológico , Tiques/tratamento farmacológico , Agonistas alfa-Adrenérgicos/administração & dosagem , Agonistas alfa-Adrenérgicos/efeitos adversos , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Benzamidas/uso terapêutico , Toxinas Botulínicas/administração & dosagem , Toxinas Botulínicas/efeitos adversos , Toxinas Botulínicas/uso terapêutico , Comorbidade , Humanos , Transtornos de Tique/epidemiologia , Transtornos de Tique/psicologia , Tiques/epidemiologia , Tiques/psicologia , Síndrome de Tourette/tratamento farmacológico , Síndrome de Tourette/epidemiologia , Síndrome de Tourette/psicologia
15.
Biochem Biophys Res Commun ; 525(3): 589-594, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32115150

RESUMO

Uveitis is a sight-threatening intraocular inflammatory disease that accounts for almost 10% of blindness worldwide. NF-κB signaling plays pivotal roles in inflammatory diseases. We have reported that IMD-0354, which inhibits NF-κB signaling via selective blockade of IKK-ß, suppresses inflammation in several ocular disease models. Here, we examined the therapeutic effect of IMD-0354 in an experimental autoimmune uveoretinitis (EAU) model, a well-established animal model for endogenous uveitis in humans. Systemic administration of IMD-0354 significantly suppressed the clinical and histological severity, inflammatory edema, and the translocation of NF-κB p65 into the nucleus of retinas in EAU mice. Furthermore, IMD-0354 treatment significantly inhibited the levels of several Th1/Th17-mediated pro-inflammatory cytokines in vitro. Our current data demonstrate that inhibition of IKKß with IMD-0354 ameliorates inflammatory responses in the mouse EAU model, suggesting that IMD-0354 may be a promising therapeutic agent for human endogenous uveitis.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Benzamidas/uso terapêutico , Quinase I-kappa B/antagonistas & inibidores , Retinite/tratamento farmacológico , Uveíte/tratamento farmacológico , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Benzamidas/administração & dosagem , Benzamidas/farmacologia , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Citocinas/biossíntese , Edema/complicações , Edema/patologia , Quinase I-kappa B/metabolismo , Inflamação/complicações , Inflamação/patologia , Masculino , Camundongos , NF-kappa B/metabolismo , Retinite/imunologia , Retinite/patologia , Índice de Gravidade de Doença , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Uveíte/imunologia , Uveíte/patologia
16.
Toxicol Appl Pharmacol ; 395: 114971, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32217144

RESUMO

MS-275 has been demonstrated to inhibit the growth of esophageal squamous cell carcinoma (ESCC) cells in our previous study, but its role in ESCC remains to be further explored. Cisplatin (cis-diamminedichloroplatinum II, DDP) is the first-line chemotherapeutic drug widely used in clinic for ESCC patients. However, the side effects of nephrotoxicity and drug resistance limit its clinical use. This study aimed to evaluate the anticancer effects of MS-275 combined with DDP on ESCC cell line EC9706 both in vitro and in vivo, and to investigate the possible mechanisms that mediate these effects. We found that MS-275 combined with DDP showed synergistic antitumor effects on EC9706 cells in vitro by decreasing cell proliferation, increasing apoptosis and oxidative damage, and inhibiting migration and stemness. The combination of MS-275 and DDP triggered pro-survival autophagy in EC9706. Moreover, MS-275 combined with DDP suppressed EC9706 xenografts growth and promoted apoptosis in vivo. Further study displayed that MS-275 combined with DDP suppressed Wnt/ß-catenin signaling in EC9706 cells and xenografts. These results indicate that MS-275 combined with DDP exerts synergistic antitumor effects by enhancing the chemosensitivity of EC9706 cells to DDP, which may be a potential therapeutic strategy for the treatment of patients with ESCC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzamidas/administração & dosagem , Cisplatino/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Piridinas/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Headache Pain ; 21(1): 20, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32093628

RESUMO

BACKGROUND: Migraine is recognized as the second leading cause of disability globally. Lasmiditan is a novel, selective serotonin 5-HT1F receptor agonist developed for acute treatment of migraine. Here we analyzed effects of lasmiditan on migraine disability assessed with the Migraine Disability Assessment (MIDAS) scale for interim data from a long-term safety study. METHODS: Completers of two single-attack parent studies were offered participation in the 1 year GLADIATOR study, that randomized participants to treatment with lasmiditan 100 mg or 200 mg taken as needed for migraine attacks of at least moderate severity. Changes in MIDAS were modeled using a mixed model repeated measures analysis. RESULTS: The sample included 1978 patients who received ≥1 lasmiditan dose and were followed for a median of 288 days. Baseline mean MIDAS scores for the lasmiditan 100-mg and 200-mg groups were 29.4 and 28.9, respectively, indicating severe migraine-related disability. Relative to baseline, MIDAS total scores were significantly lower at 3, 6, 9, and 12 months for both dose groups. At 12 months, changes in MIDAS scores were - 12.5 and - 12.2 for lasmiditan 100 mg and 200 mg, respectively, with 49% and 53% of patients, respectively, achieving at least a 50% decrease in MIDAS total score. Statistically significant improvements were also seen for work and/or school absenteeism and presenteeism, monthly headache days, and mean headache pain intensity at all time points up to 1 year. Findings for patients who completed all visits versus those dropping out early were similar. Responses were generally similar for the lasmiditan 100 mg or 200 mg doses, between subgroups defined based on the number of baseline monthly migraine attacks (≤5 vs. >5), and also between subgroups defined by pain-free response (yes/no) during initial attacks. CONCLUSIONS: Long-term treatment with lasmiditan was associated with significant reductions in migraine-related disability, including both work or school absenteeism and presenteeism. The similarity of responses in completers and those who dropped out suggests that selective attrition does not account for the improvements. Benefits were significant at 3 months and maintained through 12 months. TRIAL REGISTRATION: clinicaltrials.govNCT02565186; first posted October 1, 2015.


Assuntos
Benzamidas/administração & dosagem , Avaliação da Deficiência , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Agonistas do Receptor de Serotonina/administração & dosagem , Absenteísmo , Adulto , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/psicologia , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
19.
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
20.
Eur J Pharmacol ; 867: 172838, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31794709

RESUMO

Dopamine, a neurotransmitter with 5 receptor subtypes, is critical to the dependence-forming properties of drugs of abuse. The role of the dopamine D4 receptor subtype in substance use disorders has remained somewhat elusive but the recent development of selective ligands holds promise for future investigations of this receptor subtype in substance use disorders, including alcohol use disorder. The purpose of the present study was to further elucidate the effects of a selective antagonist (L-745,870) and agonist (PD 168,077) on alcohol self-administration and reinstatement induced either by cues or stress. It was found that the D4 antagonist, but not agonist, reduced alcohol intake at the highest doses. Further, the D4 antagonist reduced stress-induced reinstatement, with no effects on cue-induced reinstatement; the agonist was without effect on either form of reinstatement. The dopamine D4 receptor antagonist was without effect on food reinforcement. This work deepens existing lines of evidence that the dopamine D4 receptor is involved in substance use disorders and suggests that dopamine D4 receptor blockade diminishes motivation for alcohol-taking without influencing natural food rewards. Furthermore, there appears to be a plausible effect of dopamine D4 receptor blockade interfering with stress- but not cue-induced alcohol-seeking.


Assuntos
Alcoolismo/tratamento farmacológico , Antagonistas de Dopamina/administração & dosagem , Dopamina/metabolismo , Etanol/efeitos adversos , Receptores de Dopamina D4/antagonistas & inibidores , Alcoolismo/etiologia , Alcoolismo/metabolismo , Alcoolismo/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Benzamidas/administração & dosagem , Condicionamento Operante/efeitos dos fármacos , Sinais (Psicologia) , Modelos Animais de Doenças , Agonistas de Dopamina/administração & dosagem , Comportamento de Procura de Droga/efeitos dos fármacos , Etanol/administração & dosagem , Extinção Psicológica/efeitos dos fármacos , Humanos , Masculino , Piperazinas/administração & dosagem , Piridinas/administração & dosagem , Pirróis/administração & dosagem , Ratos , Receptores de Dopamina D4/agonistas , Receptores de Dopamina D4/metabolismo , Autoadministração , Estresse Psicológico/complicações , Estresse Psicológico/psicologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...