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1.
Trials ; 21(1): 691, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32736596

RESUMO

OBJECTIVES: Stage 1: To evaluate the safety and efficacy of candidate agents as add-on therapies to standard of care (SoC) in patients hospitalised with COVID-19 in a screening stage. Stage 2: To confirm the efficacy of candidate agents selected on the basis of evidence from Stage 1 in patients hospitalised with COVID-19 in an expansion stage. TRIAL DESIGN: ACCORD is a seamless, Phase 2, adaptive, randomised controlled platform study, designed to rapidly test candidate agents in the treatment of COVID-19. Designed as a master protocol with each candidate agent being included via its own sub-protocol, initially randomising equally between each candidate and a single contemporaneous SoC arm (which can adapt into 2:1). Candidate agents currently include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin. For each candidate a total of 60 patients will be recruited in Stage 1. If Stage 1 provides evidence of efficacy and acceptable safety the candidate will enter Stage 2 where a total of approximately 126 patients will be recruited into each study arm sub-protocol. Enrollees and outcomes will not be shared across the Stages; the endpoint, analysis and sample size for Stage 2 may be adjusted based on evidence from Stage 1. Additional arms may be added as new potential candidate agents are identified via candidate agent specific sub-protocols. PARTICIPANTS: The study will include hospitalised adult patients (≥18 years) with confirmed SARS-CoV-2 infection, the virus that causes COVID-19, that clinically meet Grades 3 (hospitalised - mild disease, no oxygen therapy), Grades 4 (hospitalised, oxygen by mask or nasal prongs) and 5 (hospitalised, non-invasive ventilation or high flow oxygen) of the WHO Working Group on the Clinical Characteristics of COVID-19 9-point category ordinal scale. Participants will be recruited from England, Northern Ireland, Wales and Scotland. INTERVENTION AND COMPARATOR: Comparator is current standard of care (SoC) for the treatment of COVID-19. Current candidate experimental arms include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin with others to be added over time. Bemcentinib could potentially reduce viral infection and blocks SARS-CoV-2 spike protein; MEDI3506 is a clinic-ready anti-IL-33 monoclonal antibody with the potential to treat respiratory failure caused by COVID; acalabrutinib is a BTK inhibitor which is anti-viral and anti-inflammatory; zilucoplan is a complement C5 inhibitor which may block the severe inflammatory response in COVID-19 and; nebulised heparin has been shown to bind with the spike protein. ACCORD is linked with the UK national COVID therapeutics task force to help prioritise candidate agents. MAIN OUTCOMES: Time to sustained clinical improvement of at least 2 points (from randomisation) on the WHO 9-point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29 (this will also define the "responder" for the response rate analyses). RANDOMISATION: An electronic randomization will be performed by Cenduit using Interactive Response Technology (IRT). Randomisation will be stratified by baseline severity grade. Randomisation will proceed with an equal allocation to each arm and a contemporaneous SoC arm (e.g. 1:1 if control and 1 experimental arm; 1:1:1 if two experimental candidate arms etc) but will be reviewed as the trial progresses and may be changed to 2:1 in favour of the candidate agents. BLINDING (MASKING): The trial is open label and no blinding is currently planned in the study. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This will be in the order of 60 patients per candidate agent for Stage 1, and 126 patients for Stage 2. However, sample size re-estimation may be considered after Stage 1. It is estimated that up to 1800 patients will participate in the overall study. TRIAL STATUS: Master protocol version ACCORD-2-001 - Master Protocol (Amendment 1) 22nd April 2020, the trial has full regulatory approval and recruitment is ongoing in the bemcentinib (first patient recruited 6/5/2020), MEDI3506 (first patient recruited 19/5/2020), acalabrutinib (first patient recruited 20/5/2020) and zilucoplan (first patient recruited 19/5/2020) candidates (and SoC). The recruitment dates of each arm will vary between candidate agents as they are added or dropped from the trial, but will have recruited and reported within a year. TRIAL REGISTRATION: EudraCT 2020-001736-95 , registered 28th April 2020. FULL PROTOCOL: The full protocol (Master Protocol with each of the candidate sub-protocols) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Antivirais/efeitos adversos , Benzamidas/uso terapêutico , Hospitalização , Humanos , Pandemias , Pirazinas/uso terapêutico , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Padrão de Cuidado
2.
Life Sci ; 258: 118179, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32758626

RESUMO

OBJECTIVE: To evaluate whether approved gastroprokinetic agent, acotiamide exerts a direct excitatory effect on bladder to help explain the reported meaningful reduction of post-void residual urine volume (PVR) in detrusor underactivity (DU) patients after thrice daily oral intake of acotiamide 100 mg for 2 weeks. METHODS: Effect of acotiamide [1-16 µM] was assessed on nerve-mediated contractions evoked by electrical field stimulation (EFS) for 5 s with 5 ms pulse trains of 10 V in longitudinal, mucosa intact rat and human bladder strips to construct frequency response curve (1-32 Hz) and repeat 10 Hz stimulation at 60s interval. Effect of acotiamide 2 µM on spontaneous and carbachol evoked contractions was also assessed. RESULTS: Acotiamide 2 µM significantly enhanced the Atropine and Tetrodotoxin (TTX)-sensitive EFS evoked contractions of rat and human bladder at 8-32 Hz (Two-way ANOVA followed Sidak's multiple comparison; *p < 0.01) and on repeat 10 Hz stimulation (Paired Student's t-test; *p < 0.05), while producing a modest effect on the spontaneous contractions and a negligible effect on the carbachol evoked contractions. CONCLUSIONS: Enhancement of TTX-sensitive evoked contractions of rat and human bladder by acotiamide is consistent with the enhancement of excitatory neuro-effector transmission mainly through prejunctional mechanisms. Findings highlight immense therapeutic potential of antimuscarinics with low M3 receptor affinity like acotiamide in Underactive bladder (UAB)/DU treatment.


Assuntos
Benzamidas/uso terapêutico , Tiazóis/uso terapêutico , Bexiga Inativa/tratamento farmacológico , Bexiga Urinária/patologia , Animais , Benzamidas/química , Benzamidas/farmacologia , Carbacol/farmacologia , Estimulação Elétrica , Humanos , Masculino , Contração Muscular/efeitos dos fármacos , Ratos Sprague-Dawley , Tiazóis/química , Tiazóis/farmacologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/inervação
3.
Nat Commun ; 11(1): 3344, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620751

RESUMO

Diamond Blackfan Anemia (DBA) is a congenital bone marrow failure syndrome associated with ribosomal gene mutations that lead to ribosomal insufficiency. DBA is characterized by anemia, congenital anomalies, and cancer predisposition. Treatment for DBA is associated with significant morbidity. Here, we report the identification of Nemo-like kinase (NLK) as a potential target for DBA therapy. To identify new DBA targets, we screen for small molecules that increase erythroid expansion in mouse models of DBA. This screen identified a compound that inhibits NLK. Chemical and genetic inhibition of NLK increases erythroid expansion in mouse and human progenitors, including bone marrow cells from DBA patients. In DBA models and patient samples, aberrant NLK activation is initiated at the Megakaryocyte/Erythroid Progenitor (MEP) stage of differentiation and is not observed in non-erythroid hematopoietic lineages or healthy erythroblasts. We propose that NLK mediates aberrant erythropoiesis in DBA and is a potential target for therapy.


Assuntos
Anemia de Diamond-Blackfan/patologia , Células-Tronco Hematopoéticas/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Anemia de Diamond-Blackfan/dietoterapia , Anemia de Diamond-Blackfan/genética , Animais , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células , Células Cultivadas , Dioxóis/farmacologia , Dioxóis/uso terapêutico , Modelos Animais de Doenças , Eritropoese/efeitos dos fármacos , Eritropoese/genética , Humanos , Camundongos , Camundongos Transgênicos , Mutação , Cultura Primária de Células , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , RNA Interferente Pequeno/metabolismo , Proteínas Ribossômicas/genética
5.
Sci Immunol ; 5(48)2020 06 05.
Artigo em Inglês | MEDLINE | ID: covidwho-545978

RESUMO

Patients with severe COVID-19 have a hyperinflammatory immune response suggestive of macrophage activation. Bruton tyrosine kinase (BTK) regulates macrophage signaling and activation. Acalabrutinib, a selective BTK inhibitor, was administered off-label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen; 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10-14 day treatment course, acalabrutinib improved oxygenation in a majority of patients, often within 1-3 days, and had no discernable toxicity. Measures of inflammation - C-reactive protein and IL-6 - normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4/8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2/8 (25%) discharged on room air. Ex vivo analysis revealed significantly elevated BTK activity, as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. These results suggest that targeting excessive host inflammation with a BTK inhibitor is a therapeutic strategy in severe COVID-19 and has led to a confirmatory international prospective randomized controlled clinical trial.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/metabolismo , Idoso , Idoso de 80 Anos ou mais , Infecções por Coronavirus/virologia , Estado Terminal , Feminino , Seguimentos , Humanos , Inflamação/tratamento farmacológico , Inflamação/virologia , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Pandemias , Pneumonia Viral/virologia , Estudos Prospectivos , Respiração Artificial , Resultado do Tratamento
6.
Sci Immunol ; 5(48)2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503877

RESUMO

Patients with severe COVID-19 have a hyperinflammatory immune response suggestive of macrophage activation. Bruton tyrosine kinase (BTK) regulates macrophage signaling and activation. Acalabrutinib, a selective BTK inhibitor, was administered off-label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen; 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10-14 day treatment course, acalabrutinib improved oxygenation in a majority of patients, often within 1-3 days, and had no discernable toxicity. Measures of inflammation - C-reactive protein and IL-6 - normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4/8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2/8 (25%) discharged on room air. Ex vivo analysis revealed significantly elevated BTK activity, as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. These results suggest that targeting excessive host inflammation with a BTK inhibitor is a therapeutic strategy in severe COVID-19 and has led to a confirmatory international prospective randomized controlled clinical trial.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/metabolismo , Idoso , Idoso de 80 Anos ou mais , Infecções por Coronavirus/virologia , Estado Terminal , Feminino , Seguimentos , Humanos , Inflamação/tratamento farmacológico , Inflamação/virologia , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Pandemias , Pneumonia Viral/virologia , Estudos Prospectivos , Respiração Artificial , Resultado do Tratamento
7.
Drugs Today (Barc) ; 56(6): 377-387, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32525136

RESUMO

Epigenetic alterations contributing to malignancy have become a more prominent field of investigation over the past several years, as several hallmarks of cancer are substantially altered by changes in the epigenome. Enhancer of zeste homologue 2 (EZH2), an enzyme involved in silencing the transcription of various genes, is overexpressed or mutated in multiple cancers and can lead to proliferation of dedifferentiated cells. Both gain-of-function and loss-of-function mutations have been noted in hematologic cancers, with gain-of-function mutations prevalent among non-Hodgkin lymphomas. Tazemetostat is a first-in-class EZH2 inhibitor developed to target this overexpression. Phase I trials have shown it is generally well tolerated and efficacious in solid tumors as well as hematological malignancies. Tazemetostat was approved by the U.S. Food and Drug Administration (FDA) for use in epithelioid sarcoma in January 2020 on the basis of the results of a recent phase II trial, but with several clinical trials ongoing, the use of tazemetostat for hematological malignancies is a promising avenue for treatment.


Assuntos
Benzamidas/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias/tratamento farmacológico , Piridonas/uso terapêutico , Ensaios Clínicos como Assunto , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Epigênese Genética , Inativação Gênica , Humanos
8.
J Headache Pain ; 21(1): 66, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503415

RESUMO

BACKGROUND: Migraine has been recognized as one of common diseases in the world whose current treatment options are not ideal. Lasmiditan, an oral 5-hydroxytryptamine (HT)1F receptor agonist, appears more promising for the acute treatment of migraine because of considerably better effect profiles with no severe adverse events (AEs). This review aimed to systematically evaluate the efficacy and safety of lasmiditan from the results of randomized controlled trials (RCTs). METHODS: PubMed, Cochrane Library, Embase were searched on lasmiditan for the acute treatment of migraine from inception of the databases to Feb 1, 2020. Pain free and pain relief, global impression (very much/much better), and no/mild disability at 2 h in efficacy; total treatment-emergent adverse events (TEAEs), dizziness, nausea, fatigue, paraesthesia and somnolence in safety were extracted from the included studies. A systematic review and meta-analysis was performed using Review Manager Software version 5.3 (RevMan 5.3). RESULTS: Four RCTs with a total of 4960 subjects met our inclusion criteria. The overall effect estimate showed that lasmiditan was significantly superior to placebo in terms of pain free (RR 1.71, 95% CI 1.55-1.87), pain relief (RR 1.40, 95% CI 1.33-1.47), global impression (very much/much better) (RR 1.55, 95% CI 1.44-1.67), and no/mild disability (RR 1.15, 95% CI 1.10-1.20) at 2 h. For the safety, significant number of patients experienced TEAEs with lasmiditan than with placebo (RR 2.77, 95% CI 2.53-3.03), most TEAEs were central nervous system (CNS)-related and included dizziness (RR 5.81, 95% CI 4.72-7.14), nausea (RR 2.58, 95% CI 1.87-3.57), fatigue (RR 5.38, 95% CI 3.78-7.66), paraesthesia (RR 4.48, 95% CI 3.33-6.02), and somnolence (RR 2.82, 95% CI 2.18-3.66). CONCLUSIONS: This meta-analysis suggests that lasmiditan is effective for the acute treatment of migraine with a higher incidence of CNS-related adverse reactions compared with placebo. Long-term, open-label, multi-dose trials are required to verify the current findings.


Assuntos
Benzamidas/uso terapêutico , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Receptores de Serotonina/fisiologia , Agonistas do Receptor de Serotonina/uso terapêutico , Benzamidas/efeitos adversos , Tontura/induzido quimicamente , Humanos , Náusea/induzido quimicamente , Piperidinas/efeitos adversos , Piridinas/efeitos adversos , Agonistas do Receptor de Serotonina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Vertigem/induzido quimicamente
9.
Adv Exp Med Biol ; 1257: 75-83, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32483732

RESUMO

The prognosis for metastatic osteosarcoma (OS) is poor and has not changed in several decades. Therapeutic paradigms that target and exploit novel molecular pathways are desperately needed. Recent preclinical data suggests that modulation of the Fas/FasL pathway may offer benefit in the treatment of refractory osteosarcoma. Fas and FasL are complimentary receptor-ligand proteins. Fas is expressed in multiple tissues, whereas FasL is restricted to privilege organs, such as the lung. Fas expression has been shown to inversely correlate with the metastatic potential of OS cells; tumor cells which express high levels of Fas have decreased metastatic potential and the ones that reach the lung undergo cell death upon interaction with constitutive FasL in the lung. Agents such as gemcitabine and the HDAC inhibitor, entinostat/Syndax 275, have been shown to upregulate Fas expression on OS cells, potentially leading to decreased OS pulmonary metastasis and improved outcome. Clinical trials are in development to evaluate this combination as a potential treatment option for patients with refractory OS.


Assuntos
Benzamidas , Neoplasias Ósseas , Osteossarcoma , Piridinas , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/enzimologia , Proteína Ligante Fas/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/enzimologia , Piridinas/farmacologia , Piridinas/uso terapêutico
10.
PLoS One ; 15(6): e0234617, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555665

RESUMO

Semicarbazide-sensitive amine oxidase (SSAO) is an enzyme with a unique dual function in controlling inflammation as well as reactive oxygen species (ROS) generation. We have demonstrated benefit of SSAO inhibition in acute kidney fibrosis. However the function of SSAO in chronic kidney disease (CKD) and diabetic kidney disease (DKD) is yet to be determined. We aimed to assess the effectiveness of a SSAO inhibitor (SSAOi; PXS-4728A) as an antifibrotic agent using a diabetic model of CKD. Diabetic mice were treated with SSAOi for 24 weeks and outcomes compared with untreated diabetic mice and telmisartan treated animals as a standard of care comparator. Extracellular matrix markers, fibronectin and oxidative stress, were downregulated in diabetic mice treated with SSAOi compared with untreated diabetic mice. Expression of the pan-leukocyte marker CD45 was also supressed by SSAOi. SSAO inhibition in diabetic mice resulted in a significant reduction in glomerulosclerosis and associated albuminuria compared to untreated diabetic mice. However, the effect of SSAO inhibition was less obvious in the tubulointerstitial compartment than in the glomeruli. Therefore, SSAO may be a potential target for diabetic glomerulosclerosis.


Assuntos
Albuminúria/tratamento farmacológico , Alilamina/análogos & derivados , Amina Oxidase (contendo Cobre)/antagonistas & inibidores , Benzamidas/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Glomérulos Renais/patologia , Túbulos Renais/patologia , Insuficiência Renal Crônica/tratamento farmacológico , Alilamina/farmacologia , Alilamina/uso terapêutico , Animais , Benzamidas/farmacologia , Diabetes Mellitus Experimental , Nefropatias Diabéticas/patologia , Inibidores Enzimáticos/farmacologia , Fibronectinas/metabolismo , Fibrose , Glomérulos Renais/efeitos dos fármacos , Túbulos Renais/efeitos dos fármacos , Antígenos Comuns de Leucócito/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal Crônica/patologia , Telmisartan/farmacologia , Telmisartan/uso terapêutico
11.
Am J Med ; 133 Suppl 1: 1-27, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32362349

RESUMO

Hospitalized patients with acute medical illnesses are at risk for venous thromboembolism (VTE) during and after a hospital stay. Risk factors include physical immobilization and underlying pathophysiologic processes that activate the coagulation pathway and are still present after discharge. Strategies for optimal pharmacologic VTE thromboprophylaxis are evolving, and recommendations for VTE prophylaxis can be further refined to protect high-risk patients after hospital discharge. An early study of extended VTE prophylaxis with a parenteral agent in medically ill patients yielded inconclusive results with regard to efficacy and bleeding. In the Acute Medically Ill VTE Prevention with Extended Duration Betrixaban (APEX) trial, extended use of betrixaban halved symptomatic VTE, decreased hospital readmission, and reduced stroke and major adverse cardiovascular events compared with standard enoxaparin prophylaxis. Based on findings from APEX, the Food and Drug Administration approved betrixaban in 2017 for extended VTE prophylaxis in acute medically ill patients. In the Reducing Post-Discharge Venous Thrombo-Embolism Risk (MARINER) study, extended use of rivaroxaban halved symptomatic VTE in high-risk medical patients compared with placebo. In 2019, rivaroxaban was approved for extended thromboprophylaxis in high-risk medical patients, thus making available a new strategy for in-hospital and post-discharge VTE prevention. To address the critical unmet need for VTE prophylaxis in medically ill patients at the time of hospital discharge, the North American Thrombosis Forum (NATF) is launching the Anticoagulation Action Initiative, a comprehensive consensus document that provides practical guidance and straightforward, patient-centered recommendations for VTE prevention during hospitalization and after discharge.


Assuntos
Anticoagulantes/uso terapêutico , Tromboembolia Venosa/prevenção & controle , Adulto , Idoso , Benzamidas/uso terapêutico , Hospitalização , Humanos , Adesão à Medicação , Pessoa de Meia-Idade , Alta do Paciente , Guias de Prática Clínica como Assunto , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Piridonas/uso terapêutico , Medição de Risco , Fatores de Risco , Rivaroxabana/uso terapêutico , Tromboembolia Venosa/etiologia
12.
Zhonghua Xue Ye Xue Za Zhi ; 41(4): 292-296, 2020 Apr 14.
Artigo em Chinês | MEDLINE | ID: mdl-32447932

RESUMO

Objective: To explore the effect and mechanism of low-dose chidamide on the treatment of primary immune thrombocytopenia (ITP) . Methods: Passive ITP animal model and active ITP animal model were established by C57BL/6J mice. Different doses of chidamide (0, 0.01, 0.1, 0.5, and 5 mg/kg) were orally administrated twice a week for 120 hours in passive ITP mice. Secondly, low-dose chidamine (0.1 mg/kg) was given intragastrically administrated twice a week in active ITP mice. The platelet counts in the peripheral blood before and after treatment were detected. Four weeks later, mice were executed to prepare splenocyte suspension; natural regulatory T cells (CD4(+)CD25(+)Foxp3(+) nTreg cells) in splenocyte suspension were detected by flow cytometry. Serum IL-6 was measured by ELISA. Peripheral blood mononuclear cells from ITP patients were co-cultured with low-dose chidamide in vitro. After incubation for 72 hours, CD4(+)CD25(+)Foxp3(+) Treg cells of mononuclear cells was detected. CD4(+)CD25(+) Treg cells and CD4(+)CD25(-) effector T cells were separated by immunomagnetic beads. The Treg cells and effector T cells were co cultured in a ratio of 1∶4, and treated with low-dose chidamide. The proliferation of effector T cells was detected. Results: Chidamide with low dose (0.1 mg/kg) significantly improved platelet counts in passive ITP mouse model, as well as in the ITP active mouse model and reduced the mortality related to bleeding. Low-dose chidamide significantly increased the number and proportion of nTreg cells in mouse splenocytes, and decreased serum IL-6 level in active ITP mice. In ITP patients, low-dose chidamide also significantly expanded Treg cells in the PBMC culture system. Besides, the proliferation of effector T cells was suppressed. Conclusion: Low-dose chidamide enhances the proliferation of CD4(+)CD25(+)Foxp3(+) regulatory T cells to mediate immunosuppressive function. Serum IL-6 is inhibited for further immune tolerance. In vivo animal study suggestes that low-dose chidamide has a novel therapeutic effect on ITP.


Assuntos
Aminopiridinas/uso terapêutico , Benzamidas/uso terapêutico , Púrpura Trombocitopênica Idiopática , Animais , Fatores de Transcrição Forkhead , Humanos , Leucócitos Mononucleares , Camundongos , Camundongos Endogâmicos C57BL , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Linfócitos T Reguladores
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.
Medicine (Baltimore) ; 99(16): e19758, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32311977

RESUMO

BACKGROUND: Functional dyspepsia (FD) is a highly prevalent functional gastrointestinal disorder which brings a significant impact on patients' quality of life. Although there are many available treatments to alleviate dyspepsia symptoms, most of them are far from satisfactory. Traditional Chinese medicine (TCM) has shown good potential in the treatment of FD, especially in terms of improving symptoms and adverse effects of Western medicine. Qizhi Weitong granule (QZWTG), a TCM preparation, has been utilized in treating FD for a long time and has achieved good clinical results. However, the existing evidence of its efficacy and mechanism of action is insufficient. Hence, the purpose of this study is to evaluate the efficacy and safety of QZWTG in the treatment of FD. METHODS: This study is a multicenter, randomized, double-blinded, double-placebo, positive drug parallel controlled clinical study. The experiment will be carried out in 8 hospitals at the same time, and a total of 384 cases of participants will be randomly assigned to the experimental group and the control group (n = 192). The experimental group will be given QZWTG and Mosapride citrate tablet placebo, and the control group will be given QZWTG placebo and Mosapride citrate tablet. After 4 weeks of intervention and 2 weeks of follow-up, the efficacy and safety of QZWTG in patients with FD will be observed. The primary outcomes are the change in the main symptom score. The secondary outcomes include TCM syndrome evaluation, the change of the Hamilton anxiety scale and the Hamilton depression scale, and advanced events. This study will explore the biological mechanism of QZWTG in the treatment of FD through the results of blood and urine metabolomics. DISCUSSION: This trial will provide first-hand evidence on whether QZWTG is noninferior to Mosapride citrate tablet. There will be a new option for the treatment of FD if noninferiority is set up. In addition, the efficacy and safety of QZWTG in the treatment of FD will be evaluated, and the mechanism of QZWTG in the treatment of FD will be explored through the metabolomics of blood and urine. On the other hand, as far as we know, this study may be the largest trial of efficacy and safety of QZWTG in the treatment of FD, which has important application value.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Dispepsia/tratamento farmacológico , Benzamidas/uso terapêutico , Método Duplo-Cego , Fármacos Gastrointestinais/uso terapêutico , Humanos , Morfolinas/uso terapêutico , Fitoterapia
17.
Expert Opin Pharmacother ; 21(9): 997-1004, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32237914

RESUMO

INTRODUCTION: In chronic obstructive pulmonary disease (COPD), inhaled long-acting antimuscarinic agents (LAMA) are effective maintenance therapies used across all severity stages of the disease. Most of them are administered via dry powder inhalers, but these devices require a potent inspiratory flow which cannot be effectively achieved by patients with advanced disease. In such patients, inhaled therapy via nebulization might be an option. AREAS COVERED: Revefenacin is a LAMA that was specifically formulated for once daily nebulization and which was authorized by the FDA as a maintenance therapy for COPD. In phase II and III clinical studies discussed in this review, revefenacin demonstrated its rapid onset of action and sustained effect on lung function on both a short- and long-term basis. EXPERT OPINION: Nebulized revefenacin with once daily use does not require any particular effort of administration and hence can be used by patients with severe airways obstruction or by those having milder cognitive deficits. Further studies are needed, however, to better document the long-term cardiovascular safety and its ability to reduce the exacerbation rate.


Assuntos
Benzamidas/uso terapêutico , Carbamatos/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Benzamidas/farmacocinética , Benzamidas/farmacologia , Carbamatos/farmacocinética , Carbamatos/farmacologia , Humanos , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacologia
18.
Clin Cancer Res ; 26(14): 3514-3516, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32345646

RESUMO

As the SARS-CoV-2 (COVID-19) pandemic spreads and the number of Bruton's tyrosine kinase inhibitor (BTKi)-treated COVID-19-affected patients grows, we must consider the pros and cons of BTKi discontinuation for our patients. In favor of BTKi continuation, BTK plays an active role in macrophage polarization. By modulating key transcription factors, BTK may regulate macrophage polarization downstream of classic M1 and M2 polarizing stimuli and mitigate the hyperinflammatory state associated with COVID-19. In favor of BTKi discontinuation, we note a potentially increased risk of secondary infections and impaired humoral immunity. We hypothesize that the potential benefit of blunting a hyperinflammatory response to SARS-CoV-2 through attenuation of M1 polarization outweighs the potential risk of impaired humoral immunity, not to mention the risk of rapid progression of B-cell malignancy following BTKi interruption. On the basis of this, we suggest continuing BTKi in patients with COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Anti-Inflamatórios/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/patologia , Humanos , Inflamação/prevenção & controle , Macrófagos/imunologia , Pandemias , Piperidinas/uso terapêutico , Pneumonia Viral/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Pirazinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico
19.
Nat Med ; 26(5): 760-768, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32231295

RESUMO

The National Institute of Mental Health (NIMH) 'fast-fail' approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n = 45) and placebo (n = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F(1,86) = 5.58, P < 0.01; effect size = 0.58 (95% confidence interval, 0.13-0.99)). JNJ-67953964, generally well tolerated, was not associated with any serious adverse events. This study supports proceeding with assessment of the clinical impact of target engagement and serves as a model for implementing the 'fast-fail' approach.


Assuntos
Anedonia/efeitos dos fármacos , Benzamidas/uso terapêutico , Transtornos do Humor/tratamento farmacológico , Antagonistas de Entorpecentes/uso terapêutico , Pirrolidinas/uso terapêutico , Receptores Opioides kappa/antagonistas & inibidores , Adulto , Transtornos de Ansiedade/complicações , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/psicologia , Fármacos do Sistema Nervoso Central/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/complicações , Transtornos do Humor/psicologia , Estudo de Prova de Conceito , Fatores de Tempo , Resultado do Tratamento
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