RESUMEN
Importance: Delirium is common among older hospitalized adults. In addition to presenting immediate management issues, delirium can increase the long-term risk of dementia, institutionalization, and mortality. Delirium is associated with disrupted sleep, and prior studies suggest that some specific sleep-promoting agents may reduce delirium. Objective: To evaluate the orexin receptor antagonist suvorexant for reducing delirium in older adults at high risk for delirium after hospitalization. Design, Setting, and Participants: This double-blind, placebo-controlled, phase 3 randomized clinical trial was conducted at 50 hospitals in Japan between October 22, 2020, and December 23, 2022. The study population included Japanese adults aged 65 to 90 years who were at high risk for delirium (mild cognitive impairment or mild dementia, history of delirium at prior hospitalization, or both) and had been hospitalized for acute disease or elective surgery. Data analysis was performed between January 23 and March 13, 2023. Intervention: Participants were randomized 1:1 to suvorexant (15 mg) or placebo taken at bedtime for up to 7 days while in the hospital. Main Outcomes and Measures: Delirium, the primary end point, was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria while participants were hospitalized. The treatment difference in the proportion of participants with delirium was analyzed. Results: This study included 203 participants: 101 were treated with suvorexant (mean [SD] age, 81.5 [4.5]; years; 52 men [51.5%] and 49 women [48.5%]) and 102 received placebo (mean [SD] age, 82.0 [4.9] years; 45 men [44.1%] and 57 women [55.9%]). There were 17 participants with delirium (16.8%) in the suvorexant group compared with 27 (26.5%) in the placebo group (difference, -8.7% [95% CI, -20.1% to 2.6%]; P = .13). Adverse events were similar between the 2 groups. Conclusions and Relevance: In this randomized clinical trial of suvorexant in older adults at high risk for delirium after hospitalization, fewer participants taking suvorexant had delirium compared with placebo, but the difference was not statistically significant. Further studies are needed to determine whether suvorexant may be useful for reducing delirium, particularly delirium with a hyperactive component, in this population. Trial Registration: ClinicalTrials.gov Identifier: NCT04571944.
Asunto(s)
Azepinas , Delirio , Hospitalización , Triazoles , Humanos , Anciano , Masculino , Femenino , Delirio/tratamiento farmacológico , Delirio/prevención & control , Anciano de 80 o más Años , Método Doble Ciego , Hospitalización/estadística & datos numéricos , Triazoles/uso terapéutico , Azepinas/uso terapéutico , Antagonistas de los Receptores de Orexina/uso terapéutico , Japón , Fármacos Inductores del Sueño/uso terapéuticoRESUMEN
OBJECTIVE: This study aimed to elucidate the molecular mechanisms by which BRD4 play a role in atrial fibrillation (AF). METHODS AND RESULTS: We used a discovery-driven approach to detect BRD4 expression in the atria of patients with AF and in various murine models of atrial fibrosis. We used a BRD4 inhibitor (JQ1) and atrial fibroblast (aFB)-specific BRD4-knockout mice to elucidate the role of BRD4 in AF. We further examined the underlying mechanisms using RNA-seq and ChIP-seq analyses in vitro, to identify key downstream targets of BRD4. We found that BRD4 expression is significantly increased in patients with AF, with accompanying atrial fibrosis and aFB differentiation. We showed that JQ1 treatment and shRNA-based molecular silencing of BRD4 blocked ANG-II-induced extracellular matrix production and cell-cycle progression in aFBs. BRD4-related RNA-seq and ChIP-seq analyses in aFBs demonstrated enrichment of a subset of promoters related to the expression of profibrotic and proliferation-related genes. The pharmacological inhibition of BRD4 in vivo or in aFB-specific BRD4-knockout in mice limited ANG-II-induced atrial fibrosis, atrial enlargement, and AF susceptibility. CONCLUSION: Our findings suggest that BRD4 plays a key role in pathological AF, at least partially by activating aFB proliferation and ECM synthesis. This study provides mechanistic insights into the development of BRD4 inhibitors as targeted antiarrhythmic therapies.
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Fibrilación Atrial , Azepinas , Proteínas de Ciclo Celular , Fibrosis , Atrios Cardíacos , Ratones Noqueados , Factores de Transcripción , Triazoles , Fibrilación Atrial/genética , Fibrilación Atrial/metabolismo , Fibrilación Atrial/patología , Fibrilación Atrial/tratamiento farmacológico , Animales , Factores de Transcripción/genética , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Atrios Cardíacos/patología , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/metabolismo , Humanos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Ratones , Azepinas/farmacología , Azepinas/uso terapéutico , Masculino , Triazoles/farmacología , Triazoles/uso terapéutico , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Proliferación Celular/efectos de los fármacos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/antagonistas & inhibidores , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Angiotensina II/farmacología , Matriz Extracelular/metabolismo , Matriz Extracelular/efectos de los fármacos , Terapia Molecular Dirigida , Proteínas que Contienen BromodominioRESUMEN
Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are life-threatening hematopoietic malignancies characterized by clonal expansion of leukemic blasts in the bone marrow and peripheral blood. The epigenetic reader BRD4 and its downstream effector MYC have recently been identified as potential drug targets in human AML and ALL. We compared anti-leukemic efficacies of the small-molecule BET inhibitor JQ1 and the recently developed BRD4 degraders dBET1 and dBET6 in AML and ALL cells. JQ1, dBET1, and dBET6 were found to suppress growth and viability in all AML and ALL cell lines examined as well as in primary patient-derived AML and ALL cells, including CD34+/CD38- and CD34+/CD38+ leukemic stem and progenitor cells, independent of the type (variant) of leukemia or molecular driver expressed in leukemic cells. Moreover, we found that dBET6 overcomes osteoblast-induced drug resistance in AML and ALL cells, regardless of the type of leukemia or the drug applied. Most promising cooperative or even synergistic drug combination effects were seen with dBET6 and the FLT3 ITD blocker gilteritinib in FLT3 ITD-mutated AML cells, and with dBET6 and the multi-kinase blocker ponatinib in BCR::ABL1+ ALL cells. Finally, all BRD4-targeting drugs suppressed interferon-gamma- and tumor necrosis factor-alpha-induced expression of the resistance-related checkpoint antigen PD-L1 in AML and ALL cells, including LSC. In all assays examined, the BRD4 degrader dBET6 was a superior anti-leukemic drug compared with dBET1 and JQ1. Together, BRD4 degraders may provide enhanced inhibition of multiple mechanisms of therapy resistance in AML and ALL.
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Azepinas , Proteínas de Ciclo Celular , Resistencia a Antineoplásicos , Leucemia Mieloide Aguda , Células Madre Neoplásicas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Factores de Transcripción , Triazoles , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Triazoles/farmacología , Triazoles/uso terapéutico , Azepinas/farmacología , Azepinas/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas de Ciclo Celular/antagonistas & inhibidores , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Línea Celular Tumoral , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Pirazinas/farmacología , Pirazinas/uso terapéutico , Sinergismo Farmacológico , Piridazinas/farmacología , Piridazinas/uso terapéutico , Proteínas que Contienen Bromodominio , Compuestos de AnilinaRESUMEN
BACKGROUND: Atogepant is an oral calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of migraine in adults. These analyses evaluated the proportions of clinical trial participants who experienced sustained responses to atogepant over 12 or 52 weeks of treatment. METHODS: These were post hoc analyses of ADVANCE, a 12-week, double-blind, randomized trial of atogepant 10, 30, and 60 mg once daily vs. placebo for the preventive treatment of episodic migraine, and a separate open-label long-term safety (LTS) trial of atogepant 60 mg once daily over 52 weeks. The 60 mg dose of atogepant was used to detect safety issues. An initial response was defined as ≥50%, ≥75%, or 100% reduction from baseline in MMDs in month 1 for ADVANCE or quarter 1 for the LTS trial. The proportions of participants who continued to experience a response above each response-defining threshold through each subsequent month (for ADVANCE) or each quarter (for LTS) were calculated. RESULTS: In ADVANCE, sustained response rates during months 2 and 3 varied with dose and were as follows: 70.8-81.1% following an initial ≥50% response, 47.3-61.9% following an initial ≥75% response, and 34.8-41.7% following an initial 100% response. Of those who experienced an initial ≥75% or 100% response during month 1, more than 79% continued to experience at least a 50% response during both months 2 and 3. During the LTS trial, sustained response rates through quarters 2, 3, and 4 were 84.7% following an initial ≥50% response, 72.6% following an initial ≥75% response, and 37.8% following an initial 100% response. Of those who experienced an initial ≥75% or 100% response during quarter 1, more than 90% continued to experience at least a 50% response through quarters 2, 3, and 4. CONCLUSION: Over 70% of participants who experienced an initial response with atogepant treatment had a sustained response with continued treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03777059 (submitted: December 13, 2018); NCT03700320 (submitted: September 25, 2018).
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Trastornos Migrañosos , Humanos , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/prevención & control , Método Doble Ciego , Femenino , Masculino , Adulto , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/administración & dosificación , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/efectos adversos , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/uso terapéutico , Persona de Mediana Edad , Relación Dosis-Respuesta a Droga , Azepinas/efectos adversos , Azepinas/administración & dosificación , Azepinas/uso terapéutico , Resultado del Tratamiento , Piperidinas , Piridinas , Pirroles , Compuestos de EspiroRESUMEN
BACKGROUND: New sleep-inducing drugs (eg, ramelteon, suvorexant, and lemborexant) have been shown to prevent delirium in high-risk groups. However, no single study has simultaneously evaluated the delirium-preventing effects of all novel sleep-inducing drugs in hospitalized patients. Therefore, this study aimed to clarify the relationship between sleep-inducing drugs and delirium prevention in patients hospitalized in general medical-surgical settings for nonpsychiatric conditions who underwent liaison interventions for insomnia. METHODS: This retrospective cohort study included patients treated in general medical-surgical settings for nonpsychiatric conditions with consultation-liaison psychiatry consult for insomnia. Delirium was diagnosed by fully certified psychiatrists using the Diagnostic and Statistical Manual of Mental Disorders 5 th edition. The following items were retrospectively examined from medical records as factors related to delirium development: type of sleep-inducing drugs, age, sex, and delirium risk factors. The risk factors of delirium development were calculated using adjusted odds ratios (aORs) via multivariate logistic regression analysis. RESULTS: Among the 710 patients analyzed, 257 (36.2%) developed delirium. Suvorexant (aOR, 0.61; 95% confidence interval [CI], 0.40-0.94; P = 0.02) and lemborexant (aOR, 0.23; 95% CI, 0.14-0.39; P < 0.0001) significantly reduced the risk of developing delirium. Benzodiazepines (aOR, 1.90; 95% CI, 1.15-3.13; P = 0.01) significantly increased this risk. Ramelteon (aOR, 1.30; 95% CI, 0.84-2.01; P = 0.24) and Z-drugs (aOR, 1.27; 95% CI, 0.81-1.98; P = 0.30) were not significantly associated with delirium development. CONCLUSIONS: The use of suvorexant and lemborexant may prevent delirium in patients with a wide range of medical conditions.
Asunto(s)
Azepinas , Delirio , Indenos , Triazoles , Humanos , Delirio/prevención & control , Delirio/tratamiento farmacológico , Masculino , Femenino , Estudios Retrospectivos , Indenos/efectos adversos , Triazoles/uso terapéutico , Triazoles/efectos adversos , Anciano , Azepinas/uso terapéutico , Azepinas/efectos adversos , Persona de Mediana Edad , Fármacos Inductores del Sueño/uso terapéutico , Fármacos Inductores del Sueño/efectos adversos , Hospitalización/estadística & datos numéricos , Anciano de 80 o más Años , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Adulto , Factores de Riesgo , Piridinas , PirimidinasRESUMEN
Multiple myeloma (MM) stands as a prevalent hematological malignancy, primarily incurable, originating from plasma cell clones. MM's progression encompasses genetic abnormalities and disruptions in the bone marrow microenvironment, leading to tumor proliferation, immune dysfunction, and compromised treatment outcomes. Emerging evidence highlights the critical role of regulatory T cells (Tregs) in MM progression, suggesting that targeting Tregs could enhance immune functionality and treatment efficacy. In this study, a notable increase in Treg proportions within MM patients' bone marrow (BM) compared to healthy individuals is observed. Additionally, it is found that the bromodomain and extraterminal domain (BET) inhibitor JQ1 selectively diminishes Treg percentages in MM patients' BM and reduces TGF-ß1-induced Tregs. This reduction occurs via inhibiting cell viability and promoting apoptosis. RNA sequencing further indicates that JQ1's inhibitory impact on Tregs likely involves upregulating STAT3 and suppressing PD-1 expression. Collectively, these findings suggest JQ1's potential to modulate Tregs, bolstering the immune response in MM and introducing a promising avenue for MM immunotherapy.
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Azepinas , Mieloma Múltiple , Receptor de Muerte Celular Programada 1 , Factor de Transcripción STAT3 , Linfocitos T Reguladores , Triazoles , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/inmunología , Mieloma Múltiple/genética , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Humanos , Azepinas/farmacología , Azepinas/uso terapéutico , Triazoles/farmacología , Triazoles/uso terapéutico , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Masculino , Persona de Mediana Edad , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas que Contienen Bromodominio , ProteínasRESUMEN
The most common oncogenic driver mutations for non-small cell lung cancer (NSCLC) activate EGFR or KRAS. Clinical trials exploring treatments for EGFR- or KRAS-mutated (EGFRmut or KRASmut) cancers have focused on small-molecule inhibitors targeting the driver mutations. Typically, these inhibitors perform more effectively based on combination with either chemotherapies, or other targeted therapies. For EGFRmut NSCLC, a combination of inhibitors of EGFR and Aurora-A kinase (AURKA), an oncogene commonly overexpressed in solid tumors, has shown promising activity in clinical trials. Interestingly, a number of recent studies have indicated that EGFR activity supports overall viability of tumors lacking EGFR mutations, and AURKA expression is abundant in KRASmut cell lines. In this study, we have evaluated dual inhibition of EGFR and AURKA in KRASmut NSCLC models. These data demonstrate synergy between the EGFR inhibitor erlotinib and the AURKA inhibitor alisertib in reducing cell viability and clonogenic capacity in vitro, associated with reduced activity of EGFR pathway effectors, accumulation of enhanced aneuploid cell populations, and elevated cell death. Importantly, the erlotinib-alisertib combination also synergistically reduces xenograft growth in vivo. Analysis of signaling pathways demonstrated that the combination of erlotinib and alisertib was more effective than single-agent treatments at reducing activity of EGFR and pathway effectors following either brief or extended administration of the drugs. In sum, this study indicates value of inhibiting EGFR in KRASmut NSCLC, and suggests the specific value of dual inhibition of AURKA and EGFR in these tumors. SIGNIFICANCE: The introduction of specific KRAS G12C inhibitors to the clinical practice in lung cancer has opened up opportunities that did not exist before. However, G12C alterations are only a subtype of all KRAS mutations observed. Given the high expression of AURKA in KRASmut NSCLC, our study could point to a potential therapeutic option for this subgroup of patients.
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Aurora Quinasa A , Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Clorhidrato de Erlotinib , Neoplasias Pulmonares , Mutación , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas p21(ras) , Ensayos Antitumor por Modelo de Xenoinjerto , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa A/genética , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Animales , Clorhidrato de Erlotinib/farmacología , Clorhidrato de Erlotinib/uso terapéutico , Ratones , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Sinergismo Farmacológico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Azepinas/farmacología , Azepinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
One major obstacle in the drug treatment of pancreatic ductal adenocarcinoma (PDAC) is its highly fibrotic tumor microenvironment, which is replete with activated pancreatic stellate cells (a-PSCs). These a-PSCs generate abundant extracellular matrix and secrete various cytokines to form biophysical and biochemical barriers, impeding drug access to tumor tissues. Therefore, it is imperative to develop a strategy for reversing PSC activation and thereby removing the barriers to facilitate PDAC drug treatment. Herein, by integrating chromatin immunoprecipitation (ChIP)-seq, Assays for Transposase-Accessible Chromatin (ATAC)-seq, and RNA-seq techniques, this work reveals that super-enhancers (SEs) promote the expression of various genes involved in PSC activation. Disruption of SE-associated transcription with JQ1 reverses the activated phenotype of a-PSCs and decreases stromal fibrosis in both orthotopic and patient-derived xenograft (PDX) models. More importantly, disruption of SEs by JQ1 treatments promotes vascularization, facilitates drug delivery, and alters the immune landscape in PDAC, thereby improving the efficacies of both chemotherapy (with gemcitabine) and immunotherapy (with IL-12). In summary, this study not only elucidates the contribution of SEs of a-PSCs in shaping the PDAC tumor microenvironment but also highlights that targeting SEs in a-PSCs may become a gate-opening strategy that benefits PDAC drug therapy by removing stromal barriers.
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Carcinoma Ductal Pancreático , Inmunoterapia , Neoplasias Pancreáticas , Células Estrelladas Pancreáticas , Microambiente Tumoral , Células Estrelladas Pancreáticas/efectos de los fármacos , Células Estrelladas Pancreáticas/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/inmunología , Humanos , Animales , Ratones , Inmunoterapia/métodos , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/inmunología , Modelos Animales de Enfermedad , Gemcitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Azepinas/farmacología , Azepinas/uso terapéutico , Línea Celular Tumoral , Triazoles/farmacología , Triazoles/uso terapéuticoAsunto(s)
Enfermedad de Parkinson , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Antagonistas de los Receptores de Orexina/farmacología , Antagonistas de los Receptores de Orexina/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Azepinas/farmacología , Azepinas/uso terapéutico , Triazoles/farmacología , Triazoles/uso terapéuticoRESUMEN
Se estudaron 20 pacientes de uno u otro sexo, entre 20 y 60 años de edad, con patología común de insomnio y cuadro depresivo. Durante 15 días consecutivos recibieron 0,250 mg de brotizolam antes de irse a dormir. El tiempo de inducción del seuño se redujo de 30 minutos en 79.32% de los ciclos oníricos estudiados. Los despertares nocturnos se redujeron a dos o menos en 90.33%. El tiempo total de sueño se prolongó por seis o más horas de 88.66% de los ciclos oníricos. Al despertar, presentó sensación de descnaso el 69.33% y con poco cansancio el 26.66%. Los efectos secundarios se limitaron a somnolencia discreta diurna en dos pacientes
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Adulto , Persona de Mediana Edad , Humanos , Masculino , Femenino , Azepinas/uso terapéutico , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Trastornos del Inicio y del Mantenimiento del Sueño/prevención & controlRESUMEN
Se estudió el efecto inductor del sueño en 40 pacientes psiquiátricos que recibieron, en forma cruzada, 0.25 mg de brotizolam o 30 mg de fluracepam durante cinco noches cada medicamento, suspendido todo fármaco hipnógeno durante dos días al inicio del estudio, al cruzamiento del tratamiento y al final del estudio. Ambos medicamentos demonstraron su eficacia como inductores del sueño, proporcionando a los pacientes mayor número de horas de sueño durante la noche. En los distintos parámetros estudiados (tiempo de inducción del sueño, duración del sueño, profundidad del sueño y sensación de descanso al despertar), brotizolam mostró un efecto superior a fluracepam