Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 120
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Circ J ; 87(6): 775-782, 2023 05 25.
Artículo en Inglés | MEDLINE | ID: mdl-36709982

RESUMEN

BACKGROUND: Several studies have reported some sex differences in patients with coronary artery diseases. However, the results regarding long-term outcomes in patients with chronic coronary syndrome (CCS) are inconsistent. Therefore, the present study investigated sex differences in long-term outcomes in patients with CCS after percutaneous coronary intervention (PCI).Methods and Results: This was a retrospective, multicenter cohort study. We enrolled patients with CCS who underwent PCI between April 2013 and March 2019 using the Clinical Deep Data Accumulation System (CLIDAS) database. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, or hospitalization for heart failure. In all, 5,555 patients with CCS after PCI were included in the analysis (4,354 (78.4%) men, 1,201 (21.6%) women). The median follow-up duration was 917 days (interquartile range 312-1,508 days). The incidence of MACE was not significantly different between the 2 groups (hazard ratio [HR] 1.20; 95% confidential interval [CI] 0.97-1.47; log-rank P=0.087). After performing multivariable Cox regression analyses on 4 different models, there were still no differences in the incidence of MACE between women and men. CONCLUSIONS: There were no significant sex differences in MACE in patients with CCS who underwent PCI and underwent multidisciplinary treatments.


Asunto(s)
Enfermedad Coronaria , Intervención Coronaria Percutánea , Femenino , Humanos , Masculino , Estudios de Cohortes , Pueblos del Este de Asia , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/métodos , Estudios Retrospectivos , Factores Sexuales , Enfermedad Coronaria/epidemiología
2.
Circ J ; 87(2): 336-344, 2023 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-36216562

RESUMEN

BACKGROUND: The optimal heart rate (HR) and optimal dose of ß-blockers (BBs) in patients with coronary artery disease (CAD) have been unclear. We sought to clarify the relationships among HR, BB dose, and prognosis in patients with CAD using a multimodal data acquisition system.Methods and Results: We evaluated the data for 8,744 CAD patients who underwent cardiac catheterization from 6 university hospitals and the National Cerebral and Cardiovascular Center and who were registered using the Clinical Deep Data Accumulation System. Patients were divided into quartile groups based on their HR at discharge: Q1 (HR <60 beats/min), Q2 (HR 60-66 beats/min), Q3 (HR 67-74 beats/min), and Q4 (HR ≥75 beats/min). Among patients with acute coronary syndrome (ACS) and patients with chronic coronary syndrome (CCS), those in Q4 (HR ≥75 beats/min) had a significantly greater incidence of major adverse cardiac and cerebral events (MACCE) compared with those in Q1 (ACS patients: hazard ratio 1.65, P=0.001; CCS patients: hazard ratio 1.45, P=0.019). Regarding the use of BBs (n=4,964), low-dose administration was significantly associated with MACCE in the ACS group (hazard ratio 1.41, P=0.012), but not in patients with CCS after adjustment for covariates. CONCLUSIONS: HR ≥75 beats/min was associated with worse outcomes in patients with CCS or ACS.


Asunto(s)
Síndrome Coronario Agudo , Enfermedad de la Arteria Coronaria , Humanos , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Frecuencia Cardíaca/fisiología , Pronóstico , Antagonistas Adrenérgicos beta/efectos adversos
3.
J Med Syst ; 47(1): 100, 2023 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-37740823

RESUMEN

BACKGROUND: The application of standardized patient summaries would reduce the risk of information overload and related problems for physicians and nurses. Although the International Patient Summary (IPS) standard has been developed, disseminating its applications has challenges, including data conversion of existing systems and development of application matching with common use cases in Japan. This study aimed to develop a patient summary application that summarizes and visualizes patient information accumulated by existing systems. METHODS: We converted clinical data from the Standardized Structured Medical Information eXchange version 2 (SS-MIX2) storage at Tohoku University Hospital into the Health Level 7 Fast Healthcare Interoperability Resource (FHIR) repository. Subsequently, we implemented a patient summary web application concerning the IPS and evaluated 12 common use cases of the discharge summary. RESULTS: The FHIR resources of seven of the necessary IPS sections were successfully converted from existing SS-MIX2 data. In the main view of the application we developed, all the minimum necessary patient information was summarized and visualized. All types of mandatory or required sections in the IPS and all structured information items of the discharge summary were displayed. Of the discharge summary, 75% of sections and 61.7% of information items were completely displayed, matching 12 common use cases in Japan. CONCLUSIONS: We implemented a patient summary application that summarizes and visualizes patient information accumulated by existing systems and is evaluated in common use cases in Japan. Efficient sharing of the minimum necessary patient information for physicians is expected to reduce information overload, workload, and burnout.


Asunto(s)
Intercambio de Información en Salud , Médicos , Humanos , Japón , Estándar HL7 , Programas Informáticos
4.
Pharmacoepidemiol Drug Saf ; 31(5): 524-533, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35224801

RESUMEN

PURPOSE: We aimed to develop a reliable identification algorithm combining diagnostic codes with several treatment factors for inpatients with acute ischemic stroke (AIS) to conduct pharmacoepidemiological studies using the administrative database MID-NET® in Japan. METHODS: We validated 11 identification algorithms based on 56 different diagnostic codes (International Classification of Diseases, Tenth Revision; ICD-10) using Diagnosis Procedure Combination (DPC) data combined with information on AIS therapeutic procedures added as "AND" condition or "OR" condition. The target population for this study was 366 randomly selected hospitalized patients with possible cases of AIS, defined as relevant ICD-10 codes and diagnostic imaging and prescription or surgical procedure, in three institutions between April 1, 2015 and March 31, 2017. We determined the positive predictive values (PPVs) of these identification algorithms based on comparisons with a gold standard consisting of chart reviews by experienced specialist physicians. Additionally, the sensitivities of them among 166 patients with the possible cases of AIS at a single institution were evaluated. RESULTS: The PPVs were 0.618 (95% confidence interval [CI]: 0.566-0.667) to 0.909 (95% CI: 0.708-0.989) and progressively increased with adding or limiting information on AIS therapeutic procedures as "AND" condition in the identification algorithms. The PPVs for identification algorithms based on diagnostic codes I63.x were >0.8. However, the sensitivities progressively decreased to a maximum of ~0.2 after adding information on AIS therapeutic procedures as "AND" condition. CONCLUSIONS: The identification algorithms based on the combination of appropriate ICD-10 diagnostic codes in DPC data and other AIS treatment factors may be useful to studies for AIS at a national level using MID-NET®.


Asunto(s)
Accidente Cerebrovascular Isquémico , Algoritmos , Bases de Datos Factuales , Humanos , Clasificación Internacional de Enfermedades , Valor Predictivo de las Pruebas
5.
Palliat Med ; 36(8): 1207-1216, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35773973

RESUMEN

BACKGROUND: Few studies have developed automatic systems for identifying social distress, spiritual pain, and severe physical and phycological symptoms from text data in electronic medical records. AIM: To develop models to detect social distress, spiritual pain, and severe physical and psychological symptoms in terminally ill patients with cancer from unstructured text data contained in electronic medical records. DESIGN: A retrospective study of 1,554,736 narrative clinical records was analyzed 1 month before patients died. Supervised machine learning models were trained to detect comprehensive symptoms, and the performance of the models was tested using the area under the receiver operating characteristic curve (AUROC) and precision recall curve (AUPRC). SETTING/PARTICIPANTS: A total of 808 patients was included in the study using records obtained from a university hospital in Japan between January 1, 2018 and December 31, 2019. As training data, we used medical records labeled for detecting social distress (n = 10,000) and spiritual pain (n = 10,000), and records that could be combined with the Support Team Assessment Schedule (based on date) for detecting severe physical/psychological symptoms (n = 5409). RESULTS: Machine learning models for detecting social distress had AUROC and AUPRC values of 0.98 and 0.61, respectively; values for spiritual pain, were 0.90 and 0.58, respectively. The machine learning models accurately identified severe symptoms (pain, dyspnea, nausea, insomnia, and anxiety) with a high level of discrimination (AUROC > 0.8). CONCLUSION: The machine learning models could detect social distress, spiritual pain, and severe symptoms in terminally ill patients with cancer from text data contained in electronic medical records.


Asunto(s)
Registros Electrónicos de Salud , Neoplasias , Humanos , Aprendizaje Automático , Neoplasias/psicología , Dolor , Estudios Retrospectivos , Enfermo Terminal/psicología
6.
Tohoku J Exp Med ; 255(3): 183-194, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34853210

RESUMEN

Disaster response procedures have been developed and improved following the Great East Japan Earthquake. Innovative services have also been created through digital transformation, including an acceleration and deepening of artificial intelligence technology. Things that were once technically impossible are now possible. These innovative technologies will spread across various fields, and disaster response will not be an exception. The Ministry of Health, Labour and Welfare is promoting the use of personal health records in a way that effectively supports the management of treatments by using data from wearable devices and specific applications. During the COVID-19 pandemic, the trade-off between protecting personal information and enabling social benefits, such as in the use of digital tracking, and infodemics, including misinformation, have become new social challenges. Reviewing past disaster preparedness and the services and value provided by digital transformation indicates what new disaster preparedness should be. Digital transformation does not require literacy (ability to collect, analyze, and use information) but competence (beneficial behavioral traits derived from experience). Understanding behavior through data and enabling rational behavior are crucial. By increasing human productivity, we can save time and improve self- and mutual-help in times of disaster. Medical information and digital services must be properly used in normal times. A society that uses such services will be more disaster resilient.


Asunto(s)
Inteligencia Artificial , Planificación en Desastres , Informática Médica , COVID-19 , Comunicación , Empoderamiento , Humanos , Infodemia , Japón , Pandemias
7.
Langmuir ; 36(19): 5227-5235, 2020 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-32347730

RESUMEN

A fluorine-doped tin oxide-coated glass electrode modified with a bilayer film of underlying α-Co(OH)2 and overlying Mg-intercalated and Co-doped δ-type (layered) MnO2 (Mg|Co-MnO2) preferentially yielded oxygen with a Faradaic efficiency as high as 79% in the presence of chloride ions at high concentration (0.5 M). This noble metal-free electrode was fabricated by cathodic electrolysis of aqueous Co(NO3)2 followed by anodic electrolysis of a mixture of Mn2+, Co2+, and cetyltrimethylammonium (CTA+) ions in water. The CTA+ ions accommodated in the interlayer spaces of Co-doped δ-MnO2 were replaced with Mg2+ by ion exchange. The upper Mg|Co-MnO2 could effectively block the permeation of Cl- ions and allow only H2O and O2, while the under α-Co(OH)2 acted as an oxidation catalyst for the H2O penetrated through the upper coating. Thus, the oxygen evolution reaction (OER) was preferred to the chlorine evolution reaction (CER). In artificial seawater (pH 8.3), the blocking effect against Cl- decreased because of ion exchange of the intercalated Mg2+ ions with Na+ in solution, but the OER efficiency still remained at 57%, much higher than that (28%) without the upper Mg|Co-MnO2. This demonstrates that the interlayer spaces between MnO2 layers acted as pathways for H2O molecules to reach the active sites of the underlying Co(OH)2. Density functional theory (DFT) calculations revealed that the most stable structure of hydrated Mg2+ ion, in which a part of coordinated H2O molecules is hydrolyzed, has less affinity toward Cl- ion than that of hydrated Na+ ion.

8.
Bioorg Med Chem Lett ; 30(5): 126963, 2020 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-31980341

RESUMEN

Herein we report an efficient method for the synthesis of a highly functionalized 2-pyrrolidinone, tert-butyl 3-cyano-3-cyclopropyl-2-oxopyrrolidine-4-carboxylate, from readily available starting materials. Utility of this compound was demonstrated in the synthesis of a novel series of macrocyclic Tyk2 inhibitors, leading to the identification of a potent and selective macrocyclic Tyk2 inhibitor (26).


Asunto(s)
Inhibidores de Proteínas Quinasas/síntesis química , Pirrolidinonas/síntesis química , TYK2 Quinasa/antagonistas & inhibidores , Humanos , Células Jurkat , Estructura Molecular , Inhibidores de Proteínas Quinasas/farmacología , Pirrolidinonas/farmacología , Relación Estructura-Actividad
9.
Pharmacoepidemiol Drug Saf ; 28(5): 601-608, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30945387

RESUMEN

PURPOSE: To examine the potential role of Medical Information Database Network (MID-NET® ), a newly established Japanese medical information database network, in postmarketing drug safety assessments through the characterization of its advantages and limitations in five pilot studies. METHODS: The pilot studies were designed to address three major objectives in postmarketing drug safety assessments, ie, the examination of actual drug utilization, the impact of safety-related regulatory actions, and drug-associated risks. The five studies were conducted on the following topics: (a) utilization of codeine-containing products and its relationship with respiratory depression, (b) impact of a Dear Healthcare Professional letter on hypocalcemia incidence associated with denosumab (Ranmark® ) use, (c) risk of acute myocardial infarction associated with antidiabetic drug use, (d) risk of glucose metabolism disorders associated with atypical antipsychotic drug use, and (e) prospective monitoring of abnormal laboratory test results during new drug prescriptions. RESULTS: The pilot studies were successfully conducted and demonstrated the value of MID-NET® in postmarketing drug safety assessments. In particular, the ability to utilize laboratory test results as objective clinical indicators is a major advantage of this database. Potential limitations include a relatively small sample size and a lack of patient-level data linkages among hospitals. CONCLUSIONS: MID-NET® was confirmed to be a valuable database for postmarketing drug safety assessments. The use of laboratory test results to define clinical outcomes may allow more objective and accurate analyses to be conducted. These studies furthered our understanding of the characteristics of MID-NET® , including its advantages and limitations.


Asunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Bases de Datos Farmacéuticas/estadística & datos numéricos , Utilización de Medicamentos/estadística & datos numéricos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Vigilancia de Productos Comercializados/métodos , Incidencia , Japón , Farmacoepidemiología , Proyectos Piloto , Vigilancia de Productos Comercializados/estadística & datos numéricos , Factores de Riesgo
10.
Pharmacoepidemiol Drug Saf ; 28(10): 1395-1404, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31464008

RESUMEN

PURPOSE: To establish a new medical information database network (designated MID-NET® ) to provide real-world data for drug safety assessments in Japan. METHODS: This network was designed and developed by the Ministry of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices Agency in collaboration with 23 hospitals from 10 healthcare organizations across Japan. MID-NET® is a distributed and closed network system that connects all collaborative organizations through a central data center. A wide variety of data are available for analyses, including clinical and administrative information. Several coding standards are used to standardize the data stored in MID-NET® to allow the integration of information originating from different hospitals. A rigorous and consistent quality management system was implemented to ensure that MID-NET® data are of high quality and meet Japanese regulatory standards (good post-marketing study practice and related guidelines). RESULTS: MID-NET® was successfully established as a reliable and valuable medical information database and was officially launched in April 2018. High data quality with almost 100% consistency was confirmed between original data in hospitals and the data stored in MID-NET® . A major advantage is that approximately 260 clinical laboratory test results are available for analysis. CONCLUSIONS: MID-NET® is expected to be a major data source for drug safety assessments in Japan. Experiences and best practices established in MID-NET® may provide a model for the future development of similar database networks.


Asunto(s)
Manejo de Datos/organización & administración , Bases de Datos Factuales , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Farmacovigilancia , Vigilancia de Productos Comercializados/métodos , Codificación Clínica/organización & administración , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Registros Electrónicos de Salud/organización & administración , Humanos , Japón/epidemiología , Reproducibilidad de los Resultados
11.
Tohoku J Exp Med ; 248(1): 19-25, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31080195

RESUMEN

On March 11, 2011, the Great East Japan Earthquake and ensuing tsunami that hit the northeastern coastal region of Japan caused about 18,000 casualties and destroyed numerous buildings. Additionally, many medical facilities were damaged and patient medical records lost. In order to maintain patient clinical information, a prefectural medical network system, the Miyagi Medical and Welfare Information Network (MMWIN), began providing backup data storage services in 2013 for hospitals, clinics, pharmacies, and other care facilities as a precaution for upcoming disasters. This system also facilitates the sharing of clinical information trans-institutionally as long as patients provide consent for this. In the present study, we examined the development of the MMWIN and its efficiency during the 5 years from its launch, and identified general problems to maintain such a backup system. At the end of 2018, the system contained backup data from more than 11 million patients with more than 420 million data items; more than 900 facilities were MMWIN users, and the number of patients consenting to sharing their clinical information reached 90,000. The use of the system has become widespread and the accumulating data should be utilized for research in the future. Maintaining a balance between income and cost is critical to make this project independent from local government subsidies.


Asunto(s)
Información de Salud al Consumidor , Terremotos , Planificación en Salud , Servicios de Información , Tsunamis , Instituciones de Salud , Humanos , Difusión de la Información , Japón , Diálisis Renal
12.
Tohoku J Exp Med ; 249(2): 113-119, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31656241

RESUMEN

Clinical application of accumulated medical big data is a hot topic in medical informatics. Not only for suggesting possible diagnoses in each individual, large medical database can be possibly used for detecting undiagnosed patients in the general population. In this study, we tried to develop a computerized system of detecting overlooked undiagnosed patients with rare chronic diseases in the community population by utilizing the uniformed national medical insurance record database. A cumulative total of 489,823 hospital visits at one tertiary medical center were collected for this project. As the target disease, we selected esophagogastric junction outflow obstruction (EGJOO), including achalasia, which is known to be easily overlooked without performing a barium swallow test. Patient selection software automatically picked out 17,814 individuals with the given suspected diagnoses that could be misdiagnosed in patients with the target disease, from which the software further picked out 526 individuals who underwent upper endoscopy but did not undergo barium swallow test. Of them, the hospital medical records suggested that 39 people still suffered from prolonged symptoms lasting for more than 6 months after the first hospital visit. Among them, 16 individuals agreed to undergo the barium swallow test. One of them was confirmed to suffer from EGJOO, possibly based on some undiagnosed connective tissue diseases. An automated computerized detection system with uniform big medical data would realize more efficient and less expensive screening system for undiagnosed chronic diseases in the general population based on symptoms and previously performed examinations in each individual.


Asunto(s)
Bases de Datos como Asunto , Registros Electrónicos de Salud , Adolescente , Adulto , Inteligencia Artificial , Niño , Unión Esofagogástrica/patología , Femenino , Fluoroscopía , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
13.
Int Heart J ; 60(2): 264-270, 2019 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-30799376

RESUMEN

The utilization of electronic medical records and multimodal medical data is an ideal approach to build a real-time and precision registry type study with a smaller effort and cost, which may fill a gap between evidence-based medicine and the real-world clinical practice. The Japan Ischemic heart disease Multimodal Prospective data Acquisition for preCision Treatment (J-IMPACT) project aimed to build an clinical data registry system that electronically collects not only medical records, but also multimodal data, including coronary angiography and percutaneous coronary intervention (PCI) report, in standardized data formats for clinical studies.The J-IMPACT system comprises the standardized structured medical information exchange (SS-MIX), coronary angiography and intervention reporting system (CAIRS), and multi-purpose clinical data repository system (MCDRS) interconnected within the institutional network. In order to prove the concept, we acquired multimodal medical data of 6 consecutive cases that underwent PCI through the J-IMPACT system in a single center. Data items regarding patient background, laboratory data, prescriptions, and PCI/cardiac catheterization report were correctly acquired through the J-IMPACT system, and the accuracy of the multimodal data of the 4 categories was 100% in all 6 cases.The application of J-IMPACT system to clinical studies not only fills the gaps between randomized clinical trials and real-world medicine, but may also provide real-time big data that reinforces precision treatment for each patient.


Asunto(s)
Angiografía Coronaria/estadística & datos numéricos , Exactitud de los Datos , Sistemas de Registros Médicos Computarizados , Isquemia Miocárdica , Intervención Coronaria Percutánea/estadística & datos numéricos , Anciano , Medicina Basada en la Evidencia/métodos , Femenino , Humanos , Japón/epidemiología , Masculino , Sistemas de Registros Médicos Computarizados/organización & administración , Sistemas de Registros Médicos Computarizados/normas , Persona de Mediana Edad , Isquemia Miocárdica/epidemiología , Isquemia Miocárdica/terapia , Estudios Prospectivos , Mejoramiento de la Calidad , Sistema de Registros/estadística & datos numéricos , Resultado del Tratamiento
14.
Bioorg Med Chem ; 26(3): 721-736, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-29342416

RESUMEN

Novel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of inflammatory and autoimmune diseases. A hit compound, 1, was discovered by high-throughput screening of our compound library. The structure-activity relationship (SAR) study of compound 1 showed that the introduction of a chlorine group at the 3-position of 4-cyanophenyl moiety increased the potency and a 3-methylpentane-1,5-diamide linker is favorable for the activity. The carbazole moiety of 1 was also optimized; a quinazolinedione derivative 18i suppressed the increase of IL-17A mRNA level in the lymph node of a rat model of experimental autoimmune encephalomyelitis (EAE) upon oral administration. These results indicate that the novel quinazolinedione derivatives have great potential as orally available small-molecule RORγt inverse agonists for the treatment of Th17-driven autoimmune diseases. A U-shaped bioactive conformation of this chemotype with RORγt protein was also observed.


Asunto(s)
Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Quinazolinonas/química , Administración Oral , Animales , Sitios de Unión , Agonismo Inverso de Drogas , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/veterinaria , Femenino , Humanos , Concentración 50 Inhibidora , Interleucina-17/genética , Interleucina-17/metabolismo , Células Jurkat , Simulación del Acoplamiento Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Unión Proteica/efectos de los fármacos , Estructura Terciaria de Proteína , Quinazolinonas/administración & dosificación , Quinazolinonas/metabolismo , Quinazolinonas/farmacología , Ratas , Ratas Endogámicas Lew , Solubilidad , Relación Estructura-Actividad , Células Th17/citología , Células Th17/efectos de los fármacos , Células Th17/metabolismo
15.
Bioorg Med Chem ; 26(2): 483-500, 2018 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-29262987

RESUMEN

A series of novel phenylglycinamides as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists were discovered through optimization of a high-throughput screen hit 1. (R)-N-(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methylisoxazole-5-carboxamide (22) was identified as one of the best of these compounds. It displayed higher subtype selectivity and specificity over other nuclear receptors and demonstrated in vivo potency to suppress the transcriptional activity of RORγt in a mouse PD (pharmacodynamic) model upon oral administration.


Asunto(s)
Descubrimiento de Drogas , Glicina/análogos & derivados , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Administración Oral , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Glicina/administración & dosificación , Glicina/química , Glicina/farmacología , Humanos , Células Jurkat , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Animales , Modelos Moleculares , Estructura Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Relación Estructura-Actividad
16.
Pharmacology ; 102(5-6): 244-252, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30134246

RESUMEN

BACKGROUND/AIMS: Retinoid-related orphan receptor gamma t (RORγt) is a master regulator of T helper 17 cells that plays a pivotal role in the production of inflammatory cytokines including interleukin (IL)-17. Therefore, RORγt has attracted much attention as a target receptor for the treatment of inflammatory diseases including rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, and psoriasis. This study aims to characterize TAK-828F, a potent and selective RORγt inverse agonist. METHODS: The biochemical properties of TAK-828F were evaluated using Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) binding assay, surface plasmon resonance (SPR) biosensor assay, cofactor recruitment assay, reporter assay, and IL-17 expression assay. RESULTS: TR-FRET binding assay and SPR biosensor assay revealed rapid, reversible, and high affinity binding of TAK-828F to RORγt. The cofactor recruitment assay showed that TAK-828F inhibited the recruitment of steroid receptor coactivator-1 to RORγt. Furthermore, TAK-828F inhibited the transcriptional activity of human and mouse RORγt with selectivity against human RORα and RORß. TAK-828F also suppressed IL-17 production in Jurkat cells, overexpressing human RORγt. CONCLUSION: These favorable properties will be of advantage in the evaluation of TAK-828F in clinical studies for inflammatory diseases. Furthermore, these findings demonstrate that TAK-828F could serve as a pharmacological tool for further studies of RORγt and inflammatory diseases.


Asunto(s)
Benzofuranos/química , Benzofuranos/farmacología , Receptores Nucleares Huérfanos/agonistas , Sulfonas/química , Sulfonas/farmacología , Animales , Benzofuranos/farmacocinética , Cromatografía de Afinidad , Transferencia Resonante de Energía de Fluorescencia , Humanos , Interleucina-17/metabolismo , Células Jurkat , Cinética , Ratones , Receptores Nucleares Huérfanos/metabolismo , Unión Proteica , Sulfonas/farmacocinética , Activación Transcripcional
17.
Langmuir ; 33(19): 4647-4653, 2017 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-28464611

RESUMEN

Aqueous Mn2+ ions were anodized at 70 °C with Co2+ in the presence of cationic surfactant, cetyltrimethylammonium (CTA). X-ray diffraction (XRD) analysis revealed that the deposited film possesses a layered structure of MnO2, the interlayer of which is occupied with the assembled CTA molecules. Inclusion of Co ions in the MnO2 film was evidenced by X-ray photoelectron spectroscopy (XPS). They were located in the MnO2 framework, not in the interlayer. The thus-obtained film, CTA-intercalated Co-framework-doped layered MnO2 (CTA/Co-MnO2), was applied as an electrochemical sensor toward iodide (I-), a hydrophobic anion. The organic phase between MnO2 layers could extract I- ions from solution, providing a better sensitivity than a film consisting of layered MnO2 with hydrated alkali metals. On the other hand, the Co-doped layers of MnO2 achieved faster electron transfer kinetics for the oxidation of I-, which resulted in a drastic reduction in response time compared to the nondoped CTA/MnO2.

18.
Bioorg Med Chem Lett ; 27(11): 2331-2335, 2017 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-28438540

RESUMEN

Oxytocin (OT) is a neuropeptide involved in a wide variety of physiological actions, both peripherally and centrally. Many human studies have revealed the potential of OT to treat autism spectrum disorders and schizophrenia. OT interacts with the OT receptor (OTR) as well as vasopressin 1a and 1b receptors (V1aR, V1bR) as an agonist, and agonistic activity for V1aR and V1bR may have a negative impact on the therapeutic effects of OTR agonism in the CNS. An OTR-selective agonistic peptide, FE 202767, in which the structural differences from OT are a sulfide bond instead of a disulfide bond, and N-alkylglycine replacement for Pro at position 7, was reported. However, the effects of amino acid substitutions in OT have not been comprehensively investigated to compare OTR, V1aR, and V1bR activities. This led us to obtain a new OTR-selective analog by comprehensive amino acid substitutions of OT and replacement of the disulfide bond. A systematic amino acid scanning (Ala, Leu, Phe, Ser, Glu, or Arg) of desamino OT (dOT) at positions 2, 3, 4, 5, 7, and 8 revealed the tolerability for the substitution at positions 7 and 8. Further detailed study showed that trans-4-hydroxyproline (trans-Hyp) at position 7 and γ-methylleucine [Leu(Me)] at position 8 were markedly effective for improving receptor selectivity without decreasing the potency at the OTR. Subsequently, a combination of these amino acid substitutions with the replacement of the disulfide bond of dOT analogs with a sulfide bond (carba analog) or an amide bond (lactam analog) yielded several promising analogs, including carba-1-[trans-Hyp7,Leu(Me)8]dOT (14) with a higher potency (7.2pM) at OTR than that of OT and marked selectivity (>10,000-fold) over V1aR and V1bR. Hence, we investigated comprehensive modification of OT and obtained new OT analogs that exhibited high potency at OTR with marked selectivity. These OTR-selective agonists could be useful to investigate OTR-mediated effects on psychiatric disorders.


Asunto(s)
Disulfuros/química , Receptores de Oxitocina/agonistas , Animales , Células CHO , Cricetulus , Humanos
19.
Bioorg Med Chem Lett ; 27(15): 3542-3545, 2017 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-28596054

RESUMEN

The natriuretic peptide (NP) system is a critical endocrine, autocrine, and paracrine system and has been investigated for potential use against cardiovascular and metabolic diseases. The clearance of NPs is regulated by the proteolysis of neutral endopeptidase (NEP) and by endocytosis via natriuretic peptide receptor-3 (NPR3). A linear NPR3-selective peptide, [Cha8]-ANP(7-16)-NH2 (1), showed potent binding affinity for NPR3 but poor predicted chemical stability due to its free thiol group. A 12-mer peptide (9) without a thiol group was designed by the hybridization of two NPR3-binding peptides: a linear ANP fragment peptide analog and musclin, a murine member of the bHLH family of transcription factors, possessed high binding affinity and strict selectivity for NPR3. To increase the proteolytic resistance of 9, amino acid substitutions at the cleavage sites led to hydroxyacetyl-[d-Phe5,d-Hyp7,Cha8,d-Ser9,Hyp11,Arg(Me)14]-ANP(5-15)-NHCH3 (23), showing high and selective binding affinity for NPR3 over NPR1 and excellent stability in mouse serum. Compound 23 increased intracellular cGMP concentrations in primary cultured adipocytes, and continuous administration induced substantial plasma cGMP elevation in mice, suggesting its potential to clarify the physiological role of NPR3 and its therapeutic application.


Asunto(s)
Factor Natriurético Atrial/farmacología , Proteínas Musculares/farmacología , Fragmentos de Péptidos/farmacología , Receptores del Factor Natriurético Atrial/antagonistas & inhibidores , Factores de Transcripción/farmacología , Secuencia de Aminoácidos , Animales , Factor Natriurético Atrial/administración & dosificación , Factor Natriurético Atrial/sangre , Factor Natriurético Atrial/química , Ratones , Ratones Endogámicos C57BL , Proteínas Musculares/administración & dosificación , Proteínas Musculares/sangre , Proteínas Musculares/química , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/química , Receptores del Factor Natriurético Atrial/metabolismo , Factores de Transcripción/administración & dosificación , Factores de Transcripción/sangre , Factores de Transcripción/química
20.
Bioorg Med Chem Lett ; 27(9): 1897-1901, 2017 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-28363748

RESUMEN

We recently reported a class of novel tissue-selective androgen receptor modulators (SARMs), represented by a naphthalene derivative A. However, their pharmacokinetic (PK) profiles were poor due to low metabolic stability. To improve the PK profiles, we modified the hydroxypyrrolidine and benzonitrile substituents of 4-(pyrrolidin-1-yl)benzonitrile derivative B, which had a comparable potency as that of compound A. This optimization led us to further modifications, which improved metabolic stability while maintaining potent androgen agonistic activity. Among the synthesized compounds, (2S,3S)-2,3-dimethyl-3-hydroxylpyrrolidine derivative 1c exhibited a suitable PK profile and improved metabolic stability. Compound 1c demonstrated significant efficacy in levator ani muscle without increasing the weight of the prostate in an in vivo study. In addition, compound 1c showed agonistic activity in the CNS, which was detected using sexual behavior induction assay.


Asunto(s)
Andrógenos/química , Andrógenos/farmacología , Nitrilos/química , Nitrilos/farmacología , Pirrolidinas/química , Pirrolidinas/farmacología , Receptores Androgénicos/metabolismo , Anabolizantes/química , Anabolizantes/farmacocinética , Anabolizantes/farmacología , Andrógenos/farmacocinética , Animales , Eunuquismo/tratamiento farmacológico , Eunuquismo/metabolismo , Humanos , Masculino , Modelos Moleculares , Músculos/efectos de los fármacos , Músculos/metabolismo , Nitrilos/farmacocinética , Tamaño de los Órganos/efectos de los fármacos , Próstata/efectos de los fármacos , Próstata/metabolismo , Pirrolidinas/farmacocinética , Ratas
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA