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Background: Pneumonia is common among older adults and often recurrent. Several studies have been conducted on the risk factors for pneumonia; however, little is known about the risk factors for recurrent pneumonia. This study aimed to identify the risk factors for developing recurrent pneumonia among older adults and to investigate methods of prevention. Methods: We analysed the data of 256 patients aged 75â years or older who were admitted for pneumonia between June 2014 and May 2017. Moreover, we reviewed the medical records for the subsequent 3â years and defined the readmission caused by pneumonia as recurrent pneumonia. Risk factors for recurrent pneumonia were analysed using multivariable logistic regression analysis. Differences in the recurrence rate based on the types and use of hypnotics were also evaluated. Results: Of the 256 patients, 90 (35.2%) experienced recurrent pneumonia. A low body mass index (OR: 0.91; 95% CI: 0.83â0.99), history of pneumonia (OR: 2.71; 95% CI: 1.23â6.13), lung disease as a comorbidity (OR: 4.73; 95% CI: 2.13â11.60), taking hypnotics (OR: 2.16; 95% CI: 1.18â4.01) and taking histamine-1 receptor antagonist (H1RA) (OR: 2.38; 95% CI: 1.07â5.39) were risk factors. Patients taking benzodiazepine as hypnotics were more likely to experience recurrent pneumonia than patients not taking hypnotics (OR: 2.29; 95% CI: 1.25-4.18). Conclusion: We identified several risk factors for recurrent pneumonia. Among them, restricting the use of H1RA and hypnotics, in particular benzodiazepines, may be useful in preventing the recurrence of pneumonia in adults aged 75â years or older.
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Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitutes a group of blood vessel inflammation diseases of autoimmune origin. Myeloperoxidase (MPO) ANCA is closely related to ANCA associated AAV. The MPO-ANCA positive AAV patients have lung involvement at high rates; however, there are only a few reported cases with organizing pneumonia (OP). A 78-year-old man was presented to our hospital due to a fever of 38 °C despite a whole month of antibiotics treatment. Chest computed tomography image revealed restricted consolidations visible in the middle lobe of the right lung and the upper lobe of the left lung, which suggested an OP pattern. MPO-ANCA and urine occult blood tests were positive. Histopathological examination of the transbronchial biopsy revealed OP and mucus plug. Histological findings on renal biopsy showed necrotizing glomerulonephritis related to AAV. The patient was diagnosed with MPO-ANCA positive AAV and was treated with systemic corticosteroid therapy, from which he recovered rapidly. Thus, when diagnosing OP, the possibility of AAV should be considered by ordering patients' serum ANCA and occult hematuria tests.
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BACKGROUND: Non-small-cell lung cancer (NSCLC) has been reported to develop in patients with interstitial pneumonia (IP); however, clinical, radiological, and pathological features remain to be elucidated. METHODS: We retrieved the records of 120 consecutive NSCLC patients associated with IP who underwent surgery at Toranomon Hospital between June 2011 and May 2017. We classified the patients into three groups according to NSCLC location using high-resolution computed tomography: group A, within a fibrotic shadow and/or at the interface of a fibrotic shadow and normal lung; group B, within emphysematous tissue and/or at the interface of emphysematous tissue and normal lung; and group C, within normal lung. In 64 patients, programmed death ligand-1 (PD-L1) status was assessed with immunohistostaining. RESULTS: Most of the patients (89; 70%) were classified as group A. This group tended to have squamous cell carcinoma with the usual interstitial pneumonia (UIP). These cancers were located mainly in the lower lobes and seven of the eight postoperative acute exacerbations (pAE) of IP developed in this group. NSCLC in the group B were mainly squamous cell carcinomas located in the upper lobes. No patient with PD-L1 negative was classified into group B. None of the patients in group C showed UIP. and most of the cancers were adenocarcinoma. The frequency of epidermal growth factor receptor mutation-positive NSCLC was the highest in this group. CONCLUSIONS: The three groups each showed characteristic features in terms of tumor location, histopathology, PD-L1 expression, and frequency of pAEof IP.
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Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Enfermedades Pulmonares Intersticiales/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/cirugía , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Bases de Datos Factuales , Progresión de la Enfermedad , Femenino , Humanos , Inmunohistoquímica , Japón , Enfermedades Pulmonares Intersticiales/diagnóstico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Neumonectomía/métodos , Neumonectomía/mortalidad , Cuidados Posoperatorios , Enfisema Pulmonar/complicaciones , Estudios Retrospectivos , Análisis de Supervivencia , Cirugía Torácica Asistida por Video , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Factors affecting the safety of bronchoscopy in patients with malignant hematologic disorders have not been well described. We evaluated the safety of bronchoscopy and describe factors affecting its complication rate in such patients. METHODS: Between January 2009 and December 2018, 316 bronchoscopies in 282 patients with malignant hematologic disorders and pulmonary infiltrates were performed at our institution. The bronchoscopic procedure used and its complications were evaluated. RESULTS: The most common underlying disease was acute myeloid leukemia (134/282 patients, 47.5%). Platelet transfusion was performed the day before or the day of bronchoscopy in 42.4%, supplemental oxygen was administered before the procedure in 23.1%, and midazolam was used in 74.4%. Thirty-five bronchoscopies (11.1%) were complicated by hemoptysis and 7 patients developed pneumothorax, 4 of whom required thoracic drainage. Two patients (0.6%) were intubated within 48 h of the procedure and prolonged oxygen desaturation (> 48 h) occurred in 3.8%. Multivariate analysis showed that only use of midazolam significantly reduced the risk of prolonged oxygen desaturation (hazard ratio 0.28, 95% confidence interval 0.09-0.85, p = 0.03). Transbronchial lung biopsy significantly increased the risk of hemoptysis (hazard ratio 10.40, 95% confidence interval 4.18-25.90, p = 0.00), while use of midazolam significantly reduced the risk (hazard ratio 0.31, 95% confidence interval 0.14-0.73, p = 0.01). CONCLUSIONS: Bronchoscopy is relatively safe in patients with malignant hematologic disorders. Caution and judicious use of sedatives may improve the patient's procedural tolerance and lower complications.
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Broncoscopía/efectos adversos , Neoplasias Hematológicas/complicaciones , Complicaciones Posoperatorias/etiología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Deoxyhypusine synthase (DHPS) utilizes spermidine and NAD as cofactors to incorporate a hypusine modification into the eukaryotic translation initiation factor 5A (eIF5A). Hypusine is essential for eIF5A activation, which, in turn, plays a key role in regulating protein translation of selected mRNA that are associated with the synthesis of oncoproteins, thereby enhancing tumor cell proliferation. Therefore, inhibition of DHPS is a promising therapeutic option for the treatment of cancer. To discover novel lead compounds that target DHPS, we conducted synthetic studies with a hit obtained via high-throughput screening. Optimization of the ring structures of the amide compound (2) led to bromobenzothiophene (11g) with potent inhibitory activity against DHPS. X-ray crystallographic analysis of 11g complexed with DHPS revealed a dramatic conformational change in DHPS, which suggests the presence of a novel allosteric site. These findings provide the basis for the development of novel therapy distinct from spermidine mimetic inhibitors.
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Inhibidores Enzimáticos/química , Indoles/química , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/antagonistas & inhibidores , Tiofenos/química , Sitio Alostérico , Cristalografía por Rayos X , Descubrimiento de Drogas , Pruebas de Enzimas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Guanina/análogos & derivados , Guanina/metabolismo , Ensayos Analíticos de Alto Rendimiento , Humanos , Indoles/síntesis química , Indoles/metabolismo , Estructura Molecular , NAD/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/química , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/metabolismo , Unión Proteica , Conformación Proteica/efectos de los fármacos , Espermidina/metabolismo , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/metabolismoRESUMEN
Dramatic progress in targeted therapy and immunotherapy has been changing clinical practices in lung cancer. With the accumulation of clinical practice, it has become clear that pre-existing interstitial pneumonia (IP) could be a risk factor for drug-induced lung injury, which has enhanced awareness regarding the difficulty in treating lung cancer with comorbid IP. Unfortunately, there is only low-grade evidence in the field of lung cancer with comorbid IP, because almost all clinical trials exclude such patients. There have been very few specialized clinical trials for patients with lung cancer and underlying IPs thus far. Therefore, it is necessary to treat such cases empirically or to give up on the treatment itself. Considering these circumstances, establishing how to treat lung cancer with comorbid IP is an urgent issue. This paper is a summary of the official statement reported by the Diffuse Lung Disease/Thoracic Oncology Assembly and the Japanese Respiratory Society (JRS) in 2017, which attempts to approach lung cancer with comorbid IP systematically.
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Enfermedades Pulmonares Intersticiales/terapia , Neoplasias Pulmonares/terapia , Neumología/organización & administración , Humanos , Japón/epidemiología , Enfermedades Pulmonares Intersticiales/epidemiología , Neoplasias Pulmonares/epidemiologíaRESUMEN
Objective Although rare, pulmonary tuberculosis occasionally develops in patients with interstitial pneumonia (IP). In this study, we aimed to evaluate the clinicoradiological features of pulmonary tuberculosis associated with IP. Methods In this retrospective, observational, single-center study, the medical charts, high-resolution computed tomography (HRCT) findings, and bacteriological test results of patients with IP who also tested positive for Mycobacterium tuberculosis were reviewed. Patients The study included 20 patients with IP out of 329 who tested positive for M. tuberculosis in sputum or bronchoalveolar lavage fluid cultures at Toranomon Hospital between January 2006 and December 2017. Results The HRCT patterns were usual interstitial pneumonia (UIP) in 11 patients and non-UIP in 9 patients. Consolidations (80%) were the most frequent HRCT findings, followed by cavities (60%) and nodules (45%), which are generally characteristic of pulmonary tuberculosis. Consolidations often developed in relation to fibrotic or emphysematous lesions. Tuberculosis lesions could not be identified in one patient. All patients were treated with anti-tuberculosis drugs according to WHO guidelines, and 13 patients achieved a WHO category of "Treatment success." No patient died of tuberculosis, and the median survival time for the 20 patients was 1,196 days. Conclusion Although the HRCT findings for pulmonary tuberculosis associated with IP are atypical, appropriate tuberculosis treatments can lead to favorable outcomes.
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Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/epidemiología , Tuberculosis Pulmonar/diagnóstico por imagen , Tuberculosis Pulmonar/epidemiología , Anciano , Anciano de 80 o más Años , Líquido del Lavado Bronquioalveolar , Femenino , Humanos , Enfermedades Pulmonares Intersticiales/patología , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis , Estudios Retrospectivos , Esputo/microbiología , Tomografía Computarizada por Rayos X , Tuberculosis Pulmonar/patologíaRESUMEN
BACKGROUND: To evaluate the benefits of using a CT image case database (DB) with content-based image retrieval system for the diagnosis of typical non-cancerous respiratory diseases. METHODS: Using this DB, which comprised data on 191 cases covering 69 diseases, 933 imaging findings that contributed to differential diagnoses were annotated. Ten test cases were selected. Image similarity between each marked test case lesion and the lesions of the top 10 retrieved cases were assessed and classified as similar, somewhat similar, or dissimilar by two physicians in consensus. Additionally, the accuracy of five internal medicine residents' abilities to interpret CT findings and provide disease diagnoses with and without the proposed system was evaluated by image interpretation experiments involving five test cases. The rates of concordance between the subjects' interpretations and the correct answers prepared in advance by two specialists in consensus were converted into scores. RESULTS: The mean (± SD) of image similarity among the 10 test cases was as follows: 5.1 ± 2.7 (similar), 2.9 ± 1.0 (somewhat similar), and 2.0 ± 2.4 (dissimilar). Using the proposed system, the subjects' mean score for the correct interpretation of CT findings improved from 15.1 to 28.2 points (p = 0.131) and for the correct disease diagnoses, from 9.3 to 28.2 points (p = 0.034). CONCLUSIONS: Although this was a preliminary small-scale assessment, the results suggest that this system may contribute to an improved interpretation of CT findings and differential diagnosis of non-cancerous respiratory diseases, which are difficult to diagnose for inexperienced physicians.
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Manejo de Datos/métodos , Bases de Datos Factuales , Sistemas de Información , Enfermedades Respiratorias/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Diagnóstico Diferencial , Humanos , Interpretación de Imagen Asistida por ComputadorRESUMEN
BACKGROUND: Pneumatosis intestinalis is a rare adverse event that occurs in patients with lung cancer, especially those undergoing treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). Osimertinib is the most recently approved EGFR-TKI, and its usage is increasing in clinical practice for lung cancer patients who have mutations in the EGFR gene. CASE PRESENTATION: A 74-year-old woman with clinical stage IV (T2aN2M1b) lung adenocarcinoma was determined to have EGFR gene mutations, namely a deletion in exon 19 and a point mutation (T790 M) in exon 20. Osimertinib was started as seventh-line therapy. Follow-up computed tomography on the 97th day after osimertinib administration incidentally demonstrated intra-mural air in the transverse colon, as well as intrahepatic portal vein gas. Pneumatosis intestinalis and portal vein gas improved by fasting and temporary interruption of osimertinib. Osimertinib was then restarted and continued without recurrence of pneumatosis intestinalis. Overall, following progression-free survival of 12.2 months, with an overall duration of administration of 19.4 months (581 days), osimertinib was continued during beyond-progressive disease status, until a few days before the patient died of lung cancer. CONCLUSIONS: Pneumatosis intestinalis should be noted as an important adverse event that can occur with administration of osimertinib; thus far, such an event has never been reported. This was a valuable case in which osimertinib was successfully restarted after complete recovery from pneumatosis intestinalis, such that further extended administration of osimertinib was achieved.
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Adenocarcinoma del Pulmón/complicaciones , Adenocarcinoma del Pulmón/genética , Mutación , Piperazinas/efectos adversos , Neumatosis Cistoide Intestinal/etiología , Inhibidores de Proteínas Quinasas/efectos adversos , Acrilamidas , Adenocarcinoma del Pulmón/tratamiento farmacológico , Anciano , Compuestos de Anilina , Receptores ErbB/genética , Exones , Resultado Fatal , Femenino , Humanos , Piperazinas/uso terapéutico , Neumatosis Cistoide Intestinal/diagnóstico , Mutación Puntual , Inhibidores de Proteínas Quinasas/uso terapéutico , Radiografía Torácica , Eliminación de Secuencia , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: The standard treatment for unresectable stage III non-small cell lung cancer (LC) is chemoradiation therapy (CRT); however, the optimal treatment for LC in patients with interstitial pneumonia (IP) (LC-IP) has not been determined. This study compared the clinical course of LC-IP patients to that of patients without IP (LC without IP) and determined the key factors of survival. METHODS: We retrieved the records of 52 consecutive LC patients treated at our institution between January 2011 and September 2016. The characteristics and outcomes of LC patients with and without IP were compared. Survival was analyzed using the Kaplan-Meier method and univariate and multivariate analyses of two-year survival were also conducted. RESULTS: Forty-two men and 10 women were evaluated. Eleven patients (21%) had IP as their underlying disease. Except for age, the backgrounds of LC patients with and without IP were almost identical. Among LC-IP patients, the median predicted forced vital capacity was 86% and the Gender-Age-Physiology (GAP) index was 3. None of the LC-IP patients received CRT but 32 (78%) of the LC without IP patients underwent CRT. Chemotherapy alone was the main treatment for LC-IP. The median survival times were 485 and 1271 days in LC patients with and without IP, respectively (p=0.419). Multivariate analysis of survival longer than two years revealed CRT as the only predictive factor. CONCLUSIONS: CRT was the only predictive factor for longer survival in LC patients; however, no LC-IP patients received CRT, possibly because of the underlying IP.
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Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Enfermedades Pulmonares Intersticiales/epidemiología , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/terapia , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Quimioradioterapia , Comorbilidad , Progresión de la Enfermedad , Femenino , Predicción , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
A 63-year-old man presented with persistent cough and progressive dyspnea. Computed tomography showed irregular pleural thickening and fibrotic changes with volume loss in the upper lobes, and subtle reticulation in the lower lobes. Pleuroparenchymal fibroelastosis (PPFE) was diagnosed based on the findings of a surgical lung biopsy. Bronchiolar lesions, including proliferative bronchiolitis, constrictive bronchiolitis obliterans, and peribronchiolar metaplasia were evident on pathology. A usual interstitial pneumonia (UIP) pattern was also observed in the lower lobes. Three weeks after the biopsy, an acute exacerbation occurred. We herein describe a rare case of idiopathic PPFE with various bronchiolar lesions and a UIP pattern in which an acute exacerbation developed.
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Fibrosis Pulmonar Idiopática/patología , Enfermedades Pulmonares Intersticiales/patología , Pulmón/patología , Enfermedades Pleurales/patología , Biopsia , Bronquiolitis Obliterante/complicaciones , Bronquiolitis Obliterante/patología , Enfermedades del Tejido Conjuntivo/patología , Tos/etiología , Disnea/etiología , Disnea/patología , Tejido Elástico/patología , Femenino , Humanos , Fibrosis Pulmonar Idiopática/complicaciones , Enfermedades Pulmonares Intersticiales/complicaciones , Masculino , Metaplasia/patología , Persona de Mediana Edad , Enfermedades Pleurales/complicaciones , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: This study aimed to determine the radiologic predictors and clarify the clinical features related to survival in patients with combined pulmonary fibrosis and emphysema (CPFE) and lung cancer. METHODS: We retrospectively reviewed the medical chart data and high-resolution computed tomography (HRCT) findings for 81 consecutive patients with CPFE and 92 primary lung cancers (70 men, 11 women; mean age, 70.9 years). We selected 8 axial HRCT images per patient, and visually determined the normal lung, modified Goddard, and fibrosis scores. Multivariate analysis was performed using the Cox proportional hazards regression model. RESULTS: The major clinical features were a high smoking index of 54.8 pack-years and idiopathic pulmonary fibrosis (n = 44). The major lung cancer profile was a peripherally located squamous cell carcinoma (n = 40) or adenocarcinoma (n = 31) adjacent to emphysema in the upper/middle lobe (n = 27) or fibrosis in the lower lobe (n = 26). The median total normal lung, modified Goddard, and fibrosis scores were 10, 8, and 8, respectively. TNM Classification of malignant tumors (TNM) stage I, II, III, and IV was noted in 37, 7, 26, and 22 patients, respectively. Acute exacerbation occurred in 20 patients. Multivariate analysis showed that a higher normal lung score and TNM stage were independent radiologic and clinical predictors of poor survival at the time of diagnosis of lung cancer. CONCLUSIONS: A markedly reduced area of normal lung on HRCT was a relevant radiologic predictor of survival.
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Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/mortalidad , Enfisema/complicaciones , Enfisema/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/mortalidad , Pulmón/diagnóstico por imagen , Fibrosis Pulmonar/complicaciones , Fibrosis Pulmonar/diagnóstico por imagen , Intensificación de Imagen Radiográfica , Tomografía Computarizada por Rayos X , Anciano , Carcinoma de Células Escamosas/patología , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Pneumatosis intestinalis (PI) is a rare complication of chemotherapy, characterized by multiple gas accumulations within the bowel wall. CASE PRESENTATION: A 71-year-old woman with epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma was admitted to our hospital because of reduced consciousness. She was diagnosed as having leptomeningeal carcinomatosis (LM) using lumbar puncture. Because she could not swallow a tablet, erlotinib was administered via a feeding tube. Her state of consciousness gradually improved, but she experienced diarrhea several times a day. After 3 weeks of erlotinib therapy, PI occurred. Erlotinib was discontinued and PI was resolved after treatment with conservative therapies. Erlotinib was re-administrated and PI occurred again. After improvement of erlotinib-induced PI, gefitinib was administered by a feeding tube and the patient did not experience PI or diarrhea. The patient survived 8 months from the diagnosis of LM. CONCLUSION: PI is one of the side effects of erlotinib, and consecutive therapies are useful for the treatment of PI. In this patient, gefitinib was successfully administered after erlotinib-induced PI.
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Neoplasias Pulmonares/tratamiento farmacológico , Carcinomatosis Meníngea/tratamiento farmacológico , Neumatosis Cistoide Intestinal/tratamiento farmacológico , Quinazolinas/administración & dosificación , Anciano , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib/administración & dosificación , Clorhidrato de Erlotinib/efectos adversos , Femenino , Gefitinib , Humanos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/patología , Carcinomatosis Meníngea/complicaciones , Carcinomatosis Meníngea/patología , Neumatosis Cistoide Intestinal/inducido químicamente , Neumatosis Cistoide Intestinal/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
BACKGROUND: Pneumothorax occasionally develops in patients with interstitial pneumonia (IP) and is often intractable. As there exists no well-established treatment for pneumothorax with IP, we evaluated the efficacy and safety of pleurodesis with OK-432, a lyophilized preparation of Streptococcus pyogenes Su strain that has been inactivated by benzylpenicillin. METHODS: We retrospectively evaluated the efficacy and safety of pleurodesis using OK-432 in 39 patients treated for IP-related pneumothorax between January 2006 and May 2017. Five to 10 Klinische Einheit (KE) of OK-432 was injected through the chest tube of each patient. Pleurodesis was considered successful if 1) the chest tube was removed without air leaks and 2) there was no recurrence of pneumothorax within 4 weeks after tube removal, and no additional treatment was required. RESULTS: OK-432 pleurodesis was performed 46 times in 39 patients. The median number of OK-432 intrapleural injections received was 1 (range, 1-6), and median dose was 10 KE (range, 5-55 KE). The success rate was 63% (29/46) and recurrence rate was 17.4% (8/46). Grade 5 adverse events were observed in eight patients, including two patients who developed acute exacerbation of IP. Patients in whom the first OK-432 pleurodesis was successful had a significantly longer median survival time than patients in whom it was unsuccessful (322 days vs. 70 days, p = 0.036). CONCLUSIONS: Our results show that OK-432 pleurodesis is an effective treatment for pneumothorax associated with IP; however, clinicians should be aware of the possibility of adverse events, especially in patients who are critically ill.
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Enfermedades Pulmonares Intersticiales/complicaciones , Picibanil/administración & dosificación , Pleurodesia/métodos , Neumotórax/etiología , Neumotórax/terapia , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Picibanil/efectos adversos , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Objective Pirfenidone (PFD) is often used for years, but the efficacy and safety of long-term PFD therapy in patients with idiopathic pulmonary fibrosis (IPF) are not fully understood. Methods and Patients We retrospectively evaluated 46 patients with IPF who received PFD between February 2009 and August 2014. The efficacy and safety of PFD therapy were compared between 2 groups: long-term therapy patients who received PFD for over 1 year (group L, n=30, 65%) and short-term therapy patients who could not receive PFD for more than 1 year due to worsening of their condition or side effects (group S, n=16, 35%). Results The median age of the 46 patients was 70.5 years, and the median baseline % predicted forced vital capacity (%FVC) was 70.0%. The changes in the FVC in group L were -120 mL and -170 mL at 12 and 24 months after receiving PFD, respectively. The respective median survival times after PFD therapy in groups L and S were 1,612 days and 285 days (p<0.001). The patients in group L experienced a longer time free of acute exacerbation of IPF than those in group S (947 days vs. 145 days, p=0.001). A multivariate analysis revealed that %FVC <60% was a predictor of the inability to receive PFD for over 1 year (odds ratio 0.240, 95% confidence interval 0.060-0.958; p=0.043). With regard to grade 3-5 adverse events, only one patient exhibited grade 3 hyponatremia. Conclusion Long-term PFD therapy is effective, with few severe adverse events.
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Antiinflamatorios no Esteroideos/administración & dosificación , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Piridonas/administración & dosificación , Anciano , Anciano de 80 o más Años , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Capacidad VitalRESUMEN
Human serine palmitoyltransferase (SPT) is a PLP-dependent enzyme residing in the endoplasmic reticulum. It catalyzes the synthesis of 3-ketodihydrosphingosine (3-KDS) from the substrates palmitoyl-CoA and l-serine. It is a rate-limiting enzyme for sphingolipid synthesis in cells. In the present study, we characterized and pharmacologically profiled a series of tetrahydropyrazolopyridine derivatives that potently inhibit human SPT enzymatic activity, including two cell-active derivatives and one fluorescent-labelled derivative. These SPT inhibitors exhibited dual inhibitory activities against SPT2 and SPT3. We used a fluorescent-labelled probe to molecularly assess the inhibitory mechanism and revealed its binding to the SPT2 or SPT3 subunit in the small subunit (ss) SPTa/SPT1/SPT2/or ssSPTa/SPT1/SPT3 functional complexes. One of the SPT inhibitors exhibited a significantly slow dissociation from the SPT complex. We confirmed that our SPT inhibitors suppressed ceramide content in non-small-cell lung cancer cell line, HCC4006, by performing a target engagement analysis. The potency of ceramide reduction correlated to that observed in a recombinant SPT2 enzyme assay. We thus elucidated and provided a fundamental understanding of the molecular mode of action of SPT inhibitors and developed potent, cell-active SPT inhibitors that can be used to clarify the biological function of SPT.
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Inhibidores Enzimáticos/síntesis química , Serina C-Palmitoiltransferasa/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Ceramidas/antagonistas & inhibidores , Humanos , Neoplasias Pulmonares , Pirazoles/farmacología , Piridinas/farmacologíaRESUMEN
Sphingomyelin synthase (SMS) is a membrane enzyme that catalyzes the synthesis of sphingomyelin, is required for the maintenance of plasma membrane microdomain fluidity, and has two isoforms: SMS1 and SMS2. Although these isoforms exhibit the same SMS activity, they are different enzymes with distinguishable subcellular localizations. It was reported that SMS2 KO mice displayed lower inflammatory responses and anti-atherosclerotic effects, suggesting that inhibition of SMS2 would be a potential therapeutic approach for controlling inflammatory responses and atherosclerosis. This study aimed to discover a novel small-molecule compound that selectively inhibits SMS2 enzymatic activity. We developed a human SMS2 enzyme assay with a high-throughput mass spectrometry-based screening system. We characterized the enzymatic properties of SMS2 and established a high-throughput screening-compatible assay condition. To identify human SMS2 inhibitors, we conducted compound screening using the enzyme assay. We identified a 2-quinolone derivative as a SMS2 selective inhibitor with an IC50 of 950 nM and >100-fold selectivity for SMS2 over SMS1. The 2-quinolone exhibited efficacy in a cell-based engagement assay. We demonstrated that a more potent derivative directly bound to SMS2-expressing membrane fractions in an affinity selection mass spectrometry assay. Mutational analyses revealed that the interaction of the inhibitor with SMS2 required the presence of the amino acids S227 and H229, which are located in the catalytic domain of SMS2. In conclusion, we discovered novel SMS2-selective inhibitors. 2-Quinolone SMS2 inhibitors are considered applicable for leading optimization studies. Further investigations using these SMS2 inhibitors would provide validation tools for SMS2-relevant pathways in vitro and in vivo.
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Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Transferasas (Grupos de Otros Fosfatos Sustitutos)/antagonistas & inhibidores , Animales , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Células HEK293 , Ensayos Analíticos de Alto Rendimiento , Humanos , Espectrometría de Masas , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Estructura Molecular , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/metabolismo , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad , Transferasas (Grupos de Otros Fosfatos Sustitutos)/deficiencia , Transferasas (Grupos de Otros Fosfatos Sustitutos)/metabolismoRESUMEN
Prolyl-tRNA synthetase (PRS) is a member of the aminoacyl-tRNA synthetase family of enzymes and catalyzes the synthesis of prolyl-tRNAPro using ATP, l-proline, and tRNAPro as substrates. An ATP-dependent PRS inhibitor, halofuginone, was shown to suppress autoimmune responses, suggesting that the inhibition of PRS is a potential therapeutic approach for inflammatory diseases. Although a few PRS inhibitors have been derivatized from natural sources or substrate mimetics, small-molecule human PRS inhibitors have not been reported. In this study, we discovered a novel series of pyrazinamide PRS inhibitors from a compound library using pre-transfer editing activity of human PRS enzyme. Steady-state biochemical analysis on the inhibitory mode revealed its distinctive characteristics of inhibition with proline uncompetition and ATP competition. The binding activity of a representative compound was time-dependently potentiated by the presence of l-proline with Kd of 0.76 nM. Thermal shift assays demonstrated the stabilization of PRS in complex with l-proline and pyrazinamide PRS inhibitors. The binding mode of the PRS inhibitor to the ATP site of PRS enzyme was elucidated using the ternary complex crystal structure with l-proline. The results demonstrated the different inhibitory and binding mode of pyrazinamide PRS inhibitors from preceding halofuginone. Furthermore, the PRS inhibitor inhibited intracellular protein synthesis via a different mode than halofuginone. In conclusion, we have identified a novel drug-like PRS inhibitor with a distinctive binding mode. This inhibitor was effective in a cellular context. Thus, the series of PRS inhibitors are considered to be applicable to further development with differentiation from preceding halofuginone.
Asunto(s)
Adenosina Trifosfato/metabolismo , Aminoacil-ARNt Sintetasas/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Prolina/metabolismo , Pirazinamida/farmacología , Aminoacil-ARNt Sintetasas/metabolismo , Sitios de Unión/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Células HEK293 , Humanos , Estructura Molecular , Pirazinamida/síntesis química , Pirazinamida/química , Relación Estructura-ActividadRESUMEN
[Methods] We retrospectively studied 115 con- secutive pulmonary tuberculosis patients whose sputum smear was .negative, diagnosed by positive culture and/or PCR of various samples, or positive QFT. [Results] The culture positive rate of tuberculosis by spu- tum, gastric aspirate, bronchoscopy, and computed tomogra- phy (CT)-guided needle biopsy samples was 55.7%, 45.6%, 73.2%, and 71.4%, respectively. In multivariate analysis, negative or unknown sputum PCR, negative or unknown gastric aspirate, and minimal spread of tuberculosis were risk factors for negative culture from both sputum and gas- tric aspirate. Sputum culture was positive in only one of the four patients with multi-drug resistant Mycobacterium tuberculosis. [Conclusion] Invasive diagnostic procedures such as fiber- optic bronchoscopy should be considered in patients with negative sputum PCR and minimal spread of tuberculosis.
Asunto(s)
Esputo/microbiología , Tuberculosis Pulmonar/microbiología , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tuberculosis Pulmonar/patología , Adulto JovenRESUMEN
Monoacylglycerol acyltransferase (MGAT) 2 is an endoplasmic reticulum membrane enzyme that catalyzes the synthesis of diacylglycerol (DAG) from fatty acyl-CoA and monoacylglycerol as substrates. It is important for the resynthesis of triacylglycerol in the intestine. We have identified a series of aryl-sulfonamide MGAT2 inhibitors and demonstrated pharmacological inhibition of MGAT2 improved hyperlipidemia, obesity, and diabetes in animal models. However, its mechanism of action has not been elucidated in molecular and cellular levels. In the present study, we have characterized a series of aryl-sulfonamide derivatives that potently and selectively inhibit human MGAT2 and determined their pharmacological profiles. Analyses on the molecular mechanism of a representative aryl-sulfonamide MGAT2 inhibitor revealed a reversible inhibitory activity and a binding activity to MGAT2. The aryl-sulfonamide derivatives exhibited potent inhibitory activities against both human and mouse intestinal MGAT activities, which were correlated to those determined using recombinant human and mouse MGAT enzymes. We have developed a cellular assay using Liquid Chromatography-Mass Spectrometry and confirmed that the aryl-sulfonamide derivatives suppressed DAG synthesis in the cellular context. We have thus elucidated their pharmacological profiles and provided the fundamental clues for understanding the molecular and cellular actions of the aryl-sulfonamide MGAT2 inhibitors.