Tosei General Hospital

Okazaki, Japan

Tosei General Hospital

Okazaki, Japan
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Suzuki A.,Tosei General Hospital | Kondoh Y.,Tosei General Hospital | Fischer A.,Aurora University
Expert Review of Respiratory Medicine | Year: 2017

Introduction: Interstitial lung disease (ILD) is a common manifestation of connective tissue disease (CTD). Although the majority of patients with CTD-ILD are stable or slowly progressive, a significant group exhibits a more severe and progressive decline. Interstitial pneumonia with autoimmune features (IPAF) describes the subset of patients with interstitial pneumonia who have features suggesting underlying autoimmunity, but whose features fall short of a clear diagnosis of CTD. Areas covered: In this focused review, we discuss recent advances in early detection, prognostic evaluation, and management of autoimmune forms of ILD. Expert commentary: Early detection of ILD and a better understanding of factors that impact prognostication may be helpful when making decisions regarding therapeutic interventions. The treatment of CTD-ILD should be comprehensive, is often fraught with challenges and can be complicated by comorbid conditions and extra-thoracic disease activities. Several large randomized studies have examined the impact of immunosuppressive therapy for CTD-ILD, however, additional studies are needed to determine the optimal treatment strategies. Future studies may provide additional information about the best treatments in patients with IPAF. © 2017 Informa UK Limited, trading as Taylor & Francis Group.


Richeldi L.,National Health Research Institute | Du Bois R.M.,Imperial College London | Raghu G.,University of Washington | Azuma A.,Nippon Medical School | And 19 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. METHODS: We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire, both assessed over a 52-week period. RESULTS: A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was -114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6 ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P = 0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P = 0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2. CONCLUSIONS: In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. Copyright © 2014 Massachusetts Medical Society.


Ogura T.,Kanagawa Cardiovascular and Respiratory Center | Taniguchi H.,Tosei General Hospital | Azuma A.,Nippon Medical School | Inoue Y.,National Hospital Organization Kinki Chuo Chest Medical Center | And 12 more authors.
European Respiratory Journal | Year: 2015

A randomised, double-blind, phase II, dose escalation trial was conducted to assess the safety, tolerability and pharmacokinetics of the tyrosine kinase inhibitor nintedanib, alone and when added to ongoing pirfenidone therapy, in Japanese patients with idiopathic pulmonary fibrosis. 50 Japanese patients were randomised to receive nintedanib or placebo in one of three cohorts (nintedanib 50 mg twice daily or 100 mg twice daily for 14 days, or 150 mg twice daily for 28 days). Patients receiving pirfenidone at inclusion were stratified to every nintedanib dose group and placebo. Adverse events were reported in nine out of 17 patients receiving nintedanib alone and 10 out of 21 patients receiving nintedanib added to pirfenidone. All adverse events were mild or moderate in intensity. Gastrointestinal disorders were the most common adverse event. Maximum plasma concentration and area under the curve at steady state for nintedanib and its metabolites tended to be lower when nintedanib was added to pirfenidone. Nintedanib had no effect on the pharmacokinetics of pirfenidone. In conclusion, further study is needed to evaluate the safety and tolerability profile of nintedanib when added to pirfenidone in patients with idiopathic pulmonary fibrosis. There was a trend toward lower exposure of nintedanib when it was added to pirfenidone. Copyright © ERS 2015.


Kataoka K.,Tosei General Hospital | Taniguchi H.,Tosei General Hospital | Kondoh Y.,Tosei General Hospital | Nishiyama O.,Kinki University | And 5 more authors.
Chest | Year: 2015

BACKGROUND: Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) presents as episodes of acute respiratory worsening closely associated with endothelial damage and disordered coagulopathy. Recombinant human soluble thrombomodulin (rhTM) regulates the coagulation pathway mainly by reducing thrombin-mediated clotting and enhancing protein C activation. We investigated the efficacy of rhTM for the treatment of patients with AE-IPF. METHODS: This historical control study comprised 40 patients with AE-IPF. Twenty patients treated with rhTM (0.06 mg/kg/d) for about 6 days (rhTM group) and 20 patients treated without rhTM (control group) were evaluated. The predictors of 3-month mortality (logistic regression model) were evaluated. RESULTS: There was no difference in baseline characteristics between the control group and the rhTM group. Three-month mortality of the rhTM group and control group was 30.0% and 65.0%, respectively. In univariate analysis, C-reactive protein and rhTM therapy were signifi-cant determinants for 3-month survival. In multivariate analysis, rhTM therapy (OR, 0.219; 95% CI, 0.049-0.978 P = 0.047) was an independent significant determinant for 3-month survival. CONCLUSIONS: We found that rhTM therapy improved 3-month survival of AE-IPF. The results observed here warrant further investigation of rhTM in randomized control trials. © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS.


Watanabe N.,Tosei General Hospital
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society | Year: 2011

Therapy with sildenafil has been shown to decrease pulmonary vascular resistance and may improve functional status in patients with interstitial pneumonia (IP) and pulmonary hypertension (PH). Patients with IP and PH defined by a mean pulmonary artery pressure (MPAP) of > or = 25mm Hg on right-heart catheterization were followed up in an open-label study of sildenafil. A multilateral evaluation was conducted before, and after 3 months of therapy. We studied 11 patients [8 men and 3 women, mean age 66.5] 6 of whom had IPF (1 with usual interstitial pneumonia {UIP}), 2 with IIP, and 3 with collagen-vascular disease interstitial pneumonia (CVD-IP). The mean modified Medical Research Council (MRC) score was 3.0 +/- 0.89, baseline dyspnea index (BDI) score was 4.5 +/- 1.9, % VC was 58.7 +/- 15.6%, percentage of carbon monoxide diffusing capacity (%DLco) was 20.0 +/- 10.9%, six-minute walk distance (6MWD) was 269.8 +/- 105.5m, shuttle walking test (SWT) was 179.1 +/- 99.7m, St. George Respiratory Questionnaire (SGRQ) was 70.9 +/- 15.6, mean pulmonary artery pressure (MPAP) was 33.8 +/- 7.61mm Hg, and pulmonary vascular resistance index (PVRI) was 658.9 +/- 236.1 dynes x s x cm(-5) x m2. After 3 months of therapy, improvements in BDI (< or = -1), 6MWD (> or = 20%), SWT (> or = 20%), and SGRQ (< or = -7) were observed in 4, 2, 3, and 6 patients, respectively. Improvements in MPAP (< or = - 20%) and PVRI (< or = -20%) were observed in 2 and 3 patients, respectively. No parameter showed statistically significant differences. We conclude that sildenafil may improve dyspnea, exercise tolerance and health-related quality of life (QOL) in some IP patients with PH.


Sato I.,Tosei General Hospital
Nagoya journal of medical science | Year: 2011

A 58-year-old woman was referred to our hospital because of liver dysfunction. Her serum levels of AST (619 IU/l) and ALT (603 IU/l) had increased. Histological findings in the liver biopsy were compatible to autoimmune hepatitis (AIH), and the diagnosis of AIH was confirmed by the diagnostic criteria. She was admitted to a nearby hospital 3 years ago, and diagnosed with Graves' disease. She received methimazole (MMI) at first, which was discontinued due to liver injury in one month, then propylthiouracil (PTU) was administered. One year later, transaminase increased and was decreased by stopping PTU administration. PTU was restarted after her transaminase decreased, but a recurrence of hepatotoxicity was observed, and she was referred to our hospital. Oral prednisolone decreased liver function immediately. In this case, PTU-induced liver injury was suspected as a possible trigger of AIH. While PTU remains a commonly used drug in the treatment of hyperthyroidism, severe liver injury is reported in some cases. If liver injury is observed in patients treated with PTU, rechallenge is not recommended in order to avoid severe hepatotoxicity.


Fukihara J.,Tosei General Hospital | Kondoh Y.,Tosei General Hospital
Expert Review of Respiratory Medicine | Year: 2016

Introduction: Nintedanib is a new anti-fibrosis agent that is an intracellular tyrosine kinase inhibitor targeting platelet derived growth factor receptor, fibroblast growth factor receptor and vascular endothelial growth factor receptor. Although nintedanib is attracting much attention as a new treatment option for patients with idiopathic pulmonary fibrosis (IPF), the clinical evidence is limited mainly to the results from the dose-deciding phase II TOMORROW trial and phase III INPULSIS trials, which evaluated efficacy and safety of nintedanib for patients with IPF, prespecified subgroup analyses, pooled analyses and meta-analyses derived from those trials. Areas covered: In this document, we mainly reviewed reports on working mechanisms of nintedanib, and efficacy and safety of nintedanib for patients with IPF. The literature search was undertaken using Pub Med. Expert commentary: It is unknown whether the efficacy of nintedanib in patients enrolled in the clinical trials will be the same for the entire spectrum of patients, including patients unfit for the clinical trials due to age, severity, timing of IPF diagnosis or diagnosis of interstitial pneumonias other than IPF. Sufficient consideration should be given when selecting candidates for nintedanib in the real world. © 2016 Informa UK Limited, trading as Taylor & Francis Group


Kondoh Y.,Tosei General Hospital
Japanese Journal of Chest Diseases | Year: 2013

I discribe interpretation and summary of new international IPF guidelines for diagnosis and clinical management. IPF is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of UIR The diagnosis of IPF requires specific combinations of HRCT and surgical lung biopsy pattern in patients subjected to surgical lung biopsy. The accuracy of the diagnosis of IPF increases with multidisciplinary discussion (MDD) among ILD experts. Clinicians are required to spend adequate time with patients to discuss patients' values, preferences, and prognosis. Patients at increased risk of mortality should be considered for lung transplantation. Pharmacological treatment should be limited to a carefully selected minority of patients who are willing to accept possible adverse consequences even if expected benefits are small. In such cases, it is recommended to discuss indications of weak no recommendation therapies with patients based on their individual values and preferences. Oxygen supplementation (if hypoxemic) and pulmonary rehabilitation are recommended treatments. Symptom control (palliative care) focuses on reducing symptoms (e. g., cough and dyspnea) and providing comfort to patients, rather than treating patients' disease, is also important.


Kimura T.,Tosei General Hospital
Japanese Journal of Chest Diseases | Year: 2013

The current and future problems of Noninvasive Positive-Pressure Ventilation (NPPV) for acute exacerbation of chronic respiratory failure were discussed. For acute exacerbation of COPD, evidence of the efficacy of NPPV has been established, and NPPV should be considered. For pulmonary tuberculosis sequelae, although evidence of the efficacy of NPPV is still somewhat lacking, NPPV should still be considered as it is useful. Investigations of NPPV for acute exacerbation of IPF that have been reported mainly in Japan showed potential benefit, but there was insufficient evidence, so NPPV should be considered only if you are familiar with it. NPPV withdrawal criteria and sedation during NPPV are future research topics.


Taniguchi H.,Tosei General Hospital | Kondoh Y.,Tosei General Hospital
Respirology | Year: 2016

Idiopathic interstitial pneumonias (IIPs) may have an acute or subacute presentation, or acute exacerbation may occur in a previously subclinical or unrecognized chronic IIP. Acute or subacute IIPs include acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia (COP), nonspecific interstitial pneumonia (NSIP), acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) and AE-NSIP. Interstitial lung diseases (ILDs) including connective tissue disease (CTD) associated ILD, hypersensitivity pneumonitis, acute eosinophilic pneumonia, drug-induced lung disease and diffuse alveolar haemorrhage need to be differentiated from acute and subacute IIPs. Despite the severe lack of randomized controlled trials for the treatment of acute and subacute IIPs, the mainstream treatment remains corticosteroid therapy. Other potential therapies reported in the literature include corticosteroids and immunosuppression, antibiotics, anticoagulants, neutrophil elastase inhibitor, autoantibody-targeted treatment, antifibrotics and hemoperfusion therapy. With regard to mechanical ventilation, patients in recent studies with acute and subacute IIPs have shown better survival than those in previous studies. Therefore, a careful value-laden decision about the indications for endotracheal intubation should be made for each patient. Noninvasive ventilation may be beneficial to reduce ventilator associated pneumonia. © 2016 Asian Pacific Society of Respirology

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