Nrf2 Is a Protective Factor against Oxidative Stresses Induced by Diesel Exhaust Particle in Allergic Asthma

Epidemiological studies have shown that air pollutants, such as diesel exhaust particle (DEP), are implicated in the increased incidence of allergic airway disorders. In vitro studies of molecular mechanisms have focused on the role of reactive oxygen species generated directly and indirectly by the exposure to DEP. Antioxidants effectively reduce the allergic inflammatory effects induced by DEP both in vitro and in vivo. On the other hand, Nrf2 is a transcription factor essential for the inducible and/or constitutive expression of phase II and antioxidant enzymes. Disruption of Nrf2 enhances susceptibility to airway inflammatory responses and exacerbation of allergic inflammation induced by DEP in mice. Host responses to DEP are regulated by a balance between antioxidants and proinflammatory responses. Nrf2 may be an important protective factor against oxidative stresses induced by DEP in airway inflammation and allergic asthma and is expected to contribute to chemoprevention against DEP health effects in susceptible individuals

Continued treatment with nintedanib in patients with systemic sclerosis-associated interstitial lung disease: data from SENSCIS-ON

OBJECTIVES In the SENSCIS trial in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) versus placebo, with adverse events that were manageable for most patients. An open-label extension trial, SENSCIS-ON, is assessing safety and FVC decline during longer term nintedanib treatment. METHODS Patients who completed the SENSCIS trial or a drug-drug interaction (DDI) study of nintedanib and oral contraceptive on treatment were eligible to enter SENSCIS-ON. Adverse events and changes in FVC over 52 weeks of SENSCIS-ON were assessed in patients who received nintedanib in SENSCIS and continued nintedanib in SENSCIS-ON ('continued nintedanib' group) and in patients who received placebo in SENSCIS and initiated nintedanib in SENSCIS-ON or who received nintedanib for ≤28 days in the DDI study ('initiated nintedanib' group). RESULTS There were 197 patients in the continued nintedanib group and 247 in the initiated nintedanib group. Diarrhoea was reported in 68.0% and 68.8% of patients in these groups, respectively. Adverse events led to discontinuation of nintedanib in 4.6% and 21.5% of the continued nintedanib and initiated nintedanib groups, respectively. Mean (SE) changes in FVC from baseline to week 52 of SENSCIS-ON were -58.3 (15.5) mL in the continued nintedanib group and -44.0 (16.2) mL in the initiated nintedanib group. CONCLUSIONS The safety profile of nintedanib over 52 weeks of SENSCIS-ON was consistent with that reported in SENSCIS. The change in FVC over 52 weeks of SENSCIS-ON was similar to that observed in the nintedanib group of SENSCIS

The clinical significance of 5% change in vital capacity in patients with idiopathic pulmonary fibrosis: extended analysis of the pirfenidone trial

<p>Abstract</p> <p>Background</p> <p>Our phase III clinical trial of pirfenidone for patients with idiopathic pulmonary fibrosis (IPF) revealed the efficacy in reducing the decline of vital capacity (VC) and increasing the progression-free survival (PFS) time by pirfenidone. Recently, marginal decline in forced VC (FVC) has been reported to be associated with poor outcome in IPF. We sought to evaluate the efficacy of pirfenidone from the aspects of 5% change in VC.</p> <p>Methods</p> <p>Improvement ratings based on 5% change in absolute VC, i.e., "improved (VC ≥ 5% increase)", "stable (VC < 5% change)", and "worsened (VC ≥ 5% decrease)" at month 3, 6, 9 and 12 were compared between high-dose pirfenidone (1800 mg/day; n = 108) and placebo (n = 104) groups, and (high-dose and low-dose (1200 mg/day; n = 55)) pirfenidone (n = 163) and placebo groups. PFS times with defining the disease progression as death or a ≥ 5% decline in VC were also compared between high-dose pirfenidone and placebo groups, and low-dose pirfenidone and placebo groups. Furthermore, considering "worsened" and "non-worsened (improved and stable)" of the ratings at months 3 and 12 as "positive" and "negative", respectively, and the positive and negative predictive values of the ratings were calculated in each group.</p> <p>Results</p> <p>In the comparison of the improvement ratings, the statistically significant differences were clearly revealed at months 3, 6, 9, and 12 between pirfenidone and placebo groups. Risk reductions by pirfenidone to placebo were approximately 35% over the study period. In the comparison of the PFS times, statistically significant difference was also observed between pirfenidone and placebo groups. The positive/negative predictive values in placebo and pirfenidone groups were 86.1%/50.8% and 87.1%/71.7%, respectively. Further, the baseline characteristics of patients worsened at month 3 had generally severe impairment, and their clinical outcomes including mortality were also significantly worsened after 1 year.</p> <p>Conclusions</p> <p>The efficacy of pirfenidone in Japanese phase III trial was supported by the rating of 5% decline in VC, and the VC changes at month 3 may be used as a prognostic factor of IPF.</p> <p>Trial Registration</p> <p>This clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13^th, 2005 (Registration Number: JAPICCTI-050121).</p

Efficacy and safety of nintedanib in Japanese patients with progressive fibrosing interstitial lung diseases : Subgroup analysis of the randomised, double-blind, placebo-controlled, phase 3 INBUILD trial

Background: The efficacy of nintedanib in progressive fibrosing interstitial lung diseases (ILDs) was demonstrated in the randomised, double-blind, placebo-controlled INBUILD trial. This subgroup analysis evaluated the efficacy and safety of nintedanib in the Japanese population. Methods: Patients with progressive fibrosing ILDs (evaluated by physicians within 24 months of screening) were randomised (1:1) to twice-daily 150-mg nintedanib or placebo; treatment continued until the last patient completed 52 weeks. The primary endpoint was the annual rate of decline in forced vital capacity (FVC) over 52 weeks. Time-to-first acute ILD exacerbation or death and time-to-death up until the last patient had completed the week 52 visit were evaluated. This subgroup analysis included 108 Japanese patients. Results: The adjusted annual rates of FVC decline (mL/year) over 52 weeks for Japanese patients were −148.31 (nintedanib) and −240.36 (placebo), adjusted difference: 92.05 (95% CI: −10.69–194.80) and for non-Japanese patients were −67.41 (nintedanib) and −177.65 (placebo), adjusted difference: 110.24 (95% CI: 64.97–155.52). No heterogeneity in treatment effect between Japanese and non-Japanese subgroups was observed (treatment-by-subgroup interaction, p = 0.75). The risks of “acute exacerbation or death” (hazard ratio, 0.30 [95% CI: 0.10–0.91]) and mortality (hazard ratio, 0.54 [95% CI: 0.14–2.11]) in Japanese patients were numerically lower for nintedanib than placebo. There were no new or unexpected safety findings. Conclusions: In Japanese patients, nintedanib slowed ILD progression, evidenced by a reduction in the annual rate of decline in FVC vs placebo. The efficacy and safety of nintedanib in Japanese patients were consistent with the overall INBUILD population

Pixel-wise segmentation of severely pathologic retinal pigment epithelium and choroidal stroma using multi-contrast Jones matrix optical coherence tomography

Tissue segmentation of retinal optical coherence tomography (OCT) is widely used in ophthalmic diagnosis. However, its performance in severe pathologic cases is still insufficient. We propose a pixel-wise segmentation method that uses the multi-contrast measurement capability of Jones matrix OCT (JM-OCT). This method is applicable to both normal and pathologic retinal pigment epithelium (RPE) and choroidal stroma. In this method, “features,” which are sensitive to specific tissues of interest, are synthesized by combining the multi-contrast images of JM-OCT, including attenuation coefficient, degree-of-polarization-uniformity, and OCT angiography. The tissue segmentation is done by simple thresholding of the feature. Compared with conventional segmentation methods for pathologic maculae, the proposed method is less computationally intensive. The segmentation method was validated by applying it to images from normal and severely pathologic cases. The segmentation results enabled the development of several types of en face visualizations, including melano-layer thickness maps, RPE elevation maps, choroidal thickness maps, and choroidal stromal attenuation coefficient maps. These facilitate close examination of macular pathology. The melano-layer thickness map is very similar to a near infrared fundus autofluorescence image, so the map can be used to identify the source of a hyper-autofluorescent signal

Oficjalne wytyczne ATS/ERS/JRS/ALAT dotyczące postępowania w praktyce klinicznej: leczenie idiopatycznego włóknienia płuc

WPROWADZENIE: Niniejszy dokument uaktualnia wytyczne Amerykańskiego Towarzystwa Chorób Klatki Piersiowej (ATS) / Europejskiego Towarzystwa Pulmonologicznego (ERS) / Japońskiego Towarzystwa Pulmonologicznego (JRS) / Latynoamerykańskiego Towarzystwa Chorób Klatki Piersiowej (ALAT) dotyczące leczenia idiopatycznego włóknienia płuc. METODY: Przeprowadzono przeglądy systematyczne, a jeśli było to możliwe, metaanalizy, w celu podsumowania wszystkich dostępnych dowodów istotnych do sformułowania odpowiedzi na zadane pytania. Dowody oceniano za pomocą systemu Grading of Recommendations, Assessment, Development and Evaluation (GRADE), a następnie dyskutowano nad nimi w ramach panelu multidyscyplinarnego. Zastosowano strategie wcześniejszego określenia konfliktów interesów, a zalecenia zostały opracowane, napisane i ocenione wyłącznie przez członków paneli niezgłaszających konfliktów. WYNIKI: Zalecenia przemawiające za określonymi interwencjami leczniczymi lub przeciw nim sformułowano po uwzględnieniu danych dotyczących skuteczności, znaczenia zbadanych punktów końcowych, pożądanych i niepożądanych następstw leczenia, kosztów, wykonalności, akceptowalności interwencji i równych szans dostępu do opieki zdrowotnej. WNIOSKI: Panel opracował i przedstawił podstawy do stworzenia zaleceń przemawiających za interwencjami leczniczymi lub przeciw nim w idiopatycznym włóknieniu płuc.WPROWADZENIE: Niniejszy dokument uaktualnia wytyczne Amerykańskiego Towarzystwa Chorób Klatki Piersiowej (ATS) / Europejskiego Towarzystwa Pulmonologicznego (ERS) / Japońskiego Towarzystwa Pulmonologicznego (JRS) / Latynoamerykańskiego Towarzystwa Chorób Klatki Piersiowej (ALAT) dotyczące leczenia idiopatycznego włóknienia płuc. METODY: Przeprowadzono przeglądy systematyczne, a jeśli było to możliwe, metaanalizy, w celu podsumowania wszystkich dostępnych dowodów istotnych do sformułowania odpowiedzi na zadane pytania. Dowody oceniano za pomocą systemu Grading of Recommendations, Assessment, Development and Evaluation (GRADE), a następnie dyskutowano nad nimi w ramach panelu multidyscyplinarnego. Zastosowano strategie wcześniejszego określenia konfliktów interesów, a zalecenia zostały opracowane, napisane i ocenione wyłącznie przez członków paneli niezgłaszających konfliktów. WYNIKI: Zalecenia przemawiające za określonymi interwencjami leczniczymi lub przeciw nim sformułowano po uwzględnieniu danych dotyczących skuteczności, znaczenia zbadanych punktów końcowych, pożądanych i niepożądanych następstw leczenia, kosztów, wykonalności, akceptowalności interwencji i równych szans dostępu do opieki zdrowotnej. WNIOSKI: Panel opracował i przedstawił podstawy do stworzenia zaleceń przemawiających za interwencjami leczniczymi lub przeciw nim w idiopatycznym włóknieniu płuc

Pirfenidone treatment of idiopathic pulmonary fibrosis

Pirfenidone is the first antifibrotic agent to be approved for the treatment of pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is one of the idiopathic interstitial pneumonias with the worst prognoses; approximately half of patients die within 3–5 years, and the need for an effective treatment has been unmet until recently. The etiology of IPF is still unknown and its pathogenesis is poorly understood. Anti-inflammatory drugs, such as corticosteroids and some immunosuppressants, have been empirically used to treat IPF, although they have not been objectively proven to be effective by large-scale randomized, controlled trials. Pirfenidone is an agent that can inhibit the decline of forced vital capacity (FVC)/vital capacity (VC) and that thereby can be hoped to decrease the mortality rate. The number of clinical trials of pirfenidone completed, ongoing, or planned is growing, and the present status of pirfenidone as treatment for IPF is summarized in this review