Comparison between tools for measuring breathlessness: Cross-sectional validation of the Japanese version of the Dyspnoea-12.

INTRODUCTION: The Dyspnoea-12 (D-12) is a brief, easy to complete questionnaire for measuring breathlessness. OBJECTIVES: To facilitate further efforts to measure dyspnoea in real clinical settings, the authors aimed to develop and validate a Japanese version of the D-12 and also compare the D-12 with the Baseline Dyspnea Index (BDI) and the Activity component of the St. George's Respiratory Questionnaire (SGRQ). METHODS: The standardized procedure in accordance with international guidelines was used to create the translation. A validation study with a cross-sectional observational design was conducted on 122 subjects with stable chronic obstructive pulmonary disease (COPD). RESULTS: The internal consistency of the D-12 was high (Cronbach's coefficient α = 0.883) and similar to that of the BDI (α = 0.824) and SGRQ Activity (α = 0.872). The relationships between tools were statistically significant (|Rs | = 0.53 to 0.66). Although the scores obtained from all three tools were skewed toward the milder end of the respective scales, this deviation was most prominent in the D-12 with a floor effect of 48.4%. CONCLUSION: The Japanese version of the D-12 was successfully validated, but we should be careful of any floor effect and marked skew to the mild end of the scale, especially in subjects with mild COPD.

Multi-Institutional Prospective Cohort Study of Patients With Pulmonary Hypertension Associated With Respiratory Diseases.

BACKGROUND: There is limited evidence for pulmonary arterial hypertension (PAH)-targeted therapy in patients with pulmonary hypertension associated with respiratory disease (R-PH). Therefore, we conducted a multicenter prospective study of patients with R-PH to examine real-world characteristics of responders by evaluating demographics, treatment backgrounds, and prognosis.Methods and Results:Among the 281 patients with R-PH included in this study, there was a treatment-naïve cohort of 183 patients with normal pulmonary arterial wedge pressure and 1 of 4 major diseases (chronic obstructive pulmonary diseases, interstitial pneumonia [IP], IP with connective tissue disease, or combined pulmonary fibrosis with emphysema); 43% of patients had mild ventilatory impairment (MVI), whereas 52% had a severe form of PH. 68% received PAH-targeted therapies (mainly phosphodiesterase-5 inhibitors). Among patients with MVI, those treated initially (i.e., within 2 months of the first right heart catheterization) had better survival than patients not treated initially (3-year survival 70.6% vs. 34.2%; P=0.01); there was no significant difference in survival in the group with severe ventilatory impairment (49.6% vs. 32.1%; P=0.38). Responders to PAH-targeted therapy were more prevalent in the group with MVI. CONCLUSIONS: This first Japanese registry of R-PH showed that a high proportion of patients with MVI (PAH phenotype) had better survival if they received initial treatment with PAH-targeted therapies. Responders were predominant in the group with MVI.

Impact of post-capillary pulmonary hypertension on mortality in interstitial lung disease.

BACKGROUND: Pulmonary hypertension (PH) influences mortality in patients with interstitial lung disease (ILD). Almost all studies on patients with ILD, have focused on the clinical impact of pre-capillary PH on survival. Therefore, little is known about the influence of post-capillary PH. We aimed to assess the prevalence of post-capillary PH and its clinical impact on survival in patients with ILD, followed by comparison with pre-capillary PH. METHODS: This retrospective study enrolled 1152 patients with ILD who were diagnosed with PH using right heart catheterization between May 2007 and December 2015. We analyzed the demographics and composite outcomes (defined as death from any cause or lung transplantation) of patients with post-capillary PH and compared them with patients with pre-capillary PH. RESULTS: Thirty-two (20%) of the 157 patients with ILD-PH were diagnosed with post-capillary PH. Patients with post-capillary PH had significantly lower modified Medical Research Council scores, higher diffusion capacity for carbon monoxide, higher resting PaO2, lower pulmonary vascular resistance (PVR), and higher lowest oxygen saturation during the 6-min walk test compared to those with pre-capillary PH. Cardiovascular diseases were associated with a higher risk of mortality in patients with post-capillary PH. Multivariate Cox proportional hazards analysis demonstrated no significant difference between the composite outcomes in pre-capillary and post-capillary PH, while PVR and the ILD Gender-Age-Physiology Index were significantly associated with the composite outcome. CONCLUSIONS: We found that approximately one-fifth of patients with ILD-PH were diagnosed with post-capillary PH, and that PVR and not post-capillary PH was associated with mortality.

Structural and Mechanical Properties of a-BCN Films Prepared by an Arc-Sputtering Hybrid Process.

Amorphous boron carbon nitride (a-BCN) films exhibit excellent properties such as high hardness and high wear resistance. However, the correlation between the film structure and its mechanical properties is not fully understood. In this study, a-BCN films were prepared by an arc-sputtering hybrid process under various coating conditions, and the correlations between the film's structure and mechanical properties were clarified. Glow discharge optical emission spectroscopy, X-ray photoelectron spectroscopy, Fourier-transform infrared spectroscopy, and Raman spectroscopy were used to analyze the structural properties and chemical composition. Nanoindentation and ball-on-disc tests were performed to evaluate the hardness and to estimate the friction coefficient and wear volume, respectively. The results indicated that the mechanical properties strongly depend on the carbon content in the film; it decreases significantly when the carbon content is <90%. On the other hand, by controlling the contents of boron and nitrogen to a very small amount (up to 2.5 at.%), it is possible to synthesize a film that has nearly the same hardness and friction coefficient as those of an amorphous carbon (a-C) film and better wear resistance than the a-C film.

Acute exacerbation of idiopathic interstitial pneumonias related to chemotherapy for lung cancer: nationwide surveillance in Japan.

BACKGROUND: Chemotherapy-induced acute exacerbation (AEx) of idiopathic interstitial pneumonias (IIPs) seriously compromises the success of treatment of Japanese lung cancer patients. Here, we conducted a nationwide surveillance to clarify the risk of AEx and compare it with the survival benefit of chemotherapy for this population. METHODS: Advanced nonsmall cell lung cancer (NSCLC) or small cell lung cancer (SCLC) patients with IIPs were retrospectively analysed. For the surveillance of first-line chemotherapy in 2009, we gathered clinical data from 396 patients who received chemotherapy at 19 institutions between January 1990 and July 2009. In a consecutive retrospective study in 2012, we analysed data from 278 patients from 17 institutions who received second-line chemotherapy between April 2002 and March 2012. RESULTS: Of the 396 patients analysed, 13.1% developed chemotherapy-related AEx. Combination chemotherapies of carboplatin plus paclitaxel (CP) or carboplatin plus etoposide (CE) were frequently used as first-line treatments. The lowest incidence of AEx was 3.7% in CE, followed by 8.6% in CP. In the retrospective study, 16.2% of the 278 patients developed a second-line chemotherapy-related AEx. The overall response rate by second-line chemotherapy was 7.4% in NSCLC and 25.7% in SCLC. The median overall survival from second-line and first-line chemotherapy was 8.0 and 14.3 months in NSCLC, and 8.7 and 16.0 months in SCLC, respectively. CONCLUSION: Combination chemotherapies consisting of CP or CE are candidates for standard first-line treatments for patients with advanced lung cancer accompanied by IIP. Second-line chemotherapy should be considered for patients remaining fit enough to receive it.

Supplemental oxygen improves exercise capacity in IPF patients with exertional desaturation.

BACKGROUND AND OBJECTIVE: The efficacy of supplemental oxygen during exercise remains unclear for patients with IPF, as there have been conflicting results from recent prospective studies with small sample sizes. METHODS: This prospective, single-blind, randomized, crossover trial evaluated the efficacy of supplemental oxygen compared with placebo air during exercise in consecutive patients with IPF without resting hypoxaemia at initial evaluation. Patients with <90% SpO2 in a 6MWT using room air were randomly assigned to a CWRET at 80% of peak work rate with oxygen or placebo air gas via nasal cannula at 4 L/min. The primary endpoint was the effect of supplemental oxygen on endurance time. RESULTS: We recruited 72 consecutive patients (median age: 66.5 years, % FVC: 84.6%, % DLCO : 61.4%). Supplemental oxygen significantly increased the endurance time (340-424 s; P < 0.001) and minimum SpO2 (88.0-94.0%; P < 0.001) compared with placebo air. Furthermore, supplemental oxygen significantly improved dyspnoea and leg fatigue. In a multivariate linear regression analysis, the endurance time on air was an independent explanatory variable of the improvement rate of endurance time (P = 0.02). CONCLUSION: In mild-moderate IPF with exercise-induced hypoxaemia even without resting hypoxaemia, supplemental oxygen during exercise improved the endurance time, desaturation and subjective symptoms. Patients with shorter endurance times with placebo air showed better improvement with supplemental oxygen.

Early decrease in erector spinae muscle area and future risk of mortality in idiopathic pulmonary fibrosis.

Computed tomography (CT) assessment of the cross-sectional area of the erector spinae muscles (ESMCSA) can be used to evaluate sarcopenia and cachexia in patients with lung diseases. This study aimed to confirm whether serial changes in ESMCSA are associated with survival in patients with idiopathic pulmonary fibrosis (IPF). Data from consecutive patients with IPF who were referred to a single centre were retrospectively reviewed. We measured the ESMCSA at the level of the 12th thoracic vertebra on CT images at referral and 6 months later (n = 119). The follow-up time was from 817-1633 days (median, 1335 days) and 59 patients (49.6%) died. A univariate Cox regression analysis showed that the decline in % predicted forced vital capacity (FVC) (Hazard ratios [HR] 1.041, 95% confidence interval [CI] 1.013-1.069, P = 0.004), the decline in body mass index (BMI) (HR 1.084, 95% CI 1.037-1.128; P < 0.001) and that in ESMCSA (HR 1.057, 95% CI 1.027-1.086; P < 0.001) were prognostic factors. For multivariate analyses, the decline in ESMCSA (HR 1.039, 95% CI 1.007-1.071, P = 0.015) was a significant prognostic factor, while those in % FVC and BMI were discarded. Early decrease in ESMCSA may be a useful predictor of prognosis in patients with IPF.

Thrombomodulin Alfa for Acute Exacerbation of Idiopathic Pulmonary Fibrosis. A Randomized, Double-Blind Placebo-controlled Trial.

Rationale: Acute exacerbation during the course of idiopathic pulmonary fibrosis causes a poor prognosis. Coagulation abnormalities and endothelial damage are involved in its pathogenesis. Thrombomodulin alfa, a recombinant human soluble thrombomodulin, has anticoagulant and antiinflammatory effects. Several clinical studies have shown that thrombomodulin alfa may improve survival of acute exacerbation.Objectives: To determine the efficacy and safety of thrombomodulin alfa compared with placebo in acute exacerbation of idiopathic pulmonary fibrosis.Methods: This randomized, double-blind placebo-controlled phase 3 study conducted at 27 sites in Japan involved patients with an acute exacerbation of idiopathic pulmonary fibrosis. Subjects were randomized 1:1 to receive placebo or thrombomodulin alfa (380 U/kg/d for 14 d by intravenous drip infusion). All subjects were treated with high-dose corticosteroid therapy. The primary endpoint was the survival proportion on Day 90.Measurements and Main Results: Of the 82 randomized subjects, 77 completed the study and were included in the full analysis set (thrombomodulin alfa, n = 40; placebo, n = 37). The survival proportions on Day 90 were 72.5% (29 of 40) in the thrombomodulin alfa group and 89.2% (33 of 37) in the placebo group, a difference of -16.7 percentage points (95% confidence interval, -33.8 to 0.4%; P = 0.0863). In the safety population (n = 80), bleeding adverse events occurred in the thrombomodulin alfa group (10 of 42; 23.8%) and the placebo group (4 of 38; 10.5%).Conclusions: Thrombomodulin alfa did not improve the 90-day survival proportion. The present results suggest that the use of thrombomodulin alfa for the treatment of acute exacerbation of idiopathic pulmonary fibrosis not be recommended.Clinical trial registered with www.clinicaltrials.gov (NCT02739165).

Antipsychotic-like effects of a novel phosphodiesterase 10A inhibitor T-251 in rodents.

Phosphodiesterase 10A (PDE10A) is a dual-substrate PDE that hydrolyzes both cAMP and cGMP. PDE10A is selectively expressed in medium spiny neurons in the striatum, suggesting the potential of PDE10A inhibitors in the treatment of schizophrenia. This study presents the pharmacological profile of a novel PDE10A inhibitor, 2-[(E)-2-(7-fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine hydrochloride (T-251) in rodent models of schizophrenia. T-251 showed a potent inhibitory activity against human PDE10A (IC50 = 0.050 nmol/L) and showed high selectivity over other PDE families which have over 10,000-fold IC50 values. Oral administration of T-251 (0.1-1.0 mg/kg) increased cAMP and cGMP in the striatum in a dose-dependent manner. Oral administration of T-251 attenuated MK-801 induced hyperactivity (ED50 = 0.68 mg/kg) and suppressed conditioned avoidance response (ID50 = 0.87 mg/kg) in rats in a dose dependent manner. Furthermore, T-251 significantly attenuated MK-801 induced prepulse inhibition deficits and cognitive deficits in rats. Unlike haloperidol and olanzapine, T-251 (1.0-30 mg/kg) did not cause catalepsy in rats. Moreover, T-251 (0.6 and 6.0 mg/kg) did not increase plasma levels of prolactin at 1 h after administration, whereas haloperidol and olanzapine significantly increased them. The antipsychotic-like effects and cognitive enhancement of T-251 without catalepsy or plasma prolactin elevation observed in rats suggests that T-251 would be a novel antipsychotic with an improved side-effect profile.

Diagnostic Likelihood Thresholds That Define a Working Diagnosis of Idiopathic Pulmonary Fibrosis.

Rationale: The level of diagnostic likelihood at which physicians prescribe antifibrotic therapy without requesting surgical lung biopsy (SLB) in patients suspected of idiopathic pulmonary fibrosis (IPF) is unknown.Objectives: To determine how often physicians advocate SLB in patient subgroups defined by IPF likelihood and risk associated with SLB, and to identify the level of diagnostic likelihood at which physicians prescribe antifibrotic therapy with requesting SLB.Methods: An international cohort of respiratory physicians evaluated 60 cases of interstitial lung disease, giving: 1) differential diagnoses with diagnostic likelihood; 2) a decision on the need for SLB; and 3) initial management. Diagnoses were stratified according to diagnostic likelihood bands described by Ryerson and colleagues.Measurements and Main Results: A total of 404 physicians evaluated the 60 cases (24,240 physician-patient evaluations). IPF was part of the differential diagnosis in 9,958/24,240 (41.1%) of all physician-patient evaluations. SLB was requested in 8.1%, 29.6%, and 48.4% of definite, provisional high-confidence and provisional low-confidence diagnoses of IPF, respectively. In 63.0% of provisional high-confidence IPF diagnoses, antifibrotic therapy was prescribed without requesting SLB. No significant mortality difference was observed between cases given a definite diagnosis of IPF (90-100% diagnostic likelihood) and cases given a provisional high-confidence IPF diagnosis (hazard ratio, 0.97; P = 0.65; 95% confidence interval, 0.90-1.04).Conclusions: Most respiratory physicians prescribe antifibrotic therapy without requesting an SLB if a provisional high-confidence diagnosis or "working diagnosis" of IPF can be made (likelihood ≥ 70%). SLB is recommended in only a minority of patients with suspected, but not definite, IPF.

Discovery of a pyrazolo[1,5-a]pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety.

We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a]pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-á-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration.

Pulmonary interstitial emphysema is a risk factor for poor prognosis and a cause of air leaks.

BACKGROUND: Pulmonary interstitial emphysema is a rare, abnormal condition in which air pressure from the alveolar airspace tears the adjacent interstitial tissues of the lung and causes the formation of cystic spaces. Pulmonary interstitial emphysema is a known indication for mechanical ventilation in premature infants with neonatal respiratory distress syndrome, and it can be observed in various types of interstitial lung disease. Nevertheless, its pathogenesis and clinical impact remain unknown. METHODS: We reviewed data from 433 cases of interstitial lung disease from an external consultation archive. Multidisciplinary diagnosis along with clinical and follow-up data, including events of air leaks such as pneumothorax and mediastinal emphysema, were obtained and compared to those of 150 control cases of interstitial lung disease without pulmonary interstitial emphysema. RESULTS: We found 22 (5.1%) cases of interstitial lung disease with pulmonary interstitial emphysema. The diagnoses included idiopathic pulmonary fibrosis (5/22 [22.7%]), pleuroparenchymal fibroelastosis (4/22 [18.2%]), chronic hypersensitivity pneumonia (4/22 [18.2%]), and others (9/22 [40.9%]). Cases involving pulmonary interstitial emphysema demonstrated a significantly higher frequency of air leaks than did those without pulmonary interstitial emphysema (12/22 [54.5%] versus 23/150 [15.3%]; P < 0.001; odds ratio, 6.63) and were associated with worse prognosis (P = 0.009 [log-rank]) and a lower median percent forced vital capacity (73.2% versus 84.0%; P < 0.001). CONCLUSIONS: We found that pulmonary interstitial emphysema is an independent factor for poor prognosis, which also shows a trend to cause air leaks, including pneumothorax and mediastinal emphysema.

Proposed method of histological separation between connective tissue disease-associated interstitial pneumonia and idiopathic interstitial pneumonias.

OBJECTIVES: Idiopathic interstitial pneumonia (IIP) and connective tissue disease -associated interstitial pneumonia (CTD-IP) are the two most common types of interstitial pneumonia. IIP and CTD-IP share common histological features, yet their clinical management is different. Separation of the two conditions based solely on histology can be challenging, and there are no established criteria. MATERIALS AND METHODS: We selected 105 consecutive cases of IIP (79 usual interstitial pneumonia and 26 non-specific interstitial pneumonia) and 49 cases of CTD-IP for derivation and 32 cases of IIP and 10 cases of CTD-IP for validation. Fourteen histological parameters were evaluated independently by two pathologists for derivation group and graded into 0 to 3. The association between the score for each marker and a diagnosis of CTD was investigated using Fisher's exact test and stepwise logistic regression analysis. A formula for calculating the probability of IIP and CTD-IP was constructed by the markers identified in the regression test with coefficients for each finding. The formula was confirmed using validation case group. RESULTS: Stepwise logistic regression analysis showed that plasmacytosis, lymphoid follicle with germinal center, and airspace fibrin were suggestive of CTD-IP and that fibroblastic foci, smooth muscle hyperplasia, cellular IP, dense perivascular collagen, and fat metaplasia were suggestive of IIP. The formula used to calculate the probabilities based on estimated values for each finding was created, and user-friendly web based app was composed at www.ctdip.com. On the validation study, 30 out of 32 IIP and eight out of 10 CTD-IPs were distinguished correctly by the app (Specificity: 93%, Sensitivity: 80%). CONCLUSIONS: We identified histological markers and derived a practical formula and user-friendly app to distinguish CTD-IPs from IIP.

Validation of the prediction rules identifying drug-resistant pathogens in community-onset pneumonia.

BACKGROUND: Appropriate initial antibiotic treatment and avoiding administration of unnecessary broad-spectrum antibiotics are important for the treatment of pneumonia. To achieve this, assessment of risk for drug-resistant pathogens (DRPs) at diagnosis is essential. PURPOSE: The aim of this study was to validate a predictive rule for DRPs that we previously proposed (the community-acquired pneumonia drug-resistant pathogen [CAP-DRP] rule), comparing several other predictive methods. PATIENTS AND METHODS: A prospective observational study was conducted in hospitalized patients with community-onset pneumonia at four institutions in Japan. Pathogens identified as not susceptible to ceftriaxone, ampicillin-sulbactam, macrolides, and respiratory fluoroquinolones were defined as CAP-DRPs. RESULTS: CAP-DRPs were identified in 73 (10.1%) of 721 patients analyzed. The CAP-DRP rule differentiated low vs high risk of CAP-DRP at the threshold of ≥3 points or 2 points plus any of methicillin-resistant Staphylococcus aureus specific factors with a sensitivity of 0.45, specificity of 0.87, positive predictive value of 0.47, negative predictive value of 0.87, and accuracy of 0.79. Its discrimination performance, area under the receiver operating characteristic curve, was 0.73 (95% confidence interval 0.66-0.79). Specificity of the CAP-DRP rule against CAP-DRPs was the highest among the six predictive rules tested. CONCLUSION: The performance of the predictive rules and criteria for CAP-DRPs was limited. However, the CAP-DRP rule yielded high specificity and could specify patients who should be treated with non-broad-spectrum antibiotics, eg, a non-pseudomonal ß-lactam plus a macrolide, more precisely.

Outcomes with newly proposed classification of acute respiratory deterioration in idiopathic pulmonary fibrosis.

BACKGROUND: Respiratory-related hospitalization, in particular acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), is common and associated with increasing mortality in patients with IPF. We aimed to evaluate the implications of a newly proposed framework of acute respiratory deterioration (ARD) and AE-IPF in hospitalized patients. METHODS: Using the data of an IPF cohort consisting of 225 consecutive patients, we retrospectively studied first hospitalizations from January 2008 to December 2017. We analysed the demographics and 90-day mortality of patients with AE-IPF and those with parenchymal cause of ARD other than AE. RESULTS: Among 122 patients with first hospitalization for ARD, 35 patients were diagnosed with AE-IPF, including 11 patients with triggered AE. Parenchymal cause of ARD other than AE was diagnosed in 71 patients, and extra-parenchymal cause in 16 patients. Almost all hospitalized patients (93%) underwent chest CT, and 83% of patients with AE-IPF underwent bronchoalveolar lavage. There was a significant difference in the anti-inflammatory therapy between the AE-IPF group and parenchymal cause of ARD other than AE group (p < 0.001). AE-IPF was independently associated with poor survival in multivariate Cox proportional regression analysis. CONCLUSIONS: AE-IPF accounted for about 30% of first hospitalizations for ARD, and differentiation between AE-IPF and the other categories in ARD is important from a therapeutic and a prognostic point of view.

Japanese guideline for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology which accounts for a large proportion of cases of idiopathic interstitial pneumonia. It has a very poor prognosis with a 5-year survival rate of 30% or below, and so far there has been no guideline in Japan offering an established effective therapy based on evidence. In addition to the establishment of basic therapies, there is also an urgent need to establish therapies to deal with complications, as death occurs in many cases due to acute exacerbation or comorbid lung cancer. It was therefore decided to formulate a guideline in order to promote evidence-based clinical practice, to further improve the quality of medical treatment in the clinical setting, and to allow the benefits to be enjoyed by the public.

Multidimensional improvement in connective tissue disease-associated interstitial lung disease: Two courses of pulse dose methylprednisolone followed by low-dose prednisone and tacrolimus.

BACKGROUND AND OBJECTIVE: Corticosteroids and immunosuppressive agents are considered mainstays of therapy for connective tissue disease-related interstitial lung disease (CTD-ILD); however, tacrolimus with corticosteroid therapy has not been fully investigated. Our objectives were to examine the multidimensional therapeutic benefit and tolerability of the combined therapy for the initial treatment of patients with CTD-ILD. METHODS: In this retrospective case series, we identified consecutive CTD-ILD patients treated with tacrolimus plus intravenous (i.v.) methylprednisolone (1000 mg i.v. 3 days a week for 2 weeks) followed by low-dose prednisolone (10 mg/day). We assessed the multidimensional therapeutic benefit and tolerability including lung physiology, exercise capacity, exercise oxygen desaturation, modified Medical Research Council (MMRC) and St George's Respiratory Questionnaire (SGRQ). RESULTS: A total of 26 ILD patients with the underlying CTD diagnoses included 11 with rheumatoid arthritis, 9 with dermatomyositis, 4 with Sjögren's syndrome and 2 others. From baseline to 12 months, the combined therapy significantly improved forced vital capacity (FVC; 77.8% to 94.6%, P < 0.001), diffusing capacity of the lung for carbon monoxide (DLCO ; 66.1% to 75.1%, P < 0.001), 6-min walk distance (6MWD; 530 to 568 m, P = 0.02), lowest oxygen saturation on pulse oximetry (SpO2 ; 85% to 89%, P = 0.01), MMRC (1.3 to 0.8, P = 0.01) and SGRQ (38 to 21, P < 0.001). During the study period, only one patient's therapy was discontinued due to an adverse event and none had a life-threatening adverse event attributed to the combined therapy. CONCLUSION: In our cohort of CTD-ILD, two courses of pulse dose methylprednisolone therapy followed by prednisone and oral tacrolimus appeared to be well tolerated, and to have multidimensional efficacy.

Clinical spectrum and prognostic factors of possible UIP pattern on high-resolution CT in patients who underwent surgical lung biopsy.

BACKGROUND: Few studies have reported the diagnostic variability in patients with a possible usual interstitial pneumonia (UIP) pattern on high-resolution CT (HRCT) who underwent surgical lung biopsy (SLB), and the prognostic factors for these patients have not been fully evaluated. We retrospectively investigated the frequency of idiopathic pulmonary fibrosis (IPF) and prognostic factors in patients with possible UIP pattern on HRCT. METHODS: Consecutive patients who had a possible UIP pattern on HRCT, underwent SLB, and had a diagnosis of IIPs before SLB were retrospectively recruited from 10 hospitals. Diagnoses were made based on multidisciplinary discussion using the criteria for current IPF guidelines and multidisciplinary classification for IIPs in each hospital. RESULTS: 179 patients who underwent SLB were enrolled. The diagnoses were IPF in 91 patients (51%), unclassifiable IIPs in 47 (26%), idiopathic NSIP in 18 (10%), and chronic hypersensitivity pneumonia in 17 (9%). One-year FVC changes showed significant differences between IPF and non-IPF (-138.6 mL versus 18.2 mL, p = 0.014). Patients with IPF had a worse mortality than those with non-IPF (Logrank test, p = 0.025). Multivariable Cox regression analysis demonstrated that diagnoses of IPF (HR, 2.961; 95% CI, 1.183-7.410; p = 0.02), high modified MRC score (HR, 1.587; 95% CI, 1.003-2.510; p = 0.049), and low %FVC (HR, 0.972; 95% CI, 0.953-0.992; p = 0.005). CONCLUSIONS: About a half of patients with a possible UIP pattern on HRCT had diagnoses other than IPF, and patients with IPF had a worse mortality than those with an alternative diagnosis. We reaffirmed that multidisciplinary discussion is crucial in patients with possible UIP pattern on HRCT.

Discovery of 2-[(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor.

Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics.

A scoring system to predict the elevation of mean pulmonary arterial pressure in idiopathic pulmonary fibrosis.

Elevated mean pulmonary arterial pressure (MPAP; ≥21 mmHg) is sometimes seen in patients with idiopathic pulmonary fibrosis (IPF) and has an adverse impact upon survival. Although early diagnosis is crucial, there is no established screening tool that uses a combination of noninvasive examinations.We retrospectively analysed IPF patients at initial evaluation from April 2007 to July 2015 and, using logistic regression analysis, created a screening tool to identify elevated MPAP. Internal validation was also assessed for external validity using a bootstrap method.Using right-heart catheterisation (RHC), elevation of MPAP was determined to be present in 55 out of 273 patients. Multivariate models demonstrated that % predicted diffusing capacity of the lung for carbon monoxide (DLCO) <50%, ratio of pulmonary artery diameter to aorta diameter (PA/Ao) on computed tomography (CT) ≥0.9 and arterial oxygen tension (PaO2 ) <80 Torr were independent predictors. When we assigned a single point to each variable, the prevalence of elevation of MPAP with a score of zero, one, two or three points was 6.7%, 16.0%, 29.1% and 65.4%, respectively. The area under curve (AUC) for the receiver operating characteristic (ROC) curve was good at 0.757 (95% CI 0.682-0.833).A simple clinical scoring system consisting of % predicted DLCO, PA/Ao ratio on CT and PaO2 can easily predict elevation of MPAP in patients with IPF.