Absorption,distribution, metabolism and excretion of novel phosphodiesterase type 4 inhibitor ASP3258 in rats

The potent and selective phosphodiesterase 4 inhibitor ASP3258 is a novel therapeutic agent for asthma and chronic obstructive pulmonary disease (COPD). After a single oral administration to rats, ASP3258 is rapidly absorbed with a bioavailability of 106%. In situ absorption data indicated that ASP3258 is mainly absorbed in the small intestine. Tissue distribution data after oral administration of ¹⁴C‐ASP3258 showed rapid and extensive distribution to various tissues. Excluding the gastrointestinal tract, the tissues with the highest concentrations were liver, heart and plasma. Liquid chromatography‐nuclear magnetic resonance spectroscopy data revealed that O‐glucuronidation of the carboxylic acid moiety of ASP3258 (formation of an acyl glucuronide) plays a key role in metabolism. No indication was found that the acyl glucuronide reacted with proteins in plasma or tissues. When ¹⁴C‐ASP3258 was orally administered to intact rats, urinary and fecal excretion accounted for 1.3% and 100.6% of the administered radioactivity, respectively. After a single oral administration of ¹⁴C‐ASP3258 to bile‐cannulated rats, urinary and biliary excretion accounted for 0.7% and 93.8% of the administered radioactivity, respectively. These findings suggest that fecal excretion via bile plays an important role in the elimination of ASP3258‐derived radioactivity. In vitro metabolic profiles were relatively similar among the species examined, suggesting that our findings in rats may help us to understand pharmacokinetics, efficacy and safety profiles in humans and other species. Copyright © 2014 John Wiley & Sons, Ltd.     

Angioscopic assessments and clinical outcomes one year after polymer-free biolimus A9-coated coronary stent implantation

BackgroundPolymer-free biolimus A9-coated coronary stent (DCS) has novel features which lead to the expectation of better arterial healing. However, comparisons of intravascular status between DCS and drug-eluting stents (DES), and robust real-word clinical assessments of DCS have been lacking to date.MethodsFrom September 2017 to September 2018, we evaluated the intra-vascular status of 74 DCS implanted in 55 lesions from 43 patients using coronary angioscopy (CAS) approximately one year after implantation from a cohort of 219 lesions in 158 patients. We set 239 second-generation durable-polymer DES (DP-DES) implanted in 211 lesions from 180 patients from a cohort of 2652 lesions in 1914 patients as the control. Angioscopic images were analyzed to determine (1) the dominant degree of neointimal coverage (NIC) over the stent; (2) the heterogeneity of NIC; (3) yellow color grade of the stented segment; and (4) the presence of intra-stent thrombus. The primary outcome was the incidence of thrombus and secondary outcomes were the other CAS findings, and the 1-year clinical outcomes which included target lesion revascularization (TLR) and major adverse cardiac events (MACE). To minimize inter-group differences in baseline characteristics, propensity score matching was performed for clinical outcomes.ResultsIncidence of thrombus adhesion was similar in DCS and DP-DES groups (28.4% versus 22.6%, p = 0.31). However, the dominant NIC grade was significantly higher in DCS (p < 0.001), while NIC was more heterogeneous in DCS than in DP-DES (p = 0.001). Maximum yellow color grade was similar (p = 0.22). After propensity score matching, 202 lesion pairs from 146 patient pairs were retained for analysis. The cumulative incidence of TLR (4.6% versus 3.8%, p = 0.38) and MACE (11.6% versus 11.7%, p = 0.84) was similar for DCS and DP-DES.ConclusionsDCS showed thrombus adhesion and clinical outcomes at 1 year similar to DP-DES. DCS can thus be used with similar safety and efficacy as DP-DES.     

Allograft liver failure awaiting liver transplantation in Japan

Journal of Gastroenterology - Following liver transplantation (LT), allograft liver failure can be developed by various causes and requires re-LT. Hence, this study aimed to clarify the...     

Nationwide survey for patients with acute-on-chronic liver failure occurring between 2017 and 2019 and diagnosed according to proposed Japanese criteria

Journal of Gastroenterology - The significance of the 2018 Japanese diagnostic criteria for acute-on-chronic liver failure (ACLF) has not yet been evaluated. A nationwide survey was performed for...     

Efficacy and safety of endoscopic submucosal dissection for gastric tube cancer: A multicenter retrospective study

BACKGROUNDRecent improvements in the prognosis of patients with esophageal cancer have led to the increased occurrence of gastric tube cancer (GTC) in the reconstructed gastric tube. However, there are few reports on the treatment results of endoscopic submucosal dissection (ESD) for GTC.AIMTo evaluate the efficacy and safety of ESD for GTC after esophagectomy in a multicenter trial.METHODSWe retrospectively investigated 48 GTC lesions in 38 consecutive patients with GTC in the reconstructed gastric tube after esophagectomy who had undergone ESD between January 2005 and December 2019 at 8 institutions participating in the Okayama Gut Study group. The clinical indications of ESD for early gastric cancer were similarly applied for GTC after esophagectomy. ESD specimens were evaluated in 2-mm slices according to the Japanese Classification of Gastric Carcinoma with curability assessments divided into curative and non-curative resection based on the Gastric Cancer Treatment Guidelines. Patient characteristics, treatment results, clinical course, and treatment outcomes were analyzed.RESULTSThe median age of patients was 71.5 years (range, 57-84years), and there were 34 men and 4 women. The median observation period after ESD was 884 d (range, 8-4040 d). The median procedure time was 81 min (range, 29-334 min), the en bloc resection rate was 91.7% (44/48), and the curative resection rate was 79% (38/48). Complications during ESD were seen in 4% (2/48) of case, and those after ESD were seen in 10% (5/48) of case. The survival rate at 5 years was 59.5%. During the observation period after ESD, 10 patients died of other diseases. Although there were differences in the procedure time between institutions, a multivariate analysis showed that tumor size was the only factor associated with prolonged procedure time.CONCLUSIONESD for GTC after esophagectomy was shown to be safe and effective.     

The physical activity patterns of cardiac rehabilitation program participants

PURPOSE: This investigation aimed to examine the physical activity patterns of cardiac rehabilitation program (CRP) participants. METHODS: The investigation enrolled 53 male and 24 female CRP participants between 46 and 88 years of age. By means of a uniaxial accelerometer (Life-Corder), the amount of physical activity (in kilocalories) and the time spent in physical activity at light (<3 metabolic equivalents [METs]), moderate (3 to 6 METs), and vigorous (>6 METs) intensity were evaluated. In addition to these variables, the MET levels for the CRP and non-CRP periods were calculated. RESULTS: The weekly amount of physical activity energy expenditure averaged 1597 +/- 846 kcal/week, and the time spent in light, moderate, and vigorous physical activity averaged, respectively, 375.5 +/- 124.5 minutes, 125.2 +/- 109.4 minutes, and 5.7 +/- 12.8 minutes per week. These levels were significantly lower on non-CRP days than on CRP days: 177 +/- 113 versus 299 +/- 161 kcal/day and, respectively, 49.3 +/- 19.3 versus 59.7 +/- 19.8 minutes, 10.5 +/- 14.6 versus 26.4 +/- 20.4 minutes, and 0.4 +/- 1.7 versus 1.4 +/- 3.0 minutes per day. CONCLUSIONS: These results indicate that the amount of physical activity was generally adequate on CRP days, but failed to reach target levels on non-CRP days. Thus CRP participants, when it is medically appropriate, should be encouraged to incorporate lifestyle physical activity, additional exercise, or both on non-CRP days to supplement their caloric expenditure from CRP exercise sessions.     

Direct demonstration of the cross-bridge recovery stroke in muscle thick filaments in aqueous solution by using the hydration chamber

Despite >50 years of research work since the discovery of sliding filament mechanism in muscle contraction, structural details of the coupling of cyclic cross-bridge movement to ATP hydrolysis are not yet fully understood. An example would be whether lever arm tilting on the myosin filament backbone will occur in the absence of actin. The most direct way to elucidate such movement is to record ATP-induced cross-bridge movement in hydrated thick filaments. Using the hydration chamber, with which biological specimens can be kept in an aqueous environment in an electron microscope, we have succeeded in recording ATP-induced cross-bridge movement in hydrated thick filaments consisting of rabbit skeletal muscle myosin, with gold position markers attached to the cross-bridges. The position of individual cross-bridges did not change appreciably with time in the absence of ATP, indicating stability of time-averaged cross-bridge mean position. On application of ATP, individual cross-bridges moved nearly parallel to the filament long axis. The amplitude of the ATP-induced cross-bridge movement showed a peak at 5–7.5 nm. At both sides of the filament bare region, across which the cross-bridge polarity was reversed, the cross-bridges were found to move away from, but not toward, the bare region. Application of ADP produced no appreciable cross-bridge movement. Because ATP reacts rapidly with the cross-bridges (M) to form complex (M·ADP·Pi) with an average lifetime >10 s, the observed cross-bridge movement is associated with reaction, M + ATP → M·ADP·Pi. The cross-bridges were observed to return to their initial position after exhaustion of ATP. These results constitute direct demonstration of the cross-bridge recovery stroke.     

Fcγ receptor expression on hepatic macrophages and histological activity of chronic hepatitis

Abstract: Aims/Background: Activated liver macrophages in chronic hepatitis express a high affinity receptor for IgG named FcγRI. This study was performed to find the difference in FcγRI expression between chronic hepatitis B (CHB) and C (CHC) with reference to histological activity. Methods: Consecutive patients with CHB (20 cases) and CHC (25 cases) were enrolled in the study. Inflammatory activity was evaluated using the modified histological activity index (HAI). FcγRI-positive macrophages were quantitatively measured by computer assisted morphometry. Results: Total HAI score was significantly higher in CHB than in CHC. Confluent necrosis was observed in significantly higher frequency in CHB at Stages 3–5 than in CHC. The percentage area of FcγRI-positive macrophages was significantly higher in CHB than in CHC. In CHB, the percentage area of FcγRI-positive macrophages correlated with total HAI (< 0.01) as well as the degree of confluent necrosis (< 0.01), interface hepatitis (< 0.05) and portal inflammation (< 0.05). FcγRI-positive macrophages accumulated mainly at the site of confluent necrosis. In CHC, no correlation was observed between activated macrophages and any histological categories. Conclusion: These results suggest that FcγRI-positive macrophages are associated with confluent necrosis in CHB, which is more common in CHB patients than in CHC.     

A case of Farmer's lung accompaign with caseous granuloma, monitored with serum KL-6 and SP-D]

A 65-year-old man was admitted to our hospital with a productive cough, fever, and dyspnea; his chest radiographs revealed diffuse nodular and ground-glass opacities. He had worked on a farm for 11 years. Six months earlier, he had presented with similar symptoms at another hospital, and was admitted with suspected atypical pneumonia. After treatment with antibiotics, his condition improved and he was discharged. Examination on admission to our hospital revealed markedly elevated serum KL-6 levels. Histological findings from specimens obtained by video-assisted thoracic surgical lung biopsy showed caseating and non-caseating epitheloid cell granuloma, lymphocyte infiltration, and alveolitis. Bacteriological tests for mycobacteria and fungi were all negative. Farmer's lung was diagnosed in accordance with the criteria for hypersensitive pneumonia. It is generally accepted that the distinguishing histological finding for Farmer's lung disease is non-caseating epitheloid cell granuloma, but in this case, caseous granuloma was also present.