A Japanese herbal medicine (kampo), hochuekkito (TJ-41), has anti-inflammatory effects on the chronic obstructive pulmonary disease mouse model.

Chronic obstructive pulmonary disease (COPD) is a progressive disease that is characterized by chronic airway inflammation. A Japanese herbal medicine, hochuekkito (TJ-41), is prominently used for chronic inflammatory diseases in Japan. This study aimed to analyze the anti-inflammatory effect of TJ-41 in vivo and its underlying mechanisms. We created a COPD mouse model using intratracheal administration of porcine pancreatic elastase and lipopolysaccharide (LPS) and analyzed them with and without TJ-41 administration. A TJ-41-containing diet reduced inflammatory cell infiltration of the lungs in the acute and chronic phases and body weight loss in the acute phase. In vitro experiments revealed that TJ-41 treatment suppressed the LPS-induced inflammatory cytokines in BEAS-2B cells. Furthermore, TJ-41 administration activated the AMP-activated protein kinase (AMPK) pathway and inhibited the mechanistic target of the rapamycin (mTOR) pathway, both in cellular and mouse experiments. We concluded that TJ-41 administration reduced airway inflammation in the COPD mouse model, which might be regulated by the activated AMPK pathway, and inhibited the mTOR pathway.

The Japanese Herbal (Kampo) Medicine Hochuekkito Attenuates Lung Inflammation in Lung Emphysema.

Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disorder. It often causes weight loss, which is considered a poor prognostic factor. A Japanese herbal Kampo medicine, Hochuekkito (TJ-41), has been reported to prevent systemic inflammation and weight loss in COPD patients, but the underlying biological mechanisms remain unknown. In the present study, we investigated the role of TJ-41 in vivo using a mouse model of lung emphysema. We used lung epithelium-specific Taz conditional knockout mice (Taz CKO mice) as the lung emphysema model mimicking the chronic pulmonary inflammation in COPD. Acute inflammation was induced by intratracheal lipopolysaccharide administration, simulating COPD exacerbation. Mice were fed a diet containing 2% TJ-41 or a control diet. Taz CKO mice showed increased numbers of inflammatory cells in the bronchoalveolar lavage fluid compared to control mice. This effect was reduced by TJ-41 treatment. In the acute exacerbation model, TJ-41 mitigated the increased numbers of inflammatory cells in the bronchoalveolar lavage fluid and attenuated lung inflammation in histopathological studies. Additional in vitro experiments using the human macrophage cell line U-937 demonstrated that lipopolysaccharide-induced tumor necrosis factor-alpha expression was significantly downregulated by TJ-41. These results suggest that TJ-41 has anti-inflammatory effects in lung emphysema both in the chronic phase and during an acute exacerbation. In conclusion, our study sheds light on the anti-inflammatory effects of TJ-41 in lung emphysema. This establishes its potential as a new anti-inflammatory therapy and a preventive medicine for exacerbations during the long-time maintenance of COPD patients.

Dual EGFR and ABL Tyrosine Kinase Inhibitor Treatment in a Patient with Concomitant EGFR-Mutated Lung Adenocarcinoma and BCR-ABL1-Positive CML.

Tyrosine kinase inhibitor (TKI) combination is expected to increase in the era of precision medicine. TKI combination may be required to treat double primary cancers, each having a targetable gene, or to treat a single malignancy with multiple targetable genes. Here, we demonstrate the first report of dual EGFR and ABL TKI treatment in a patient with concomitant EGFR-mutated lung adenocarcinoma and BCR-ABL1-positive chronic myeloid leukemia (CML). A 60-year-old man with an 8-year history of CML was diagnosed as advanced EGFR-mutated lung adenocarcinoma. Complete molecular response of CML had been achieved by imatinib, and ABL-TKI had been switched to nilotinib four years previously due to muscle cramps. We discontinued nilotinib and started afatinib. Although partial response of lung adenocarcinoma was achieved, cytogenetic relapse of CML was observed following nilotinib discontinuation. We applied the previously described framework of cytochrome P450 3A4-mediated oral drug-drug interactions and selected gefitinib and nilotinib to treat both malignancies. We effectively and safely administered this combination for seven months. The present report is the first to demonstrate the safety and efficacy of dual EGFR and ABL TKI treatment in a patient with concomitant EGFR-mutated lung adenocarcinoma and CML.

Antithrombotic properties of hemofilter coated with polymer having a hydrophilic blood-contacting layer.

OBJECTIVE:: Extracorporeal circulation devices are coated with a biocompatible polymer coating agent (BPCA) that has a hydrophilic blood-contacting layer, but hemofilters are not. We aimed to investigate the antithrombotic properties of a BPCA-coated hemofilter. METHODS:: Four experiments using BPCA-coated circuits and non-coated hemofilters and four experiments using BPCA-coated circuits and BPCA-coated hemofilters were performed with whole human blood and compared by measuring the circuit pressure every 5 min, antithrombin activity every 40 min, and thrombin-antithrombin complex every 40 min, for a total of 240 min of recirculation. RESULTS:: The mean time required for the pressure at the inlet of the hemofilter to increase sharply was longer in BPCA-coated than in non-coated hemofilters (66 ± 11 min vs 25 ± 9 min, p < 0.01). The mean antithrombin activity value at 200 and 240 min of recirculation was significantly higher in the experiments with BPCA-coated versus non-coated hemofilters (43.3 ± 2.87 vs 33.3 ± 5.74, p = 0.04; 42.8 ± 3.59 vs 31.0 ± 5.35, p = 0.01, respectively); the antithrombin activity values at the other time points were not significantly different. Furthermore, all thrombin-antithrombin complex values in experiments with the BPCA-coated hemofilters achieved overrange at 80 min of recirculation, whereas those with the non-coated hemofilter achieved overrange at 40 min. CONCLUSION:: This study suggests that BPCA-coated hemofilters can inhibit antithrombin consumption, contributing to antithrombotic effects in extracorporeal circulation circuits.

Hemodialysis membrane coated with a polymer having a hydrophilic blood-contacting layer can enhance diffusional performance.

PURPOSE: Currently, the foreign surfaces of various extracorporeal circulation devices are coated with a biocompatible polymer coating agent (BPA), which creates a hydrophilic blood-contacting layer to reduce thrombogenicity, while the membranes in hemodialyzers are not. We aimed to clarify other side effects of BPA-coated membranes by examining the diffusion performance in in vitro experiments. METHODS: We used a polyethersulfone membrane (sieving coefficient of albumin is ≤0.01) coated with BPA product, SEC-1TM (Toyobo), in a hemodialyzer. To estimate the diffusion rates of a wide range of molecules, 2 L of saline containing vancomycin, lysozyme, and albumin were recirculated in the circuit configured with a hemodialyzer, and dialyzed continuously using water. The concentrations of sodium, vancomycin, lysozyme, and albumin were measured every 5 minutes for 30 minutes and compared in experiments with BPA-coated (n = 4) and BPA-noncoated (n = 4) membranes. RESULTS: The removal rates of sodium and vancomycin after 5 minutes of dialysis (n = 24) were significantly higher in BPA-coated than noncoated membranes, while those of lysozyme and albumin were not significantly different. The removal rates of sodium and vancomycin after 30 minutes of dialysis (n = 4) were significantly higher, and those of lysozyme were significantly lower in BPA-coated than noncoated membranes, while those of albumin were not significantly different. CONCLUSIONS: The preliminary study suggests that BPA-coated membranes enhanced the diffusion rate of molecules with low and middle molecular weight without affecting the sieving coefficient of albumin. Thus, BPA coating can enhance the dialysis performance of membranes.