Author: SHIBUYA, Marin ; KATO, Miki ; CHEN, I-Ying ; HIROKAWA, Taku ; ITAMI, Takaharu ; SUGITA, Chihiro ; TSUKUI, Haruki ; YAMASHITA, Kazuto ; SANO, Yuto ; MIYASHO, Taku ; KATO, Keiko

Endotoxemia is a systemic inflammatory condition caused by lipopolysaccharide (LPS) stimulation, which produces inflammatory cytokines. Fuzapladib (FZP) inhibits the activation of adhesion molecules found on the surface of inflammatory cells, mitigating inflammation. In this study, we evaluated the therapeutic effects of fuzapladib on inflammatory cytokines and cardio-respiratory function using an LPS-induced endotoxemic porcine model. Fifteen pigs were separated into three groups: low-FZP (n=5), high-FZP (n=5), and control (n=5). Pigs were administered LPS under general anesthesia, and complete blood cell count, blood biochemistry, inflammatory cytokines, and cardio-respiratory function were evaluated. Statistical analysis was performed using a linear mixed-effects model and the Steel-Dwass test, with a significance threshold of P<0.05. During the 4 hr experimental period, one pig in the control group and two pigs in the low-FZP group died due to hypoxemia and hypotension. In the early acute changes following LPS administration, the high-FZP group maintained significantly higher arterial oxygen partial pressure and normal blood pressure compared to the control group. Although interleukin-6 levels increased in all groups during the experiment, they were significantly lower in the high-FZP group compared to the control group. Other parameters showed no clinically significant differences. In conclusion, while high-dose fuzapladib did not reduce organ damage in the porcine endotoxemia model, it suppressed interleukin-6 production, delayed the progression of deterioration, and contributed to a reduction in mortality during the observation period.

01 Oct 2009·LungQ4 · MEDICINE

Effects of IS-741, a Synthetic Anti-Inflammatory Agent, on Bleomycin-Induced Lung Injury in Mice

Q4 · MEDICINE

Article

Author: Masashi Bando ; Cristiane Yamabayashi ; Ichiei Narita ; Toshinori Takada ; Fumio Fujimori ; Yukihiko Sugiyama ; Yuichi Shimaoka ; Eiichi Suzuki ; Masaki Terada ; Hiroshi Moriyama ; Shunji Tajima

Bleomycin (BLM)-induced lung injury consists of excessive inflammatory cell infiltration and fibrosis. IS-741 has been reported to be an anti-inflammatory drug through an inhibitory action on cell adhesion. In this study we investigated whether IS-741 could inhibit the progression of pulmonary fibrosis through inflammatory cell infiltration. Lung injury was induced in female C57BL/6 mice by intratracheal instillation of BLM. IS-741 was administered daily intraperitoneally. The hydroxyproline content and fluid content in the lung on Day 28 were significantly lower in the IS-741-treated mice. The histological degree of lung injury or fibrosis was reduced in IS-741-treated mice. Administration of IS-741 caused significant reduction in the absolute number of total cells, monocyte chemoattractant protein (MCP)-1, and cysteinyl leukotriene (cysLTs) levels in bronchoalveolar lavage fluid on Day 7. Furthermore, the hydroxyproline content was significantly lower in IS-741-treated mice even though IS-741 was started on Day 14 after BLM instillation. Treatment with IS-741 had an inhibitory effect on BLM-induced lung injury and fibrosis via the repression of MCP-1 or cysLTs in this murine experimental model.

01 Apr 2007·PancreasQ3 · MEDICINE

IS-741 Attenuates Local Migration of Monocytes and Subsequent Pancreatic Fibrosis in Experimental Chronic Pancreatitis Induced by Dibutyltin Dichloride in Rats

Q3 · MEDICINE

Article

Author: Junya Gibo ; Toyoma Kaku ; Tetsuhide Ito ; Haifeng Zhao ; Ken Kawabe ; Takamasa Oono ; Ryoichi Takayanagi

OBJECTIVESChronic pancreatitis consists of excessive leukocyte infiltration and fibrosis. IS-741 has been reported to be an antiinflammatory drug through an inhibitory action on cell adhesion. In this study, we investigated whether IS-741 could inhibit the progression of pancreatic fibrosis through monocyte infiltration. Moreover, we investigated the effect of IS-741 on rat pancreatic stellate cells (PSCs).METHODSChronic pancreatitis was induced by dibutyltin dichloride in rats. From days 7 to 28 after dibutyltin dichloride application, IS-741 or distilled water was administered. At days 14 and 28, histological [hematoxylin-eosin stain and immunostain for ED1 and [alpha] smooth muscle actin (alpha-SMA)] and biochemical evaluations (intrapancreatic amylase, protein, cytokines, chemokines, and alpha-SMA) were performed. In vitro, rat PSCs were incubated with cytokine, chemokine, and growth factor simultaneously with IS-741, and their proliferation and activation were examined.RESULTSHistologically, IS-741 inhibited pancreatic fibrosis and decreased the number of ED1- and [alpha]-SMA-positive cells. The intrapancreatic expression of cytokines, chemokine, and [alpha]-SMA were also decreased. In vitro, IS-741 has no direct effect on the proliferation, alpha-SMA expression, and collagen synthesis of PSCs.CONCLUSIONSThese results suggest that IS-741 suppressed macrophage infiltration and subsequent pancreatic fibrosis and that the infiltration of monocytes into pancreas is essential for pancreatic fibrosis.

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Indication	Highest Phase	Country/Location	Organization	Date
Pancreatitis	Phase 2	-	Sumitomo Pharma Co., Ltd.	-
Pancreatitis	Phase 2	-	ISHIHARA SANGYO KAISHA LTD.	-

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