Gabexate mesilate (FOY) therapy of disseminated intravascular coagulation due to sepsis

Taenaka, Nobuyuki; Shimada, Yasuhiro; Hirata, Toshifumi; Nishijima, Masako K.; Takezawa, Jun; Yoshiya, Ikuto; Kambayashi, Junichi

doi:10.1097/00003246-198309000-00013

Cited by 46 publications

(22 citation statements)

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“…Repeated measurements of ANOVA revealed a significant group difference [F(1,16) = 13.04, P<0.01], a significant effect of time [F(10,160) = 2.36, P<0.05], and a significant group × time interaction [F(10,160) = 4.39, P<0.0001]. Post hoc analysis revealed that cellular uptake of PI was higher in GM-treated cells than in control cells (3,6,9, and 24 min: P<0.05; 12, 15, 18, 21, 27, and 30 min: P<0.01 by Student's t-test, respectively). Fig.…”

Section: Effect Of Gm On Pi Uptakementioning

confidence: 99%

Characteristics of Gabexate Mesilate–Induced Cell Injury in Porcine Aorta Endothelial Cells

et al. 2008

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Abstract. Gabexate mesilate (GM), a serine protease inhibitor, often causes severe vascular injury, when injected in high concentration. In the present study, we investigated the mechanisms for the cytotoxicity of GM on porcine aorta endothelial cells (PAECs). GM (0.5 -5.0 mM) decreased cell viability in a dose-dependent manner and caused cell injury, whilst nafamostat mesilate (NM), another serine protease inhibitor, or mesilate itself had no effect on cell viability. zVAD-fmk, a pancaspase inhibitor, or zDEVD-fmk, a caspase-3 inhibitor, did not affect the GM (1.5 mM)-induced decrease of cell viability. Apoptotic cells or DNA fragmentation were also not observed after GM treatment. Moreover, Ca 2+ chelators, a nitric oxide (NO) synthase inhibitor, antioxidants, and radical scavengers had no effect on the GM-induced cell injury. On the other hand, cellular ATP content was decreased in the GM (2.0 mM)-treated cells. Surprisingly, GM (2.0 mM) immediately increased cellular uptake of propidium iodine. These findings suggest that GM induces necrotic cell death via injury of the cell membrane.

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Section: Effect Of Gm On Pi Uptakementioning

confidence: 99%

Characteristics of Gabexate Mesilate–Induced Cell Injury in Porcine Aorta Endothelial Cells

et al. 2008

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“…Gabexate mesilate has been used to treat patients with DIC associated with sepsis probably due to its anticoagulant properties (Taenaka et al, 1983). Because TNF-␣ is critically involved in the activation of the extrinsic pathway of the coagulation system, thereby inducing DIC in the pathological condition of sepsis (Okajima, 2001), inhibition of TNF-␣ production by gabexate mesilate might at least partly contribute to reduce the coagulation abnormalities in patients with sepsis.…”

Section: Inhibition Of Tnf-␣ Production By Gabexate Mesilate In Vitromentioning

confidence: 99%

“…Gabexate mesilate was shown to be effective in treating patients with DIC associated with sepsis (Taenaka et al, 1983). We previously demonstrated that gabexate mesilate reduced pulmonary vascular injury as well as coagulation abnormalities in rats administered endotoxin by inhibiting TNF-␣ production (Murakami et al, 1996).…”

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confidence: 99%

Gabexate Mesilate, a Synthetic Protease Inhibitor, Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-α Production by Inhibiting Activation of Both Nuclear Factor-κB and Activator Protein-1 in Human Monocytes

Yüksel¹,

Okajima²,

Uchiba³

et al. 2003

J Pharmacol Exp Ther

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Gabexate mesilate, a synthetic protease inhibitor, was shown to be effective in treating patients with sepsis-associated disseminated intravascular coagulation in which tumor necrosis factor-␣ (TNF-␣) plays a critical role. We demonstrated that gabexate mesilate reduced lipopolysaccharide (LPS)-induced tissue injury by inhibiting TNF-␣ production in rats. In the present study, we analyzed the mechanism(s) by which gabexate mesilate inhibits LPS-induced TNF-␣ production in human monocytes in vitro. Gabexate mesilate inhibited the production of TNF-␣ in monocytes stimulated with LPS. Gabexate mesilate inhibited both the binding of nuclear factor-B (NF-B) to target sites and the degradation of inhibitory B␣. Gabexate mesilate also inhibited both the binding of activator protein-1 (AP-1) to target sites and the activation of mitogen-activated protein kinase pathways. These observations strongly suggest that gabexate mesilate inhibited LPS-induced TNF-␣ production in human monocytes by inhibiting activation of both NF-B and AP-1. Inhibition of TNF-␣ production by gabexate mesilate might explain at least partly its therapeutic effects in animals given LPS and those in patients with sepsis.

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“…On the other hand, a synthetic serine protease inhibitor, gabexate mesilate, exhibits various degrees of biological activity against the inflammatory process and the coagulation system (Ohno et al, 1981;Taenaka et al, 1983). The pharmacological activity of this agent is as an anticoagulant via the blockade of thrombin and active coagulation factors (Ohno et al, 1981) and has been shown to be clinically effective in treating disseminated intravascular coagulation (Taenaka et al, 1983).…”

Section: Introductionmentioning

confidence: 99%

“…The pharmacological activity of this agent is as an anticoagulant via the blockade of thrombin and active coagulation factors (Ohno et al, 1981) and has been shown to be clinically effective in treating disseminated intravascular coagulation (Taenaka et al, 1983). However, gabexate mesilate directly prevented the activation of NF-B in lipopolysaccharide (LPS) -stimulated murine macrophages and human monocytes resulting in reduced production of proinflammatory cytokines, including tumor necrosis factor (TNF), interleukin (IL)-6, high mobility group box 1 (HMGB1), etc Murakami et al, 1996;Yuksel et al, 2003;Uchiba et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Effects of a synthetic protease inhibitor (gabexate mesilate) and a neutrophil elastase inhibitor (sivelestat sodium) on acid-induced lung injury in rats

Yoshikawa

Tsushima

Koizumi

et al. 2010

European Journal of Pharmacology

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The present study was designed to examine the combined effects of a synthetic protease inhibitor (gabexate mesilate) with a specific neutrophil elastase inhibitor (sivelestat sodium) on acid-induced lung injury. Adult male Sprague-Daley rats weighing 300-350 g were anesthetized intraperitoneally with pentobarbital sodium and the right jugular vein was cannulated. Following tracheostomy, rats were ventilated mechanically and underwent intratracheal instillation of hydrochloric acid (HCl, 0.1N 1.5 ml/kg) or normal saline. Thirty minutes before HCl instillation, gabexate mesilate (10 mg/kg, i.p.) and/or sivelestat sodium (10mg/kg/h, i.v.) were administered. Bronchoalveolar lavage fluid samples were obtained 5 h after HCl instillation. In bronchoalveolar lavage fluid, the HCl-induced increases in total nucleated cell counts, neutrophil counts, optical density at 412 nm, as an index of pulmonary hemorrhage, concentrations of albumin and cytokine-induced neutrophil chemoattractant (CINC) were significantly attenuated by either gabexate mesilate or sivelestat sodium treatment. Gabexate mesilate or sivelestat sodium treatment also significantly attenuated the wet to dry weight ratio induced by HCl. However, combined treatment with both gabexate mesilate and sivelestat sodium did not exhibit additive effects on HCl-induced lung injury, compared with the single treatment. These findings suggest that gabexate mesilate and sivelestat sodium each exhibited protective effects on acid-induced lung injury, respectively, but that synergistic effects of both agents are limited in this acid-induced lung injury model. Word counts: 216

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Gabexate mesilate (FOY) therapy of disseminated intravascular coagulation due to sepsis

Cited by 46 publications

References 0 publications

Characteristics of Gabexate Mesilate–Induced Cell Injury in Porcine Aorta Endothelial Cells

Characteristics of Gabexate Mesilate–Induced Cell Injury in Porcine Aorta Endothelial Cells

Gabexate Mesilate, a Synthetic Protease Inhibitor, Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-α Production by Inhibiting Activation of Both Nuclear Factor-κB and Activator Protein-1 in Human Monocytes

Effects of a synthetic protease inhibitor (gabexate mesilate) and a neutrophil elastase inhibitor (sivelestat sodium) on acid-induced lung injury in rats

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