Gabexate mesilate, a synthetic protease inhibitor, attenuates carbon tetrachloride-induced liver injury in rats

Mikami, Koji; Goto, Takashi; Miura, Kouichi; Ohshima, Shigetoshi; Yoneyama, Kazuo; Lin, Jiun-Guey; Watanabe, Dai; Segawa, Daisuke; Kataoka, Ei; Shibuya, Tomomi; Watanabe, Sumio

doi:10.1007/s00535-004-1534-3

Cited by 17 publications

(13 citation statements)

References 38 publications

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“…In contrast, we have already reported the DPD activity was lower in acute hepatic failure 6. In histopathological examination, there were necrotic areas around the central vein of liver in CCl 4 ‐treated acute hepatic failure rats 14, 15. Meanwhile, hepatic fibrosis model rats in this study did not show signs of hepatocellular necrosis.…”

Section: Resultscontrasting

confidence: 78%

Hepatic fibrosis does not affect the pharmacokinetics of 5‐fluorouracil in rats

Nagata

Hidaka

Hatakeyama

et al. 2010

Biopharm & Drug Disp

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In the case of cancer chemotherapy for hepatocellular carcinoma, 5-fluorouracil (5-FU) is used widely, and has typically been given by intrahepatic arterial (i.a.) infusion to increase treatment efficacy and to reduce systemic toxicity. 5-Fluorouracil is eliminated primarily by the liver, and so its use in patients with hepatic disease can be difficult. This study investigated the effect of hepatic fibrosis on the pharmacokinetics of 5-FU in rats. Experimental hepatic fibrosis was induced by carbon tetrachloride treatment. 5-fluorouracil was infused for 15 min into the hepatic artery or the saphenous vein of the rats at a dose of 1.25 mg/kg. There were no significant differences in the plasma concentration and AUC of 5-FU between hepatic disease rats and their controls after both intravenous and intraarterial injection. This result is probably attributed to the fact that there were no significant differences in hepatic blood flow and dihydropyrimidine dehydrogenase (DPD; an initial and rate-limiting enzyme in 5-FU catabolism) activity between hepatic disease rats and their controls, because the total clearance of 5-FU after intravenous and intraarterial administration is mainly limited by hepatic blood flow and DPD activity, respectively. In conclusion, the pharmacokinetics of 5-FU is not affected by hepatic fibrosis, unlike that of many hepatically metabolized drugs.

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Section: Resultscontrasting

confidence: 78%

Hepatic fibrosis does not affect the pharmacokinetics of 5‐fluorouracil in rats

Nagata

Hidaka

Hatakeyama

et al. 2010

Biopharm & Drug Disp

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“…Furthermore, patients with SIRS are reported to have more highly elevated serum tumor necrosis factor α levels than those without 24 . Protease inhibitor is reported to attenuate liver injury by suppression of tumor necrosis factor α production 25,26 . Protease inhibitor may attenuate hepatic inflammation in fulminant hepatic failure.…”

Section: Discussionmentioning

confidence: 99%

“…24 Protease inhibitor is reported to attenuate liver injury by suppression of tumor necrosis factor a production. 25,26 Protease inhibitor may attenuate hepatic inflammation in fulminant hepatic failure.…”

Section: Figurementioning

confidence: 99%

Prognostic factors for fatal outcomes prior to receiving liver transplantation in patients with non‐acetaminophen‐related fulminant hepatic failure

Miyake

Iwasaki

Makino

et al. 2007

J of Gastro and Hepatol

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“…The patients also received systemic administration of gabexate mesilate, a strong serine protease inhibitor [4, 5]. This drug has been shown to be more effective in the treatment of disseminated intravascular coagulation as compared to heparin [4], since it shows a protective effect on endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

“…This drug has been shown to be more effective in the treatment of disseminated intravascular coagulation as compared to heparin [4], since it shows a protective effect on endothelial cells. In fact, we have previously reported that serine protease inhibitors have cytoprotective effects on endothelial cells in ischemia-reperfusion injury [5].…”

Section: Introductionmentioning

confidence: 99%

The Effects of Endothelial Cells-Preserving Technique on Microsurgical Vascular Reconstruction in Biliary Tract Malignancy: Report of Twenty Cases

Miyagi

Nakanishi

Kawagishi

et al. 2014

Case Rep Gastroenterol

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We describe our experience of resectional surgery with microsurgical reconstruction of the hepatic arteries in 20 cases with biliary tract malignancy. Hepatic artery thrombosis (HAT) is a lethal complication; therefore, it is important to perform microsurgical reconstruction safely. Recently, we adopted the back wall support suture technique with double needle sutures that does not require the damaged short arteries to be turned over. In this technique, each stitch is placed from the inner side to the outer side to keep endothelial cells. The purpose of this study was to develop safety methods. From 2003 to 2012, 20 patients with biliary tract malignancy with possible involvement of the hepatic arteries underwent resectional surgery with microvascular reconstruction (cholangiocarcinoma: n = 15; others: n = 5). For this cohort study, patients were divided into two groups: group I (n = 5) included patients who underwent the conventional ‘twist technique' and group II (n = 15) included patients who underwent the microsurgical back wall support suture technique with double needle sutures and received gabexate mesilate, a strong serine protease inhibitor (40 mg/kg/day) for 7 days. We investigated HAT using Doppler ultrasonography for 10 days. No postoperative mortality was observed. The incidence of HAT was only one case in group I, and there was no significant difference between the two groups. However, the value of the pulsatile index and acceleration time were significantly improved in group II. In conclusion, the back wall support suture technique with gabexate mesilate administration during microvascular reconstruction was found to be safe. It is important to keep endothelial cells healthy for microvascular reconstruction.

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Gabexate mesilate, a synthetic protease inhibitor, attenuates carbon tetrachloride-induced liver injury in rats

Abstract: Gabexate mesilate treatment attenuated CCl4-induced liver injury via a suppression of proinflammatory cytokine production. In addition, these investigations suggest that gabexate mesilate treatment may provide therapeutic strategies for human acute liver failure.

Cited by 17 publications

References 38 publications

Hepatic fibrosis does not affect the pharmacokinetics of 5‐fluorouracil in rats

Hepatic fibrosis does not affect the pharmacokinetics of 5‐fluorouracil in rats

Prognostic factors for fatal outcomes prior to receiving liver transplantation in patients with non‐acetaminophen‐related fulminant hepatic failure

The Effects of Endothelial Cells-Preserving Technique on Microsurgical Vascular Reconstruction in Biliary Tract Malignancy: Report of Twenty Cases

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