Lack of therapeutic effects of gabexate mesilate on the hepatic encephalopathy in rats with acute and chronic hepatic failure.
OBJECTIVE
Inflammation plays a pivotal role in liver injury. Gabexate mesilate (GM, a protease inhibitor) inhibits inflammation by blocking various serine proteases. This study examined the effects of GM on hepatic encephalopathy in rats with acute and chronic liver failure.


METHODS
Acute and chronic liver failure (cirrhosis) were induced by intraperitoneal TAA administration (350 mg/kg/day for 3 days) and common bile duct ligation, respectively, in male Sprague-Dawley rats. Rats were randomized to receive either GM (50 mg/10 mL/kg) or saline intraperitoneally for 5 days. Severity of encephalopathy was assessed by the Opto-Varimex animal activity meter and hemodynamic parameters, mean arterial pressure and portal pressure, were measured (only in chronic liver failure rats). Plasma levels of liver biochemistry, ammonia, nitrate/nitrite, interleukins (IL) and tumor necrosis factor (TNF)-alpha were determined.


RESULTS
In rats with acute liver failure, GM treatment significantly decreased the plasma levels of alanine aminotransferase (P = 0.02), but no significant difference of motor activity, plasma levels of ammonia, IL-1beta, IL-6, IL-10 and TNF-alpha or survival was found. In chronic liver failure rats, GM significantly lowered the plasma TNF-alpha levels (P = 0.04). However, there was no significant difference of motor activity, other biochemical tests or survival found. GM-treated chronic liver failure rats had higher portal pressure (P = 0.04) but similar mean arterial pressure in comparison with saline-treated rats.


CONCLUSIONS
Chronic GM treatment does not have a major effect on hepatic encephalopathy in rats with TAA-induced acute liver failure and rats with chronic liver failure induced by common bile duct ligation.
Hsu
Chia-Yang
CY
Divisions of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Lee
Fa-Yauh
FY
Huo
Teh-Ia
TI
Chan
Cho-Yu
CY
Huang
Hui-Chun
HC
Lin
Han-Chih
HC
Chang
Ching-Chih
CC
Teng
Tzu-Hua
TH
Wang
Sun-Sang
SS
Lee
Shou-Dong
SD
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D002908:Chronic Disease; D003135:Common Bile Duct / Q000601:surgery; D004195:Disease Models, Animal; D004798:Enzymes / Q000097:blood; D016670:Gabexate / Q000494:pharmacology*; D006501:Hepatic Encephalopathy / Q000097:blood / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000097:blood; D008026:Ligation; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D017093:Liver Failure / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D017114:Liver Failure, Acute / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D017082:Portal Pressure / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D012720:Severity of Illness Index; D013853:Thioacetamide; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D004798:Enzymes; D018836:Inflammation Mediators; D015842:Serine Proteinase Inhibitors; D013853:Thioacetamide; D016670:Gabexate