Protection Of Endotoxin Induced Disseminated Intravascular Coagulation In Rats By Gabexate Mesilate

1981 ◽  
Author(s):  
T Yoshikawa ◽  
Y Furukawa ◽  
M Murakami ◽  
S Takemura ◽  
M Kondo
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Femoral Vein ◽  
Inhibitory Effect ◽  
Female Rats ◽  
Gabexate Mesilate ◽  
Intravascular Coagulation ◽  
Wistar Strain ◽  
Potent Inhibitory Effect ◽  
Strong Inhibitory Effect ◽  
Hemorrhagic Tendency

Gabexate mesilate[ methane sulfonic acid salt of ethyl-p- (6-guanidino hexanoyloxy) benzoate : FOY ] has recently been developed in Japan, and has been known to have potent inhibitory effects on trypsin, kallikrein, plasmin, thrombin and C1-esterase. Advantage of clinical use of this agent is that FOY has smaller molecular weight than aproti- nin so that production of antibody against FOY is hardly observed. In the present investigation, effect of FOY on disseminated intravascular coagulation (DIC) was examined using experimental animal models, in comparison with that of heparin.Female rats of Wistar strain (8-weeks) were infused with l00mg/kg of bacterial endotoxin (Lipopolysaccharide B; E. coli; 055, Difco) continuously for 4 hours through femoral vein. Blood samples were serially taken from abdominal artery using catheter and examined for plasma fibrinogen, FDP, platelet counts, prothrombin time and partial thromboplastin time. After the experiment, kidneys were removed to examine the deposition of fibrin to glomeruli.Different concentrations of FOY were intraperitoneally injected to the rats prior to the infusion of endotoxin, and it was found that the administration of 10 mg/kg of FOY showed the most potent inhibitory effect on the development of DIC, either hematologically or histologically. In comparison, heparin showed a strong inhibitory effect on DIC over a dosage of 5 U/kg.It is concluded that, although inhibitory effect of FOY was less significant than heparin, FOY might be valuable agent for the treatment of DIC especially when heparin is difficult to use in such cases as severe hemorrhagic tendency.

Inhibitory Effect Of Gabexate Mesilate On Experimental Disseminated Intravascular Coagulation

1981 ◽  
Author(s):  
H Ohno ◽  
S W Chang ◽  
J Kambayashi ◽  
S Imaoka ◽  
G Kōsaki
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Factor Xa ◽  
Inhibitory Effect ◽  
Rat Plasma ◽  
Gabexate Mesilate ◽  
Antithrombotic Agent ◽  
Continuous Administration ◽  
Intravascular Coagulation ◽  
Relevant Compound

Gabexate mesilate:[Ethyl p-(6-guanidinohexanoyloxy)benzoate]methanesulfonate, which is clinically used as a potent trypsin inhibitor in Japan, inhibits competitively the hydrolytic reactions with synthetic substrates by thrombin and factor Xa. However, its virtual anticoagulant effect in vivo remains to be evaluated, because of its short halflife due to the presence of plasma esterase. In the present study, the inhibitory effect of gabexate mesilate on experimental disseminated intravascular coagulation was investigated in comparison with those of heparin and aprotinin. 125I-Fibrinogen was injected into rats along with t-AMCHA to prevent lysis of fibrin formed. Five minutes after a infusion of gabexate mesilate, heparin, aprotinin or saline, intravascular cogulation was triggered by a continuous infusion of thrombin or tissue thromboplstin. The deposition of fibrin in kidney was continuously monitored by scintillation detector. Platelet count and 125I-fibrinogen in blood were determined. The formation of fibrin induced by thrombin and tissue thromboplastin was completely inhibited by continuous administration of 120 μmol gabexate mesilate/kg/h or 200 U heparin/kg/h. On the other hand, aprotinin failed to prevent the deposition of fibrin even at dose of 50,000 U/kg/h. Also, other parameters corroborated the same aspect. The naturally occuring lysis of the microthrombi previously formed by thrombin was not blocked by the infusion of 120 μmol gabexate mesilate/kg/h or 200 U heparin/kg/h. However, aprotinin, at 5,000 U/kg/h, completely blocked the lysis. Using clotting assay, the biological half life of gabexate mesilate in human plasma was found to be ten times longer than that in rat plasma, suggesting that much lower dose would be effective in human. In conclusion, gabexate mesilate is a relevant compound as an antithrombotic agent.

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

1983 ◽  
Vol 11 (9) ◽  
pp. 735-738 ◽  
Author(s):  
NOBUYUKI TAENAKA ◽  
YASUHIRO SHIMADA ◽  
TAKAHIKO HIRATA ◽  
MASAKO K. NISHIJIMA ◽  
JUN TAKEZAWA ◽  
...  
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Gabexate Mesilate ◽  
Intravascular Coagulation

Protective Effect of Gabexate Mesilate against Experimental Disseminated Intravascular Coagulation in Rats

1983 ◽  
Vol 13 (4) ◽  
pp. 262-267 ◽  
Author(s):  
Toshikazu Yoshikawa ◽  
Yasumasa Furukawa ◽  
Masashi Murakami ◽  
Shuhei Takemura ◽  
Motoharu Kondo
Keyword(s):  
Protective Effect ◽  
Disseminated Intravascular Coagulation ◽  
Gabexate Mesilate ◽  
Intravascular Coagulation

Infusion of Phospholipid Vesicles Amplifies the Local Thrombotic Response to TNF and Anti-Protein C into a Consumptive Response

1996 ◽  
Vol 75 (04) ◽  
pp. 578-584 ◽  
Author(s):  
F B Taylor ◽  
S E He ◽  
A C K Chang ◽  
J Box ◽  
G Ferrell ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Bacterial Infection ◽  
Venous Thrombosis ◽  
Disseminated Intravascular Coagulation ◽  
Protein C ◽  
Tumor Necrosis ◽  
Femoral Vein ◽  
Phospholipid Vesicles ◽  
Intravascular Coagulation ◽  
Necrosis Factor

SummaryInflammation often is considered a contributing factor to both thrombosis and disseminated intravascular coagulation. The molecular mechanisms that dictate which of these clinical manifestations will result from the inflammatory stimulus remain obscure. Bacterial infection and certain tumors are common initiators of the disseminated intravascular coagulant response. Complement activation resulting from bacterial infection shares with selected tumors the capacity to generate or release membrane particles that lack functional adhesion receptors and hence could circulate to amplify a disseminated intravascular coagulant response. We developed a model of venous thrombosis that resulted in localized thrombus formation without disseminated intravascular coagulation. The model involves infusion of tumor necrosis factor, blockade of protein C and a partial decrease in venous flow caused by ligation of the superficial femoral vein without obstruction of the deep femoral vein. Infusion of phospholipid vesicles into this model resulted in amplification of a localized thrombotic response into a consumptive response.Seven different groups of animals were studied. The first three groups established the conditions necessary to produce deep vein thrombosis. The second four groups established the conditions necessary to produce disseminated intravascular coagulation. The infusion of phospholipid vesicles plus tumor necrosis factor and anti-protein C antibody resulted in consumption of fibrinogen, the production of thrombin/antithrombin complexes, a fall in platelet count, and venous thrombosis. Without ligation and catheterization phospholipid vesicles failed to produce the consumptive response. We conclude, therefore, that phospholipid vesicles can amplify a local thrombotic response into a consumptive response, and that vesiculation accompanying inflammation is one means by which localized coagulant activity may be amplified to produce disseminated intravascular coagulation.

Effect of Urinary Protein C Inhibitor on Lipopolysaccharide-induced Disseminated Intravascular Coagulation in Rats

2000 ◽  
Vol 84 (07) ◽  
pp. 54-58 ◽  
Author(s):  
Wakako Izutani ◽  
Yoshikazu Komurasaki ◽  
Mitsugu Fujita
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Protein C ◽  
Degradation Products ◽  
Femoral Vein ◽  
Activated Partial Thromboplastin Time ◽  
Urinary Protein ◽  
Fibrinogen Concentration ◽  
Intravascular Coagulation ◽  
Protein C Inhibitor ◽  
Chemotactic Factors

SummaryThe effect of urinary protein C inhibitor (uPCI) on disseminated intravascular coagulation (DIC) was investigated using an experimental DIC in rats. uPCI (0.5 and 1.0 mg/kg) was continuously administrated into the left femoral vein of the rats with lipopolysaccharide (50 mg/kg)-induced DIC. In all doses, uPCI significantly prevented the drastic changes in the parameters such as fibrinogen concentration, activated partial thromboplastin time (APTT), prothrombin time (PT), fibrin/fibrinogen degradation products (FDP) level, aspartate aminotransferase (AST) level and alanine aminotransferase (ALT) level. Furthermore, uPCI significantly inhibited the increase in the levels of plasma kallikrein and thrombin which act not only as the procoagulant proteases but also as the chemotactic factors to neutrophils and monocytes. These results show that uPCI may prevent hypercoagulation, the induction of secondary fibrinolysis and organ failure in the DIC model. Therefore, uPCI may be a useful agent for the clinical treatment of DIC.

scholarly journals Contractile and endothelium-dependent dilatation aortic reactions in hyperthyroidism

2000 ◽  
Vol 46 (6) ◽  
pp. 38-41
Author(s):  
L. S. Luksha ◽  
I. M. Bagel ◽  
L. M. Lobanok
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Inhibitory Effect ◽  
Female Rats ◽  
Adrenergic System ◽  
Isolated Aorta ◽  
Strong Inhibitory Effect ◽  
Low Sensitivity

То prove the hypothesis that onset of hyperthyroidism may be attributed not only to hyperactivity of beta-adrenergic system but also to enhanced endothelial impacts on the tone of smooth muscle cells, the authors studied the role of endothelium in regulation of functional activity of arterial vessels in hypothyroidism. The experiments were made on isolated aortic segments of euthyroid and hyperthyroid female rats. Contractile and endothelium-dependent dilatations of the aortic segments in response to noradrenaline and carbacholine, respectively, were studied. It was shown that in hyperthyroidism contractile reactions of the aorta to noradrenalin are less expressed as a result of low sensitivity of the smooth muscle cells to this agonist and strong inhibitory effect of endothelium on these reactions. Dilatatory endothelium-dependent reactions of the isolated aorta in hyperthyroidism are more expressed. Enhancement of carbacholine dilatotory effects may be due to endothelial hyperpolarising factor, whose eficiency grows with a thyroxin-stimulated rise in the number of units of the Na*K*A TPase pump. The findings indicate an essential role of endothelium in mechanisms of hyperthyroid circulatory disorders.

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