Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rats which were infected with the gramnegative pathogen Klebsiella pneumoniae develop disseminated intravascular coagulation (DIC), multi-organ failure (MOF) and finally die in a septic shock. We investigated the therapeutic effect of antibiotic (tobramycin) treatment combined with the infusion of the highly specific thrombin inhibitor rec. hirudin. Although administration of 2 mg/kg tobramycin alone leads to a decrease of the bacterial burden, DIC could not be prevented. Infusion of rec. hirudin (0.25 mg/kg x h) for 4 h (start of treatment 1 h post infection), in addition to a bolus administration of tobramycin, led to an amelioration of DIC parameters as fibrinogen, thrombin-antithrombin complex (TAT) and platelets. Serum transaminase levels (GOT, GPT) as a marker of MOF were significantly improved by rec. hirudin, the T50 value increased from 17 h in the tobramycin group to 42 h in the tobramycin+rec. hirudin group, mortality rates were 90% or 60%, respectively. Combination of heparin (100 U/kg x h) and tobramycin was not effective on survival.
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PMID:Combination of antibiotic treatment with the thrombin inhibitor recombinant hirudin for the therapy of experimental Klebsiella pneumoniae sepsis. 797 45

In our current study, we examined the antithrombotic effect of Chinese hamster ovary cell-derived human recombinant tissue factor pathway inhibitor (h-rTFPI) by intravenous injection of h-rTFPI with or without antithrombin into endotoxin-treated rats. An injection of h-rTFPI at a high dose (4 mg/kg of h-rTFPI or three doses of 1 mg/kg) significantly prevented the decrease of fibrinogen and factor VIII and the increase of fibrin/fibrinogen degradation products and glutamic-pyruvic transaminase in rats, while a single injection of 1 mg/kg of h-rTFPI or 250 U/kg of antithrombin did not significantly prevent intravascular coagulation. However, a simultaneous injection of 1 mg/kg of h-rTFPI and 250 U/kg of antithrombin did significantly prevent intravascular coagulation. From the studies on the clearance rate and immunohistochemical staining of injected h-rTFPI into normal rats, we found that most of the intravenously-injected h-rTFPI was localized on the central vein and sinusoids in the liver and catabolized via the proteoglycan-mediated pathway with a half-life of 48 min. These results suggest that h-rTFPI and antithrombin prevented endotoxin-induced intravascular coagulation in concert by binding to the vascular walls of the liver and by inhibiting fibrin formation on Kupffer cells in hepatic sinusoids.
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PMID:Antithrombotic effect of human recombinant tissue factor pathway inhibitor on endotoxin-induced intravascular coagulation in rats: concerted effect with antithrombin. 890 6

The results of hematologic, biochemical research and research of clotting system after intraperitoneal implantation of absorbed synthetic threads Dexon S are presented in this work. The research was made on rats of Wistar type. Blood for the research was taken 3, 7, 14, 30 and 60 days after the implantation. Morphology (Ht, Hb, MCH, WBC, the number of platelets), activity of aspartic and alanine aminotransferase and antithrombin activity, concentration of comolete protein and its fraction and concentration of glucose, urea, creatinine and also concentration of ions Na+, K+, Mg2+, Ca2+ and fibrinogen, protein C3 and C4 of complement system as well as kaolin-kephalin time and prothrombin time of plasma were marked. On the basis of the obtained results of the research it was noticed that the used methods of research constitute supplement of biological estimation of absorbed grafting materials.
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PMID:[Usefulness of selected parameters from the diagnostic laboratory for evaluating absorbed grafting materials]. 912 61

To determine whether decreases in plasma antithrombin (AT) level, as seen in non-gestational acquired AT deficiency, result from a hypercoagulable state and/or liver/kidney damage, AT activity was measured in 24 uncomplicated and 30 preeclamptic women. The fifth percentile of AT levels in the normal pregnancies was used as a cut-off value to subdivide the preeclamptic patients into two groups. Markers of activated coagulation, i.e, levels of thrombin-antithrombin complex (TAT), fibrin D-dimer, soluble fibrin, von Willebrand factor (vWF) and platelet counts, were determined. Indicators of hepatic or renal function, i.e. concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, urinary albumin (U-albumin) and serum albumin (S-albumin), were assayed. AT levels were lower in those with preeclampsia than in the normal pregnancy group (P < 0.01). In the group with AT levels less than the cut-off point, levels of fibrin D-dimer (P < 0.05), soluble fibrin (P < 0.05), vWF (P < 0.05), ALT (P < 0.05), AST (P < 0.05), creatinine (P < 0.01) and U-albumin (P < 0.01) were increased, whereas platelet counts (P < 0.05) and S-albumin (P < 0.05) were decreased. All patients with ALT levels > 0.46 mu kat/1, AST > 0.58 mu kat/1, S-albumin < 23 g/1 and/or U-albumin > 4.9 g/24 h had AT levels < or = cut off. AT levels correlated with vWF (rs = - 0.73, P < 0.01) and creatinine (Rs = -0.70, P < 0.01). It is suggested that in preeclampsia, acquired AT deficiency is secondary to a hypercoagulable state, and/or associated with impaired hepatic and/or renal function.
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PMID:Acquired deficiency of antithrombin in association with a hypercoagulable state and impaired function of liver and/or kidney in preeclampsia. 919 20

This study was performed to determine whether human urinary soluble thrombomodulin plays a role in liver ischemia-reperfusion injury. Liver ischemia was induced in two groups of dogs. Group 1 was exposed to 60 min ischemia, and group 2 was exposed to 60 min ischemia after preischemic administration of human urinary soluble thrombomodulin. In group 1, the thrombin-antithrombin complex and hyaluronic acid were significantly elevated after ischemia, compared with the preischemic values. While liver issue blood flow and the plasmin-alpha(2)-plasmin inhibitor complex significantly decreased, AST, ALT and m-AST dramatically increased after reperfusion. In group 2, the increase in the thrombin-antithrombin complex and hyaluronic acid was significantly suppressed, and AST, ALT and liver tissue blood flow significantly improved, compared with group 1. Histologically, in group 2, the hepatic tissue structure, including endothelial cells, was relatively intact. These findings suggest that administration of thrombomodulin inhibits endothelial cell injury and coagulopathy and offers protection from liver ischemia-reperfusion injury.
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PMID:Protective effect of human urinary thrombomodulin on ischemia- reperfusion injury in the canine liver. 1081 Feb 13

We investigated the relationship between endothelin, a potent vasoconstrictor peptide, and the pathophysiology of disseminated intravascular coagulation (DIC), using two models of DIC. Experimental DIC was induced by sustained infusion of 50 mg/kg lipopolysaccharide (LPS), or 3.75 U/kg thromboplastin, for 4 h via the rat tail vein. The effect of administration of a non-selective endothelin receptor antagonist (TAK-044) (2, 10, or 50 mg/kg, from -0.5 to 4 h) on thromboplastin-induced DIC was not significant. However, LPS-induced elevation of alanine aminotransferase, creatinine and glomerular fibrin deposition was significantly suppressed by co-administration of TAK-044 in a dose-dependent manner, although no effect of TAK-044 was observed on the platelet count, fibrinogen concentration or the level of thrombin-antithrombin complex. Moreover, plasma levels of D-dimer, which reflect the grade of fibrinolysis of cross-linked fibrin, were significantly increased by co-administration of each dose of TAK-044 in the LPS-induced DIC model in rats. Our results suggest that vasoconstriction, as well as depressed fibrinolysis, contribute to severe organ dysfunction in LPS-induced, but not thromboplastin-induced, DIC, and that endothelin plays a role in the development of organ injury in LPS-induced DIC in rats.
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PMID:Relationship between endothelin and the pathophysiology of tissue factor-induced and lipopolysaccharide-induced disseminated intravascular coagulation in rats: a study examining the effect of an endothelin receptor antagonist. 1538 27

Coadministration of nonhepatotoxic doses of the histamine 2-receptor antagonist ranitidine (RAN) and bacterial lipopolysaccharide (LPS) results in hepatocellular injury in rats, the onset of which occurs in 3 to 6 hours. This reaction resembles RAN idiosyncratic hepatotoxicity in humans. Early fibrin deposition occurs in livers of rats cotreated with LPS/RAN. Accordingly, we tested the hypothesis that the hemostatic system contributes to liver injury in LPS/RAN-treated rats. Rats were given either LPS (44.4 x 10(6) EU/kg) or its vehicle, then RAN (30 mg/kg) or its vehicle 2 hours later. They were killed 2, 3, 6, 12, or 24 hours after RAN treatment, and liver injury was estimated from serum alanine aminotransferase activity. A modest elevation in serum hyaluronic acid, which was most pronounced in LPS/RAN-cotreated rats, suggested altered sinusoidal endothelial cell function. A decrease in plasma fibrinogen and increases in thrombin-antithrombin dimers and in serum concentration of plasminogen activator inhibitor-1 occurred before the onset of liver injury. Hepatic fibrin deposition was observed in livers from LPS/RAN-cotreated rats 3 and 6 hours after RAN. Liver injury was abolished by the anticoagulant heparin and was significantly attenuated by the fibrinolytic agent streptokinase. Hypoxia, one potential consequence of sinusoidal fibrin deposition, was observed in livers of LPS/RAN-treated rats. In conclusion, the results suggest that the hemostatic system is activated after LPS/RAN cotreatment and that fibrin deposition in liver is important for the genesis of hepatic parenchymal cell injury in this model.
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PMID:Role of hepatic fibrin in idiosyncrasy-like liver injury from lipopolysaccharide-ranitidine coexposure in rats. 1556 32

In a rat model of lipopolysaccharide (LPS)-induced disseminated intravascular coagulation (DIC), we used urokinase (UK) in an attempt to clarify the role of fibrinolysis and to investigate changes in plasma endothelin levels. Two kinds of experiment were performed. The first one: experimental DIC was induced by sustained infusion of 30 mg/kg LPS for 4 h via the tail vein, and two doses of UK (2.0 or 10.0 IU/g/4.5 h) were administered to rats 30 min before infusion of LPS, after which UK infusion was continued for a further 4 h. The second one: experimental DIC was induced by sustained infusion of 1 mg/kg/10 min LPS for 10 min, and two doses of UK (2.0 or 10.0 IU/g/4 h) were administered to rats at 30 min after LPS infusion. The parameters described below were determined at 4 h in the first experiment, at 4 h and 8 h in the second one. The similar results were observed in both kinds of experiment. There were no significant differences in plasma thrombin-antithrombin complex, fibrinogen or platelet number among the three DIC groups, in both kinds of experiment. Plasma levels of D-dimer were significantly increased in the LPS + higher dose of UK group when compared with the LPS group. The increased plasma plasminogen activator inhibitor (PAI) activity seen in the LPS group was significantly suppressed in the groups receiving UK (especially higher dose of UK). In addition, the increased plasma levels of creatinine and alanine aminotransferase seen in the LPS group were significantly suppressed in the groups receiving UK (especially higher dose of UK). Plasma levels of endothelin, known to be a potent vasoconstrictive agent, were markedly elevated by LPS infusion, and were significantly suppressed in the groups receiving UK of both kinds of experiment, in a dose-dependent fashion compared with LPS group. Glomerular fibrin deposition was significantly suppressed in the groups receiving UK when compared with the LPS group. No manifestations of bleeding were observed in any of the groups. Enhanced fibrinolysis and depressed endothelin induced by UK thus appear to play an important role in preventing the development of organ failure in the LPS-induced DIC model.
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PMID:Beneficial effects of urokinase on lipopolysaccharide-induced disseminated intravascular coagulation in rats: focus on organ function and endothelin levels. 1584 19

We examined the role of nitric oxide (NO) produced by an inducible isoform of NO synthase (iNOS) using N[6]-(iminoethyl)-lysine (L-NIL), a selective iNOS inhibitor, in the rat model of lipopolysaccharide (LPS)-induced disseminated intravascular coagulation (DIC) and investigated changes in organ function, plasma levels of NOX (metabolites of NO) and endothelin. We induced experimental DIC by the sustained infusion of 30 mg kg(-1) LPS for 4 h via the tail vein. We then investigated the effect of L-NIL (6 mg kg(-1), from - 0.5 to 4 h) on LPS-induced DIC. Blood was withdrawn at 4 and 8 h, and all four groups (LPS with or without L-NIL at 4 and 8 h) consisted of eight rats. Three of the animals in the 8-h LPS group died, and we examined blood samples from five rats in this group. None of the other rats died. The LPS-induced elevation of creatinine, alanine aminotransferase, glomerular fibrin deposition and plasminogen activator inhibitor was significantly suppressed by L-NIL coadministration, although L-NIL did not affect the platelet count, fibrinogen concentration or the level of thrombin-antithrombin complex. Moreover, plasma levels of the D-dimer that reflect the lysis of cross-linked fibrin were significantly increased by L-NIL coadministration in the LPS-induced DIC model. Plasma levels of NOX and endothelin were obviously increased by LPS infusion. However, both levels were significantly suppressed in the LPS + L-NIL group, when compared with the LPS group. Although mean arterial pressure (MAP) was significantly decreased between 2 and 8 h compared with the control in the LPS group, this depression was significantly attenuated in the LPS + L-NIL group. Our results suggest that NO induced by iNOS contributes to hypotension (depressed MAP), the progression of hepatic and renal dysfunction, microthrombus deposition and elevated endothelin levels in the rat model of LPS-induced DIC.
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PMID:Selective inducible nitric oxide synthase inhibition attenuates organ dysfunction and elevated endothelin levels in LPS-induced DIC model rats. 1586 3

The limitations of heparin and warfarin have prompted the development of new anticoagulant drugs for prevention and treatment of venous and arterial thromboembolism. Novel parenteral agents include synthetic analogs of the pentasaccharide sequence of heparin that mediates its interaction with antithrombin. Fondaparinux, the first synthetic pentasaccharide, is licensed for prevention of venous thromboembolism (VTE) after major orthopedic surgery and for initial treatment of patients with VTE. Idraparinux, a long-acting pentasaccharide that is administered subcutaneously once-weekly, is being compared with warfarin for treatment of VTE and for prevention of cardioembolic events in patients with atrial fibrillation. New oral anticoagulants include direct inhibitors of thrombin, factor Xa and factor IXa. Designed to provide more streamlined anticoagulation than warfarin, these agents can be given without routine coagulation monitoring. Ximelagatran, the first oral direct thrombin inhibitor, is as effective and safe as warfarin for prevention of cardioembolic events in patients with atrial fibrillation. However, ximelagatran produces a three-fold elevation in alanine transaminase levels in 7.9% of patients treated for more than a month, the long-term significance of which is uncertain. Whether other direct thrombin inhibitors or inhibitors of factors Xa or IXa also have this problem is under investigation. After a brief review of coagulation pathways, this paper focuses on new anticoagulants in advanced stages of clinical testing.
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PMID:New anticoagulants. 1610 51


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