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:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The goal of this report is to evaluate in a prospective randomized fashion the effect of flushing hepatic allografts with tacrolimus before transplantation. A prospective, double-blinded, randomized trial was performed. Twenty patients receiving orthotopic liver transplants from October 2000 to October 2001 were randomized into two groups. Group 1 (active) was administered tacrolimus, 20 ng/mL, plus Plasma-lyte A (Baxter Healthcare Corp, Deerfield, IL) liver flush solution; and group 2 (placebo) was administered only Plasma-lyte A. Ischemia/reperfusion injury was assessed in both groups after transplantation by means of serum laboratory values to assess hepatocellular damage, synthetic function, and ion transport capacity. Peak values were recorded for each parameter, and their distributions were compared. There were no statistically significant differences between groups for age, sex, total ischemia time, or cause of liver disease. Global multivariate comparison of peak changes in all measures of liver function indicated liver injury was significantly lower with tacrolimus treatment than placebo (P =.01). The sample median for group 1 was less than for group 2 in all parameters measured. Individual statistical comparison showed that peak changes from baseline aspartate aminotransferase and activated partial thromboplastin time values were significantly improved (P </=.05) with tacrolimus treatment than placebo treatment. In this prospective, double-blinded, randomized trial, we show that flushing the liver before transplantation with Plasma-lyte A containing tacrolimus results in superior early graft function and decreased hepatocellular injury after reperfusion compared with flushing with Plasma-lyte A alone.
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PMID:Tacrolimus as a liver flush solution to ameliorate the effects of ischemia/reperfusion injury following liver transplantation. 1254 8

Kupffer cell depletion by gadolinium chloride (GdCl(3)) in rat livers has previously been proven to minimize hepatic ischemia/reperfusion injury after experimental liver transplantation (LTX). In the current study, we evaluated the effects of donor pretreatment with GdCl(3) on hepatic ischemia/reperfusion injury, macro- and microcirculation, and endotoxin clearance of the liver in a porcine model of experimental LTX. Two groups of 12 pigs were treated either with intravenous NaCl (0.9%; control) or GdCl(3) (20 mg/kg). Twenty-four hours after pretreatment, hepatic macrocirculation was quantified by Doppler flowmetry and liver parenchymous microcirculation by implanted thermodiffusion electrodes. The liver grafts were transplanted after 4-6 h of cold ischemia in University of Wisconsin (UW) solution. At 1 and 24 h after LTX, the perfusion values were re-evaluated and histology, biochemical (aspartate aminotransferase, AST) and functional parameters (partial thromboplastin time, prothrombin time, and bilirubin) were analyzed. Furthermore, endotoxin clearance of the liver was evaluated at all time points. In GdCl(3)-treated animals 80% of the Kupffer cells were destroyed, and 24 h after LTX ischemia/reperfusion injury in treated grafts was significantly lower in comparison to controls, as shown by histology, AST levels (741+/-490 U/l in controls vs 379+/-159 U/l in treated grafts, P<0.05), survival (67% vs 92%), and enhanced macro- (total transhepatic blood flow [THBF]=112+/-22 ml/min per 100 g in controls vs 157+/-45 ml/min per 100 g in treated grafts, P<or=0.05) and microcirculation (thermodiffusion [TD]=73+/-9 ml/min per 100 g in controls vs 90+/-16 ml/min per 100 g in treated grafts, P<or=0.05). Despite destruction of the macrophage system in the liver, the transhepatic endotoxin gradient of treated livers was enhanced before and 1 h after transplantation (58% in controls vs 85% in treated grafts, P<0.05). Destruction of Kupffer cells of donors by pretreatment with GdCl(3) in pigs is effective in preventing liver graft dys- and nonfunction after LTX. Pretreatment with GdCl(3) does not diminish but increase hepatic endotoxin clearance.
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PMID:Donor pretreatment with gadolinium chloride improves early graft function and survival after porcine liver transplantation. 1287 29

Antithrombin (AT) reveals its antiinflammatory activity by promoting endothelial release of prostacyclin (PGI(2)) in vivo. Since neuroinflammation is critically involved in the development of ischemia/reperfusion (I/R)-induced spinal cord injury (SCI), it is possible that AT reduces the I/R-induced SCI by attenuating the inflammatory responses. We examined this possibility using rat model of I/R-induced SCI in the present study. AT significantly reduced the mortality and motor disturbances by inhibiting reduction of the number of motor neurons in animals subjected to SCI. Microinfarctions of the spinal cord seen after reperfusion were markedly reduced by AT. AT significantly enhanced the I/R-induced increases in spinal cord tissue levels of 6-keto-PGFIalpha, a stable metabolite of PGI2. AT significantly inhibited the I/R-induced increases in spinal cord tissue levels of TNF-alpha, rat interleukin-8 and myeloperoxidase. In contrast,Trp(49) -modified AT did not show any protective effects. Pretreatment with indomethacin significantly reversed the protective effects of AT. An inactive derivative of factor Xa, which selectively inhibits thrombin generation, has been shown to fail to reduce SCI. Taken together, these observations strongly suggested that AT might reduce I/R-induced SCI mainly by the antiinflammatory effect through promotion of endothelial production of PGI(2). These findings also suggested that AT might be a potential neuroprotective agent.
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PMID:Antithrombin reduces the ischemia/reperfusion-induced spinal cord injury in rats by attenuating inflammatory responses. 1469 82

We investigated the effect of smaller dose, weight-adjusted heparin with earlier monitoring of activated partial thromboplastin time on the incidence of ischemic and hemorrhagic complications in patients with ST-elevation myocardial infarction treated with full-dose tenecteplase. We compared the outcomes of patients enrolled in the Second Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT-2; n = 8,461) who received heparin stratified by weight (patients weighing >67 kg received a 5,000-U bolus plus infusion at 1,000 U/hour; those weighing < or =67 kg received a 4,000-U bolus plus infusion at 800 U/hour) with patients in ASSENT-3 who received weight-adjusted heparin (60-U/kg bolus, maximum 4,000 U/hour, followed by a 12-U/kg/hour infusion, maximum 1,000 U/hour). Compared with patients in ASSENT-2, those in ASSENT-3 had similar rates of 30-day mortality, recurrent infarction, and intracranial hemorrhage, less major bleeding (2.2% vs 4.7%, p <0.001), and less refractory ischemia (6.5% vs 8.6%, p <0.001). After adjustment for baseline characteristics, patients in ASSENT-3 had similar rates of 30-day mortality (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.77 to 1.19) and intracranial hemorrhage (OR 1.02, 95% CI 0.61 to 1.69) but less major bleeding (OR 0.49, 95% CI 0.35 to 0.67) than did patients in ASSENT-2. These findings support the use of smaller dose, weight-adjusted heparin in patients with ST-elevation myocardial infarction treated with tenecteplase.
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PMID:Efficacy and safety of two unfractionated heparin dosing strategies with tenecteplase in acute myocardial infarction (results from Assessment of the Safety and Efficacy of a New Thrombolytic Regimens 2 and 3). 1527 88

This study was conducted to determine which isoform of cyclooxygenase (COX) is more significantly involved in the anti-thrombin (AT)-induced increase in prostaglandin production in the liver of rats, subjected to hepatic ischemia/reperfusion (I/R). Hepatic tissue levels of 6-keto-PGF(1alpha), a stable metabolite of prostacyclin (PGI(2)), and PGE(2) were transiently increased 1 hour after reperfusion. Thereafter, hepatic PGE2 levels were gradually increased until 6 hours after reperfusion, while hepatic 6-keto-PGF(1alpha) levels were decreased to the pre-ischemia levels at 6 hours after reperfusion. AT significantly enhanced increases in hepatic tissue levels of 6-keto-PGF(1alpha) and PGE(2) seen 1 hour after reperfusion, while it inhibited increases in hepatic PGE(2) levels seen 6 h after reperfusion. Neither dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, nor Trp(49)-modified AT which lacks affinity for heparin, showed any effects on these changes. Pretreatment with indomethacin (IM), a non-selective inhibitor of COX, inhibited AT-induced increases in hepatic tissue levels of 6-keto-PGF(1alpha) and PGE(2) seen 1 hour after reperfusion, whereas pretreatment with NS-398, a selective inhibitor of COX-2, did not. The increase in hepatic tissue blood flow and inhibition of hepatic inflammatory responses seen in animals given AT were reversed by pretreatment with IM, but were not affected by pretreatment with NS-398. Administration of ilo-prost, a stable analog of PGI(2), and PGE(2) produced effects similar to those induced by AT. Increases in hepatic tissue levels of PGE(2) 6 hours after reperfusion were inhibited by pretreatment with NS-398. Although AT did not affect COX-1 mRNA levels 1 hour after reperfusion, it inhibited the I/R-induced increases in hepatic tissue levels of both PGE(2) and COX-2 mRNA 6 hours after reperfusion. These observations strongly suggested that AT might reduce the I/R-induced liver injury by increasing the production of PGI2 and PGE2 through activation of COX-1. Furthermore, since TNF-alpha is capable of inducing COX-2, inhibition of TNF-alpha production by AT might inhibit COX-2-mediated PGE(2) production. These effects induced by AT might contribute to its anti-inflammatory activity.
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PMID:Antithrombin reduces ischemia/reperfusion-induced liver injury in rats by activation of cyclooxygenase-1. 1535 51

Several glycosaminoglycans (GAGs) have been demonstrated to protect the ischemic heart against reperfusion injury, in part, by modulating activation of the complement cascade. The present study assessed the cardioprotective effects of sulodexide (KRX-101), a mixture of GAGs composed of 80% low-molecular mass heparin and 20% dermatan sulfate. KRX-101 differs from other GAGs (e.g., heparin) in that it has limited anticoagulant efficacy and can be administered orally. The experimental protocol was designed to determine whether KRX-101 could protect the ischemic myocardium. Anesthetized New Zealand white rabbits underwent 30 min of coronary artery occlusion. Intravenous doses of KRX-101 (0.5 mg/kg, n = 10) or drug diluent (n = 10) were administered at the end of regional ischemia and at each hour of reperfusion. Infarct size, as a percentage of the area at risk, was calculated for both groups. Myocardial infarct size was 31.3 +/- 4.1% in the vehicle- and 17.3 +/- 3.2% in the KRX-101-treated animals (p < 0.05 versus vehicle). Activated partial thromboplastin times determined at baseline (preischemia) and at each hour of reperfusion (n = 4) were not significantly different between vehicle- and KRX-101-treated groups (p = N.S.). Myocardial injury was further assessed by measuring serum levels of cardiac-specific troponin I. KRX-101 administration significantly reduced (p < 0.05) the serum concentration of troponin I during reperfusion. The results suggest that KRX-101 may be an effective adjunctive agent in myocardial revascularization procedures, without the risk of increased bleeding.
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PMID:Sulodexide attenuates myocardial ischemia/reperfusion injury and the deposition of C-reactive protein in areas of infarction without affecting hemostasis. 1536 91

Gastrointestinal bleeding has been described as related complication of pancreas transplantation. Of 166 simultaneous pancreas kidney transplantations, 61 were enteric-drained pancreas transplants (eight done with and 53 without Roux-en-Y loop). The patients were divided into two groups according to Roux (group I, n = 8) or no Roux (group II, n = 53) technique. Seven patients experienced anastomotic hemorrhage between the jejunum and duodenal stump (11%), five cases in group I and two in group II (P < 0.001). No relationships between gastrointestinal bleeding duodenal stump and recipient jejunum blood flow, mean pancreatic cold ischemia time, platelet count, and prothrombin time were observed. Donor age over 40 years and abnormal activated partial thromboplastin time constituted risk factors for hemorrhage from the duodenojejunal anastomosis. There were no significant differences in pancreas graft and patient survival rates between the two groups. Anastomotic hemorrhage did not influence patient and graft survival.
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PMID:Gastrointestinal bleeding from enterically drained transplanted pancreas. 1573 Apr 89

Ischemia-reperfusion (I/R) injury is associated with activation of coagulation and inflammation. Interestingly, various anticoagulants have been shown to reduce both coagulation and inflammation in animal models of kidney I/R injury. Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa (FXa) in the coagulation cascade. The aim of this study was to investigate the effect of fondaparinux in a lethal murine model of kidney I/R injury. A murine model of kidney I/R was established. In this model, we measured activation of the coagulation cascade and induction of inflammation. Administration of fondaparinux to I/R-injured mice reduced fibrin deposition in the kidney, reduced serum creatinine levels and increased survival from 0 to 44% compared with saline-treated control mice. Fondaparinux also reduced interleukin-6 and macrophage inflammatory protein-2 expression and decreased neutrophil accumulation in the injured kidneys. Finally, we showed that fondaparinux reduced thioglycollate-induced recruitment of neutrophils into the peritoneum and inhibited the binding of U937 cells to P-selectin in vitro. Our data suggest that fondaparinux reduces kidney I/R injury primarily by inhibiting the recruitment of neutrophils.
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PMID:The synthetic pentasaccharide fondaparinux reduces coagulation, inflammation and neutrophil accumulation in kidney ischemia-reperfusion injury. 1574 44

Microvascular thrombosis is a prominent feature in cardiac delayed xenograft rejection (DXR). We investigated the impact of warfarin or low-molecular-weight heparin (LMWH) anti-coagulation on xenograft function using a heterotopic pig-to-primate model. Donor hearts were from CD46 transgenic pigs and baboon immunosuppression included tacrolimus, sirolimus, anti-CD20 and TPC, an alpha-galactosyl-polyethylene glycol conjugate. Three groups of animals were studied. Group 1 (n = 9) was treated with warfarin, Group 2 (n = 13) with LMWH and Group 3, received no anti-coagulant drugs. The median duration of xenograft function was 20 days (range 3-62 days), 18 days (range 5-109 days) and 15 days (range 4-53 days) in Groups 1 to 3 respectively. Anti-coagulation achieved the targeted international normalized prothrombin ratio (INR) and anti-factor Xa levels consistent with effective in vivo therapy yet, no significant impact on median xenograft function was observed. At rejection, a similar histology of thrombosis and ischemia was apparent in each group and the levels of fibrin deposition and platelet thrombi in rejected tissue was the same. Anti-coagulation with warfarin or LMWH did not have a significant impact on the onset of DXR and microvascular thrombosis. However, a role for specific anti-coagulant strategies to achieve long-term xenograft function cannot be excluded.
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PMID:Warfarin or low-molecular-weight heparin therapy does not prolong pig-to-primate cardiac xenograft function. 1581 81

The aim of this study was to investigate the therapeutic effect of platonin, a cyanine photosensitizing dye as well as an inhibitor of proinflammatory cytokines, in an animal model of heat stroke. Anesthetized rats, immediately after the onset of heat stroke, were divided into two major groups and given the following: normal saline (1 mL per kg body weight) intravenously, or platonin (12.5-50 microg/mL per kg body weight) intravenously. They were exposed to ambient temperature of 43 degrees C to induce heat stroke. Another group of rats was exposed to room temperature (26 degrees C) and used as normothermic controls. Their physiologic and biochemical parameters were continuously monitored. When the vehicle-treated rats underwent heat exposure, their survival time values were found to be 18 to 22 min. Resuscitation with intravenous doses of platonin, but not normal saline, immediately at the onset of heat stroke, significantly improved survival during heat stroke (41-147 min). All heat-stressed animals displayed systemic inflammation and activated coagulation, evidenced by increased tumor necrosis factor-alpha, prothrombin time, activated partial thromboplastin time, fibrinogen degradation products, and D-dimer, and decreased platelet count and protein C. Biochemical markers evidenced cellular ischemia and injury/dysfunction: plasma levels of blood urea nitrogen, creatinine, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and alkaline phosphatase, and striatal levels of partial pressure of oxygen, local cerebral blood flow, glycerol, glutamate, and lactate/pyruvate were all elevated during heat stroke. The systemic inflammation, hypercoagulable state, and cerebral ischemia and injury during heat stroke were all significantly suppressed by platonin. The data demonstrate that platonin therapy may resuscitate heat stroke victims by reducing circulatory shock, systemic inflammation, hypercoagulable state, and tissue ischemia and injury.
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PMID:Platonin, a cyanine photosensitizing dye, causes attenuation of circulatory shock, hypercoagulable state, and tissue ischemia during heat stroke. 1631 90


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