Plasma procarboxypeptidase B, also known as thrombin-activatable fibrinolysis inhibitor (TAFI), is converted by thrombin into the active enzyme, carboxypeptidase B (CPB)/activated TAFI. Plasma CPB down-regulates fibrinolysis by removing carboxy-terminal lysines, the ligands for plasminogen and tissue-type plasminogen activator (tPA), from partially degraded fibrin. To target thrombosis in a new way, we have identified and optimized a phosphinic acid-containing inhibitor of CPB,heptanoic acid] and determined both the pharmacological profile and pathophysiological role of CPB in rat thrombolysis. EF6265 specifically inhibited plasma CPB activity with an IC 50 (50% inhibitory concentration) of 8.3 nM and enhanced tPA-mediated clot lysis in a concentrationdependent manner. EF6265 decreased detectable thrombi (percentage of glomerular fibrin deposition; control, 98 Ϯ 1.1; EF6265, 0.1 mg/kg, 27 Ϯ 9.1) that had been generated by tissue factor in a rat microthrombosis model with concomitant increases in plasma D-dimer concentration (control, Ͻ0.5 g/ml; EF6265, 0.1 mg/kg, 15 Ϯ 3.5 g/ml). EF6265 reduced plasma ␣2-antiplasmin activity to a lesser extent than tPA. In an arteriovenous shunt model, EF6265 (1 mg/kg) enhanced exogenous tPA-mediated thrombolysis under the same conditions that neither EF6265 nor tPA (600 kIU/kg) alone reduced thrombi. EF6265 (1 and 30 mg/kg) did not affect the bleeding time in rats. Moreover, it did not prolong the bleeding time evoked by tPA (600 kIU/kg). These results confirm that circulating procarboxypeptidase B functions as a fibrinolysis inhibitor's zymogen and validates the use of CPB inhibitors as both an enhancer of physiological fibrinolysis in microcirculation and as a novel adjunctive agent to tPA for thromboembolic diseases while maintaining a small effect on primary hemostasis.Thrombosis-related diseases, including myocardial infarction, cerebral infarction, and disseminated intravascular coagulation are life-threatening and the search for treatments remains challenging. Although thrombolytics including tissue-type plasminogen activator (tPA) or urokinase-type plasminogen activator and anticoagulants including heparin have been developed over the last few decades, the risk of hemorrhaging with these antithrombotic agents restricts their clinical use. The dose of tPA must be high enough to overcome the inhibitory effects of plasminogen activator inhibitor-1 in the plasma, and results in the generation of plasmin in circulating blood (Rijken and Sakharov, 2001). Consequently, these large quantities of generated plasmin can induce thrombolysis and result in hemorrhaging as a side effect (Bloom et al., 1988). Many efforts have therefore been made to identify and develop pharmacologically distinct antithrombotic agents while maintaining a low risk of hemorrhaging.Plasma procarboxypeptidase B (proCPB; EC 3.4.17.20), also known as thrombin-activatable fibrinolysis inhibitor (TAFI) or procarboxypeptidase U, is produced in the liver and Article, publication date, and citation informa...
Pulmonary resection of metastatic lesions from colorectal adenocarcinoma was performed in 35 patients. The cumulative 5-year survival was 38%. The primary site of cancer was the colon in about half of the patients. Patients with a solitary metastasis or tumors smaller than 3 cm in diameter survived longer than did patients with multiple metastases or tumors larger than 3 cm but the differences were not significant. Other factors, including age, sex, histologic grade of tumor, location and stage of primary carcinoma, location of pulmonary metastases, disease-free interval, and type of pulmonary resection, had no apparent influence on survival time. The lung was the major site of recurrence following pulmonary resection. Seven patients underwent two or more pulmonary resections for metastasis from a colorectal carcinoma. At the time of last follow-up, four patients were alive and free of recurrent disease at 5, 34, 39, and 58 months after the second pulmonary resection. These data suggest that some patients will survive for a long time following pulmonary resection of colorectal metastases, and for highly selected patients, repeated pulmonary resection may further extend survival.
Purified bovine Cu,Zn-superoxide dismutase was nonenzymatically glycosylated in vitro at a rate proportional to incubation time (2 to 120 hrs) and glucose concentration (10 to 100 mM). Inverse correlation between glycosylation and the enzyme activity showed that increased glycosylation was accompanied with inactivation of the enzyme. Specific activities of glycosylated and non-glycosylated enzymes incubated with 100 mM glucose for 120 hrs were 1150 and 2860 units/mg protein, respectively. This indicates that nonenzymatic glycosylation declined the enzyme activity approximately to 40%. All these results were consistent with the in vivo studies that Cu,Zn-superoxide dismutase activity in erythrocytes of non-insulin dependent diabetic patients was inversely correlated with their plasma glucose. Inactivation of Cu,Zn-superoxide dismutase demonstrated by both in vitro and in vivo studies may be important for the development of diabetic complications, because the enzyme has a crucial role in protecting the body against the damaging effects of the superoxide radicals.
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