Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

All thrombolytic agents convert plasminogen to plasmin, either directly as urokinase, saruplase and alteplase or indirectly as streptokinase. In the majority of recent clinical trials with streptokinase, a high-dose (0.7 to 1.5 mega-units), brief-duration (30 to 90 minutes) drug regimen has been used. After a mean time interval of 4.2 hours from onset of pain to intravenous infusion of streptokinase, a repeat angiography performed 60 to 90 min after start of thrombolytic treatment gives a reperfusion rate of 43%, the corresponding figures for anistreplase, saruplase and alteplase are 56%, 67% and 69%. The patency rates of similar studies with the same endpoint are for streptokinase 56%, for anistreplase 77%, for urokinase 62%, for saruplase 71% and for alteplase 75%. The reduction in hospital mortality in randomized trials with intravenous streptokinase (high-dose) is in 6 large studies in a total of 23,267 randomized patients from 10.7% in the control group to 7.0% in the streptokinase group. In a mortality study involving 1,004 patients randomized to intravenous anistreplase or placebo the 30-day mortality was reduced by 47%, from 12.2% to 6.4%. A large trial in which 5,011 patients were randomized to alteplase or placebo, the 30-day mortality was 7.2% compared to 9.8% in controls, a reduction of 27% by alteplase. In another trial 721 patients were randomized to placebo or alteplase; all patients were on aspirin. The 14-day mortality was only 2.8%, 51% less than that in the control group. It is most important that the favourable impact on hospital survival is maintained at 1 year with any thrombolytic drug. Large scale trials directly comparing mortality after alteplase, streptokinase or anistreplase are being performed or in the planning phase. The risk of bleeding exists with any thrombolytic agent but intracranial bleeding is the most serious one. In a large trial on 5,011 patients with acute myocardial infarction, stroke occurred in 1.1% of alteplase treated patients compared with 1.0% in placebo treated controls. Crucial problems are residual stenosis of the coronary artery and reocclusion. Urgent angioplasty does not seem to be the right answer; more effective antithrombotic strategies still have to be developed.
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PMID:[Thrombolytic therapy in acute myocardial infarct]. 219 44

Thrombolytic therapy has recently gained ascendance as an accepted form of treatment for acute myocardial infarction. Since the majority of patients with acute infarction have an occlusive coronary thrombus, plasminogen activators administered to these patients generate plasmin that proteolysis the fibrin elements of the thrombus and thereby reestablishes coronary patency. In addition to the conventional agents streptokinase and urokinase, newer, more fibrin-selective plasminogen activators are currently available for use or study, including tissue plasminogen activator and pro-urokinase. In acute myocardial infarction, the agents that have been studied most extensively are streptokinase and tissue plasminogen activator. Among the major recent studies of the use of these activators, several important observations have been made, including the need for administration of agent within 3 hours of the onset of pain, the efficacy of the intravenous route of administration, significant reduction in mortality with early administration, and significantly improved left ventricular function with early administration. Haemorrhagic complications remain a problem, but with judicious dosing their incidence can be kept to a minimum. Early studies in patients with unstable angina suggest that plasminogen activators may also have a role in the management of this clot-dependent disorder.
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PMID:Thrombolysis in the management of acute myocardial infarction and unstable angina pectoris. 264 55

Recent trials have shown that recombinant tissue plasminogen activator (rt-PA) is an effective thrombolytic agent in patients with acute myocardial infarction. Because rt-PA converts plasminogen to plasmin, which is known to activate complement in vitro, we tested the hypothesis that rt-PA can induce in vivo activation of complement. Studies were performed in 12 patients with acute myocardial infarction. Six control patients had patent coronary arteries and did not receive rt-PA; these patients had normal values of the components of the complement system C4a (409 +/- 111 ng/ml) and C5a (8.8 +/- 1.8 ng/ml) with a slight elevation of C3a (204 +/- 6.6 ng/ml) in samples collected before coronary arteriography (253 +/- 25 minutes after onset of pain). After coronary arteriography, there was a slight decrease in the values of C4a (224 +/- 37 ng/ml), C5a (7.3 +/- 1.3 ng/ml) and C3a (164 +/- 35 ng/ml). The remaining six patients had complete coronary occlusion and received rt-PA (80 to 150 mg intravenously). In this treated group, before coronary arteriography the values of C4a (406 +/- 51.6 ng/ml) and C5a (8.1 +/- 1.9 ng/ml) were normal, and those of C3a were slightly elevated (250 +/- 76 ng/ml). All complement values obtained before rt-PA were similar to those in the untreated group. However, after administration of rt-PA (but before any angiographically detectable reperfusion), there was a striking increase in C4a (2,265 +/- 480 ng/ml; p less than 0.01), C3a (600 +/- 89 ng/ml; p less than 0.05) and C5a (30.0 +/- 4.5 ng/ml; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of the complement system by recombinant tissue plasminogen activator. 311 50

To assess the thrombolytic efficacy and the effect on the systemic fibrinolytic system of recombinant tissue plasminogen activator doses of 20 mg, 50 mg, and 100 mg were compared in a randomised study. Tissue plasminogen activator was infused intravenously over 90 minutes in 50 consecutive patients with acute myocardial infarction of four hours' duration or less; on average the infusion was started 135 minutes (range 20 to 240) after the onset of pain. The affected artery was patent at the end of the 90 minute infusion in 14/17 (82%) of those who received 100 mg, 12/17 (71%) of those who received 50 mg, and 8/16 (50%) of those who received 20 mg. Regardless of dose, reperfusion rates were significantly better for patients treated within two hours of the onset of symptoms (81%) than for those treated in the third and fourth hours (54%). At the end of the infusion serum fibrinogen concentrations fell to 86% of the preinfusion value after 20 mg, 75% after 50 mg, and 63% after 100 mg, and similar dose dependent changes occurred in plasminogen, (alpha 2 anti-plasmin, and fibrinogen and fibrin degradation products. The mean infarct related regional third ejection fraction was 46% for patients with grade 2 or 3 reperfusion and 35% for those with grade 0 or 1. Ventricular fibrillation occurred in six (12%) patients during the infusion of tissue plasminogen activator, but no late ventricular fibrillation occurred. Bleeding was minimal, reocclusion occurred in three patients, and four patients died from cardiac causes. Recombinant tissue plasminogen activator is an effective thrombolytic agent which produces better reperfusion rates after a 50 or 100 mg dose than after a 20 mg dose. The effect on the systemic fibrinolytic system is dose dependent. Successful reperfusion results in improvement of left ventricular function.
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PMID:A randomised dose ranging study of recombinant tissue plasminogen activator in acute myocardial infarction. 313 31

One of the striking features of the proteolytic enzymes as a group is the immense variety of biological functions served by enzymes employing one of a few basic mechanisms. For example, in the higher animals, enzymes for activation of zymogens (trypsin), for digestion of dietary proteins (trypsin, chymotrypsin, elastase), for blood clotting (thrombin), for clot lysis (plasmin), and for sensing pain (kallikrein) all appear to use the same mechanism and to have evolved from the same ancestral gene by the process of gene duplication and subsequent divergent evolution. Equally striking is the variety of chemical solutions of the same functional problem, such as the peptide-bond cleavage by sulfhydryl proteases on the one hand and serine proteases on the other.
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PMID:Evolution of structure and function of proteases. 486 30

Kinins, which are vasodilatory, permeability-increasing, pain-producing polypeptides, are formed from inactive precursors: kininogens. Their actions make kinins a particularly powerful potential pro-inflammatory factor. However the absence of specific antagonists has so far made it impossible to ascribe them a definite role in inflammation. Two studies of experimental endotoxemia in burns patients, septicemia and septic shock have demonstrated the following facts: activation occurs of specific ( pKK ) and non-specific (plasminogen-plasmin system) kininogenases , K-HMW and K-LMW levels are significantly decreased. Kininogen consumption corresponds to increased BDK production. This would therefore appear to be one of the humoral factors responsible for haemodynamic changes. Though measurement of kininogen levels is still a painstaking process, the development of chromogenic substrates has made pKK and KK measurement simple and fast. Once they have been validated physico-pathologically in a large number of patients, such assays should take their place among the diagnostic weapons of clinical biology at the disposal of clinicians.
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PMID:[Role of the kallikrein-kininogen-kinin system in the inflammatory reaction and septic shock]. 623 19

Urokinase, or two-chain urokinase-type plasminogen activator (tcu-PA), is an effective thrombolytic agent. Its single-chain precursor (scu-PA), unlike tcu-PA, is able to selectively activate fibrin-bound plasminogen. The induced clot lysis is amplified by plasmin-triggered conversion of scu-PA to tcu-PA. The aim of our study was to compare the hemostatic effects of recombinant unglycosylated scu-PA, INN saruplase, and urokinase, at doses considered optimal (80 mg saruplase and 3 million units urokinase) in patients with acute myocardial infarction, within 6 h of onset of pain. Complete sample sets from more than 230 patients in each treatment group have been analyzed. The median hemostatic changes caused by saruplase and urokinase were virtually identical indicating that saruplase is converted early in vivo to its active tcu-PA derivative with the dose regimen used. Fibrinogen degradation products were higher for saruplase with a maximum at 2h. They rose markedly after saruplase from 0.43 mg/l at 0 h to a maximum of 160 mg/l at 2 h, whereas the increase after urokinase (from 0.45 mg/l to 89.0 mg/l) was significantly smaller (P < 0.001).
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PMID:Hemostatic changes after thrombolytic therapy with saruplase (unglycosylated single-chain urokinase-type plasminogen activator) and urokinase (two-chain urokinase-type plasminogen activator). 903 56

This article summarizes the discussions of the faculty and chairpersons on four major topics on postsurgical adhesions examined at the symposium, "Adhesions: Pathogenesis and Prevention". These topics are: 1) clinical significance; 2) pathogenesis; 3) research status and directions; and 4) recommendations for reduction or prevention. Abdominal postsurgical adhesions develop following trauma to the mesothelium, which is damaged often by surgical handling and instrument contact, foreign materials such as sutures and glove dusting powder, desiccation, and overheating. Postoperative adhesions occur after most surgical procedures and can result in serious complications, including intestinal obstruction, infertility, and pain. A long-term and unpredictable problem, postoperative adhesions impact the surgical workload and hospital resources, resulting in considerable health care expenditures. Although understanding of the pathogenesis of adhesions has improved recently, the molecular mechanisms involved continue to be delineated. Adhesions result from the normal peritoneal wound healing response and develop in the first five to seven days after injury. Adhesion formation and adhesion-free re-epithelialization are alternative pathways, both of which begin with coagulation which initiates a cascade of events resulting in the buildup of fibrin gel matrix. If not removed, the fibrin gel matrix serves as the progenitor to adhesions by forming a band or bridge when two peritoneal surfaces coated with it are apposed. The band or bridge becomes the basis for the organization of an adhesion. Protective fibrinolytic enzyme systems of the peritoneum, such as the plasmin system, can remove the fibrin gel matrix. However, surgery dramatically diminishes fibrinolytic activity. The pivotal events determining whether the pathway taken is adhesion formation or re-epithelialization are therefore the apposition of two damaged surfaces and the extent of fibrinolysis. Research in postsurgical adhesion formation and prevention abounds in a variety of avenues of investigation, including: 1) identification on a molecular level of the components involved in adhesiogenesis and their interactions; 2) clarification of the role of fibrin and fibrinolysis in adhesion formation; 3) standardization of design in preclinical and clinical studies of adhesion formation and prevention; 4) delineation of the relationship between adhesion formation and adhesive complications; and 5) elucidation of efficient, site-specific methods of prophylactic drug delivery. Currently, it seems logical to focus preventive research on development of barriers, fibrinolytic drugs, and selected agents such as phospholipids. The major strategies for adhesion prevention or reduction are adjusting surgical practice and applying adjuvants. Surgeons should adjust their major practices by: 1) becoming aware of the potential adhesive complications of a procedure; 2) minimizing the invasiveness of surgery; and 3) minimizing surgical trauma, ischemia, exposure to intestinal contents, introduction of foreign material into the body, and the use of talc- or starch-containing gloves. Available adjuvants include a newly developed by hyaluronic acid-phosphate-buffered saline solution applied intraoperatively to protect peritoneal surfaces from indirect surgical trauma and three mechanical barriers. One of these, a bioresorbable membrane consisting of hyaluronic acid and carboxymethylcellulose, has demonstrated efficacy and safety in both general and gynecological surgery. The other two barriers, one made of expanded polytetrafluoroethylene and one developed from oxidized regenerated cellulose, are indicated only for use in gynecological surgery.
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PMID:Adhesions: pathogenesis and prevention-panel discussion and summary. 907 53

In order to evaluate whether different clinical presentations of unstable angina are associated with a different degree or pattern of activation of the hemostatic, fibrinolytic and inflammatory systems, we measured plasma levels of thrombin-antithrombin III, plasmin-alpha2- antiplasmin complexes and C-reactive protein, as markers of activation of coagulation, fibrinolysis and inflammation respectively, in two groups of patients: 7 patients with de novo unstable angina (Group 1) and 7 patients with destabilizing unstable angina (Group 2). Blood samples were taken on admission for measuring levels of C-reactive protein and during ischemic episodes at the onset of ECG changes and pain (0 min) and after 5, 15 and 60 min in order to assess the peak values of thrombin-antithrombin III and plasmin-alpha2-antiplasmin during the episode. Thrombin-antithrombin III levels in Group 1 were 1.8 microgram/l (0.3-4.15) at 0 min and increased to 17 micrograms/l (2.8-60) after 5 to 15 min (p = 0.013); conversely thrombin-antithrombin III levels in Group 2 were 2.15 microgram/l (1.4-3.8) at 0 min and raised to 4 micrograms/l (2-43) after 5 to 15 min (NS). No significant differences in both groups were observed in plasmin-alpha2-antiplasmin levels (Group 1:650 micrograms/l, ranged 492-956, at 0 min vs 670 microgram/l, range 415-977, at peak; Group 2: 480 micrograms/l, range 274-955, at 0 min vs 502 micrograms/l, range 304-1027, at peak; NS). Inversely, C-reactive protein levels on admission were 4 mg/dl (range 2-27) in Group 1, and 1 mg/dl (range 0.6-4) in Group 2 (p = 0.006). In conclusion, patients with de novo unstable angina have significantly enhanced thrombin (but not plasmin) production during spontaneous ischemic episodes than patients with destabilizing unstable angina. Furthermore, patients with de novo unstable angina have enhanced acute phase responses than patients with destabilizing unstable angina. Our data suggest that different pathogenetic mechanisms may be responsible for acute ischemic episodes in unstable angina and may explain different response to antithrombotic therapy in unstable angina patients.
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PMID:[Clinical presentation of unstable angina may influence the formation of thrombin during spontaneous episodes of ischemia]. 970 80

The association of intramedullary haematoma of the left femoral diaphysis and congenital alpha2-plasmin inhibitor deficiency in a 6-year-old boy is reported. Congenital deficiency of this fibrinolytic system component is very rare and can result in severe bleeding. Clinically, an intramedullary haematoma causes pain but no swelling, and there is no history of trauma. X-rays show a hyperlucent lesion without sclerotic edges in the medulla of the diaphysis of a long bone with thinning of the cortex. MRI is diagnostic with the haematoma generating a specific hyperintense signal on T1-weighted and T2-weighted spin-echo images.
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PMID:A case of intramedullary haematoma associated with congenital alpha2-plasmin inhibitor deficiency. 988 Jun 45


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