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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombolysis with tissue plasminogen activator (alteplase, Activase trade mark, rtPA; Genentech Inc) has proven beneficial for acute stroke management, even though only 1 - 2% of stroke patients in the US are treated with the drug [1]. Part of the reason for the under utilisation of alteplase may be the narrow therapeutic window and frequent occurrence of serious side effects, such as increased haemorrhage incidence [2,3]. It is because of these shortcomings, that recent efforts have attempted to identify new thrombolytics that might improve the benefit/risk ratio in treating stroke. Second generation derivatives of alteplase have attempted to counteract the side effects of the drug by increasing fibrin specificity (tenecteplase, TNK-tPA; Genentech Inc) or half-life (lanoteplase, SUN-9216; Genetics Institute Inc.). New recombinant DNA methodology has led to the revival of plasmin or a truncated form of plasmin (microplasmin; ThromboGenics Ltd), a direct-acting thrombolytic with non-thrombolytic related neuroprotective activities, as a therapeutic. Other promising approaches for the treatment of stroke include the development of novel plasminogen activators, such as recombinant desmodus rotundus salivary plasminogen activator (rDSPA) alpha-1 (Schering/Teijin Pharmaceuticals) and a mutant fibrin-activated human plasminogen (BB10153; British Biotech Inc.). These important areas of drug discovery and development will be reviewed.
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PMID:Development of thrombolytic therapy for stroke: a perspective. 1243 8

Thrombolytic agents are in widespread use for the dissolution of arterial and venous pathologic thrombi. Clinical settings where thrombolysis has played an important role include the acute coronary syndromes, peripheral arterial occlusion, ischemic stroke, deep venous thrombosis, and pulmonary embolism. Thrombolytic agents have been successfully employed in each of these areas, achieving dissolution of the occluding thrombus, reconstitution of blood flow, and improvement in the status of the tissue bed supplied or drained by the involved vascular segment. All clinically available thrombolytic agents act through cleavage of the plasminogen molecule to its active form, plasmin. Despite this similar mechanism of action, the thrombolytic agents differ in several biochemical parameters, including fibrin specificity, fibrin affinity, and relative resistance to inactivating factors in the plasma. Whether these differences account for significant differences in clinical outcome is a matter of some dispute. It is quite possible that in vitro biochemical differences do not have meaningful clinical correlates. However, there exists some evidence to suggest that differences in the risk of distant hemorrhage, idiosyncratic reactions, and the rapidity of clot dissolution do exist. An ideal agent for peripheral vascular thrombolysis would be one that was specific in its actions at the site of pathologic thrombi yet left the important and desirable pathologic thrombi that seal vascular defects unscathed. Although such an agent has not yet been identified, an understanding of the mechanism of action and principles underlying pharmacologic thrombolysis provides the necessary foundation of knowledge to choose a particular thrombolytic agent for a given clinical scenario.
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PMID:Comparison of safety and efficacy of the various thrombolytic agents. 1255 39

The notion that fibrinogen is strongly, consistently, and independently related to cardiovascular risk has been widely accepted. The evidence is based on numerous prospective epidemiological studies and clinical observations. In meta-analysis, an association between even modest increases (10%) in fibrinogen and future coronary heart disease (CHD) endpoints has been found with an odds ratio for CHD of 1.8; 95% CI, 1.6 to 2.0, if the top tertile of the fibrinogen distribution was compared to the bottom tertile; but fibrinogen levels were also associated with unstable and stable coronary artery disease, and coronary complications after interventions. Similar results have been obtained for incident stroke, progression of peripheral arterial disease, and finally for total mortality. The reasons however, why fibrinogen is elevated in cardiovascular disease and in atherosclerosis in general, are only incompletely understood; but all cells involved in the atherogenetic process are able to produce cytokines which induce an acute phase reaction, and thus increase fibrinogen plasma levels. The potential pathophysiological mechanisms by which elevated fibrinogen levels mediate cardiovascular risk are manyfold: It forms the substrate for thrombin and represents the final step in the coagulation cascade; it is essential for platelet aggregation; it modulates endothelial function; it promotes smooth muscle cell proliferation and migration; it interacts with the binding of plasmin with its receptor, and finally it represents a major acute phase protein. Whether or not fibrinogen is causally involved in atherothrombogenesis still remains to be determined, and even though other unsolved issues await conclusive answers, fibrinogen has emerged as an important additional marker of cardiovascular risk.
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PMID:Fibrin(ogen) in cardiovascular disease: an update. 1266 13

We evaluated the expression of two extra-cellular protease systems in a model of spontaneous cerebrovascular pathology: spontaneously hypertensive stroke-prone rats (SHRSP). The appearance of brain damage in individual animals was imaged and followed by means of magnetic resonance imaging (MRI). In situ zymography of brain slices obtained 3 days after the appearance of brain damage showed an increase in plasminogen activator (PA)/plasmin activity that co-localised with the cerebral damage detected by MRI; there was also concomitant accumulation/activation of inflammatory cells in the damaged area. Proteolytic activity was inhibited by the urokinase-specific inhibitor amiloride but not by an antibody against tissue-type plasminogen activator (t-PA). SDS-PAGE zymography of brain extracts revealed the presence of 58 kDa plasminogen-dependent lysis areas in the ischemic and non-ischemic tissues, and a 33 kDa lysis area in ischemic tissue only. An antibody against t-PA inhibited the former, whereas the latter was inhibited by amiloride. The specific induction of urokinase-type plasminogen activator (u-PA) in the damaged tissue was further confirmed by the fact that both u-PA protein mass and mRNA were markedly increased in the damaged cerebral areas. Concomitant metalloproteinase-2 (MMP-2) activation was only observed in the damaged area. These data suggest that u-PA is expressed and selectively catalyses proteolysis in the injured area of spontaneous brain damage in SHRSP.
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PMID:Endogenous proteolytic activity in a rat model of spontaneous cerebral stroke. 1274 36

The effect of recombinant human microplasmin was studied in ischemic stroke models in mice and in an extracorporeal loop thrombosis model in rabbits. Human microplasminogen ( micro Plg), which lacks the five 'kringle' domains of plasminogen was expressed with high yield in Pichia pastoris. It was purified, converted to microplasmin ( micro Pli) and equilibrated with 5 mmol L(-1) citrate, pH 3.1, yielding a stable preparation. In mice with middle cerebral artery (MCA) ligation, an intravenous (i.v.) bolus of 5.0 mg kg(-1) micro Pli reduced infarct size at 24 h from 27 (26-30) to 25 (21-28) mm3 (median and range, n= 16 each, P= 0.0001), whereas 4.0 mg kg(-1) rt-PA and 40 mg kg(-1) micro Plg had no effect. Infarct reduction was observed with administration at 4 h after occlusion. In mice with MCA, infarct size at 24 h was reduced from 20 (14-30) to 9.1 (3.1-25) mm3 with 5.0 mg kg(-1) micro Pli (n = 15 each, P < 0.002) and to 11 (5.2-27) mm3 with 4.0 mg kg(-1) rt-PA (n = 6; P= 0.02). Infarct reduction was still observed at 10 h after occlusion with micro Pli but not with t-PA. In rabbits with radiolabeled clots in an extracorporeal arteriovenous loop, local infusion of 2.5 mg kg(-1) micro Pli over 2 h, induced 51 +/- 15% lysis (mean +/- SD, n= 11) vs. a control value of 23 +/- 5.5%. micro Pli did not prolong template bleeding times, whereas equipotent doses of rt-PA were associated with extensive rebleeding. The potency of micro Pli in both models was similar to that of intact plasmin. These findings indicate that recombinant micro Pli may be useful for treatment of ischemic stroke and arterial thrombosis.
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PMID:Recombinant human microplasmin: production and potential therapeutic properties. 1287 5

One type of therapy for thromboembolism is plasmatic thrombolysis. Several plasminogen activators (PA) are clinically available, including urokinase (u-PA), tissue plasminogen activator (t-PA), streptokinase (SK), plasminogen-streptokinase-activator-complex (PSAC), or mutants of t-PA such as reteplase (RP) or tenecteplase (TP). Therapeutic plasmatic fibrinolysis was simulated, using the PA at relevant plasma concentrations, and plasmin (Pli) and PA activities were determined. Normal citrated plasma was supplemented with 31 to 1,000 IU/mL u-PA, 0.31 to 20 microg/mL t-PA, 125 to 4,000 IU/mL SK, 12.5 to 400 U/mL PSAC, 125 to 4,000 U/mL RP, or 0.31 to 10 microg/mL TP. Ten IU/mL urokinase was also incubated with pooled plasma of stroke patients, that was previously oxidized with the singlet oxygen (1O2) donor chloramine T (CT), to destroy plasmatic PAI-1 and alpha2-antiplasmin. After 0 to 80 minutes (37 degrees C), 50-microL samples were withdrawn and added to 100 microL 1.5 M arginine, pH 8.7, and oxidized with 50 microL of 20 mM CT. For determination of plasmin activity, 10 microL thereof was incubated with 150 microL 1.5 M arginine, pH 8.7, and 100 microL 20 mM CT preoxidized (15 minutes 37 degrees C) pooled normal citrate buffered EDTA-plasma for 30 minutes (37 degrees C). For determination of [PA+Pli]-activity, arginine was added after this incubation. 25-microL 6 mM Val-Leu-Lys-pNA were added and deltaA/h at room temperature (RT) was monitored, using a microtiterplate reader. [PA+Pli]-Pli = PA. The PA concentration required to induce 25% [ED25] of the maximally inducible Pli-activity in plasma (= 1 U/mL = 45 mg/L = 0.53 micromol/L active Pli; deltaA = 363 +/- 8 mA/h RT) after 10 minutes (37 degrees C) were 320 IU/mL u-PA, 8 microg/mL t-PA, 140 U/mL PSAC, 6,000 IU/mL SK, 720 U/mL RP, and approximately 150 microg/mL TP. The approximate activity half-lives of the PA in plasma were 30 minutes for u-PA, 30 minutes for t-PA, greater than 80 minutes for SK, greater than 80 minutes for PSAC, 50 minutes for RP, and 80 minutes for TP. The present study shows--for the first time--a combined kinetic in vitro simulation of the plasmatic activity of six different PAs. At clinically used concentrations, RP induces the highest plasmatic Pli activity. Due to unselective generation of plasmin in plasma, all PA are of some danger in inducing severe hemorrhagias. Clinical thrombolysis might be improved by usage of more physiologic activators of thrombolysis, such as activators of polymorphonuclear neutrophils.
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PMID:In vitro simulation of therapeutic plasmatic fibrinolysis. 1450 9

The developments and trends of hemostatic and antithrombotic drugs in Japan were investigated chronologically for the last 50 years after the 2nd World War. 1. Hemostatic drugs are classified into three groups ; capillary stabilizers, blood coagulants and antifibrinolytics. l) As to capillary stabilizers, flavonoid (rutin, 1949), adrenochrome derivative (carbazochrome, 1954) and conjugated estrogen (Premarin, 1964) were introduced therapeutically. Especially, the soluble types of adrenochrome compounds (Adona 1956, S-Adchnon, 1962) were devised and used widely in Japan. 2) Drugs concerning blood coagulation, thrombin, introduced in 1953, and hemocoagulase, a snake venom introduced in 1966, were used clinically. V.K. groups producing various coagulation factors were introduced as V.K1 (Phytonadione, 1962) and V.K2 (rnenatetrenone,1972), and they were admitted in "The Japanese Pharmacopoeia"editions 8 and 14, respectively). 3) Regarding antifibrinolytic drugs, Japanese researchers have made remarkable contributions. e-Aminocapronic acid (Ipsilon, 1962) and tranexamic acid (Transamin, 1965) were developed and used for various abnormal bleedings or hemorrhage associated with plasmin over-activation. tranexamic acid also proved to suppress inflammations of the throat such as tonsillitis, pharyngitis or laryngitis. 2. Antithrombotic drugs are also divided into three groups; anticoagulants, antiplatelet drugs and fibrinolytics.1) The anticoagulants used therapeutically by injection are heparins (Na-salt, 1951; Ca-salt, 1962) and low-molecular-weight heparins such as dalteparin (1992), parnaparin (1994) and reviparin (1999). The low molecule compounds are superior to the original heparins in reducing the risk of bleeding. As oral anticoagulants, coumarin derivatives, dicumarol (1950), ethylbiscoumacetate (1954), phenylindandione (1956) and warfarin (1962) are known. Warfarin potassium is the main drug for oral therapy of thromboembolism lately. Gabexate mesilate (1989) and nafamostat mesilate (1989) were developed in Japan and used for DIC and acute pancreatitis to inhibit protease enzymes. Argatroban is a unique antithrombin product developed by Japanese researchers in 1990, and is used for vascular or cerebral thrombosis. After noticing in 1968 that aspirin inhibits platelet aggregation and prevents myocardial infraction, projects for developing antiplatelet drugs were initiated worldwide. Ticlopidine, originally developed in France, was introduced in 1981 and prevailed widely in Japan for reducing the risk of thrombotic stroke. Aspirin itself was recognized by the FDA (USA) as an antithrombotic drug in 1988, and was also approved by Japanese authorities in 2000. PGE1 clathrate compounds have also been developed as antiplatelet drugs; alprostadil alfadex for injection (1979), and limaprost alfadex for oral use (1988). The PGI2 product, beraprost sodium, for oral use followed them in 1992. Other antiplatelet drugs with unique mechanisms explored in Japan: Ozagrel (1988), which inhibits TXA2 synthetase, cilostazol (1988), which inhibits cAMP phosphodiesterase, and sarpogrelate (1993), which blocks 5HT in platelets, are the notable drugs in this field. Ethyl icosapentate, from fish oil, is available for antiplatelet therapy. Concerning the fibrinolytic system, plasminogen activators are useful for thromboembolism. The streptokinase from bacterial origin developed in the USA and Europe was not introduced, and urokinase (1965) was the first plasminogen activator developed in Japan. Then tissue plasminogen activators (t-PA) tisokinase (cell culture, 1991), alteplase (genetical recombination, 1991), nateplase (genetical recombination, 1996), monteplase (1998) and pamiteplase (1998) were developed and approved for acute myocardial infarction. Nasaruplase (prourokinase, cell culture,1991) was also approved for the same indication. While the development of the hemostatic drugs ceased in the 1960s, avid project studies for antithrombotic drugs including fibrinolytics began in the 1980s and are progressing now towards new molecular targets. This may be due to the increasing tendency of cardiovascular thromboembolic diathesis in Japan. (The figures in parentheses are the years approved by the Japanese Ministry of Health, Labor and Welfare.)
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PMID:[A 50-year history of new drugs in Japan-the development and trends of hemostatics and antithrombotic drugs]. 1457 69

BEta(2)-glycoprotein I (beta(2)-GPI) is proteolytically cleaved by plasmin in domain V (nicked beta(2)-GPI), being unable to bind to phospholipids. This cleavage may occur in vivo and elevated plasma levels of nicked beta(2)-GPI were detected in patients with massive plasmin generation and fibrinolysis turnover. In this study, we report higher prevalence of elevated ratio of nicked beta(2)-GPI against total beta(2)-GPI in patients with ischemic stroke (63%) and healthy subjects with lacunar infarct (27%) when compared to healthy subjects with normal findings on magnetic resonance imaging (8%), suggesting that nicked beta(2)-GPI might have a physiologic role beyond that of its parent molecule in patients with thrombosis. Several inhibitors of extrinsic fibrinolysis are known, but a negative feedback regulator has not been yet documented. We demonstrate that nicked beta(2)-GPI binds to Glu-plasminogen with K(D) of 0.37 x 10(-6) M, presumably mediated by the interaction between the fifth domain of nicked beta(2)-GPI and the fifth kringle domain of Glu-plasminogen. Nicked beta(2)-GPI also suppressed plasmin generation up to 70% in the presence of tissue plasminogen activator, plasminogen, and fibrin. Intact beta(2)-GPI lacks these properties. These data suggest that beta(2)-GPI/plasmin-nicked beta(2)-GPI controls extrinsic fibrinolysis via a negative feedback pathway loop.
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PMID:Nicked beta2-glycoprotein I: a marker of cerebral infarct and a novel role in the negative feedback pathway of extrinsic fibrinolysis. 1472 99

Stroke is a heterogeneous disorder with significantly high morbidity and mortality. The relationship between serum cholesterol level and the incidence of stroke remains controversial. Recent evidence from primary and secondary prevention trials suggests that treatment with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors may reduce the incidence of stroke in patients with coronary artery disease (CAD). In this review, we attempt to outline and describe the potential mechanisms of HMG-CoA reductase inhibitors in the prevention of stroke. In addition to their lipid-lowering action HMG-CoA reductase inhibitors appear to exert their beneficial effects by various nonlipid-lowering mechanisms including anti-inflammatory effects, effect on endothelial function and coagulation cascade. Treatment with HMG-CoA reductase inhibitors is associated with decreased progression, plaque stablization and even regression of atheromatous plaque in the carotid arteries. HMG-CoA reductase inhibitors also inhibit the coagulation cascade at various levels such as activation of prothrombin, factor V, factor X and liberation of tissue factor in response to vascular injury. Inhibition of fibrinolysis occurs secondary to inhibition of plasmin generation. Pravastatin therapy is associated with a reduction in the size of aortic atheroma which is an independent risk factor for stroke. Lastly, left ventricular dysfunction after acute myocardial infarction is associated with an increased risk of stroke and HMG-CoA reductase inhibitors may indirectly decrease the incidence of stroke by reducing coronary events. Most of these effects are independent of the cholesterol-lowering effects of HMG-CoA reductase inhibitors. In conclusion, HMG-CoA reductase inhibitors may have a role in primary prevention of stroke in patients with CAD.
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PMID:How do HMG-CoA reductase inhibitors prevent stroke? 1472 94

The activation of plasmin from its circulating precursor plasminogen is the mechanism of several clot-busting drugs used to clinically treat patients who have suffered a stroke; however, plasmin thus generated has been shown to activate platelets directly. There has been speculation as to whether plasmin interacts with the protease-activated receptors (PARs) because of its similarity in amino acid specificity with the classic platelet activator thrombin. We have investigated whether plasmin activates platelets via PAR activation through multiple complementary approaches. At concentrations sufficient to induce human platelet aggregation, plasmin released very little calcium compared with that induced by thrombin, the PAR-1 agonist peptide SFLLRN, or the PAR-4 agonist peptide AYPGKF. Stimulation of platelets with plasmin initially failed to desensitize additional stimulation with SFLLRN or AYPGKF, but a prolonged incubation with plasmin desensitized platelets to further stimulation by thrombin. The desensitization of PAR-1 had no effect on plasmin-induced platelet aggregation and yielded an aggregation profile that was similar to plasmin in response to a low dose of thrombin. However, PAR-4 desensitization completely eliminated aggregation in response to plasmin. Inclusion of the PAR-1-specific antagonist BMS-200261 inhibited platelet aggregation induced by a low dose of thrombin but not by plasmin. Additionally, mouse platelets naturally devoid of PAR-1 showed a full aggregation response to plasmin in comparison to thrombin. Furthermore, human and mouse platelets treated with a PAR-4 antagonist, as well as platelets isolated from PAR-4 homozygous null mice, failed to aggregate in response to plasmin. Finally, a protease-resistant recombinant PAR-4 was refractory to activation by plasmin. We conclude that plasmin induces platelet aggregation primarily through slow cleavage of PAR-4.
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PMID:Plasmin-mediated activation of platelets occurs by cleavage of protease-activated receptor 4. 1497 36


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