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

Strokes following cardiac surgery occur in about 5% of patients. Intra-arterial thrombolysis is a good option in such a setting where intravenous thrombolysis is contraindicated, and when in-hospital strokes are detected well within the window for treatment and the chances of complete reperfusion are maximum. On postoperative day 4 after atrial septal defect correction, a 34-year-old woman with paroxysmal atrial fibrillation developed left middle cerebral artery stroke causing severe neurological deficits. Intra-arterial thrombolysis with urokinase led to remarkable recovery.
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PMID:Neurovascular rescue for embolic stroke following atrial septal defect closure. 1221 33

In Japan, all of the stroke center hospital equipped by high level diagnostic systems including MRI. Number of MRI is twice as that of U.S.A. Therefore, we can perform correct and effective treatment for ultra-acute cerebral infarction if rt-PA is permitted to clinical use for cerebral infarction. We are making Japan Standard Stroke Registry Study (JSSR Study) now, and already registered 2,740 acute stroke cases in 25 hospitals. Atherothrombotic embolism (artery to artery embolism) was found in 16.5% of the all atherothrombotic infarction. It suggests that diagnostic accuracy of our database is high level. Concerning with ultra acute thrombolysis, about 10,000 stroke patients per year are estimated to be treatable with rt-PA in Japan. Yamaguchi's study for acute cerebral infarction showed intra-arterial thrombolytic therapy using urokinase was significantly effective. Our JSSR Study also showed effectiveness of thrombolytic therapy using rt-PA or high dose urokinase in the patients with cerebral infarction treated within 6 hours. Therapeutic time windows for acute cerebral infarction using rt-PA is expected to be more longer by the newly developed free radical scavenger (edarabin). We must create evidence based medicine for Japanese stroke patients based on database system (JSSR).
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PMID:[Brain attack in Japan, now and future]. 1223 92

A meta-analysis by the Cochrane Stroke Group (CSG) showed that thrombolytic therapy increased deaths as well as symptomatic and fatal intracranial hemorrhage within the first seven to 10 days and at final follow-up, although these risks are offset by a reduction in disability in survivors, so that there is overall a significant net reduction in the proportion of patients dead or dependent. Trials testing intravenous (i.v.) tPA suggest that it may be associated with less hazard and more benefit. A recent trial demonstrated that intra-arterial pro-urokinase improved long-term outcome in patients with M 1 or M 2 occlusion within 6 hours of onset. Trials of the third generation of thrombolytic agents are ongoing in patients with acute ischemic stroke. The latest CSG's meta-analysis showed that immediate anticoagulant therapy in patients with acute ischemic stroke was not associated with net short or long-term benefit because there was no evidence that anticoagulant therapy reduced deaths or non-fatal stroke during treatment or patients dead or dependent at the end of follow-up. However, an i.v. low-molecular-weight heparinoid showed a trend toward improving long-term outcome in subgroup of patients with atherothrombotic stroke. The thrombin inhibitor argatroban was proven to be comparable to the thromboxane A2 synthetase inhibitor ozagrel in the effect on the outcome at one month in patients with atherothrombotic stroke within 48 hours of onset in Japan, and a trial of the agent is ongoing in patients with ischemic stroke within 12 hours of onset in the United States. Two large trials of aspirin in patients with ischemic stroke within 48 hours of onset indicated that aspirin had a modest effect on reducing patients dead or dependent at the end of follow-up. An international trial of abciximab, a monoclonal antibody directed against platelet glycoprotein IIb/IIIa, is ongoing in patients with ischemic stroke within 6 hours of onset.
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PMID:[Strategy for circulatory disturbance]. 1223 94

By delivering a higher concentration of drug directly into a clot, intra-arterial (IA) thrombolysis may be more effective than intravenous therapy at opening a blocked artery. The clinical efficacy and safety of IA thrombolysis with the selective thrombolytic r-pro-urokinase (r-pro-UK) has been demonstrated in two randomized acute stroke treatment trials, PROACT I and PROACT II. However, IA pro-UK is not yet FDA approved, and it is not known if IA thrombolysis with other agents would have the same results. However the American Heart Association has deemed IA thrombolysis an 'acceptable alternative therapy' and many stroke centres are offering it to patients with a major acute stroke presenting within 6 h.
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PMID:The role of recombinant pro-urokinase (r-pro-UK) and intra-arterial thrombolysis in acute ischaemic stroke: the PROACT trials. Prolyse in Acute Cerebral Thromboembolism. 1236 28

Two consecutive cases of children with vertebrobasilar thrombosis (VBT) were treated with high-dose intra-arterial urokinase within 4 h of presenting to the emergency room, after full evaluation by CT scan, MRI and MR angiography. Complete resolution of neurologic symptoms was achieved in both cases. Based on our limited pediatric experience, previous treatment of VBT at our institution and a review of the relevant literature, the authors suggest that VBT be specifically ruled out at initial diagnosis, and if present, full consideration be given to immediate treatment with intra-arterial thrombolytic therapy. This may lead to a significant reduction in the morbidity and mortality associated with VBT in children. A large prospective multi-institution study is needed to further evaluate the efficacy of this approach to childhood stroke.
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PMID:Vertebrobasilar thrombosis in children: report of two cases and recommendations for treatment. 1247 22

Acute ischaemic stroke is a leading cause of mortality and morbidity around the world. An arterial occlusive lesion is found in the majority of patients with acute ischaemic stroke, and recanalisation has been shown to result in a better clinical outcome. The only widely approved recanalisation strategy is the use of intravenous alteplase (recombinant tissue-type plasminogen activator; tPA) within 3 hours of stroke onset. However, this therapy has limitations, and alternative or supplemental recanalisation strategies need to be considered in a large number of patients with acute ischaemic stroke. One such promising strategy is intra-arterial thrombolysis. This article reviews the pharmacology of the various drugs used for intra-arterial thrombolysis in the setting of acute ischaemic stroke and the results of the clinical trials that have studied their benefit. Three generations of thrombolytic agents have been available for clinical use so far. The first-generation agents such as streptokinase and urokinase were the first to be studied in acute stroke, and a number of positive case reports and series of their intra-arterial use have been reported from around the world. Second-generation products include alteplase and pro-urokinase. The clinical benefits of intra-arterial pro-urokinase were recently proven in a randomised, placebo-controlled study. Third-generation agents, such as reteplase, lanoteplase and tenecteplase, offer superior recanalisation rates with limited systemic adverse effects and might prove to be the agents of choice for intra-arterial acute stroke thrombolysis in the future. The exact administration regimens as well as the identification of patient sub-populations most likely to benefit from intra-arterial thrombolysis are subjects of current investigations, and hopefully firmer guidelines will be established in the next few years, once the results of the clinical trials are available.
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PMID:Clinical potential of intra-arterial thrombolytic therapy in patients with acute ischaemic stroke. 1266 95

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

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

Plasminogen activators have immense clinical significance as thrombolytic agents for management of stroke and myocardial infarction. Tissue-type plasminogen activator (tPA) is generally preferred as being effective and safer than either urokinase or streptokinase type activators. Large-scale production of tPA became possible through groundbreaking developments in cell lines and bioprocess technology. Nevertheless, at thousands of dollars per treatment, tPA remains expensive. Enhancing cellular productivity and downstream product recovery through new approaches continue to be major challenges as discussed in this review. Recent clinical experience suggests the need for yet better fibrinolytic agents and attempts are underway to modify the tPA molecule to second generation products. Emerging trends in this field are outlined.
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PMID:Tissue-type plasminogen activator: characteristics, applications and production technology. 1453 55

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


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