Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental thrombosis which developed exclusively in glomerular capillary walls was induced in rats by the combined injection of nephrotoxic antiserum (0.2 ml of pooled material) as a preparatory agent and 20 micrograms or more of lipopolysaccharide as a provoking agent. Effects of some antiplatelet and anticoagulant drugs on the glomerular lesions were tested in this experimental glomerular thrombosis. With administration of 2000 units/kg or more of heparin at the time of provoking injection, coagulation time was prolonged for over 5 hr, and the glomerular thrombosis was adequately prevented. Prolongation of prothrombin time (PT) for over 60 sec to prevent thrombosis required warfarin, but with this drug there was only a narrow margin between an effective dose and that which produced a fatal hemorrhage. Low levels of fibrinogen (less than 50 mg/dl) induced by batroxobin seemed to protect partially and high doses of urokinase did not seem to protect from glomerular thrombosis. OP-41483, a derivative of prostacyclin which is about five times more active than PGE1 in inhibiting platelet aggregation, and other anti-platelet drugs except for ticlopidine were not effective in preventing glomerular thrombosis. These findings were in accordance with the fact that thrombocytopenia induced by antiplatelet antiserum did not prevent glomerular thrombosis. Ticlopidine may have a unique and valuable therapeutic potential for the control of this condition.
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PMID:Effect of drug administration on experimental renal glomerular thrombosis. 328 90

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

About 80% of strokes are ischaemic. Approximately 12% of patients die within 3 months following stroke, and another 20% are institutionalised or become highly dependent. In early 2013, what is the harm-benefit balance of antithrombotic treatments used in the acute phase of ischaemic stroke? To answer this question, we reviewed the available data using the standard Prescrire methodology. Clinical trials of aspirin in the acute phase of ischaemic stroke consist mainly of two randomised trials including a total of 40 541 patients. After 1 to 6 months, 13 deaths or sequelae resulting in dependence are prevented when 1000 patients are treated with aspirin during the acute phase. Aspirin increases the risk of symptomatic intracranial haemorrhage when it is introduced less than 24 hours after treatment with alteplase. Abciximab, an injectable antiplatelet agent, showed no tangible clinical benefit in 5 randomised placebo-controlled trials in a total of 1275 patients. Clopidogrel and prasugrel, two other antiplatelet agents, have not been evaluated in this setting. However, in case of allergy to aspirin, clopidogrel is a useful alternative in other situations associated with a risk of arterial ischaemia. In a randomised trial including 458 patients, cilostazol and aspirin were similarly effective after 3 months of follow-up, but cilostazol caused cardiac arrhythmias. Ticlopidine has too many adverse effects to consider it a useful drug. Anticoagulant therapy during the acute phase of stroke has an unfavourable harm-benefit balance, including in patients with stroke secondary to cardiac embolism. Low-molecular-weight heparin reduces the risk of pulmonary embolism but has no impact on overall mortality. The aim of thrombolysis is to unclog the affected artery. Intravenous alteplase administration is the best-assessed thrombolytic method. Twelve randomised trials have compared intravenous thrombolysis with alteplase versus no thrombolytic therapy in 7012 patients. Among patients treated within 3 hours after stroke onset, 41% survived without sequelae after alteplase administration, versus 32% in the absence of thrombolysis; alteplase had no statistically significant impact on mortality at the end of follow-up. Efficacy appeared to be similar in patients over 80 years old.The harm-benefit balance may also be favourable when thrombolysis is started more than 3 hours after stroke onset, but when it is initiated more than 4.5 hours after stroke onset, it increases mortality. Four randomised trials showed that intra-arterial thrombolysis with urokinase or pro-urokinase had a beneficial effect, versus no thrombolysis, in a total of 356 patients. In a randomised trial including 362 patients, intra-arterial thrombolysis did not have a better harm-benefit balance than intravenous thrombolysis. Among the various physical and mechanical methods used to remove or dissolve clots, the best-evaluated is ultrasound plus intravenous alteplase thrombolysis; initial results with this procedure warrant further clinical trials. Rapid intervention and patient selection are both crucial in optimising the harm-benefit balance of intravenous alteplase thrombolysis. This treatment should only be used when management begins within the first hours following stroke symptom onset, and when there are no risk factors for bleeding, especially intracranial bleeding. For other patients, aspirin is the only antithrombotic drug known to reduce, albeit only slightly, the risk of death and sequelae following ischaemic stroke.
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PMID:Antithrombotic drugs and ischaemic stroke. 2442 42