Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1997-03-18
1998-04-21
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 17, 435217, 435212, 435214, 530324, 530329, A61K 3849, A61K 3848
Patent
active
057417717
DESCRIPTION:
BRIEF SUMMARY
This invention relates to products and methods for improved thrombolytic treatment of patients having, or at risk of developing, a thrombus or thrombi. In particular, the invention relates to thrombolytic combination therapy by the administration of an agent capable of activating native plasminogen, and a non-native plasminogen analogue which is cleavable by native thrombin to generate plasmin activity.
BACKGROUND OF THE INVENTION
Agents capable of activating native plasminogen are known and are in use in thrombolytic therapy, are in clinical trial or have been proposed for that purpose. Examples of such compounds include tissue-type plasminogen activator (tPA), urokinase, streptokinase, and desmodus salivary plasminogen activator (DSPA). Intravenous treatment with tPA and streptokinase has been successful in reducing mortality from acute myocardial infarction.
Despite this success, it is widely recognised that thrombolysis has major limitations which are due to the shortcomings of the agents available (reviewed by Marder and Sherry, New England Journal of Medicine 1989, 318: 1513-1520). For example, for tPA these are its rapid elimination from the body and its relative lack of thrombus specificity at clinically useful doses. The rapid clearance of tPA means that a large quantity of the protein has to be given by intravenous infusion, delaying the start of therapy until the patient is admitted to hospital. A further problem associated with the rapid clearance of tPA is that reocclusion of the reperfused blood vessel commonly occurs when tPA administration is stopped. Finally, the relative lack of thrombus specificity of therapeutic doses of tPA produces a risk of haemorrhage. Risk of haemorrhage is a problem common to current thrombolytics because they are not thrombus specific at clinically useful doses and they activate plasminogen to produce plasmin in the general circulation.
Urokinase has a similar rapid plasma clearance and also requires administration by continuous infusion.
Many attempts have been made to increase the half-life of tPA to overcome its rapid clearance, but tPA variants in clinical development appear to be cleared only 3-5 times more slowly than tPA (Thromb. Haemostas. 66:569-574, 1991; Thromb. Haemostas. 70:307-312, 1993); the plasma half-life of tPA is around five minutes in man (Bounameaux et al. in: "Contemporary issues in Haemostasis and Thrombosis" vol 1 p5-91, 1985. Collen et al. eds, Churchill Livingstone). These tPA variants may well allow bolus administration and/or dose reduction but they are unlikely to remain in circulation long enough to be effective in preventing reocclusion. They are also unlikely to reduce the haemorrhagic risk significantly, and it may increase due to persistence in the circulation.
Another approach to improving the clinical efficacy of plasminogen activators is via adjunctive therapy with anticoagulant and antiplatelet agents. There has been limited success in improving the therapeutic efficiency of tPA with the adjunct use of heparin and aspirin. However, such a therapeutic regime still has limitations of a 15-20% rate of failure to recanalize the infarct-related artery and by a reocclusion rate of 5-10%. As a result, the reinfarction rate at 30 days is 4-6%, cardiogenic shock and congestive heart failure occur in 5-7% and 15-17% of patients, respectively, and mortality is in the range of 5-8% (Am. J. Cardiol. 75:7-13 1995). Both the initial failure of thrombolysis and reocclusion despite the use of heparin and aspirin are thought to be the result of ongoing thrombin activity. Hence, more potent and selective agents are under investigation. Hirudin is a potent inhibitor of thrombin which, in animal models has been shown to be superior to heparin in decreasing platelet deposition and thrombus formation (Circulation 79: 657-665, 1989) and in models of coronary thrombosis has been shown to both speed thrombolysis and decrease reocclusion (Circulation 83:1048-1056 and Circulation Research 70:829-834, 1992). U.S. Pat. No. 4,944,943 discloses the use
REFERENCES:
patent: 4996050 (1991-02-01), Tsukada et al.
patent: 5637492 (1997-06-01), Dawson et al.
patent: 5645833 (1997-07-01), Dawson et al.
patent: 5688664 (1997-11-01), Dawson et al.
Dawson et al. J. Biol. Chemistry, 269: 15989-15992, Jun. 1994.
Comer Michael Berisford
Dawson Keith Martyn
Wood Lars Michael
Borin Michael
British Biotech Pharmaceuticals Ltd.
Tsang Cecilia J.
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