Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1989-07-21
1992-09-29
Nucker, Christine M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530363, 530380, 530382, 5303919, 530395, 530400, 514 2, 514 6, 514 21, 424 8591, 435177, A61K 3712, A61K 4748, A61K 3714, C07K 1702
Patent
active
051514125
DESCRIPTION:
BRIEF SUMMARY
This invention relates to pharmaceutically active conjugates having improved binding specificity for specified body tissue. The invention further relates to methods of preparing these conjugates and to pharmaceutical preparations that contain them. In particular embodiments, the invention relates to pharmaceutically-active conjugates containing either plasminogen activators or anti-rheumatic drugs.
It is common practice to administer large doses of various drugs to the body to treat conditions which may only affect a small region of the body. Large doses are often required in order to attain a sufficient concentration of the drug at the target area. However, these large and constantly-administered doses can produce serious side effects in patients being treated, which has often lead to treatment being suspended even though improvement in the treated condition might be taking place. This problem has existed in the past particularly in the administration of toxic anti-tumour drugs for destroying cancer cells and in the administration of toxic anti-rheumatic drugs, especially gold compounds.
One further example of the administration of drugs where this problem exists is in the treatment of thrombotic conditions. Conventional treatment for certain thrombotic conditions, such as deep vein thrombosis or pulmonary thrombosis, involves continuous infusion of agents which stimulate fibrinolysis Fibrinolysis is the term given to the process of proteolytic degradation of a fibrin-based clot. Thrombolysis is the plasmin mediated proteolysis which brings about the break up of large vascular obstructions. It is generally accepted that the main enzyme responsible for fibrinolysis is plasminogen-plasmin. The zymogen, plasminogen, is converted by one of a range of activators to plasmin, which is an active protease capable of degrading a cross-linked fibrin clot to soluble products (FDPs). Plasmin is a serine protease, produced from plasminogen by limited proteolytic cleavage accompanied by a conformational change.
The precise mechanism of plasminogen activation depends on the plasminogen activator involved. Thus, activation can also occur without proteolytic cleavage in the case of plasminogen activators from certain microorganisms which act allosterically, e.g. streptokinase. In general activation is more effective if it occurs on the surface of the clot, a phenomenon aided by the affinity that plasminogen has for fibrin. Plasminogen activators occur in blood, a variety of tissues and in body fluids such as urine, saliva and semen. As hereinbefore indicated, they are also produced by certain microorganisms. Small quantities of a labile plasminogen activator, tissue plasminogen activator (t-PA), occur in the circulation. Its level is raised following stimuli including exercise and venous occlusion. t-PA, which carries a fibrin-binding region, has been isolated from cadaveric plasma and from culture medium of vascular endothelial cells and the Bowes melanoma cell line. More recently, this plasminogen activator has also been prepared by recombinant DNA technology (see, for example, GB-A No. 2119804).
Urokinase (UK) is a plasminogen activator present in urine. Unlike t-PA, it can be readily isolated in a highly purified, crystalline form. It is a single chain .beta.-globulin which exists in two forms of molecular weights 54,000 and 32,000 respectively. UK is (apparently) synthesised in the kidney and, unlike t-PA, it has little affinity for fibrin. UK activates plasminogen to produce plasmin which is subject to inhibition.
Streptokinase (SK) is a plasminogen activator produced by .beta.-haemolytic streotococci and available in purified preparations. SK is a single chain .alpha.2-globulin having a molecular weight around 46,000. It acts as an activator by binding to plasminogen causing a conformational change. The resultant SK-plasminogen complex possesses enzymic activity, but is not inhibited by .alpha.2-macroglobulin.
Both UK and SK have been used successfully as thrombolytic agents. SK is more commonly used since it is che
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Central Blood Laboratories Authority
Kim Kay K.
Nucker Christine M.
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