Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Enzymatic production of a protein or polypeptide
Patent
1983-11-04
1988-10-25
Rosen, Sam
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Enzymatic production of a protein or polypeptide
435212, 435217, 4352401, C12P 2100
Patent
active
047804122
DESCRIPTION:
BRIEF SUMMARY
INTRODUCTION
This invention relates to new fibrinolytic enzymes, methods for their production and pharmaceutical compositions containing them.
Thrombotic vascular occlusion, usually of vessels with long-standing damage to their walls, is the main cause of mortality in the United Kingdom, accounting for at least 2 out of 5 of all deaths. In this group of diseases, coronary artery thrombosis alone kills as many people as all the forms of cancer added together. No comparable figures exist for the morbidity attributable to thrombotic disease (in terms of patients hospitalised, or sick at home) but the numbers must be enormous. A similar situation exists in Western Europe and North America and an article in "Time" magazine reported that cardiovascular disease accounts for one half of all deaths recorded annually in the U.S.A. (Time, June 1, 1981, 43.).
There is, therefore, a great need for effective treatments for these common disorders. It is however, symptomatic of the paucity of drug therapy in this field, that surgery plays a large part in current medical practice, as witnessed by the phenomenal rise in the number of coronary artery by-pass operations performed in America. Up to now (apart from such non-specific treatment as digitalis for the failing ischaemic heart) anticoagulants have been the most widely used type of medication. However, at best, anticoagulants can only inhibit further thrombosis, and the combination of possible haemorrhagic complications coupled with equivocal results in properly controlled clinical trials, has inhibited their more widespread use, except in a few clearly defined situations (e.g. low dosage heparin as a method of reducing the incidence of deep venous thrombosis after surgery).
The most rational medical treatment, in theory, must be to selectively dissolve the offending blood clot. In the test-tube many proteolytic enzymes will lyse coagulated blood, but these enzymes, for example trypsin, would also break down many other blood proteins, and be rapidly fatal (a state of affairs sometimes seen in fulminating acute haemorrhagic pancreatitis). What is needed is an enzyme with a high degree of specificity for fibrin, and only minimal general proteolytic activity. In the body, the naturally occurring enzyme plasmin has these properties.
In the blood stream plasmin normally exists as its inactive precursor, plasminogen. Blood clot is lysed by the plasminogen already trapped in the thrombus being activated to plasmin by substances released from the adjacent damaged vessel wall and which are known as vascular plasminogen activators. In this way, non-fatal blood clots in vessels become gradually recanalised, though the process is slow and inefficient, often taking months or years. It is thus apparent that the use of plasminogen activitors suitable for administration to patients, could be a method of treating thrombotic vascular occlusions.
In 1933, Tillet discovered that an exotoxin obtained from cultures of haemolytic streptococci, was a powerful plasminogen activator; this he called streptokinase (SK). It has never achieved general clinical acceptance for use as a fibrinolytic agent because (a) it is strongly antigenic (as would be expected of a bacterial exotoxin), and thus frequent pyrogenic reactions, and occasional instances of anaphylactic shock, have been reported, and (b) its administration is associated with a considerable risk of generalised bleeding, because SK activates both circulating plasminogen as well as clot-bound plasminogen, and the former causes widespread destruction of several of the normal blood coagulation factors, viz. Factor I (fibrinogen), Factor II (prothrombin), Factor V (labile factor) and Factor VIII (anti-haemophilic globulin).
A decade later, another plasminogen activator was found in normal human urine, and named Urokinase (UK). This is far less (if at all) antigenic, but it, too, is associated with activation of plasminogen in the blood, and hence carries a similar risk of severe haemorrhage, which restricts its clinical usefulness.
It has bee
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Atkinson Anthony
Electricwala Asgar
Griffiths John B.
Latter Amy
Riley Patrick A.
Public Health Lab Svc Bd. University Coll.
Rosen Sam
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