Complex-bound inhibitors of metabolic enzymes capable of being a

Details Complex-bound inhibitors of metabolic enzymes capable of being a Complex-bound inhibitors of metabolic enzymes capable of being a

1998-05-26

2000-04-18

Gitomer, Ralph

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving blood clotting factor

435 23, 435 24, 930250, C12Q 156, C12Q 137

Patent

active

06051390&

DESCRIPTION:

BRIEF SUMMARY
The invention relates to the use of inhibitors of activatable or activated metabolic enzymes, which inhibitors are bound to high molecular weight carriers, as molecular markers for determining the activation of the enzyme in order to indirectly diagnostically and therapeutically monitor the enzyme.
This invention in particular relates to the use of an inhibitor of an activation product of the blood clotting cascade or of an activated fibrinolysis enzyme, which inhibitor is bound to a high molecular weight carrier, as a molecular marker to indirectly monitor an activation product of the blood clotting cascade or an activated fibrinolysis enzyme. The invention preferably relates to the use of a thrombin inhibitor, which is bound to a high molecular weight carrier, as a molecular marker for determining clotting activation in clotting diagnosis and therapy monitoring. The invention relates in particular to complex-bound hirudin (CBH) as a molecular marker for determining clotting activation.
Many metabolic physiological processes are regulated via cascade mechanisms, which are often branched, and in which an initiator or a chain reaction is intensified via a series of activatable enzymes. For example, mechanisms such as these are effective in the regulation of glycogen metabolism, in the transmission of extracellular signals and in blood clotting in particular. On a molecular level, sequential phosphorylation of the factors involved in a cascade mechanism is often to be found here. The intensification of an initiator by this mechanism is due to the enzymes which participate in the different stages of the mechanism being capable of modifying a plurality of substrate molecules, which themselves are often enzymes also. The activated enzymes of a mechanism such as this are suitable as molecular markers for determining the activation reaction which is proceeding in the body in each case. In a procedure such as this, specific, high-affinity inhibitors of the respective activated key enzyme are used which are to be fed as such to a permanent diagnosis line. This so-called molecular marker principle has only been developed unsatisfactorily hitherto, however.
The search for suitable molecular markers for the determination of intravasal activation reactions of blood clotting has been intensively pursued for some years. In the course of this work a series of metabolic products of clotting activation has emerged as molecular markers. These comprise prothrombin F1+2 fragments, platelet factor IV and fibrinopeptides A and B, as well as some cleavage products of fibrin decomposition (e.g. d-dimers) which are produced by fibrinolysis, and also comprise complexes formed between natural antithrombins and the serine protease thrombin, which are known as TAT complexes.
The usability of these molecular markers has been analysed in large-scale clinical studies. It has generally been ascertained that it is possible to determine blood levels of molecular markers of this type which are definitely increased or which persist during thrombotic occurrences or thrombo-embolytic diseases. The efficiency of these markers leaves very much to be desired, however. In clinical patients who suffered from venous thromboses or from arterial thrombotic occlusion diseases, the response capacity of the most sensitive marker for clotting, namely prothrombin fragment F1+2, was less than 20%. Moreover, no correlation could be found between the severity of the thrombo-embolytic disease or thrombotic occurrence and the magnitude of the blood level of this and other molecular markers.
From experience with persons suffering from diseases of this type, it can be deduced that in haemostaseology there has hitherto not been a principle of molecular measurement which enables conclusions to be drawn on the intensity of clotting activation by determining the actual blood level of the marker. The cause of this is that the molecular markers, as metabolic products of clotting enzymes which occur naturally in the body, are removed more or less rapidly from the circulat

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