Referring to the diseases caused by hypercoagulation, disseminated intravascular coagulation (hereinafter referred to briefly as "DIC") is representative. DIC is a disease in which tissue factor exposed through cytoclasis by malignant tumors or bacterial infections (action of endotoxins produced by bacteria) gets into contact with blood to thereby cause hypercoagulation, or hyperfunction of the blood coagulation system (marked increases in blood thrombin level), with resultant formation of multiple thrombi in the systemic microvessels (the coagulation-dominant type DIC). Since the fibrinolytic system of DIC patients is normal, however, there is induced secondary fibrinolysis to dissolve the formed clots, resulting in repetition of blood coagulation-thrombolysis within the patient body at enhanced frequencies (i.e., the compensatory DIC). On the occasion of this, the blood levels of fibrin/fibrinogen degradation products (hereinafter referred to briefly as "FDP") are caused to rise. When the disease becomes severe, furthermore, consumption of blood coagulation factors (e.g., fibrinogen) exceeds their biosynthesis to create a serious bleeding tendency (i.e., the fibrinolysis-dominant type DIC), leading to occasional death.
DIC is a disease which, being accompanied with so marked an increase in blood thrombin levels as it may in some instances called thrombocythemia or thrombocytosis, is therefore characterized by hypercoagulation, and the major drugs heretofore employed for DIC treatment include heparin (a mixture of heparins with molecular weights ranging from 4,000 to 40,000), low-molecular-weight heparin (heparin with a molecular weight of 4,000 to 5,000 fractionated from heparin) and antithrombin III concentrated preparations.
Heparin currently used in the treatment of DIC exerts action not only on thrombin (the major factor of the blood coagulation system) but also blood coagulation factor Xa to thereby inhibit blood coagulation, wherein the compound acts mainly as a mediator in the reaction between thrombin and antithrombin III (a thrombin inhibitory factor present in blood); in other words, heparin inhibits indirectly blood coagulation. Heparin is repeatedly utilized many times within the living body in the said inhibition reaction, whereas antithrombin III, upon formation of a complex with thrombin, undergoes rapid metabolism and disappears. This creates a tendency for the DIC patients to become deficient in antithrombin III, with the consequent, occasional need to supplement with antithrombin III. In Japan, nevertheless, the antithrombin concentrated preparations are so highly priced that they are subject to some restrictions on their use to DIC patients in terms of benefit coverage by health insurance (e.g., such preparations are only permitted legislatively to be administered to patients with a blood antithrombin III level of 70% or below of the normal one and also at a reduced frequency of within 5 days per month). In addition, heparin prolongs the blood coagulation time and makes patients more susceptible to a bleeding tendency. As is described in the above, the heparin therapy is not only accompanied with the adverse effect of increased bleeding tendency but also incurs much more treatment expenses in association with the inherent use of antithrombin III. Because of this, there is also used low-molecular-weight heparin which exhibits enhanced specificity for the blood coagulation factor Xa. However, the drug, like thrombin, is accompanied with the adverse effect of increased bleeding tendency, depending upon the dose, and accordingly requires troublesome management of its blood levels. Moreover, low-molecular-weight heparin likewise exhibits weaker thrombin inhibitory activity than heparin, and consumes antithrombin III to thereby suppress hypercoagulation. As is evident from the above, therapy with use of either of heparin and low-molecular-weight heparin involves increased bleeding tendency and consumption of antithrombin III, though to a varying extent.
USPTO Backgrounds
USPTO Backgrounds