Pharmacology: Lysis of thrombi-emboli:
Plasminogen and fibrinogen are coexistent in the blood, and when fibrin is formed through blood coagulation, plasminogen is incorporated into the fibrin clot. Urokinase acts to convert this plasminogen into plasmin and thereby to dissolve the thrombus. The plasmin thus generated within the fibrin clot is not affected by antiplasmins.
According to Ambus et al., the plasmin thus activated by urokinase conjugates with anitplasmins and circulates in the blood. Because of its high affinity with fibrin, plasmin is liberated from the antiplasmin-conjugate upon coming into contact with a thrombus, and demonstrates its intrinsic plasmin activity there. Antiplasmins work as a vehicle for plasmin, also serve to inhibit the lysis by plasmin of other plasma proteins (blood coagulation factors and others).
Clinical efficacy: Cerebral thrombosis: The use of this product was confirmed by a double blind placebo-controlled study conducted in 126 medical centers nationwide. In open clinical studies, further, "Effective" or better responses were rated to be 50% and "Fairly effective" or better 82.5%.
Peripheral arterial-venous occlusion: The response rates to this product in arterial occlusive diseases amounted to 68.1% when assessed for systemic conditions, 70.2% for subjective symptoms (the vascular system), 65.2% for subjective symptoms (the nervous system), and 57.1% for findings of the soft parts. Moreover, the response rates in venous occlusive diseases amounted to 85.5% for subjective symptoms, 83.0% for objective findings, and 84.0% for perimeter of the extremities. The improvement in angiographic findings was rated to be 25.0% (60.0% rated as "Fairly improved" or better). Further, the efficacy and safety of this product were confirmed by a comparative clinical trial to be superior to those of heparin as control.
Out of a total of 3,794 patients surveyed through the Phase IV studies, 15 patients (0.40%) presented adverse reactions (Table). The primary reactions were hemorrhagic cerebral infarction, gastrointestinal hemorrhage and other hemorrhages (at punctured sites and from wounds). (See table.)
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Pharmacokinetics: Absorption, distribution, metabolism, and excretion in animals: 125
I-labeled urokinase at 60,000 IU/50 kg body weight was intravenously administered to beagles, and the changes in blood radioactivity and its eliminations into the urine and feces were measured. In consequence, The plasma levels of 125
I-urokinase decreased rapidly within 1 hour after administration and then decreased gradually following the equation, -dc/dt=kc (where k: velocity constant).
I-urokinase was administered via the tail vein of rats (both sexes), and the distribution of radioactivity in the body and its sequential changes were measured by the whole body autoradiography assay. In consequence, 1. The highest radioactivity was detected in the kidneys shortly after administration, followed by the liver, lungs, heart muscles, and spleen. In these organs except for kidneys, the radio-activities were eliminated rapidly to be cleared after 24 hours.
2. The radioactivity in the kidneys peaked 5 minutes after administration, which persisted for a long time, suggesting that urokinase has an affinity with kidneys.
3. Urokinase was suggested to be eliminated principally into the urine via the kidneys.
4. Male and female rats showed a similar pattern of distribution of urokinase in the organs other than genitals, indicating no intrinsic differences between both sexes.
Toxicology: Non-clinical studies:
Toxicity: Acute Toxicity: In acute toxicity studies with mice and rats, even the maximum dose technically injectable (equivalent to 3,000,000 IU/kg of urokinase) did not induce any appreciable abnormalities, and the LD50
was estimated to be more than 3,000,000 IU/kg.
Subacute toxicity: In rats given daily 100,000, 30,000 or 10,000 IU/kg of urokinase for 30 consecutive days, no appreciable adverse reactions were observed even with the top dose and hence the maximum toxicologically non-effective dose in rats was estimated to be more than 100,000 IU/kg/day.