Berthold Baldus

Coronary thrombolysis with Desmodus salivary plasminogen activator in dogs. Fast and persistent recanalization by intravenous bolus administration.

DSPA (Desmodus salivary plasminogen activator) is a new thrombolytic agent corresponding to a natural plasminogen activator discovered in the saliva of the vampire bat Desmodus rotundus. Compared with tissue plasminogen activator (TPA), DSPA, produced in a recombinant cell line, is more fibrin cofactor dependent than TPA. Methods and ResultsThe thrombolytic properties of DSPA and TPA were compared in a canine model of copper coilinduced coronary thrombosis. All dogs received heparin 200 IU/kg IV and SC. Whereas controls did not reperfuse within 180 minutes (none of six), intravenous bolus administration of DSPA at 25, 50, and 100 μg/kg resulted in a 100% incidence (6 of 6) of recanalization within 37, 23, and 18 minutes, respectively. TPA at 63 and 125 mu;g/kg reopened the coronaries in 33% (two of six) and 50% (three of six) of cases within 40 minutes. Eighty-three percent (5 of 6) of the arteries were still patent 3 hours after 50 and 100 mu;/kg DSPA, whereas only 20% (one of five) of all coronaries originally recanalized with both doses of TPA were still open at 3 hours. Plasma levels of α2-antiplasmin decreased significantly only with 125 mu;g/kg TPA. The clearance of DSPA (2.3 to 3.5 mL · min−1 · kg−1) was lower compared with TPA (11.4 to 20 mL · min−1 · kg−1) due to a prolonged terminal half- life. ConclusionsIn a canine coronary thrombosis model, DSPA exhibited higher potency and recanalized coronary arteries faster and with a lower incidence of reocclusion than TPA. Its properties may translate into a higher efficacy in patients compared with available thrombolytic agents. The long halflife of DSPA may allow for single bolus administration in the treatment of acute myocardial infarction.

Update on the toxicology and pharmacology of rDSPA alpha 1 (Bat-PA) in animals and humans

Summary The properties of the plasminogen activator of the vampire bat Desmodus rotundus (rDSPA alpha 1), have been studied in both animals and healthy volunteers. In contrast to rt-PA, the bleeding time after treatment with up to 100 nmol/kg of DSPA alpha 1, given as a single bolus injection, remained entirely unaffected in rats, and no rebleeding from older puncture sites occurred. No chronotropic or inotropic effects of DSPA alpha 1 were noted in the spontaneously-beating, oxigenized tyrode solution superperfused guinea-pig heart. In rat hearts, focal necroses of single myocytes were observed 15 days post-treatment with 1 mg/kg (1/40) up to 30 mg/kg (17/20) in a dose-dependent fashion. Similar effects were also seen after treatment with streptokinase and APSAC in supratherapeutic doses. No such effects were seen with either of the thrombolytic agents in rabbits and monkeys. Anti-DSPA antibodies were detected by means of a competitive ELISA assay in 3/10, 4/10, and 3/10 of the rats after 4 repeated injections of 1, 3 or 10 mg/kg of DSPA at weekly intervals. In monkeys which, after transient expression, had non-detectable DSPA antibody levels, an immunologic memory was observed, causing booster reactions in 3 out of 8 animals. No cross-reactivity of the DSPA antibodies with rt-PA activities was found. After single bolus injections of 0.01 to 0.05 mg/kg in healthy volunteers, DSPA alpha 1 was eliminated following a biphasic elimination curve with an alpha half-life of only 4 min and a beta half-life of 2.3 to 2.7 h; the second elimination phase being responsible for the clearance of 83% of the substance. In these bolus doses, no effect on the endogenous coagulant and fibrinolytic parameters was detected. In addition, the substance appeared to be completely fibrin selective. Unlike the other plasminogen activators, DSPA alpha 1 did not cause any procoagulant effect. No signs of the production of IgG or IgM antibodies to DSPA were detected in any of these subjects. The data accumulated on DSPA alpha 1 so far do not indicate that increased hazards are associated with the use of this drug. The favorable thrombolytic properties of DSPA alpha 1 warrant further development into this future thrombolytic agent.

Antithrombotic Profile of Iloprost in Experimental Models of Arterial and Venous Thrombosis

Clinical benefit from treatment with Iloprost in patients suffering from throm-boembolic disorders may arise from well known properties of the drug like inhibition of platelet aggregation, vasorelaxation, cytoprotection and stimulation of the plasma fibrinolytic activity [1–3]. Some, if not all, of these properties could qualify Iloprost as a drug with antithrombotic efficacy.

Successful recanalisation of experimentally occluded coronary arteries in anaesthetised dogs with recombinant single-chain tissue-type Plasminogen activator (set-PA)

Abstract In anaesthetised closed chest dogs experimental occluding coronary thrombosis was induced by introducing a copper coil into a branch of the left circumflex coronary artery (LCX). LCX-occlusion and reperfusion after thrombolysic treatment were assessed by coronary angiography and typical ECG-signs. One hour after total LCX-occlusion vehicle alone (n=5), streptokinase (500 IU/kg/min; n=5) or single-chain tissue-type plasminogen activator (set-PA; 5000IU/kg/min; n=5) were intravenously infused. In no case spontaneous recanalisation could be observed in the control group within 150 min after onset of infarction. Streptokinase as well as sct-PA reopened the occluded LCX after an infusion period of 60 ± 23.7 min (x ± SD) and 49.5 ± 14.6 min, respectively. Compared with prethrombolytic values no significant depletion of fibrinogen, α 2 -antiplasmin, and plasminogen was observed in the dogs treated with streptokinase or single-chain tissue-type plasminogen activator.