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.