Pharmacokinetics and thrombolytic effects of the recombinant tissue-type plasminogen activator in horses.
BACKGROUND
To test the efficacy of the recombinant tissue-type plasminogen activator (rt-PA) alteplase in horses, the thrombolytic effect was tested in in vitro generated equine thrombi. The extent of lysis was determined by measuring the decrease in thrombi weight over a period of 4 hours. In vivo pharmacokinetics of alteplase were determined in 6 healthy horses. A single dose (1 mg/kg) was applied via intravenous infusion over a period of 30 minutes Coagulation-related variables, blood count and clinical parameters were taken before the treatment and until 48 h after treatment. In addition, plasma rt-PA concentration was measured until 300 min after commencing the infusion.


RESULTS
In vitro, a dose dependent decrease of thrombus weight ranging from a 56 (± 6.5) % decrease for 0.5 μg/ml to 92 (± 2.1) % decrease for 5 μg/ml rt-PA was noted. The D-dimer concentration in the lysis medium correspondingly increased from 0.10 up to 10.8 mg/l. In vivo, none of the horses showed an adverse reaction to the alteplase infusion. In some horses blood parameters were slightly altered. The 1 mg/kg dose yielded the following pharmacokinetic parameters: Cmax = 1.25 ± 0.27 μg/ml; CL = 21.46 ± 5.67 ml/min/kg; dominant half life (t1/2α) = 6.81 ± 1.48 minutes; median elimination half life (t1/2β) = 171 min (range: 85–1061); AUC = 50.33 ± 17.62 μg · min /ml.


CONCLUSIONS
These findings indicate that a single dose of 1 mg/kg alteplase results in rt-PA plasma concentrations comparable to those in humans and might be sufficient for a thrombolytic therapy in horses. Further studies must be performed to determine the alteplase effectiveness in horses with jugular vein thrombosis.
Wolfgang
W
Bäumer
Gudrun M
GM
Herrling
Karsten
K
Feige
D000818:Animals; D019540:Area Under Curve; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006207:Half-Life; D006736:Horses / Q000378:metabolism*; D007262:Infusions, Intravenous / Q000662:veterinary; D008297:Male; D010314:Partial Thromboplastin Time / Q000662:veterinary; D011517:Prothrombin Time / Q000662:veterinary; D013918:Thrombin Time / Q000662:veterinary; D013927:Thrombosis / Q000188:drug therapy / Q000662:veterinary*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use
D005343:Fibrinolytic Agents; D005340:Fibrinogen; D010959:Tissue Plasminogen Activator