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Pharmacokinetics and thrombolytic effects of the recombinant tissue-type plasminogen activator in horses.

Bäumer W, Herrling GM, Feige K - BMC Vet. Res. (2013)

Bottom Line: In addition, plasma rt-PA concentration was measured until 300 min after commencing the infusion.The D-dimer concentration in the lysis medium correspondingly increased from 0.10 up to 10.8 mg/l.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.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

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.

Conclusion: 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.

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Reduction in thrombus weight of in vitro generated equine thrombi after incubation with rt-PA (n = 4 horses for concentrations 0.5,3.0 and 5.0 μg/ml, n = 7 for 0 and 1.5 μg/ml rt-PA;all thrombi for each time point and concentration were performed a minimum of three times). After four hours, there is a significant difference between 0 as well as 0.5 μg/ml and 1.5 μg/ml, whereas no significant difference was found between 3 as well as 5 μg/ml and 1.5 μg/ml, a vs. b: p < 0.001.
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Figure 1: Reduction in thrombus weight of in vitro generated equine thrombi after incubation with rt-PA (n = 4 horses for concentrations 0.5,3.0 and 5.0 μg/ml, n = 7 for 0 and 1.5 μg/ml rt-PA;all thrombi for each time point and concentration were performed a minimum of three times). After four hours, there is a significant difference between 0 as well as 0.5 μg/ml and 1.5 μg/ml, whereas no significant difference was found between 3 as well as 5 μg/ml and 1.5 μg/ml, a vs. b: p < 0.001.

Mentions: To determine the thrombolysis, the weight of the thrombi and generation of D-dimer were measured every 60 min over a period of four hours. There was a time dependent decrease in thrombus weight and an increase in D-dimer generation for equine thrombi (Figure 1, Table 1). An addition of 1.5 μg/ml rt-PA to the autologous horse plasma led to nearly 90% weight reduction of thrombi 4 hours after incubation, whereas 3.5 μg/ml and 5 μg/ml increased this thrombolytic activity only marginally.


Pharmacokinetics and thrombolytic effects of the recombinant tissue-type plasminogen activator in horses.

Bäumer W, Herrling GM, Feige K - BMC Vet. Res. (2013)

Reduction in thrombus weight of in vitro generated equine thrombi after incubation with rt-PA (n = 4 horses for concentrations 0.5,3.0 and 5.0 μg/ml, n = 7 for 0 and 1.5 μg/ml rt-PA;all thrombi for each time point and concentration were performed a minimum of three times). After four hours, there is a significant difference between 0 as well as 0.5 μg/ml and 1.5 μg/ml, whereas no significant difference was found between 3 as well as 5 μg/ml and 1.5 μg/ml, a vs. b: p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750949&req=5

Figure 1: Reduction in thrombus weight of in vitro generated equine thrombi after incubation with rt-PA (n = 4 horses for concentrations 0.5,3.0 and 5.0 μg/ml, n = 7 for 0 and 1.5 μg/ml rt-PA;all thrombi for each time point and concentration were performed a minimum of three times). After four hours, there is a significant difference between 0 as well as 0.5 μg/ml and 1.5 μg/ml, whereas no significant difference was found between 3 as well as 5 μg/ml and 1.5 μg/ml, a vs. b: p < 0.001.
Mentions: To determine the thrombolysis, the weight of the thrombi and generation of D-dimer were measured every 60 min over a period of four hours. There was a time dependent decrease in thrombus weight and an increase in D-dimer generation for equine thrombi (Figure 1, Table 1). An addition of 1.5 μg/ml rt-PA to the autologous horse plasma led to nearly 90% weight reduction of thrombi 4 hours after incubation, whereas 3.5 μg/ml and 5 μg/ml increased this thrombolytic activity only marginally.

Bottom Line: In addition, plasma rt-PA concentration was measured until 300 min after commencing the infusion.The D-dimer concentration in the lysis medium correspondingly increased from 0.10 up to 10.8 mg/l.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.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus