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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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Time curve of rt-PA plasma concentration (mean ± SD) after intravenous infusion of 1 mg/kg rt-PA over a period of 30 min in six healthy horses.
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Figure 2: Time curve of rt-PA plasma concentration (mean ± SD) after intravenous infusion of 1 mg/kg rt-PA over a period of 30 min in six healthy horses.

Mentions: Infusion of rt-PA alteplase was well tolerated in the different dosages by every horse. None of the horses showed adverse drug reactions. In a pilot study, one horse received a dose of 0.25 mg/kg alteplase. The maximal plasma concentration was 199 ng rt-PA/ml. By administration of 0.5 mg/kg rt-PA Cmax was 779 ng/ml. In order to achieve plasma rt-PA concentrations consistent with those demonstrated to be thrombolytic in vitro and in line with target concentrations in humans (Cmax around 1000 ng/ml) a dose of 1 mg/kg was used for the main experiment. When administered over 30 min via infusion, the mean maximal plasma concentration measured was 1252 (± 267) ng/ml rt-PA (Figure 2). The plasma clearance was 21.46 (± 5.67) ml/min/kg and t1/2α was 6.81 (± 1.48) min followed by a delayed β phase (t1/2β 317.93 ± 373.77 min). The high standard deviation is due to the extremely prolonged t1/2β in one horse (1061 min). The median t1/2β was 171 minutes with a range of 85–1061 min.


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

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

Time curve of rt-PA plasma concentration (mean ± SD) after intravenous infusion of 1 mg/kg rt-PA over a period of 30 min in six healthy horses.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Time curve of rt-PA plasma concentration (mean ± SD) after intravenous infusion of 1 mg/kg rt-PA over a period of 30 min in six healthy horses.
Mentions: Infusion of rt-PA alteplase was well tolerated in the different dosages by every horse. None of the horses showed adverse drug reactions. In a pilot study, one horse received a dose of 0.25 mg/kg alteplase. The maximal plasma concentration was 199 ng rt-PA/ml. By administration of 0.5 mg/kg rt-PA Cmax was 779 ng/ml. In order to achieve plasma rt-PA concentrations consistent with those demonstrated to be thrombolytic in vitro and in line with target concentrations in humans (Cmax around 1000 ng/ml) a dose of 1 mg/kg was used for the main experiment. When administered over 30 min via infusion, the mean maximal plasma concentration measured was 1252 (± 267) ng/ml rt-PA (Figure 2). The plasma clearance was 21.46 (± 5.67) ml/min/kg and t1/2α was 6.81 (± 1.48) min followed by a delayed β phase (t1/2β 317.93 ± 373.77 min). The high standard deviation is due to the extremely prolonged t1/2β in one horse (1061 min). The median t1/2β was 171 minutes with a range of 85–1061 min.

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