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

BMC Veterinary Research

Karsten Feige²  Gudrun M Herrling²  Wolfgang Bäumer¹ 

[1] Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, USA;Clinic for Horses, University of Veterinary Medicine Hannover, Foundation, Buenteweg 17, 30559 Hannover, Germany

关键词: Hypercoagulopathy;    Clot formation;    Thrombus;    Recombinant tissue plasminogen activator;    Alteplase;   

Others  :  1119480
DOI  :  10.1186/1746-6148-9-158

 received in 2013-02-22, accepted in 2013-08-06,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Bäumer et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Dolente BA, Beech J, Lindborg S, Smith G: Evaluation of risk factors for development of catheter-associated jugular thrombophlebitis in horses: 50 cases (1993–1998). J Am Vet Med Assoc 2005, 227(7):1134-1141.
• [2]Divers TJ: Prevention and treatment of thrombosis, phlebitis, and laminitis in horses with gastrointestinal diseases. Vet Clin North Am Equine Pract 2003, 19(3):779-790.
• [3]Moore BR, Hinchcliff KW: Heparin: a review of its pharmacology and therapeutic use in horses. J Vet Intern Med 1994, 8(1):26-35.
• [4]Feige K, Schwarzwald CC, Bombeli T: Comparison of unfractioned and low molecular weight heparin for prophylaxis of coagulopathies in 52 horses with colic: a randomised double-blind clinical trial. Equine Vet J 2003, 35(5):506-513.
• [5]Feige K, Dennler M, Kastner SB, Wunderli-Allenspach H, Demuth D, Huber A: Pharmacokinetics of recombinant hirudin in healthy horses. Equine Vet J 2004, 36(2):135-141.
• [6]Seifried E, Tanswell P, Rijken DC, Barrett-Bergshoeff MM, Su CA, Kluft C: Pharmacokinetics of antigen and activity of recombinant tissue-type plasminogen activator after infusion in healthy volunteers. Arzneimittelforschung 1988, 38(3):418-422.
• [7]Gillis JC, Wagstaff AJ, Goa KL: Alteplase A reappraisal of its pharmacological properties and therapeutic use in acute myocardial infarction. Drugs 1995, 50(1):102-136.
• [8]Quinn TJ, Dawson J, Lees KR: Past, present and future of alteplase for acute ischemic stroke. Expert Rev Neurother 2008, 8(2):181-192.
• [9]Thompson M, Scott-Moncrieff JCHDF F: Thrombolytic therapy in dogs and cats. J Vet Emerg Crit Care 2001, 11:111-121.
• [10]Bliss SP, Bliss SK, Harvey HJ: Use of recombinant tissue-plasminogen activator in a dog with chylothorax secondary to catheter-associated thrombosis of the cranial vena cava. J Am Anim Hosp Assoc 2002, 38(5):431-435.
• [11]Duggan VE, Holbrook TC, Dechant JE, Blaik MA, Ritchey JW: Diagnosis of aorto-iliac thrombosis in a quarter horse foal using Doppler ultrasound and nuclear scintigraphy. J Vet Intern Med 2004, 18:753-756.
• [12]Slovis N: Pericarditis: a clinical perspective during an epidemic of fibrinous pericarditis in central Kentucky. Equine Veterinary Education 2011, 23:69-72.
• [13]Rendle DI, Armstrong SK, Hughes K: Combination fibrinolytic therapy in the treatment of chronic septic pleuropneumonia in a thoroughbred gelding. Aust Vet J 2012, 90:358-362.
• [14]Hilton H, Pusterla N: Intrapleural fibrinolytic therapy in the management of septic pleuropneumonia in a horse. Vet Rec 2009, 164:558-559.
• [15]Rendle DI, Hughes KJ: Resolution of hyphaema following intracameral injection of tenecteplase in a stock horse. AustVet J 2013, 91:31-34.
• [16]Tanswell P, Seifried E, Su PC, Feuerer W, Rijken DC: Pharmacokinetics and systemic effects of tissue-type plasminogen activator in normal subjects. Clin Pharmacol Ther 1989, 46(2):155-162.
• [17]Werner RG, Bassarab S, Hoffmann H, Schluter M: Quality aspects of fibrinolytic agents based on biochemical characterization. Arzneimittelforschung 1991, 41(11):1196-1200.
• [18]Yakovlev SA, Rublenko MV, Izdepsky VI, Makogonenko EM: Activating effect of the plasminogen activators on plasminogens of different mammalia species. Thromb Res 1995, 79(4):423-428.
• [19]Wohl RC, Sinio L, Summaria L, Robbins KC: Comparative activation kinetics of mammalian plasminogens. Biochim Biophys Acta 1983, 745(1):20-31.
• [20]Schwarzwald CC, Feige K, Wunderli-Allenspach H, Braun U: Comparison of pharmacokinetic variables for two low-molecular-weight heparins after subcutaneous administration of a single dose to horses. Am J Vet Res 2002, 63(6):868-873.
• [21]Sabovic M, Keber D: Factors influencing the lysis of ex vivo human thrombi. Fibrinolysis 1996, 10:103-109.