Use of a Precise Intratracheal Delivery System to Compare the Acute Tolerance of Heparin and the Heparinoid GM2000 in Rabbits

Abstract

Summary: The pharmacological activity of heparin as a anti-inflammatory agent, has led to its proposed use in the treatment of asthma. However, the anticoagulant actions of heparin raise concerns about its long-term use due to potential bleeding complications. In the present study, heparin was compared with the heparinoid derivative GM2000, which possesses reduced anticoagulant activity relative to heparin, for acute tolerance in the rabbit. A method was developed to compare the acute tolerance of GM2000 to heparin. This method involved the instillation of compounds directly into the trachea to parallel the route of exposure used to examine the efficacy of these compounds in an animal model of asthma. The protocol utilized four groups of New Zealand White rabbits, each containing 2 males and 2 females. The rabbits were dosed with saline, heparin, or GM2000 at single, escalating doses of 0.2, 2.0, 20, 100, and 200 mg/kg, administered with an intratracheal microspray device (Penn microsprayer). Escalating doses were given 48 h apart, and blood samples were collected immediately prior to and following dosing, and at 24 h postdosing for measurements of plasma-activated partial prothrombolplastin time (aPTT). Three out of four rabbits in the heparin group died following inhaled doses of 100 or 200 mg/kg. In addition, rabbits dosed with heparin at doses of 100 or 200 mg/kg exhibited marked elevations in aPTT following dosing. No deaths or elevations in aPTT occurred in the GM2000 dose groups. Focal hemorrhaging in the lung was observed in rabbits treated with heparin and GM2000, but in heparin-treated animals hemorrhaging was also observed in other organs. These results demonstrate enhanced safety of the heparinoid GM2000 relative to heparin by inhalation exposure in rabbits, suggesting an improved therapeutic potential of this derivative in the treatment of asthma.

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• [K]Key [K]Words: Anticoagulant Activity, Asthma, Heparin, Heparinoids, Inhalation.