USE OF A PRECISE INTRATRACHEAL DELIVERY SYSTEM TO COMPARE THE ACUTE TOLERANCE OF HEPARIN AND THE HEPARINOID GM2000 IN RABBITS

The pharmacological activity of heparin as a anti-inflammatory agent, has led to its proposed use in the treatment of asthma. However, the a nticoagulant actions of heparin raise concerns about its long-term use due to potential bleeding complications. In the present study, hepari n was compared with the heparinoid derivative GM2000, which possesses reduced anticoagulant activity relative to heparin, for acute toleranc e in the rabbit. A method was developed to compare the acute tolerance of GM2000 to heparin. This method involved the instillation of compou nds directly into the trachea to parallel the route of exposure used t o 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 (P enn microsprayer). Escalating doses were given 48 h apart, and blood s amples were collected immediately prior to and following dosing, and a t 24 h postdosing for measurements of plasma-activated partial prothro mbolplastin time (aPTT). Three out of four rabbits in the heparin grou p died following inhaled doses of 100 or 200 mg/kg. In addition, rabbi ts dosed with heparin at doses of 100 or 200 mg/kg exhibited marked el evations in aPTT following dosing. No deaths or elevations in aPTT occ urred in the GM2000 dose groups. Focal hemorrhaging in the lung was ob served in rabbits treated with heparin and GM2000, but in heparin-trea ted animals hemorrhaging was also observed in other organs. These resu lts demonstrate enhanced safety of the heparinoid GM2000 relative to h eparin by inhalation exposure in rabbits, suggesting an improved thera peutic potential of this derivative in the treatment of asthma.