Objective:To study the
long term toxicity of recombinant hirudin on
Macaca mulatta . Methods: Macaca mulatta were
randomly divided into low dosage group, median dosage group, high dosage group (1.0,3.0 and 6.0 mg/kg) and control group( n =6). Recombinant human hirudin was injected iv continuously for 30 d. Half of the animals in each group were killed at the end of medication and the other half were killed after another 15 d recovery period for pathological examination. Parameters of hematologic, chemical, urinalysis, ECG, specific antibody, bone marrow, and pathologic profile were all measured. Results: On day 15 and day 30, the blood samples of each group were collected 30 min and 24 h after iv medication. Compared with control group or with day 0 data, the clotting time (CT), thrombin time (TT) and activated partial thromboplastin time (aPTT) were significantly prolonged 30 min after iv medication in a dose dependent manner.The changed indices returned to the normal level 24 h after iv medication. The histopathologic examination showed congestion and slight edema of liver and kidney in each group. On day 30, there were local hemorrhage and inflammatory reaction in injection site of some animals in each group, but none was found on day 45. Conclusion: Recombinant human hirudin has pharmacological and toxicological effects on blood system, and it can significantly prolong CT, TT, and aPTT. All these effects are reversible. The safety dose of recombinant human hirudin in
Macaca mulatta is 1.0 mg/kg.