© 1986 Oxford University Press
research-article |
Comparative Studies of Heparin and Heparin Fragments: Distribution and Toxicity in the Rat
,
,2
*Department of Applied Biological Sciences, Massachusetts Institute of Technology Cambridge, Massachusetts 02139
Department of Surgery, Children's Hospital Medical Center Boston, Massachusetts 02115
Harvard-MIT Division of Health Sciences and Technology Cambridge, Massachusetts 01239
Comparative Studies of Heparin and Heparin Fragments: Distribution and Toxicity in the Rat. Larsen, A. K., Newberne, P. M., and Langer, R. (1986). Fundam Appl. Toxicol 7, 86-93. To control blood levels of hepann during extracorporeal therapy, the use of a blood filter containing heparinase, a heparin-specific enzyme that cleaves heparin to small fragments with less anticoagulant activity, has been proposed. These fragments have anti-factor Xa activity but no anti-thrombin activity. The potential toxicity of heparin fragments as compared to heparin was examined in rats by identifying presumptive sites of drug-related toxicity by whole-body autoradiography and by histological examination of major organs. Radioautograms of rats sacrificed 5 hr after dosing with [35S]heparin fragments indicated no potential targets different from what was observed in rats dosed with [35S]heparin. In addition, the faster urinary clearance of heparin fragments resulted in a lower concentration of these fragments than of heparin in all common target organs. No hemorrhages or other lesions were found in rats injected intravenously with heparin fragments (100 mg/kg) and sacrificed after 5 hr. In addition, no mortality or delayed toxic effects were observed in a similar group of animals sacrificed 2 weeks after dosing. In contrast, 80% of rats injected with heparin (100 mg/kg) showed hemorrhages of the lungs at the time of necropsy.