Orally administered unfractionated heparin with carrier agent is therapeutic for deep venous thrombosis

Abstract

Background - Orally administered heparin (OHEP) is unreliable because of poor absorption. Sodium N-(8[2-hydroxybenzoyl]amino) caprylate (SNAC) is an amido acid that facilitates the gastrointestinal absorption of heparin. We evaluated the effectiveness of OHEP combined with SNAC (OHEP/SNAC) in the treatment of deep-vein thrombosis (DVT). Methods and Results - In internal jugular DVT was produced in 54 male Sprague-Dawley rats. Animals were assigned to 6 different groups for 7 days of treatment: untreated control, subcutaneous heparin (SC HEP) (300 U/kg SC TID), SNAC only (300 mg/kg PO TID), OHEP only (30 mg/kg PO TID), low-molecular-weight heparin (LMWH) (enoxaparin 5 mg/kg SC QD), and OHEP/SNAC (30 mg/kg:300 mg/kg PO TID). The activated partial thromboplastin time (aPTT) and anti-factor X (anti-Xa) levels were measured. The incidence of residual DVT after 1 week of treatment was 100% (9 of 9) in the control group versus 10% (1 of 10) in the OHEP/SNAC and 10% (1 of 10) in the LMWH groups (P < 0.001). There was also a significant reduction in clot weights between these groups. Compared with controls, there were no significant differences in the residual DVT in the SNAC-only (6 of 6), OHEP-only (9 of 9), or SC HEP (8 of 10) groups. Combination OHEP/SNAC was as effective in the resolution of the clot and reducing clot weight as LMWH. The aPTT levels in the OHEP/SNAC group peaked at 30 minutes and were significantly higher than in all other groups (P < 0.01). Anti-Xa levels were elevated at 15 minutes after dosing in the OHEP/SNAC group and remained significantly elevated at 4 hours (P < 0.001). Conclusions - OHEP combined with a novel carrier agent (SNAC) successfully treated DVT in this rat model.