Synthetic, organic compound vepoloxamer (P-188) potentiates tissue plasminogen activator.

OBJECTIVE: Poloxamer-188 is a synthetic, organic compound that acts by binding hydrophobic pockets on damaged lipid bilayers in the circulation. P-188 reduces blood viscosity and confers anti-inflammatory and cytoprotective effects. Vepoloxamer (Mast Therapeutics, San Diego, Calif) is a purified version of this compound that has limited side effects. The aim of this study was to investigate drug interactions between vepoloxamer and heparin and tissue plasminogen activator (tPA).

METHODS: An experimental rat tail transection model was used to study vepoloxamer's interaction with heparin. Sprague-Dawley rats were divided into saline (1 mL/kg; group 1) or vepoloxamer (25 mg/kg; group 2) treatment groups. The rats were then subjected to saline (n = 6), low-dose heparin (125 μg/kg; n = 6), or high-dose heparin (250 μg/kg; n = 6). After 5 minutes, the distal 2 mm of the tail was transected, and time to clot formation was measured as bleeding time. A rat internal jugular vein thrombosis model was used to assess vepoloxamer's interaction with tPA. Sprague-Dawley rats were divided into saline (1 mL/kg; group 1) or vepoloxamer (25 mg/kg; group 2) treatment groups. After internal jugular vein thrombosis, rats were treated with saline (n = 6), systemic low-dose tPA (0.5 mg/kg; n = 6), or systemic high-dose tPA (1.0 mg/kg; n = 6). Clot lysis was assessed using an ultrasound Doppler probe to detect blood flow. No flow up to 15 minutes was recorded as no lysis.

RESULTS: Interaction with heparin: Vepoloxamer by itself, without any heparin, increased tail bleeding time (10.3 vs 7.1 minutes; P = .001). Effects of heparin on tail bleeding time were enhanced by vepoloxamer at low dose (14.2 vs 6.2 minutes; P < .001). At high-dose heparin, vepoloxamer did not prolong bleeding time (17.8 vs 17.0 minutes). Interaction with tPA: No rat exhibited spontaneous clot lysis with either saline or vepoloxamer. The effect of tPA was facilitated by vepoloxamer at low dose, as more rats showed clot lysis (4/6 [66%]) compared with tPA alone, which showed no clot lysis (0/6), although statistical significance was not reached (P = .06). At high-dose tPA, vepoloxamer had no additional effects on clot lysis (5/6 [83% ] vs 4/6 [66%]).

CONCLUSIONS: Vepoloxamer alone modestly increased bleeding time. Vepoloxamer also increased bleeding time in rats treated with low-dose heparin but not with high-dose heparin. Vepoloxamer potentiated clot lysis in the setting of low-dose tPA.