Antithrombotic Activity of Argatroban in Experimental Thrombosis in the Rabbit

Abstract

Argatroban was evaluated in three models of thrombosis in the rabbit: the Wessler model (thromboplastin plus stasis of the left jugular vein), an arteriovenous shunt model, and a model of arterial thrombosis induced by endothelial and intimal damage of the left femoral artery. Calcium heparin was used as a comparator. Both substances inhibited thrombus formation in the Wessler model with ID50 values of 0.32 and 0.16 mg/kg intravenous bolus for argatroban and heparin respectively, with similar changes in thrombin time (4 to 5 times control) and activated partial thromboplastin time (APTT) (1.6 to 2.1 times control) for both substances at antithrombotic doses. The ID50 values of both substances were 2.4 micrograms/kg/min (argatroban) and 0.5 microgram/kg/min (heparin). When they were administered by continuous infusion, no significant effects on the APTT were noted. In the arteriovenous shunt, the ID50 values for argatroban and heparin (respectively) were 0.16 and 0.07 mg/kg intravenous bolus, and 4.5 and 2.8 micrograms/kg/min intravenous infusion. Vessel clamping followed immediately by electrical stimulation (5 mA direct current, 5 minutes) of the left femoral artery leads to the formation of an occlusive thrombus approximately 30 minutes after clamping. Argatroban infused for 60 minutes before the vascular lesion and throughout the 90 minute observation period led to a dose-dependent delay in arterial occlusion with significant effects seen at 5 micrograms/kg/min with five of eight animals showing normal femoral blood flow at 90 minutes postlesion at 20 micrograms/kg/min; no significant increases (Dunnett's test) in APTT were noted with argatroban. Heparin was without effect even at 40 micrograms/kg/min, despite an eight-fold increase in APTT at 20 micrograms/kg/min and values of more than 300 seconds at 40 micrograms/kg/min. Thus, in models of arterial but not venous thrombosis, argatroban is a more potent antithrombotic agent than heparin on a weight basis, with antithrombotic effects at a much lower degree of systemic anticoagulation.

Activity of a Sub-cutaneously Administered Novel Mixed Micellar Formulation of Argatroban in Rat and Rabbit Models of Venous Thrombosis

“…The mixed micellar formulation of argatroban was also active in the rabbit Wessler model when administered 30 min prior to thrombus induction with 50 and 73% inhibition of thrombus formation obtained after 1 and 2 mg/kg s. c. The choice of the administration time was based on the time course of the anticoagulant effect observed with mixed micellar argatroban in this species (15). We have previously shown that argatroban in the absence of mixed micelles is active in this model when given as an i. v. bolus 10 min prior to thrombus induction (10). This in itself is not surprising.…”

“…Argatroban ((2R,4R)4-methyl-{N 2 -[(3-methyl-1, 2, 3, 4, tetrahydro-8-quinolyl) sulphonyl]-L-arginyl}-2-piperidinecarboxylic acid monohydrate) is a synthetic thrombin inhibitor, which selectively inhibits the amidolytic activity of thrombin via an interaction with the active site (3,4). Argatroban is active against clot-associated thrombin (5,6), and has been shown to have antithrombotic activity in a wide variety of animal models of thrombosis when given as an intravenous infusion (7)(8)(9)(10)(11)(12). However, the solubility of argatroban in aqueous solvents (< 1 mg/ml) precludes its use for subcutaneous administration in the prevention of deep vein thrombosis due to the limitations of the volumes that can be administered by this route.…”

In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939—an oral, direct Factor Xa inhibitor

“…Rat venous stasis model Thrombus formation was induced in anesthetized rats ( n = 10 per dose group) as described previously, with minor modifications [8]. The abdominal vena cava was exposed and two loose sutures (8–10 mm apart) were placed below the left renal venous branch.…”

“…Arteriovenous shunt model in rats and rabbits An arteriovenous (AV) shunt in anesthetized rats and rabbits was performed as described previously, with minor modifications [8–10]. The right common carotid artery and the left jugular vein were cannulated with two 100‐mm‐long, saline‐filled catheters.…”

Anticoagulant Activity and Pharmacokinetic Properties of a Sub-cutaneously Administered Mixed Micellar Formulation of Argatroban in Experimental Animals

“…Argatroban ((2R,4R)4-methyl-{N 2 -[(3-methyl-1,2,3,4, tetrahydro-8-quinolyl) sulphonyl]-L-arginyl}-2-piperidinecarboxylic acid monohydrate) is a synthetic thrombin inhibitor, which selectively inhibits the amidolytic activity of thrombin via an interaction with the active site (5,6). Argatroban is active against clot-associated thrombin (7,8), and has been shown to have antithrombotic activity in a wide variety of animal models of thrombosis when given as an intravenous infusion (9)(10)(11)(12)(13)(14). However, the solubility of argatroban in aqueous solvents (1 mg/ml) precludes its use for sub-cutaneous administration in the prevention of deep vein thrombosis due to the limitations of the volumes that can be administered by this route.…”