Abstract TP283: Hemorrhagic Risk Assessment of DS-1040 in a Cerebral Ischemia/reperfusion Model of Rats With Hypertension and Hyperglycemia

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Abstract

Introduction: DS-1040 is a novel inhibitor of the activated thrombin-activatable fibrinolysis inhibitor (TAFIa) and is in clinical development for the treatment of acute ischemic stroke. The objectives of this study were to establish a tissue plasminogen activator (tPA)-sensitive cerebral hemorrhage model and to assess the hemorrhagic risk of DS-1040.

Methods: After glucose administration (i.p.), male SHR/Izm rats were subjected to middle cerebral artery occlusion (MCAO) using an intraluminal monofilament.

Establishment of tPA-sensitive model: Rats were subjected to MCAO for 1, 2, or 3 h followed by recanalization. tPA (10 mg/kg) or saline (control) was intravenously administered by 10% bolus and 90% infusion just before recanalization. At 2.5 h after recanalization, cerebral hemorrhage was quantified by measuring the excess hemoglobin in the ischemic hemisphere compared to the contralateral side.

Hemorrhagic risk assessment: Rats were subjected to MCAO for 3 h followed by recanalization. At 135 min after MCAO, saline (control) and DS-1040 (30 mg/kg) were intravenously injected as bolus. The dosage of DS-1040 was set to achieve full inhibition of TAFIa. As a positive control, tPA (7 mg/kg) was intravenously administered by 10% bolus and 90% infusion at 5 min before recanalization. The excess hemoglobin was determined at 1 h after recanalization.

Results: Establishment of tPA-sensitive model: Excess hemoglobin in the tPA group significantly increased in animals subjected to 2 and 3-h MCA occlusion compared to each corresponding control group.

Hemorrhagic risk assessment: In the rt-PA group, excess hemoglobin was significantly increased (63.03 ± 8.38 mg/dL, mean ± SE) compared to the control group (38.74 ± 2.10 mg/dL). In contrast, excess hemoglobin in the DS-1040 group was 33.21 ± 3.28 mg/dL.

Conclusions: Using hypertensive rats with transient hyperglycemia, we have established a tPA-sensitive cerebral hemorrhage model. DS-1040 did not significantly increase the cerebral hemorrhage compared to the control. These data suggest DS-1040 has the potential to be a thrombolytic enhancer with low risk of cerebral hemorrhage.

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