Intravenous administration of a GPIIb/IIIa receptor antagonist extends the therapeutic window of intra-arterial tenecteplase-tissue plasminogen activator in a rat stroke model.

Abstract

BACKGROUND AND PURPOSE:

Occlusion of the middle cerebral artery triggers platelet accumulation at the site of occlusion and in downstream microvessels. The platelet-induced secondary thrombosis promotes the progressive development of ischemic brain damage and contributes to the resistance to thrombolysis and to the tight 3-hour therapeutic window. We tested the hypothesis that combination of intravenous (IV) administration of a GPIIb/IIIa receptor antagonist, 7E3 F(ab')2, with intra-arterial (IA) administration of tenecteplase-tissue plasminogen activator (TNK-tPA) increases the efficacy of thrombolysis and extends the therapeutic window of stroke.

METHODS:

Rats subjected to embolic stroke were treated with IV 7E3 F(ab')2 (6 mg/kg) in combination with IA or IV TNK-tPA (5 mg/kg) at 4 and 6 hours after onset of stroke, respectively; IA TNK-tPA (5 mg/kg) alone at 6 hours after onset of stroke; or saline at 6 hours after onset of stroke.

RESULTS:

The combination of IV 7E3 F(ab')2 (4 hours) and IA TNK-tPA (6 hours) significantly (P<0.05) reduced infarct volume and improved neurological functional deficits, which was associated with significant (P<0.05) reductions in the size of embolus at the origin of the occluded middle cerebral artery and in down-stream microvascular platelet and fibrin deposition, and enhanced microvascular patency compared with saline-treated rats. However, combination of IV 7E3 F(ab')2 (4 hours) and IV TNK-tPA (6 hours) or IA TNK-tPA (6 hours) alone failed to reduce infarct volume and improve neurological function compared with the saline-treated rats. No significant differences of the incidence of hemorrhage were detected among groups.

CONCLUSIONS:

These data suggest that the combination of IV 7E3 F(ab')2 (4 hours) and IA TNK-tPA (6 hours) extends the therapeutic window of thrombolysis to 6 hours after stroke.

• Authors: Li Zhang, Zheng Gang Zhang, Chunling Zhang, Rui Lan Zhang, Michael Chopp
• Journal: Stroke (Stroke) Vol. 35 Issue 12 Pg. 2890-5 (Dec 2004) ISSN: 1524-4628 [Electronic] United States
• PMID: 15514182 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Fibrinolytic Agents
• Platelet Aggregation Inhibitors
• Platelet Glycoprotein GPIIb-IIIa Complex
• Tissue Plasminogen Activator
• Tenecteplase

Topics

• Animals
• Cerebral Hemorrhage
• Disease Models, Animal
• Fibrinolytic Agents (administration & dosage)
• Infarction, Middle Cerebral Artery (drug therapy)
• Infusions, Intra-Arterial
• Infusions, Intravenous
• Male
• Platelet Aggregation Inhibitors (administration & dosage)
• Platelet Glycoprotein GPIIb-IIIa Complex (antagonists & inhibitors)
• Rats
• Rats, Wistar
• Stroke (drug therapy)
• Tenecteplase
• Thrombolytic Therapy
• Time Factors
• Tissue Plasminogen Activator (administration & dosage)