Incidence of cerebral hemorrhage after treatment with tissue plasminogen activator or streptokinase following embolic stroke in rabbits [corrected].

Han

Salgado

et al. 2008

Background and Purpose-Transcranial near-infrared laser therapy (TLT) is currently under investigation in a pivotal clinical trial that excludes thrombolytic therapy. To determine if combining tissue plasminogen activator (tPA; Alteplase) and TLT is safe, this study assessed the safety profile of TLT administered alone and in combination with Alteplase. The purpose for this study is to determine if the combination of TLT and thrombolysis should be investigated further in a human clinical trial. Methods-We determined whether postembolization treatment with TLT in the absence or presence of tPA would affect measures of hemorrhage or survival after large clot embolism-induced strokes in New Zealand white rabbits. Results-TLT did not significantly alter hemorrhage incidence after embolization, but there was a trend for a modest reduction of hemorrhage volume (by 65%) in the TLT-treated group compared with controls. Intravenous administration of tPA, using an optimized dosing regimen, significantly increased hemorrhage incidence by 160%. The tPA-induced increase in hemorrhage incidence was not significantly affected by TLT, although there was a 30% decrease in hemorrhage incidence in combination-treated rabbits. There was no effect of TLT on hemorrhage volume measured in tPA-treated rabbits and no effect of any treatment on 24-hour survival rate. Conclusion-In the embolism model, TLT administration did not affect the tPA-induced increase in hemorrhage incidence.TLT may be administered safely either alone or in combination with tPA because neither treatment affected hemorrhage incidence or volume. Our results support the study of TLT in combination with Alteplase in patients with stroke.

Section: Discussionmentioning

confidence: 80%

Safety Profile of Transcranial Near-Infrared Laser Therapy Administered in Combination With Thrombolytic Therapy to Embolized Rabbits

Han

Salgado

et al. 2008

“…We estimated thrombolytic efficacy by calculating the percentage of animals in each treatment group that had Ͻ20% of the total recovered radiolabel in the surface vessels of the right hemisphere of the brain at postmortem. 18 Thrombolysis was found in 49% of the tPA-treated rabbits (Figure 4), 5% of the tPA/control-treated rabbits, and 35% of the combination drug-treated rabbits. There was no measurable thrombolysis in the BB-94 -treated group.…”

Section: Thrombolysis Ratementioning

confidence: 96%

Metalloproteinase Inhibition Reduces Thrombolytic (Tissue Plasminogen Activator)–Induced Hemorrhage After Thromboembolic Stroke

Chapman

Zivin

2000

315

260

Background and Purpose-A potentially dangerous side effect associated with tissue plasminogen activator (tPA) use is cerebral hemorrhage. We have focused on developing drugs that could be administered with tPA to reduce the rate of hemorrhage. Since recent studies suggest that various matrix metalloproteinases (MMPs) are important in tumor necrosis factor-␣ production and membrane and vessel remodeling after ischemia, we investigated whether MMP inhibition affected the rate of hemorrhage and infarct production in the absence or presence of tPA treatment. Methods-We occluded the middle cerebral artery of New Zealand White rabbits with radiolabeled blood clots. Five minutes after embolization, we administered either the MMP inhibitor BB-94 (30 mg/kg SC) or its vehicle. Additional groups received BB-94 or vehicle in combination with tPA, administered 60 minutes after embolization (3.3 mg/kg tPA). After 48 hours, the rabbits were killed and brains were removed, immersion fixed for 1 week in 4% paraformaldehyde, and then cut into 5-mm coronal sections that were examined for the presence of hemorrhage, infarcts, and recanalization. Results-Hemorrhage after embolic stroke was detected in 24% of the control group. tPA induced macroscopically visible hemorrhage in 77% of the tPA-treated group. The rabbits treated with BB-94 had an 18% incidence of hemorrhage (PϾ0.05 compared with control). However, when the combination of BB-94 and tPA was administered to rabbits, there was only a 41% incidence of hemorrhage (compared with 77% in the tPA group; PϽ0.05). Both tPA and BB-94/tPA were similarly effective at lysing clots, at 49% and 35% (PϽ0.05), respectively, compared with the 5% rate of lysis in the control group. There was a trend for a reduction in the number of infarcts, but it did not reach statistical significance. Conclusions-Our data suggest that MMP inhibition attenuates mechanisms involved in tPA-induced hemorrhage. This novel form of combination therapy may show promise as a treatment strategy for acute stroke. (Stroke. 2000;31:3034-3040.)Key Words: cytokines Ⅲ intracerebral hemorrhage Ⅲ ischemia Ⅲ matrix metalloproteinases Ⅲ membranes Ⅲ neuroprotection Ⅲ tumor necrosis factor T hrombolysis is now gaining increasing acceptance for acute stroke management; however, only a small subset of potentially eligible patients are being treated with tissue plasminogen activator (tPA). 1-3 Overall, tPA is quite beneficial, even though there is a small window of opportunity for treatment and a potentially dangerous side effect of hemorrhages. 2,4 -6 A series of trials have shown that thrombolytics alone have limited efficacy, 7 suggesting that additional treatment strategies are needed. Nevertheless, the finding that at least one acute therapy is effective in reducing neurological damage was an important proof of concept. Even though tPA is efficacious, there is one major shortcoming to the drug. tPA significantly increases the intracerebral hemorrhage (ICH) rate in patients approximately 10 times greater than that observed in...

“…This success rate corresponds well with other studies involving this model. 3,4,14,17 Hemorrhage Rate, Types of Hemorrhage, and Hemorrhage Volume Tables 2 and 3 present the hemorrhage rate for the 6 different treatment groups included in this study. There was a statistically significant difference in hemorrhage rates (Table 2) between the vehicle/vehicle group and the vehicle/tPA group.…”

Section: Stroke Success Ratementioning

confidence: 99%

The Nonpeptide Glycoprotein IIb/IIIa Platelet Receptor Antagonist SM-20302 Reduces Tissue Plasminogen Activator–Induced Intracerebral Hemorrhage After Thromboembolic Stroke

Araujo²,

Song³

et al. 2002

Background and Purpose-Platelet activation and deposition in brain microvessels appear to be key events in the pathogenesis of ischemia-induced neuronal degeneration and behavioral deficits. It has been hypothesized that activated platelets in combination with polymorphonuclear leukocytes and fibrin may play a role in vessel reocclusion leading to the "no-reflow" phenomenon after administration of the thrombolytic tissue plasminogen activator (tPA). We studied the effects of the novel glycoprotein IIb/IIIa platelet receptor antagonist SM-20302 when administered in combination with tPA on infarct and hemorrhage rate and volume to determine whether activated platelets are involved in either infarct or hemorrhage generation after a thromboembolic stroke. Methods-One hundred thirty-two male New Zealand White rabbits were included in the present study. Rabbits were embolized by injecting a blood clot into the middle cerebral artery via a catheter. Five or 65 minutes after embolization, SM-20302 (5 mg/kg) was infused intravenously. In drug combination studies, tPA was infused intravenously for 30 minutes starting 60 minutes after embolization, and SM-20302 was administered 5 or 65 minutes after embolization. Postmortem analysis included assessment of hemorrhage, infarct size and location, and clot lysis. Results-In the vehicle control group, the hemorrhage rate after a thromboembolic stroke was 33%. There was a significant increase (109%) in the hemorrhage rate in the group of rabbits treated with the thrombolytic tPA. SM-20302 by itself did not significantly alter the embolism-induced hemorrhage rate when administered either 5 or 65 minutes after embolism. The SM-20302 groups had a 42% and 33% incidence of hemorrhage in the 5-and 65-minute groups, respectively. In groups treated with a combination of drugs, the SM-20302/tPA group had a 31% and 71% incidence of hemorrhage when SM-20302 was administered 5 and 65 minutes after embolization, respectively. SM-20302 in combination with tPA also significantly increased infarct rate, but not hemorrhage or infarct volume. Conclusions-This study suggests that treatment of thromboembolic stroke with the combination of a platelet inhibitor and tPA may have a beneficial outcome on the basis of the following: First, acute administration of SM-20302 did not significantly increase hemorrhage rate. Second, SM-20302 in combination with tPA significantly reduced tPA-induced intracerebral hemorrhage. Third, there appears to be a specific window of opportunity when a platelet inhibitor must be administered to produce a beneficial effect. Overall, on the basis of our results, we hypothesize that the increased rate of intracerebral hemorrhage observed after tPA administration may be partly due to increased reocclusion of cerebral vessels following lysis of the emboli and that reocclusion can be controlled by administration of a platelet inhibitor.