Background and Purpose-It has been proposed that the novel spin trap agent disodium-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (NXY-059) may be useful in the treatment of ischemic stroke. However, there is little information concerning the neuroprotective properties of NXY-059 when administered after an embolic stroke. Moreover, there is no information available concerning the combination of NXY-059 with the only Food and Drug Administration-approved pharmacological agent for the treatment of acute stroke, the thrombolytic tissue plasminogen activator (tPA). Thus, we determined the effects of NXY-059G, a generic form of NXY-059, on behavioral outcome after an embolic stroke when administered alone or in combination with tPA. Methods-Male New Zealand White rabbits were embolized by injecting a suspension of small blood clots into cerebral circulation via a carotid catheter. NXY-059G (100 mg/kg) was infused intravenously 5 minutes or 3 hours after embolization, whereas control rabbits received infusions of the saline vehicle. In tPA studies, the thrombolytic was administered intravenously starting 60 minutes or 3 hours after embolization (3.3 mg/kg). In combination studies, NXY-059G was given 5 minutes after embolization, followed by the administration of tPA beginning either 60 minutes or 3 hours after embolization. Behavioral analysis was conducted 24 hours after embolization. Results-In the vehicle control group, the ES 50 value (calculated as the amount of microclots [milligrams] that produce neurological dysfunction [impairment] in 50% of the rabbits within a specific treatment group) measured 24 hours after embolism was 1.04Ϯ0.31 mg, and this was increased by 153% to 2.54Ϯ0.72 mg if NXY-059G was administered beginning 5 minutes after embolization. However, if NXY-059G was administered beginning 3 hours after embolization, the ES 50 was 2.01Ϯ0.40 mg. The rabbits treated with tPA alone had an ES 50 of 2.64Ϯ0.66 or 0.63Ϯ0.35 mg if tPA administration started 60 minutes or 3 hours after embolization, respectively. If tPA was administered after NXY-059G (started at 5 minutes), the ES 50 values were 3.15Ϯ0.50 or 2.66Ϯ0.82 if tPA administration started 60 minutes or 3 hours after embolization, respectively. Conclusions-This study suggests that NXY-059G is neuroprotective and can increase behavioral ratings if administered early after an embolic stroke. In addition, the study shows that NXY-059G can be used in combination with tPA without negative side effects. The drug combination can improve behavioral function and increase ES 50 values. However, during the short time course of the behavioral analysis, the combination was not statistically better than either drug alone.

Background and Purpose-It has been proposed that the novel thrombolytic microplasmin may be useful in the treatment of ischemic stroke. In the present study the effects and safety profile of microplasmin were evaluated in 2 rabbit embolic stroke models that have been used successfully to develop tissue plasminogen activator (tPA) as the only Food and Drug Administration-approved treatment for stroke. The rabbit small clot embolic stroke model (RSCEM) and rabbit large clot embolic stroke model (RLCEM) were used to determine the potential neuroprotective properties and safety profile of microplasmin, respectively, after an embolic stroke. Methods-Rabbits were embolized by injecting small blood clots (RSCEM) or large blood clots (RLCEM) into the cerebral circulation. For the RSCEM, 126 rabbits were included, with behavioral analysis conducted 24 hours later, allowing for determination of the effective stroke dose (ES 50 ) or clot amount (milligrams) that produces severe neurological deficits in 50% of rabbits. For RLCEM safety study analysis, 47 rabbits were included, with postmortem analyses consisting of assessment of hemorrhage and infarct rate and size. In test animals microplasmin was infused intravenously 60 minutes after embolization, whereas control rabbits were given infusions of the saline/Plasma-Lyte vehicle with all assessments performed in a blinded fashion. Results-In the RSCEM, a drug is considered neuroprotective if it significantly increases the ES 50 compared with the vehicle-treated control group. The ES 50 of the vehicle-treated control group 24 hours after embolization was 1.36Ϯ0.42 mg (nϭ38). Microplasmin, infused starting 60 minutes after embolization, increased the ES 50 to 2.32Ϯ0.57 (nϭ21), 1.89Ϯ0.48 (nϭ21), 2.81Ϯ0.55 (nϭ22), and 1.89Ϯ0.28 mg (nϭ24) for the 1-, 2-, 4-, and 8-mg/kg doses, respectively. There was a statistically significant behavioral improvement in the 4-mg/kg dose arm (Pϭ0.040). The microplasmin dose of microplasmin that was statistically significant (4 mg/kg) was subsequently determined to be safe in the RLCEM because it did not increase the incidence of hemorrhages (56%) compared with vehicle-treated rabbits (63%), nor did it significantly alter hemorrhage volume, infarct rate, or infarct volume. Conclusions-The present study shows that microplasmin improves behavioral rating scores in the RSCEM when administered 60 minutes after embolization, at a dose that does not increase hemorrhages in the RLCEM. This is in contrast to tPA, which significantly enhances the hemorrhage rate in the RLCEM.

Background and Purpose-It has been proposed that the novel spin trap agent disodium-[(tertbutylimino)methyl]benzene-1,3-disulfonate N-oxide (NXY-059) may be useful in the treatment of ischemia and stroke.To date, there is little information concerning the safety of NXY-059 when administered in combination with the only Food and Drug Administration-approved pharmacological agent for the treatment of stroke, the thrombolytic tissue plasminogen activator (tPA). Thus, we determined the effects of NXY-059G, a generic form of NXY-059, on hemorrhage and infarct rate and volume when administered alone or in combination with tPA. In addition, we determined whether NXY-059G affected 2 physiological variables, blood glucose levels and body temperature. Methods-Male New Zealand White rabbits were embolized by injecting a large blood clot into the middle cerebral artery via a catheter. Five minutes after embolization, NXY-059G (100 mg/kg) was infused intravenously; control rabbits received infusions of saline, the vehicle required to solubilize NXY-059G. In tPA studies, the thrombolytic was administered intravenously starting 60 minutes after embolization (20% bolus injection/80% infusion over 30 minutes). Body temperature and blood glucose levels were measured throughout the study. Postmortem analysis included assessment of hemorrhage and infarct rate, size, and location. Results-In the vehicle control group, the hemorrhage rate after a thromboembolic stroke was 52% (nϭ23), and this was increased by 67% if tPA was administered (nϭ15). The rabbits treated with NXY-059G in the absence of tPA had a 79% incidence of hemorrhage (nϭ19), an increase of 52% over the control group. In the combination drug-treated groups, the NXY-059G/tPA group had a 47% incidence of hemorrhage (nϭ15). There was a decrease of hemorrhage volume in the NXY-059GϩtPA group compared with the other 3 groups included in the study. There was no significant effect of NXY-059G either alone or in combination with tPA on infarct rate or volume. NXY-059G did not significantly alter the physiological variables that were measured. Conclusions-This study suggests that NXY-059G may affect the integrity of the cerebral vasculature when administered immediately after an embolic stroke, as evidenced by an increase in hemorrhage rate. However, when NXY-059G is administered in combination with tPA, it may improve the safety of tPA by reducing the incidence of tPA-induced hemorrhage. The mechanism(s) involved in the NXY-059G-induced increase in hemorrhage rate and reduction of tPA-induced hemorrhage rate remains to be elucidated.