Effects of the spin trap agent disodium- [tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (generic NXY-059) on intracerebral hemorrhage in a rabbit Large clot embolic stroke model: combination studies with tissue plasminogen activator.
OBJECTIVE
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 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% (n=23), and this was increased by 67% if tPA was administered (n=15). The rabbits treated with NXY-059G in the absence of tPA had a 79% incidence of hemorrhage (n=19), 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 (n=15). There was a decrease of hemorrhage volume in the NXY-059G+tPA 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.
Lapchak
Paul A
PA
Department of Neuroscience, University of California at San Diego, La Jolla 92093-0624, USA. plapchak@ucsd.edu
Araujo
Dalia M
DM
Song
Donghuan
D
Wei
Jiandong
J
Purdy
Robert
R
Zivin
Justin A
JA
D000818:Animals; D001557:Benzenesulfonates; D001786:Blood Glucose / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects; D020766:Intracranial Embolism / Q000150:complications* / Q000473:pathology; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009589:Nitrogen Oxides / Q000008:administration & dosage* / Q000009:adverse effects; D011817:Rabbits; D020521:Stroke / Q000150:complications* / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
D001557:Benzenesulfonates; D001786:Blood Glucose; D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; C120851:disufenton sodium; D010959:Tissue Plasminogen Activator