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.

Abstract

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 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.

• Authors: Paul A Lapchak, Dalia M Araujo, Donghuan Song, Jiandong Wei, Robert Purdy, Justin A Zivin
• Journal: Stroke (Stroke) Vol. 33 Issue 6 Pg. 1665-70 (Jun 2002) ISSN: 1524-4628 [Electronic] United States
• PMID: 12053009 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Benzenesulfonates
• Blood Glucose
• Fibrinolytic Agents
• Neuroprotective Agents
• Nitrogen Oxides
• disufenton sodium
• Tissue Plasminogen Activator

Topics

• Animals
• Benzenesulfonates
• Blood Glucose (drug effects)
• Body Temperature (drug effects)
• Cerebral Hemorrhage (etiology, pathology, prevention & control)
• Disease Models, Animal
• Drug Therapy, Combination
• Fibrinolytic Agents (administration & dosage, adverse effects)
• Intracranial Embolism (complications, pathology)
• Male
• Neuroprotective Agents (administration & dosage)
• Nitrogen Oxides (administration & dosage, adverse effects)
• Rabbits
• Stroke (complications, pathology)
• Tissue Plasminogen Activator (administration & dosage, adverse effects)
• Treatment Outcome