New Research Clinical trials on rabbits

Since only tPA has been approved by the FDA, the translational power of the RSCEM is relatively unknown, but there are numerous new data to support our contention that the RSCEM should be used for translational research. Recently, the free radical scavenger NXY-059 was tested in multiple clinical trials based upon significant efficacy in rodent and marmoset models of stroke [–]. The following section will evaluate the preclinical and clinical results obtained with the hydrophilic nitrone-free radical scavenger NXY-059 and compare them to hydrophobic free radical scavenger edaravone, a compound that is used in Japan to treat AIS.

NXY-059

Centaur Pharmaceuticals, Renovis Inc., and Astra-Zeneca Inc. attempted to develop disodium-[(tert-butylimino)methyl]benzene-1, 3-disulfonate-N-oxide (NXY-059), a water-soluble lead nitrone . The rationale for choosing this compound is not clear since the addition of two sulfonyl groups significantly reduced the ability of the drug to effectively cross the BBB [, ], thus limiting its activity outside of the vascular compartment .

The impetus for rapid development of NXY-059 was based upon Astra-Zeneca-supported preclinical evidence from rodent studies and a marmoset permanent MCAO stroke model (reviewed in [, ]). In rats with transient focal ischemia produced by occlusion of the MCA, neuroprotection measured by improved behavioral scores could be observed if NXY-059 was administered up to 6 h following occlusion [, ]. In the primate permanent MCA occlusion model, NXY-059 reduced spatial perception neglect and decreased gray and white matter damage , with a therapeutic window of 4 h when the drug was infused for 24-48 h. However, ischemia produced by invasive permanent occlusion of the MCA (i.e., method from Marshall et al. [–]: “After turning a large cranial flap and opening the dura over the right lateral frontal cortex, the right M1 segment of the MCA, 2 mm medial to the olfactory tract, was permanently occluded. The vessel was both occluded and bisected by electrocoagulation at this site”) does not mimic the clinical presentation of embolic stroke.