Effect of NXY-059 on infarct volume after transient or permanent middle cerebral artery occlusion in the rat; studies on dose, plasma concentration and therapeutic time window.
1. The efficacy of the free radical trapping agent NXY-059 in reducing the infarct volume following both transient and permanent focal ischaemia has been examined in rats. 2. In the transient ischaemia model, rats were subjected to a 2 h occlusion of the middle cerebral artery (MCA). Intravenous infusion of NXY-059 (1, 10 and 30 mg kg(-1) h) for 21.75 h starting 2.25 h after the occlusion, produced a dose-dependent decrease in both neurological impairment and the histologically measured infarct volume (a mean 59% decrease at 10 mg kg(-1) h). 3. In the permanent ischaemia model, animals were injected (s.c.) with a loading dose of NXY-059 of 32.5, 53.8 or 75.4 mg kg(-1) and osmotic minipumps were implanted which had been primed to deliver respectively 30, 50 or 70 mg kg(-1) h. When treatment was initiated 5 min after MCA occlusion there was a dose dependent protection of both cortical and sub-cortical tissue (cortex: 63% at the mid-range dose). Protection was related linearly to plasma concentration (plasma unbound NXY-059 concentration at 1 h: 37+/-16 micromol l(-1) at the mid-range dose). 4. When the mid range dose was administered between 5 min - 4 h after MCA occlusion, a marked and statistically significant protection was seen at all time points (44% protection in cortex at 4 h). 5. These data demonstrate the substantial neuroprotective efficacy of NXY-059 at plasma concentrations that can be achieved clinically and indicate that NXY-059 also has a therapeutic window of opportunity that is clinically relevant.
Sydserff
S G
SG
AstraZeneca R&D Wilmington, Wilmington, Delaware, DE 19850-5437, USA.
Borelli
A R
AR
Green
A R
AR
Cross
A J
AJ
D000279:Administration, Cutaneous; D000818:Animals; D001557:Benzenesulfonates; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology*; D015918:Infusion Pumps, Implantable; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018696:Neuroprotective Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009589:Nitrogen Oxides / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D011921:Rats, Inbred WKY
D001557:Benzenesulfonates; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; C120851:disufenton sodium