Papers for discussion by Benjamin Hoehn and Geoffrey Meissner:
Davis, S. M., Lees, K. R., Albers, G. W., Diener, H. C., Markabi, S.,
Karlsson, G., and Norris, J. Selfotel in acute ischemic
stroke : possible neurotoxic effects of an NMDA antagonist. Stroke
31: 347-354, 2000.
Abstract: BACKGROUND AND PURPOSE: Based on neuroprotective efficacy
in animal models, we evaluated the N-methyl D-aspartate antagonist Selfotel
in patients with ischemic stroke, after doses up to 1.5 mg/kg were shown
to be safe in phase 1 and phase 2a studies. METHODS: Two pivotal phase
3 ischemic stroke trials tested the hypothesis, by double-blind, randomized,
placebo-controlled parallel design, that a single intravenous 1.5 mg/kg
dose of Selfotel, administered within 6 hours of stroke onset, would improve
functional outcome at 90 days, defined as the proportion of patients achieving
a Barthel Index score of >/=60. The trials were performed in patients aged
40 to 85 years with acute ischemic hemispheric stroke and a motor deficit.
RESULTS: The 2 trials were suspended on advice of the independent Data
Safety Monitoring Board because of an imbalance in mortality after a total
enrollment of 567 patients. The groups were well matched for initial stroke
severity and time from stroke onset to therapy. There was no difference
in the 90-day mortality rate, with 62 deaths (22%) in the Selfotel group
and 49 (17%) in the placebo-treated group (RR=1.3; 95% CI 0.92 to 1.83;
P=0.15). However, early mortality was higher in the Selfotel-treated patients
(day 30: 54 of 280 versus 37 of 286; P=0.05). In patients with severe stroke,
mortality imbalance was significant throughout the trial (P=0.05). CONCLUSIONS:
Selfotel was not an effective treatment for acute ischemic stroke. Furthermore,
a trend toward increased mortality, particularly within the first 30 days
and in patients with severe stroke, suggests that the drug might have a
neurotoxic effect in brain ischemia
Perez-Pinzon, M. A., Maier, C. M., Yoon, E. J., Sun, G. H., Giffard,
R. G., and Steinberg, G. K. Correlation of CGS 19755 neuroprotection against
in vitro excitotoxicity and focal cerebral ischemia. J.Cereb.Blood Flow
Metab 15: 865-876, 1995.
Abstract: The in vivo neuroprotective effect and brain levels of cis-4-
phosphonomethyl-2-piperidine carboxylic acid (CGS 19755), a competitive
N-methyl-D-aspartate (NMDA) antagonist, were compared with its in vitro
neuroprotective effects. The dose-response for in vitro neuroprotection
against both NMDA toxicity and combined oxygen-glucose deprivation (OGD)
was determined in murine neocortical cultures. Primary cultures of neocortical
cells from feta mice were injured by exposure to 500 microM NMDA for 10
min or to OGD for 45 min. The effect of CGS 19755 in both injury paradigms
was assessed morphologically and quantitated by determination of lactate
dehydrogenase release. Near complete neuroprotection was found at high
doses of CGS 19755. The ED50 for protection against NMDA toxicity was 25.4
micro M, and against OGD the ED50 was 15.2 microM. For the in vivo paradigm
rabbits underwent 2 h of left internal carotid, anterior cerebral, and
middle cerebral artery occlusion followed by 4 h reperfusion; ischemic
injury was assessed by magnetic resonance imaging and histopathology. The
rabbits were treated with 40 mg/kg i.v. CGS 19755 or saline 10 min after
arterial occlusion. CSF and brain levels of CGS 19755 were 12 microM and
5 microM, respectively, at 1 h, 6 microM and 5 microM at 2 h, and 13 microM
and 7 microM at 4 h. These levels were neuroprotective in this model, reducing
cortical ischemic edema by 48% and ischemic neuronal damage by 76%. These
results suggest that a single i.v. dose penetrates the blood- brain barrier,
attaining sustained neuroprotective levels that are in the range for in
vitro neuroprotection