Current Opinion in Investigational Drugs

22 Current Opinion in Investigational Drugs 2006 Vol 7 No 1
PBN has effective BBB penetration, but questions have
remained about whether NXY-059 penetrates the BBB
sufficiently for it to have a central mechanism of action. In a coculture
of endothelial cells and primary astrocytes as a model of
the BBB, uptake of PBN was high, but uptake of S-PBN and
NXY-059 was not [26]. However, the permeability of BBB by
NXY-059 increased with increasing length of ischemia,
although there was no uptake into endothelial cells [26].
In addition to acting as a spin trap for free radicals, NXY-059
may be neuroprotective by inhibiting the release of
cytochrome C, a key initiator of apoptosis. Cytochrome C
levels increased during reperfusion after a 2-h occlusion of
the rat cerebral artery, and NXY-059 treatment prevented
this increase [27].
NXY-059: Clinical studies
NXY-059 was well tolerated by healthy volunteers at an
infusion rate of 1.1 to 1.5 mg/kg/h for up to 72 h [28].
Excretion of NXY-059 occurred via the renal route and, in
individuals with renal impairment, plasma clearance was
directly proportional to glomerular filtration rate [29].
NXY-059 usually has a half-life of 2 to 4 h, but this was
extended to 10 to 12 h in individuals with moderate and
severe renal impairment [29]. Consequently, in patients with
renal impairment, the dose of NXY-059 needs to be adjusted
on the basis of creatinine clearance [29].
When administered to patients within 24 h of stroke,
NXY-059 (250 mg over 1 h, followed by 85 mg/h for 71 h, or
500 mg over 1 h, followed by 170 mg/h for 71 h) was well
tolerated [30]. In this small study of tolerability, the clinical
outcome scores were collected for descriptive purposes only,
and no improvement in clinical outcome was demonstrated
for these doses, possibly because the study was not designed
to measure efficacy [30]. Furthermore, the doses of NXY-059
used gave plasma levels (25 and 40 µmol/l) that were lower
than those associated with neuroprotection in animal studies
(200 µmol/l) [30], and thus may have been too low to be
efficacious. Subsequently, higher doses of NXY-059 were
tested in patients within 24 h of stroke onset (915 mg over 1
h, followed by 420 mg/h for 71 h, or 1820 mg over 1 h,
followed by 844 mg/h for 71 h), with the higher dose
achieving a steady-state plasma level of 260 µmol/l, which
Figure 2. The structures of STAZN and lipid- and water-soluble AZNs.
C
H 3
C
H 3
C
H 3
CH 3
N +
CH 3
O
C
H 3
CH 3
_
O
STAZN
(University of Miami)
CH 3
N +
C
H 3
CH 3
CH 3
CH 3
C
H 3
was above that associated with therapeutic benefit in
animals [31]. Furthermore, the higher doses were also well
tolerated [31]. Although these studies were not conducted to
determine effectiveness, at day 30, 58% of the 38 patients
administered the 844-mg dose of NXY-059 were assessed as
good on the Barthel Index Score, compared with 47% of
patients from the placebo group [31].
NXY-059 (as Cerovive) is currently undergoing phase III clinical
trials for the treatment of ischemic stroke. The Stroke Acute
Ischemia NXY Treatment (SAINT-1) trial is evaluating the effect
of NXY-059 on disability and neurological recovery in acute
ischemic stroke patients [32]. The Independent Data and Safety
Monitoring Board that reviewed the outcome after a 3-month
follow-up in 1000 patients recommended that the trial be
continued [32]. In May 2005, AstraZeneca announced that the
first analysis of data from the SAINT-1 trial in 1700 patients
showed a significant reduction (p = 0.038) for patients treated
with NXY-059 compared with those receiving placebo, based
on the Modified Rankin Scale for neurological impairment [33].
However, there was no significant difference between
NXY-059 and placebo on the National Institutes of Health
Stroke Scale [33].
Second-generation nitrones
Azulenyl nitrones
Azulenyl nitrones (AZNs) are a class of compounds that can
be synthesized from the natural product guaiazulene [34]
and possess oxidation potentials far lower than that of firstgeneration
nitrones [35•]. For example, the nitronylsubstituted
hydrocarbon stilbazulenyl nitrone (STAZN,
University of Miami; Figure 2) is 300-fold more potent at
inhibiting the free radical-mediated aerobic peroxidation of
cumene than PBN or NXY-059 [36•]. Furthermore, because
STAZN is lipid soluble, it is likely to cross the BBB.
STAZN has neuroprotective activity in a rat model of
traumatic brain injury. Anesthetized rats were subjected to a
right parietoccipital parasagittal fluid-percussion injury, and
neurological status was evaluated on days 1, 2 and 7 [37•]. At a
dose of 30 mg/kg, when administered 5 min and 4 h after the
trauma, STAZN improved neurological scores on days 2 and
7 compared with vehicle [37•]. The mean contusion area was
CH 3
C
H 3
_
O
CH 3
N +
O
CH3 CH3 H
O
CH 3
C
H 3
CH 3
C
H 3
_
O
CH 3
N +
H
CH3 CH3 C
H 3
H
N +
O
CH 3
lipid-soluble AZN water-soluble AZN
CH 3