Ebselen in Acute Ischemic Stroke

A Placebo-Controlled, Double-blind Clinical Trial

Takenori Yamaguchi, MD; Keiji Sano, MD; Kintomo Takakura, MD; Isamu Saito, MD;
Yukito Shinohara, MD; Takao Asano, MD; Hajime Yasuhara, MD; for the Ebselen Study Group
Background and PurposeThe effect of ebselen, a seleno-organic compound with antioxidant activity through a glutathione
peroxidaselike action, on the outcome of acute ischemic stroke was evaluated in a multicenter, placebo-controlled,
double-blind clinical trial.
MethodsPatients diagnosed as having acute ischemic stroke who could receive drug treatment within 48 hours of stroke onset
were enrolled. Oral administration of ebselen granules suspended in water (150 mg BID) or placebo was started immediately after
admission and was continued for 2 weeks. The major end points were the Glasgow Outcome Scale scores at 1 month and 3
months after the start of treatment. The modified Mathew Scale and modified Barthel Index scores at 1 month and 3 months
were also studied as secondary outcome measures.
ResultsThree hundred two patients were enrolled in the trial. Intent-to-treat analysis of 300 patients (151 given ebselen and 149
given placebo) revealed that ebselen treatment achieved a significantly better outcome than placebo at 1 month (P5.023,
Wilcoxon rank sum test) but not at 3 months (P5.056, Wilcoxon rank sum test). The improvement was significant in patients
who started ebselen within 24 hours of stroke onset but not in those who started treatment after 24 hours. There was a
corresponding improvement in the modified Mathew Scale and modified Barthel Index scores.
ConclusionsEarly treatment with ebselen improved the outcome of acute ischemic stroke. Ebselen may be a promising
neuroprotective agent. (Stroke. 1998;29:12-17.)
Key Words: clinical trials n neuroprotection n stroke outcome

bselen, 2-phenyl-1,2-benzisoselenazol-3[2H]-one, is a lipid-soluble seleno-organic compound that potently inhibits

lipid peroxidation through a glutathione peroxidaselike action.1,2 Because it is active against membrane hydroperoxides
such as phospholipid hydroperoxide glutathione peroxidase
but not glutathione peroxidase,3 this agent effectively inhibits
both nonenzymatic4 and enzymatic5 (the lipoxygenase pathway
of the arachidonate cascade) lipid peroxidation in vitro. Since
the involvement of reactive oxygen intermediates in permanent brain damage due to ischemia (ie, infarction) has been
supported by several studies,6,7 ebselen has been suggested to
have the potential to protect the brain against ischemic insults.
It was previously reported that recirculation-induced edema as
well as postischemic hypoperfusion was markedly improved in
a cat model of prolonged middle cerebral artery occlusion8 and
that infarct size was reduced in rats with transient middle
cerebral artery occlusion by ebselen pretreatment.9 Ebselen also
significantly decreased cerebral edema and reduced infarct size
in rats with permanent middle cerebral artery occlusion by
postoperative treatment.10,11 These promising results prompted
us to investigate the clinical value of ebselen in patients with
acute ischemic stroke.

Subjects and Methods

Selection of Patients
Sixty-eight Japanese neurological and neurosurgical units (see Appendix) joined the trial. Eligible patients were those who were
diagnosed as having acute ischemic stroke including thrombosis and
embolism by the assessment of symptoms and by CT12 and who could
receive drug treatment within 48 hours of onset. Patients with the
following conditions were excluded from the trial: transient ischemic
attacks; pregnancy; surgery interfering with assessment of neurological
function; previous stroke with residual neurological impairment;
major cardiopulmonary, hepatic, renal, or metabolic disease; or
hemorrhagic stroke. This clinical protocol was approved by the
institutional review board of each study site.

Drug Administration
Informed consent was obtained from the patient or the nearest
relative. Patients were randomized to ebselen or placebo with the use
of separate randomization lists balanced for each participating center.
Treatment with ebselen or placebo (fine granules dispersed in water;
150 mg BID) was started within 48 hours after acute ischemic stroke
and was continued for 14 days. The oral route (a gastric tube was used
in patients with disturbance of consciousness) was selected for administration because ebselen is insoluble in water but is rapidly absorbed
from the gastrointestinal tract and maintains a stable plasma concentration. In previous clinical trials, this method of administration was

Received July 28, 1997; final revision received October 13, 1997; accepted October 13, 1997.
From the National Cardiovascular Center, Osaka (T.Y.); Fuji Brain Institute Hospital, Shizuoka (K.S.); Tokyo Womens Medical College, Tokyo (K.T.);
Kyorin University, School of Medicine, Tokyo (I.S.); Tokai University, School of Medicine, Kanagawa (Y.S.); Saitama Medical Center School, Saitama
(T.A.); and Showa University, School of Medicine, Tokyo (H.Y.) (Japan).
Correspondence to Takenori Yamaguchi, MD, Cerebrovascular Division, National Cardiovascular Center, 57-1, Fujishirodai, Suita-shi, Osaka 565, Japan.
1998 American Heart Association, Inc.

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Yamaguchi et al

GOS
ITT
LDA
PC

Selected Abbreviations and Acronyms

5 Glasgow Outcome Scale
5 intent to treat
5 low-density area
5 protocol compatible

well tolerated and did not cause vomiting or diarrhea. The dose of 300
mg/d was found to achieve a better outcome in the preceding phase
IIb trial, a double-blind dose-finding trial involving daily doses of 100,
200, 300, and 400 mg for 2 weeks (T.Y., unpublished data, 1993).

Clinical Management
Patients were managed according to the protocol of the attending
investigator with only minor restrictions. Hypervolemia (administration of albumin or dextran combined with intravenous fluid supplements) and 10% glycerol were used as routine prophylactic measures.
Concomitant treatment with calcium channel blockers such as nifedipine and nicardipine, warfarin, heparin, and aspirin was left to the
discretion of the attending investigator. Administration of ticlopidine,
urokinase, tissue plasminogen activator, and sodium ozagrel was
prohibited for the first 2 weeks.

Assessments and End Points

On admission a medical history was obtained, and general physical and
neurological examinations were performed. Patients were monitored
clinically throughout their hospital stay by assessment of blood
pressure, pulse rate, and neurological status, including the Glasgow
Coma Scale13 and the Japan Coma Scale,14 and by hematology and
biochemical blood tests.
Angiography on admission was not mandatory in this trial, and the
decision was left to the attending investigator. All patients were
required to undergo repeated CT scanning on completion of treatment (at approximately day 14) and at approximately day 30, in
addition to routine scans on admission, at approximately day 7, and on
exacerbation of neurological deficits. The LDAs on each CT were
classified as follows: none, small (a lacunar or small infarct ,2 cm),
multiple (multiple small infarcts), medium (between small and large,
involving one cerebral lobe), and large (an infarct covering the whole
territory of the anterior, middle, or posterior cerebral artery). The
major end points were the GOS15 scores at 1 month and 3 months
after the start of treatment. The outcome at each period was
categorized as follows: good recovery, moderate disability, severe
disability, survival but in a vegetative state, and death. Neurological
status was assessed by the modified Mathew Scale,16 and functional
status was assessed by the modified Barthel Index.17 The modified
Mathew Scale evaluates 13 neurological items with a maximal value of
100 and a minimal value of 0; a score from 0 to 34 was considered to
indicate severe impairment, 35 to 74 to indicate moderate impairment, and 75 to 100 to indicate mild impairment.16 A score of 100
indicates the absence of impairment. The modified Barthel Index
evaluates 10 activities of daily living with a maximal value of 100 and
a minimal value of 0; a score from 0 to 49 was considered to indicate
severe disability, 50 to 74 to indicate moderate disability, and 75 to
100 to indicate mild disability. A score of 100 indicates the absence of
disability. A detailed neurological assessment was done on enrollment
in the trial and again on day 7 as well as 2 weeks, 1 month, and 3
months after the acute stroke. A functional assessment was done at 1
and 3 months. The modified Mathew Scale and modified Barthel
Index scores at 1 and 3 months were studied as secondary outcome
measures. Patients who died before the 3-month assessment were
given the worst possible score for all outcomes. Before code opening,
the study review committee checked the uniformity and appropriateness of each judgment by reviewing the data for each patient.

Statistical Analysis
A previous phase IIb study, a double-blind dose-finding trial conducted between March 1992 and July 1993, showed that a good

13

outcome of GOS score (good recovery or moderate disability) was

achieved in approximately 47% of patients at 3 months by 300 mg/d
of ebselen. Since the estimated percentage of the placebo group
achieving such a score was approximately 35%, it was calculated that
a minimum of 260 patients was required for the trial to have an 80%
chance of detecting a 12% increase in the GOS. Comparison of
demographic data, clinical treatment, and clinical parameters between
the groups was done by the x2 test without continuity correction, the
Wilcoxon rank sum test, and the Students t test. The a-level used in
the comparison of study end points was .05 (two-tailed). The
dependence of drug efficacy on prognostic factors such as age, sex, and
the site of LDAs, as well as the relationships between the delay of
starting treatment and the GOS score, were assessed by appropriate
stratified analyses. The data obtained by these comparisons are
presented with nominal two-tailed probability values unadjusted for
multiplicity. Complete analysis was done on an ITT basis, and a PC
analysis was also performed for the major end points.

Results
Enrollment of Patients
Between June 1994 and December 1996, 302 patients were
enrolled in the trial (152 received ebselen and 150 received
placebo). Selection of patients for the ITT and PC analyses was
performed by the review committee before code opening, and
300 patients were subjected to ITT analysis. The other 2 patients
were excluded from ITT analysis because of a diagnosis of
subarachnoid hemorrhage (ebselen group) and transient ischemic
attacks (placebo group). Fifty-eight patients were excluded from
PC analysis because of the delay of starting treatment beyond 48
hours (n516); concomitant administration of ticlopidine (n58),
urokinase or tissue plasminogen activator (n520), barbiturate
(n51), or sodium ozagrel (n510); and incomplete test drug
administration (n53). Thus, 242 patients (118 in the ebselen and
124 in the placebo group) were subjected to PC analysis.

Equivalence of the Two Groups

A clinical profile of the patients subjected to ITT analysis is shown
in Table 1. Demographic variables showed no statistically significant differences between the ebselen and placebo groups. The
mean age was 65 years (range, 33 to 85 years) in the ebselen group
and 65 years (range, 22 to 85 years) in the placebo group, and
mean time from the onset of stroke to the start of treatment was
29.7 hours (range, 3 to 91 hours) in the ebselen group and 26.9
hours (range, 4 to 96 hours) in the placebo group (P5.106,
Students t test). Distribution of the baseline modified Mathew
Scale score in three categories, ,35 (severe impairment), #35 and
,75 (moderate impairment), and #75 (mild impairment), was
not statistically significant (P5.160, Wilcoxon test). The peak
systolic and diastolic blood pressures were similar in both groups
at all times. Administration of 10% glycerol was done in a similar
percentage of both groups (88 patients in the ebselen group and
90 in the placebo group). Mild hypervolemia was used in 44% and
49% of the ebselen and placebo groups, respectively. The use of
other drugs such as calcium channel blockers, heparin, warfarin,
and aspirin was also similar in both groups, employed in 15 and
14, 10 and 10, 2 and 7, and 2 and 1 patients of the ebselen and
placebo groups, respectively. Routine physical therapy was done
in 68% and 72% of the ebselen and placebo groups, respectively.

Effect of Ebselen on Outcome

Ten patients died in the ebselen group (6.6%), and 15 died in
the placebo group (10.0%), and therefore the overall mortality
rate was not significantly reduced (P5.288, x2 test).

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Effect of Ebselen in Acute Ischemic Stroke

14
TABLE 1.

Clinical Profile of the Ebselen and Placebo Groups

Characteristic

Ebselen (%)

Placebo (%)

Sex, M/F

99 (66)/52 (34)

90 (60)/59 (40)

#65

68 (45)

70 (47)

.65

83 (55)

79 (53)

71 (47)/61 (40)

74 (50)/62 (42)

19 (13)

13 (9)

77 (51)/70 (46)

66 (45)/79 (54)

4 (3)

2 (1)

53 (35)/61 (40)

50 (34)/54 (36)

32 (21)

37 (25)

None

56 (37)/7 (5)

59 (40)/6 (4)

Small

22 (15)/34 (23)

23 (15)/30 (20)

Multiple

23 (15)/31 (21)

24 (16)/35 (24)

Medium

36 (24)/50 (34)

25 (17)/38 (26)

Large

14 (9)/27 (18)

18 (12)/39 (26)

#1

61 (40)

67 (45)

#2

80 (53)

76 (51)

.2

10 (7)

6 (4)

29.7

26.9

70620

66620

,35 (severe)

15 (10)

18 (12)

$75 (mild)

70 (47)

58 (39)

Age, y

Stroke type
Thrombosis/embolism
Unclear
Site of LDAs (1)
Left/right
Left and right
Site of LDAs (2)
Perforating/cortical
Both regions
Size of LDAs (initial/final)

Start of treatment after onset, d

Mean time from onset to

treatment, h
Modified Mathew Scale on
admission (mean6SD)

Values in parentheses do not total 100% because of rounding.

The GOS scores obtained after 1 month and 3 months in the ITT
and PC analyses are shown in Fig 1. One patient in the placebo group
missed the 1-month evaluation because of early discharge from the
hospital but returned for the 3-month evaluation at the outpatient
clinic. Four patients (3 and 1 in the ebselen and placebo groups,
respectively), who were alive but not scored on outcome scale
because of incomplete drug administration or discharge from the
hospital before the assessment, were excluded from analysis. The
difference between the ebselen and placebo groups was statistically
significant at 1 month in both ITT analysis and PC analysis (P5.023
and P5.015, respectively, Wilcoxon rank sum test) but not at 3
months in both ITT analysis and PC analysis (P5.056 and P5.052,
respectively, Wilcoxon rank sum test). The percentage of patients
with a good recovery or a good outcome (defined as good recovery
or moderate disability) was always approximately 10% higher in the
ebselen group; the difference was statistically significant at 1 month
(P5.031 and P5.040, respectively, x2 test) but not at 3 months
(P5.075 and P5.142, respectively, x2 test) in the ITT analysis. PC
analysis also showed a significant difference between the groups in the
percentage of patients with a good recovery or a good outcome at 1
month (P5.029 and P5.026, respectively, x2 test) but not at 3
months (P5.050 and P5.213, respectively, x2 test). The GOS scores

were also analyzed in relation to the time of starting ebselen treatment

after the onset of stroke (within or after 24 hours) and the site of LDAs
shown by CT scanning on day 7 or 14 (perforator or cortical vessel
territories). The GOS scores of ITT patients who started ebselen
treatment .24 or #24 hours after the onset of stroke are shown in
Fig 2. There was a significant difference between the ebselen and
placebo groups for patients who received ebselen within 24 hours in
both ITT analysis (P5.038 at 1 month and P5.049 at 3 months,
Wilcoxon test) and PC analysis (P5.016 at 1 month and P5.027 at
3 months, Wilcoxon test; data not shown). However, there were no
significant differences when ebselen treatment was started after 24
hours in both ITT analysis (P5.385 at 1 month and P5.644 at 3
months, Wilcoxon test) and PC analysis (P5.390 at 1 month and
P5.715 at 3 months, Wilcoxon test; data not shown). In the stratified
analysis of the GOS scores in relation to the site of LDAs, there were
no statistically significant differences between the ebselen and placebo
groups for the patients with perforator infarcts in both ITT analysis
(P5.537 at 1 month and P5.979 at 3 months, Wilcoxon test) and
PC analysis (P5.693 at 1 month and P5.688 at 3 months, Wilcoxon
test). The overall outcome was nearly the same in both groups.
However, there were significant differences for patients with cortical
infarcts in both ITT analysis (P5.020 at 1 month and P5.039 at 3
months, Wilcoxon test) and PC analysis (P5.016 at 1 month and
P5.033 at 3 months, Wilcoxon test). A good recovery was significantly more common in the ebselen group than in the placebo group.
There were no significant differences in the baseline characteristics of
the patients, including the type of rehabilitation, between the two
groups in these stratified analyses.

Effect of Ebselen on Secondary

Outcome Measures
Changes of the modified Mathew Scale and modified Barthel Index
scores in ITT analysis are shown in Table 2. Three patients in the
ebselen group, who were alive but not scored on both outcome
scores because of incomplete drug administration or discharge from
hospital before the assessment, were excluded from analyses. Two
patients in the placebo group, who were alive but not scored on both
outcome scores because of discontinuation of drug administration
due to aggravation of neurological status, were excluded from the
analysis of modified Barthel Index. For the modified Mathew Scale,
scores at 2-week evaluation were also regarded as the scores of 1 and
3 months for these patients. In the analysis of both scores, the ebselen
group was found to have a higher proportion of patients with no or
mild impairment (range of scale, 75 to 100) and with no or mild
disability (range of scale, 75 to 100), respectively. These differences
reached statistical significance at 1 and 3 months. There was not a
significant difference between the ebselen and placebo groups in
baseline neurological impairment. Changes of neurological status,
functional status, and GOS scores of ITT patients with severe or
moderate impairment (,75, modified Mathew Scale) are shown in
Table 3. Ebselen treatment achieved a significant improvement in
each outcome measure. Thus, there was a corresponding improvement in both secondary outcome measures, as was the case with the
GOS score.

Clinical and Laboratory Events

The following complications and clinical events were respectively
observed in the ebselen and placebo groups: new cerebral infarction (5 [3%] and 6 [4%], P5.742), new hemorrhagic infarction

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Yamaguchi et al

15

Figure 1. GOS scores of ITT and PC

patients at 1 and 3 months.

(35 [23%] and 26 [17%], P5.218), gastrointestinal bleeding (5

[3%] and 6 [4%], P5.742), nausea/vomiting (2 [1%] and 5 [3%],
P5.244), and respiratory infection (11 [7%] and 26 [17%],
P5.007). The overall incidence of adverse reaction was slightly
higher in the ebselen group than in the placebo group (7.3%
versus 3.3%), but there was no significant difference between the
two groups (P5.127, x2 test). No significant changes in laboratory
data were noted. The causes of death (presumed or confirmed) in
the ebselen and placebo groups were as follows: recurrence/
deterioration of cerebral infarction (6 and 9), sepsis (1 and 0),
pneumonia (2 and 3), brain hemorrhage (0 and 1), acute myocardial infarction (0 and 1), gastrointestinal bleeding (1 and 0), and

pulmonary embolism (0 and 1). Ebselen therapy was not suspected to have contributed to the death of any patient.

Discussion
A number of studies have shown that oxidative stress (generation of active oxygen and lipid peroxidation) occurs within
ischemic brain tissue.6,7,18 Peroxidation of cell membrane phospholipids leads to an increase of intracellular free radicals when
the intrinsic antioxidant systems is jeopardized by an energy
crisis. Such oxidative stress has been suggested to aggravate
tissue damage primarily through impairment of the cerebral
microcirculation.6 Peroxidation of membrane phospholipids

Figure 2. GOS scores of ITT patients at

1 and 3 months who started ebselen
treatment #24 or .24 hours after stroke
onset.

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Effect of Ebselen in Acute Ischemic Stroke

16

TABLE 2. Modified Mathew Scale and Modified Barthel Index Scores in the
Ebselen and Placebo Groups
Modified Mathew Scale
Time
Pretreatment

1 mo

3 mo

Score

Ebselen

Placebo

0-34

15 (10)

18 (12)

35-74

63 (43)

73 (49)

75-100

70 (47)

58 (39)

Modified Barthel Index

Score

Ebselen

Placebo

64 (44)

0-34

12 (8)

20 (13)*

0-49

53 (36)

35-74

38 (26)

54 (36)

50-74

10 (7)

21 (14)

75-100

98 (66)\

75 (50)

75-100

85 (57)#

62 (42)

12 (8)

20 (13)

0-49

44 (30)

59 (40)

9 (6)

15 (10)

0-34
35-74

31 (21)

48 (32)

50-74

75-100

105 (71)

81 (54)

75-100

95 (64)**

73 (50)

Values are number of patients, with percentages in parentheses. Values in parentheses do not total
100% because of rounding.
*P5.005, P5.004, P5.031, P5.019, Wilcoxon rank sum test, compared with placebo.
\P5.006, P5.003, #P5.009, **P5.012, x2 test (scores, 75-100), compared with placebo.

triggered by oxidative stress appears to underlie ischemic brain

damage. Ebselen is reported to reach inside cells as a result of
its reactive binding to the intracellular thiol groups such as
glutathione,19 and it inhibits the peroxidation of membrane
phospholipids,3 inhibits lipoxygenase in the arachidonate cascade,5 blocks the production of superoxide anions by activated
leukocytes,20 inhibits inducible nitric oxide synthase,21 and
exhibits a sustained defense line effect against peroxynitrite.22
Accordingly, ebselen has the potential to influence the key
reactions involved in ischemic brain damage. Among the
multiple intrinsic antioxidant systems, glutathione peroxidase
plays a major role in intracellular redox regulation. The
neuroprotective effect of ebselen demonstrated in the present
trial may be explained by these mechanisms.
In the present study both groups were well balanced, and
there were no significant differences in baseline characteristics.
Patients in three impairment categories of modified Mathew
Scale were evenly distributed on admission (P5.160, Wilcoxon test). Although the number of patients with mild impairment was slightly more in the ebselen group, the difference was
not statistically significant (P5.145, x2 test). Both ITT and PC
analyses revealed a significant difference in the overall outcome
TABLE 3.

Outcome Scores of ITT Patients With Moderate or Severe Impairment (<75, Modified Mathew Scale)
Modified Mathew Scale

Time
Pretreatment
1 mo

3 mo

scores between the ebselen and placebo groups, and the

percentage of patients with a good outcome was always
approximately 10% higher in the ebselen group. Despite the
obvious trend for spontaneous improvement from 1 month to
3 months, a difference between the groups was maintained.
The efficacy of ebselen on outcome was also observed in
patients with severe or moderate impairment, as shown in
Table 3. Stratified analysis provided the following information.
The outcome of patients who received early ebselen treatment
(#24 hours) was significantly superior to that of patients who
received later treatment (.24 hours). In addition, the effect of
ebselen on outcome was more prominent in patients with
lesions involving the brain cortex than in those with deepseated lesions. These findings may suggest that ebselen protected the brain from ischemic insults. The possible influence
of baseline characteristics on the evaluation of drug efficacy was
examined for each end point by Cochran-Mantel-Haenszel
analysis, and no significant influence was detected.
It is generally believed that a large number of centers enrolling
a small number of patients per center will increase the risk of
skews in randomization and ancillary care. To minimize this
problem, the diagnosis was done by CT, the grading of patients

Score

Ebselen

Modified Barthel Index

Placebo

0-34

15 (19)

18 (20)

35-74

63 (81)

73 (80)

Score

Ebselen

GOS

Placebo

Score

Ebselen

Placebo

0-34

12 (15)

19 (21)

0-49

48 (62)

58 (64)

16 (21)

5 (6)

35-74

36 (46)

49 (54)

50-74

5 (6)

17 (19)

14 (18)

21 (23)

75-100

30 (38)

23 (25)

75-100

25 (32)

16 (18)

#S

48 (62)

64 (71)

0-34

12 (15)

19 (21)

0-49

39 (50)

54 (59)

20 (26)

10 (11)

35-74

29 (37)

43 (47)

50-74

7 (9)

10 (11)

18 (23)

29 (32)

75-100

37 (47)*

29 (32)

75-100

32 (41)

27 (30)

#S

40 (51)

52 (57)

G, M, and S indicate good recovery, moderate disability, and severe disability of GOS score, respectively.
Values are number of patients, with percentages in parentheses. Values in parentheses do not total 100% because of rounding.
*P5.039, P5.029, P5.003, P5.013, x2 test (scores, 75-100, or good recovery of GOS score), compared with placebo.

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Yamaguchi et al
was conducted by modified Mathew Scale, and the evaluation of
efficacy was based on the GOS score. The study committee
reviewed the uniformity and appropriateness of the final judgment
of each investigator. In addition, the racial and socioeconomic
status of patients in Japan is quite homogeneous. Therefore, valid
results could be obtained with this study design.
The overall incidence of abnormal laboratory findings was
similar in the ebselen and placebo groups. The incidence of
respiratory infections was significantly lower in the ebselen group,
and this drug was not reported to cause infection in an animal
study.23 Thus, we found no evidence of the potential problems of
antioxidant therapy. There was no evidence that ebselen contributed to any of the causes of death. The present clinical trial may
support the safety of this agent at a dose of 300 mg/d.
In conclusion, the outcome of patients with ischemic stroke
was significantly improved by early treatment with ebselen.
Hence, ebselen may be a useful neuroprotective agent for the
treatment of acute ischemic stroke.

Acknowledgment
This study was supported by Daiichi Pharmaceutical Co, Ltd, Tokyo,
Japan.

Appendix
Committee Members
Keiji Sano, MD (Chairperson), Fuji Brain Institute Hospital; Hiroshi
Abe, MD, Hokkaido University; Hideo Tohgi, MD, Iwate Medical
College; Takashi Yoshimoto, MD, Tohoku University; Shunsaku
Hirai, MD, Gunma University; Takao Asano, MD, Saitama Medical
Center School; Isamu Saito, MD, Kyorin University; Ichiro
Kanazawa, MD, Tokyo University; Kintomo Takakura, MD, Tokyo
Womens Medical College; Yasuo Fukuuchi, MD, Keio University;
Akiro Terashi, MD, Nippon Medical School; Hajime Yasuhara, MD,
Showa University; Akira Tamura, MD, Teikyo University; Yukito
Shinohara, MD, Tokai University; Eiichi Ito, MD, National East
Nagoya Hospital; Haruhiko Kikuchi, MD, Kyoto University;
Takenori Yamaguchi, MD, National Cardiovascular Center; Tomio
Ohta, MD, Osaka Medical College; Toru Hayakawa, MD, Osaka
University; Masatoshi Fujishima, MD, Kyushu University.

Participating Centers
This trial was performed with the cooperation of the doctors and staff
of the following neurological and neurosurgical institutions and
hospitals in Japan: Asahikawa Red Cross Hospital, Kitami Central
Hospital, Bibai Rosai Hospital, Kushiro Rosai Hospital, Kushiro
General Hospital, Azabu Neurosurgical Hospital, Nakamura Memorial Hospital, Shinsapporo Neurosurgical Hospital, Hokkaido University, Hokkaido Neurosurgical Hospital, Otaru Neurosurgical Hospital,
Research Institute for Brain and Blood VesselsAkita, Iwate Medical
University, Iwate Prefectual Central Hospital, Sendai National Hospital, Kohnan Hospital, Fukushima Medical College, Aizu Central
Hospital, Ashikaga Red Cross Hospital, Utsunomia Saiseikai Hospital,
Jichi Medical College, Nagaoka Red Cross Hospital, Chuou General
Hospital, Kameda General Hospital, Keiai Hospital, Chiba Emergency
Medical Center, Keio University, Tokyo Womens Medical College,
Showa University, Kantou Rosai Hospital, Nippon Medical School,
Nippon Medical School First Hospital, Tokai University, Kitasato
University, Yokohama General Hospital, Juntendo University Izunagaoka Hospital, Shizuoka Prefectural General Hospital, Hamamatsu
Rosai Hospital, Fujita Health University, Nagoya Ekisaikai Hospital,
Nagoya National Hospital, Nagoya City University, East Nagoya
National Hospital, Aichi Saiseikai Hospital, Tousei Hospital, Shiga
University of Medical Science, Hikone Central Hospital, Toyama
Medical and Pharmaceutical University, Fukui Red Cross Hospital,
Maizuru City Hospital, National Cardiovascular Center, Kitano
Hospital, Iseikai Hospital, Hanwa Memorial Hospital, Oono Memo-

17

rial Hospital, Osaka University, Osaka Red Cross Hospital, Kurashiki

Central Hospital, Chugoku Rosai Hospital, Teraoka Memorial Hospital, Tottori University, Kokura Memorial Hospital, Oita Medical
College, Kyushu Rosai Hospital, Fukuoka Tokushuukai Hospital,
Kumamoto City Hospital, Atsuji Neurosurgical Hospital, and Kushikino Neurosurgical Center.

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Ebselen in Acute Ischemic Stroke: A Placebo-Controlled, Double-blind Clinical Trial

Takenori Yamaguchi, Keiji Sano, Kintomo Takakura, Isamu Saito, Yukito Shinohara, Takao
Asano and Hajime Yasuhara
for the Ebselen Study Group
Stroke. 1998;29:12-17
doi: 10.1161/01.STR.29.1.12
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 1998 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

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