112

Surg Neurol
1991 ;36 :112-8

Efficacy and Toxicity of Thromboxane Synthetase Inhibitor for
Cerebral Vasospasm After Subarachnoid Hemorrhage
Koji Tokiyoshi, M.D., Takanori Ohnishi, M .D., and Yasuo Nii, M .D.
Department of Neurosurgery, lseikai Hospital, and Department of Neurosurgery, Osaka University Medical School,
Osaka, Japan

Tokiyoshi K, Ohnishi T, Nii Y . Efficacy and toxicity of
rhromboxane synthetase inhibitor for cerebral vasospasm after
subarachnoid hemorrhage . Surg Neurol 1991 ;36 :112-8 .

spasm after SAH . However, this drug has a hazardous side
effect in that it may promote a tendency to bleed, which
caused death in one of our patients .

The efficacy and possible side effects of thromboxane A 2
(TXA2 ) synthetase inhibitor in the treatment of cerebral
vasospasm after subarachnoid hemorrhage (SAH) were
assessed for 24 patients who presented with grades I to IV
of the Hunt and Hess classification . All patients underwent aneurysmal clipping within 48 hours after SAH .
Postoperatively, TXA Z synthetase inhibitor, Cataclot®
{sodium (E)-3-fp-( IH-imidazol-l-ylmethyl)phenyl]-2-propenoate} was administered to 13 patients by continuous
drip infusion at a dose of 1 pg/kg/min for 8 to 14 days
(group A). The remaining 11 patients did not receive this
drug (group B) . Of the 13 patients in group A, seven
patients (54%) showed no symptomatic vasospasm after
SAH . Four patients (31%) developed a transient deterioration of consciousness and/or motor disturbance . Three of
these patients fully recovered, while one of them showed
a mild neurological deficit on discharge . One patient (8%)
developed permanent dysphasia and hemiparesis as a result of ischemic brain damage due to vasospasm . One patient (8%) died of the side effect . On the other hand, of
the 11 patients in group B, only three (27%) showed no
symptomatic vasospasm . One (9%) patient presented a
transient neurological deficit but fully recovered upon
discharge . Four patients (36%) showed permanent neurological deficits, although they all could lead an independent life after discharge . The three remaining patients
developed a severe disturbance of consciousness caused by
ischemia due to vasospasm, and two of them died within
1 month after the onset of SAH . In the group treated with
Cataclot, two patients developed an epidural hematoma
late during the administration of the drug. Of these two,
one patient died of increased intracranial pressure that
was accelerated by the complication . These results indicate that TXA z synthetase inhibitor is effective in not only
decreasing the occurrence of symptomatic vasospasm but
also reducing the neurological deterioration due to vaso-

KEY WORDS :

Address reprint requests to : Takanori Ohnishi, M .D ., Department of
Neurosurgery, Osaka University Medical School, 1-1-50 Fukushima,
Fukushima, Osaka 553, Japan .
Received December 13, 1990 ; accepted February 21, 1991 .
C 1991 by Elsevier Science Publishing Co ., Inc .

Subarachnoid hemorrhage ; Cerebral vasospasm ;
Ruptured aneurysm ; Thromboxane synthetase inhibitor

Vasospasm and rebleeding are two major factors related
to mortality and morbidity after subarachnoid hemorrhage (SAH) due to ruptured cerebral aneurysms . It has
been reported that an early operation of aneurysmal
clipping and extensive removal of the clots can not only
prevent rebleeding but also decrease the incidence of
cerebral vasospasm [10,22) . Ischemic brain damage due
to vasospasm, however, has not yet been successfully
controlled by any treatment modality .
Nonsurgical treatment to prevent cerebral ischemia
after SAH includes calcium entry blockers, such as nicardipine [5] ; high-dose corticosteroids [21 ; hypervolemia ;
and induced hypertension [13], all of which have been
shown to be partly effective in both experimental and
clinical studies .
Previous studies in experimental SAH have demonstrated that angiographic spasm or regional cerebral
blood flow can be improved by intravenous administration of a thromboxane A 2 (TXA Z ) synthetase inhibitor
[7,19] . Thromboxane A 2 , which is one of the prostaglandin metabolites, causes strong platelet aggregation and
vasoconstriction in the cerebral arteries 13] . In addition,
a disproportionate increase in TXA 2 after SAH may lead
to release of adenosine diphosphate and serotonin from
the platelets, thus promoting further platelet aggregation
and local vasoconstriction [8,17) .
It has been reported that the clinical application of
TXA z synthetase inhibitor in patients with aneurysmal
SAH led to favorable results, as evidenced by a decrease
in the incidence of low-density areas on postoperative
computed tomography (CT) scan [23] . In the present
study, we evaluated the effect ofTXA 2 synthetase inhibitor on the clinical outcome of patients with aneurysmal
SAH in comparison with an untreated control group . In
0090-3019/91/$3 .50

TXA2 Synthetase Inhibitor for Vasospasm

Surg Neurol

1 13

1991 ;36 :112-8

Table 1 . Age Distribution in 24 Patients
Age (yr)

Group A

Group B

Total

phy, which was carried out immediately before administration of the drug or the placebo, showed no abnormal
changes, including narrowing of cerebral vessels .

<35
36-45
46-55

2

0
1

2
5
6
9
2
54 .2

Treatment Protocol

56-65
>66
Mean age

0
50 .0

6
2
59 .1

Patients in group A received thromboxane A, synrhetase inhibitor, Cataclor,
whereas those in group B did not,

addition, two cases showing adverse effects of the drug,
which caused death in one of them, are reported .
Clinical Materials and Methods
Patient Population
Twenty-four patients with a ruptured aneurysm of the
anterior circulation who presented with Hunt and Hess's
[l 1] grade I-IV on admission were enrolled in the study .
All patients were admitted to our hospital between November 1986 and December 1989 and within 24 hours
after the onset of SAH . All patients underwent CT after
admission . Four-vessel studies were carried out to verify
the location of aneurysms in all cases . The age and aneurysmal site distributions are shown in Tables I and 2,
respectively . The intensity of preoperative SAH, which
was graded on CT scans according to the classification
of Fisher et al [4], is shown in relation to the preoperative
neurological grade classified according to Hunt and Hess
(Table 3) . Patients with severe cardiac, hepatic, or renal
insufficiency were excluded . The patients were randomly assigned to one of two treatment groups : 13 patients (group A) received intravenous TXA 2 synthetase
inhibitor, Cataclotx {sodium (E)-3-[p-(iH-imidazol-lylmethyl)phenyl}-2-propenoate} (Ono Pharmaceutical
Co ., Ltd ., Osaka, Japan) after the surgery, and 11 patients
(group B) were treated with the same modality but without the drug. When administration of the drug or the
placebo was started, both groups had comparable neurological and general conditions . Postoperative angiogra-

Table 2 . Site of Aneurysm Responsible for SAW
Artery

Group A

Group B

Total

ICA
ACA
MCA
Total cases

5
3
5
13

5

10

3
3
11

6
8
24

Abbreviations : ACA, anterior cerebral artery : ICA, internal carotid artery ;
MCA, middle cerebral artery: SAH, subarachnoid hemorrhage .
'The number of aneurysms only responsible for SAf I was counted both in
group A !with Cataclor/ and in group B (without Cataclor) .

All 24 patients underwent aneurysmal clipping within
48 hours after the onset of SAH . The frontotemporal
and transsylvian approaches with standard microsurgical
technique were employed in the surgery for these patients . Subarachnoid clots in the cisterns were removed
as much as possible, and cisternal drainage was performed on patients who had grade III and IV of Fisher's
classification .
Postoperatively, all patients were treated with induced arterial hypertension and hypervolemic therapy
using dopamine and plasma fractionates . The arterial
systolic and central venous pressure were maintained in
respective ranges from 140 to 160 mm Hg and from 5
to 8 cm H,O . Methylprednisolone was also given to all
patients for 7 days after the operation .
An intravenous continuous infusion of Cataclot was
given to 13 patients (group A) at a dose of 1 µg/kg/min
for 8 to 14 days . The remaining 11 patients (group B)
received a placebo instead of Cataclot .

Clinical Evaluation
The presence of symptomatic vasospasm was assessed
on the basis of clinical signs and symptoms, including
deterioration of consciousness, speech and/or motor
dysfunctions, and positive pathological reflex . In addition, CT scans and laboratory examinations, including
serum electrolytes, were repeated in all patients to assure
that the neurological deterioration was actually due to
vasospasm . In cases in which the occurrence of vasospasm was uncertain, angiography was carried out to
confirm the presence of vasospasm . Clinical outcome
was determined 1 month after surgery . "Excellent" corresponded to good recovery on the Glasgow Outcome
Scale 112] in which the patient could lead a full and
independent life without any or with only minimal neurological deficit . Patients with a "good outcome" had
some neurological deficit bur could lead a full and independent life . Patients with a "poor result" were not independent, or had a major neurological deficit . Statistical
analysis was evaluated with the X' test .

Results
Effect of Cataclot on Postoperative Outcome (Table 4)
Of the 13 patients in group A, seven patients (54%)
showed no clinical signs of symptoms due to vasospasm

114

Surg Neural
1991 ;36 : 1 1 2-8

Tokivoshi et al

Table 3 . Preoperative Neurological Grade Correlated with SAH Grade°
SAH grade on CT scan
Preoperative
neurological
grade
1
II
III
IV
Total cases

Group A

Group B

I

11

Ill

IV

I

17

III

IV

0
0

2
0
0

1
3
2
1
7

0
1
I

1
0
0

0
0

1
1
4

0
0

1

0
1

1
0
1

0
2

3

0
0
0

0
3
3

1
7

° Subarachnoid hemorrhage (SAH) was graded from computed tomography (CT) scan according to the classification of Fisher et al [41 . Neurological grade was
classified according to Hunt and Hess [111 . Group A, created with Caracloq group B . our treated with Cataclot .

after SAH and were discharged with excellent outcome .
Five patients (39%) developed symptomatic vasospasm
from 4 to 13 days (8 .7 ± 3 .0) after the onset of SAH .
Among these, four patients (31 %) presented a transient
disturbance of consciousness and/or motor weakness .
Three of these four patients fully recovered from their
symptomatic vasospasm and were discharged with excellent result, while one of them had a mild neurological
deficit that made no or little difference in leading an
independent life . One patient (8%) developed right
hemiparesis and motor dysphasia 9 days after SAH and
could not recover from the neurological deficits on discharge. One patient died of an epidural hematoma,
which was thought to have been the result of tendency
to bleed induced by Cataclot .
On the other hand, of the 11 patients in group B,
only three (27%) did not show any ischemic symptoms
due to vasospasm after SAH and had excellent outcome
on discharge . Eight patients (73%) developed deterioration of consciousness and/or neurological deficits such
as motor weakness from 4 to 13 days (8 .0 ± 3 .6) after

SAH . Of these, two patients died of ischemic brain damage caused by vasospasm within 1 month after the onset
of SAH . Among the remaining six patients, one who
showed symptomatic vasospasm 13 days after SAH had
excellent outcome, four had good results, and one
showed severe disability due to ischemic damage .
The number of patients with permanent neurological
deficits due to symptomatic vasospasm in group A was
one (7 .7%) and in group B, seven (63 .6%) . There was
a significant difference in the frequency of symptomatic
vasospasm between these two groups (p < 0 .005) . However, the mean period from SAH to the onset of symptomatic vasospasm in group A (8 .7 days) was not significantly different from that in group B (8 .0 days) . As for
the results I month after surgery, 10 patients in group
A (76 .9%) showed excellent, one (7 .7%)good, and one
(7 .7%) poor results, while one (7 .7%) died. Ingroup B,
four patients (36 .3%) showed excellent, four (36 .3%)
good, and one (9 .1%) poor results, while two (18 .2%)
died . The outcome for patients in group A was significantly more favorable than that for patients in group B

Table 4 . Frequency of Symptomatic Vasospasm and Outcome Correlated with Preoperative Clinical Grade
Symptomatic vasospasm

Group A
(treated
with
Cataclot)

Group B
( not treated
with
Cataclot)

Clinical
grade

No . of
cases

1
II
111
IV
Total
1
11
III
IV
Total

Transient

Permanent

3
4
4
2
13
2
1
4
4
11

Overall outcome'
Excellent

Good

Poor

Dead

4 (31%)

0
0
1
0
1 (8%)°

10 (77%)`

0
0
1
0
1 (8°%)

0
0
1
0
1 (8%)

0
0
1
0
1

0
0
0
1
1 (9%)

1
0
4
2
7 (64%)°

1
1
0
2
4 (36%)'

1
0
2
1

0
0
0
1

4 (36%)

10%)

0
0
2
0
2

°Preoperative clinical grade was classified according to Hunt and Hess [l l] .
e Clinical outcome was determined at I month after surgery .
`Died due to side effect of Cataclot.
Statistically significant between group A and B at °p < 0 .005 and `p < 0 .01 (x' test).

TXA, Synthetase Inhibitor for Vasospasm

(p < 0 .01) . Neither group showed a correlation between
preoperative neurological grade and postoperative outcome or between preoperative grade on CT scan and
postoperative outcome .

Side Effects of TXA 2 Synthetase Inhibitor, Cataclot
Two of our patients presented an epidural hematoma
relatively late during the administration of Cataclot . One
of them died of increased intracranial pressure that was
thought to have been accelerated by this complication .
Our report on these two cases follows .

Case 1 . A 35-year-old man was admitted to our hospital with a sudden onset of consciousness disturbance and
motor weakness . The neurological examination revealed
confusion and left hemiparesis . A CT scan showed a
hematoma in the right temporal lobe and SAH in the
basal cisterns (Figure 1 A) . A preoperative cerebral angiogram disclosed a saccular aneurysm of the right middle
cerebral artery . On the same day, aneurysmal neck clipping was performed and the hematoma evacuated . The
patient showed mild postoperative confusion, while the
left hemiparesis remained unchanged. A postoperative
CT scan demonstrated no more hematoma in the right
temporal lobe (Figure I B) . One day after the operation,
Cataclot was administered in accordance with the treatment protocol, but 7 days after the operation, consciousness suddenly deteriorated and he fell into a coma . A
CT scan disclosed subgaleal and massive epidural hematomas on the right side, a low-density area in the right
temporoparietal lobe, and a marked midline shift from
right to left (Figure 1 C) . Although the epidural hematoma was immediately evacuated, the patient died 10
days after the first operation .

Case 2 . A 42-year-old man was admitted to our hospital with a sudden severe headache accompanied by nausea and vomiting . Neurological examination on admission revealed only stiffness of the neck . A CT scan
showed SAH in bilateral sylvian and interhemispheric
fissures (Figure 2 A) . A cerebral angiogram disclosed a
saccular aneurysm of the anterior communicating artery .
On the same day, right frontotemporal craniotomy and
aneurysmal neck clipping were performed . In addition,
a silicone tube was placed in the basal cistern for continuous drainage . Postoperatively, the patient was well and a
CT scan showed no abnormalities except for the slightly
persistent SAH (Figure 2 B) . He was administered Cataclot from 1 day after the operation . Ten days after the
operation, the cisternal drainage was terminated because
the cerebrospinal fluid had become clear . Twelve days
after the operation, however, the patient began to show

Surg Neurol
1991 ;36 : 1 1 2 -8

115

consciousness disturbance . A CT scan disclosed hematomas in the right epidural and subgaleal regions (Figure
2 C) . After the hematomas had been evacuated, the
patient became well and was discharged without any
neurological deficit 1 month after the onset of SAH .
Discussion
Recent studies have suggested that not only vasoconstriction of the main cerebral arteries but also thrombus
formation by platelet aggregation in the peripheral arteries play an important role in symptomatic delayed ischemia after aneurysmal SAH [21] . It is well known that
free oxygen radicals and lipid peroxides, which are generated from lipid peroxidation initiated by lysis of clots
after SAH, damage the vascular endothelium and inhibit
the synthesis of prostaglandin 12 (PGI z ) [14,15] . Sasaki
et al [18] further demonstrated that PGI z synthesis in
the cerebral arteries significantly diminished after experimental SAH . The decreased level of PGI z may in turn
increase the synthesis of TXA2, which is a powerful
vasoconstrictor and platelet-aggregating substance [3] .
Thus, the shift to TXA 2 synthesis at the blood-endothelial interface could lead to disturbance of peripheral cerebral blood microcirculation . For this reason, it is supposed that inhibition of TXA z synthesis may correct the
imbalance between TXA, and PGI, and thereby protect
brains from ischemic changes after SAH, not only by
preventing vasoconstriction but also by improving cerebral microcirculation .
Cataclot, which was used in the present study, selectively decreases the production of TXA Z from prostaglandin endoperoxide (PGH_,) by inhibiting TXA 2 synthetase in human and rabbit platelets and is expected to
prevent platelet aggregation (Figure 3) . The IC 5o value
(concentration at 50% inhibition) of the drug for TXA,
synthetase is 4-11 nM, while that for cyclooxygenase,
PGI z synthetase, or PGE Z isomerase is greater than 1
MM [9] . It has been demonstrated that Cataclot inhibits
the aggregation of platelets by arachidonate or collagen,
prolongs a bleeding time at the incision of rat tails, and
can decrease the incidence of cerebral infarction induced
by injection of arachidonate into the internal carotid
artery in rabbits [9,16] .
In our study, the frequency of symptomatic vasospasm as well as the incidence of irreversible ischemic
changes was significantly lower in patients treated with
Cataclot (group A) . Since there was no significant difference in the interval from SAH to the onset of symptomatic vasospasm between the treated (group A) and untreated (group B) patients, this drug may not affect
occurrence of arterial vasospasm. In fact, Tani et al [23]
reported that TXA 2 synthetase inhibitor (OKY-1581)
did not significantly reverse angiographic vasospasm . Re-

116

Surg Neurol
1991 ;36 :112-8

Figure 1 . Case 1 . (A) Preoperative CT scan showing a hematoma in the
right temporal lobe and SAH in the basal cisterns . (B) CT scan I day after
surgery showing disappearance of the hematoma . (C) CT scan 7 days after
surgery disclosing the right subgaleal and epidural hematomas with a
marked midline shift from right to left.

Figure 2 . Case 2 . (A) Preoperative CT scan showing SAH in bilateral
sylvian and interhemispheric fissures . (B) CT scan 1 day after surgery
showing no apparent abnormalities except for the perristentSAH and postoperative changes . (C) CT scan 12 days after surgery demonstrating the right
subgaleal and epidural hematomas .

TXA, Synthetase Inhibitor for Vasospasm

Surg Neurol
1991 ;36 :112-8

PLATELETS
vWf

Coagulation
factors

Adhesion
collagen, thrombin
PlateI let activation
pnospholipase A, C

1

proth ombin

AA

1

PGG,
Jr
PGH ;

Cataclot

thrombin

X1

TxA,

Release reaction
(ADP, TSP, Fbg . etc .)
Aggregation

fibrin

J

F
Platelet plug

Figure 3 . Diagram showing the mechanism of platelet plug formation .
Cataclot inhibits thromboxane Ai (TXA,) synthetase in platelets, by which
prostaglandin endoperoxide (PGHV is converted to TXA, (shown by a
dotted line) . Abbreviations : AA, arachidanic acid; ADP, adenosine diphosphate: Fbg . fibrinogen ; TSP, thrombospondin ; a•Wf, von Willebrand factor .

cently, it has been reported that intravascular volume
expansion, which has been used to improve blood flow
in ischemic brains, affects cerebral blood flow through
decreased blood viscosity rather than through cardiac
output augmentation [1] . It is commonly observed that
the ischemic signs of patients with aneurysmal SAH, in
whom ischemic neurological syndromes tend to fluctuate
after the occurrence of symptomatic vasospasm, rapidly
improve as a result of the administration of volume expander . This suggests that cerebral microcirculation may
actually play a key role in the development of ischemic
neurological syndrome .
Thromboxane A Z synthetase inhibitor may not be
so effective in the prevention of vasoconstriction after
SAH, because a wide variety of substances found in the
cerebrospinal fluid after SAH, including catecholamines
and serotonin in addition to TXA Z , have been implicated
in the pathogenesis of cerebral vasospasm [6,24] . Since
this drug is an antiplatelet reagent, however, it can make
the peripheral circulation of the brain much better, thus
possibly preventing permanent neurological deficits due
to vasospasm. Therefore, a combination of vasodilating

1 17

reagents such as calcium entry blockers and TXA Z synthetase inhibitor may be much more effective in the
treatment of vasospasm than their single use .
Serious adverse effects of TXA Z synthetase inhibitor
have not been reported except for rare complications .
These include thrombocytopenia [23], rerupture of aneurysm, and gastrointestinal bleeding [20] . In the present study, two of our patients suffered epidural hematoma during treatment with Cataclot . In both cases, the
hematoma occurred relatively late after the administration of this drug . Therefore, this complication is not
thought to have been the direct result of the first operation . The adverse effects of TXA Z synthetase inhibitor
may occur because of an enhanced tendency to bleed,
mainly as a result of the inhibition of platelet aggregation . Of these two patients, one died of increased intracranial pressure that was thought to have been accelerated by the complication of a rapidly formed epidural
hematoma .
Although TXA Z synthetase inhibitor seems to be effective for the prevention of ischemic brain insults after
aneurysmal SAH, safe application of this drug requires
that it should be used in conjunction with an appropriate
monitoring system to check for tendency to bleed . Because Cataclot inhibits the aggregation of platelets but
has little effect on the coagulation of blood, the measurement of both bleeding time and the number of platelets
is recommended . These examinations should be performed at least once a day during the administration of
the drug . When patients begin to show thrombocytopenia or prolongation of bleeding time more than twice
the normal value, the dose must be reduced or discontinued in order to prevent any complication induced by
the drug .

References
I . Bouma GJ, Muizelaar JP . Relationship between cardiac output
and cerebral blood flow in patients with intact and with impaired
autoregulation . J Neurosurg 1990 ;73 :368-74 .
2 . Chyatte D, Forte NC, Nichols DA, Sundt TM Jr . Preliminary
report effects of high dose methylprednisolone on delayed cerebrat ischemia in patients at high risk for vasospasm after aneurysmat subarachnoid hemorrhage . Neurosurgery 1987 ;21 :157-60 .
3 . Ellis EF, Nies AS, Oates JA . Cerebral arterial smooth muscle
contraction by thromboxane A, . Stroke 1977 ;8 :480-2 .
4 . Fisher CM, Kistler JP, Davis JM . Relation of cerebral vasospasm
to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 1980;6 :1-9 .
5 . Flamm ES, Adams HP, Beck DW, Pinto RS, MarlerJR, Walker
MD, Godersky JC, Loftus CM, Biller J, Boarini DJ, O'Dell C,
Banwart K, Kongable G . Dose-escalation study of intravenous
nicardipine in patients with aneurysmal subarachnoid hemorrhage .
J Neurosurg 1988 ;68 :393-400.
6 . Flamm ES, Yasargil MG, RansohoffJ II . Alteration of experimental cerebral vasospasm by adrenergic blockade . J Neurosurg
1972 ;37 :294-301 .

1 18

Surg Neurol
1991 ;36 :112-8

Tokiyoshi et al

7 . Fukumori T, Tani E, Maeda Y, Sukenaga A . Effects of selective
inhibitor of thromboxane A, synthetase on experimental cerebral
vasospasm. Stroke 1984 ;15 :306-11 .

16 . Naito J, Komatsu H, Ujiie A, Hamano S, Kubota T, Tsuboshima
M . Effects of thromboxane synthetase inhibitors on aggregation
of rabbit platelets . Eur J Pharmacol 1983 ;91 :41-8 .

8 . Hamberg M, Svensson J, Samuelsson B . Thromboxanes : a new
group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci USA 1975 ;72 :2994-8 .

17 . Samuelsson B, Hamberg M, Malmsten C, Svensson J . The role of
prostaglandin endoperoxides and thromboxanes in platelet aggregation . Adv Prostaglandin Thromboxane Leukotriene Res
1976 ;2 :737-46 .

9 . Hiraku S, Taniguchi K, Wakitani K, Omawari N, Kira H, Miyamoto T, Okegawa T, Kawasaki A, Ujiie A . Pharmacological studies on the TXA, synthetase inhibitor (E)-3-[p-(1H-imidazol-lylmethyl)phenyl]-2-propenoic acid . Jpn J Pharmacol 1986 ;
41 :393-401 .
10 . Hugenholtz H, Elgie RG . Considerations in early surgery on
good-risk patients with ruptured intracranial aneurysms . J Neurosurg 1982 ;56 :180-5 .
11 . Hunt WE, Hess RM . Surgical risk as related to time of intervention in the repair of intracranial aneurysms . J Neurosurg
1968 ;28:14-20-

12- Jennet B, Bond M . Assessment of outcome after severe brain
damage. A practical scale. Lancet 1975 ;1 :480-4 .
13 . Kassell NF, Peerless SJ, Durward QJ, Beck DW, Drake CG,
Adams HP . Treatment of ischemic deficits from vasospasm with
intravascular volume expansion and induced arterial hypertension .
Neurosurgery 1982 ;11 :337-43 .
14. Kontos HA, Wei EP, Povlishock JT, Dietrich WD, Magiera CJ,
Ellis EF. Cerebral arteriolar damage by arachidonic acid and prostaglandin G 2 . Science 1980;209 :1242-5 .
15 . Moncada S, Gryglewski RJ, Bunting S, Vane JR . A lipid peroxide
inhibits the enzyme in blood vessel microsomes that generates
from prostaglandin endoperoxides the substance (prostaglandin
X) which prevents
platelet aggregation .
Prostaglandins
1976 ;12 :715-37 .

18 . Sasaki T, Murota 5, Wakai S, Asano T, Sano K . Evaluation of
prostaglandin biosynthetic activity in canine basilar artery following subarachnoid injection of blood . J Neurosurg 1981 ;55 :771-8 .
19 . Sasaki T, Wakai S, Asano T, Takakura K, Sano K. Prevention of
cerebral vasospasm after SAH with a thromboxane synthetase
inhibitor, OKY-1581 . J Neurosurg I982 ;57 :74-82 .
20 . Suzuki S, Iwabuchi T, Tanaka T, Kanayama S, Ottomo M, Hatanaka M, Aihara H . Prevention of cerebral vasospasm with OKY046 an imidazole derivative and a thromboxane synthetase inhibitor . A preliminary co-operative study . Acta Neurochir (Wien)
1985 ;77 :133-41 .
21 . Suzuki 5, Suzuki M, Iwabuchi T, Kamata Y . Role of multiple
cerebral microthrombosis in symptomatic cerebral vasospasm :
with a case report . Neurosurgery 1983 ;13 :199-203 .
22 . Taneda M. Effect of early operation for ruptured aneurysms on
prevention of delayed ischemic symptoms . J Neurosurg
1982 ;57 :622-8 .
23 . Tani E, Maeda Y, Fukumori T, Nakano M, Kochi N, Morimura
T, Yokota M, Matsumoto T . Effect of selective inhibitor of thromboxane A 2 synthetase on cerebral vasospasm after early surgery .
J Neurosurg 1984 ;61 :24-9 .
24 . Zabramski J, Spetzler RF, Bonstelle C . Chronic cerebral vasospasm : effect of calcium antagonists . Neurosurgery 1986 ;
18 :129-35 .