Original Paper
Piracetam in the Treatment of Acute Stroke
1.-M. Orgogozo
Department of Neurology, Pellegrin Hospital. Universityof Bordeaux II, Bordeaux, France
DThe neuroprotective properties of the nootropic agent pi-
racetam together with reported hemorrheologic and anti-
thrombotic effects provided the rationale for the evaluation of
piracetam in acute stroke. Pilot studies showed an increase in
compromised regional cerebral blood flow and Improvement in
motor function, aphasia and level of consciousness. Subse-
quently the Piracetam in Acute Stroke Study (PASS) was per-
formed and the chief results have recently been reported
(Stroke 28 (1997) 2347-2352). This was a multicenter double-
blind trial in 927 patients to determine whether, compared
with placebo, piracetam improved outcome when given within
12 hours of the onset of acute ischemic stroke, confirmed by
computed tomography within 24 hours of admission (but not
necessarily prior to treatment). Patients received an initial iv
bolus of placebo or 12 g plracetarn, 12 g piracetam daily for 4
weeks and maintenance treatment for a further 8 weeks. Neu-
rologic status at 4 weeks was the primary end point; secondary
outcome measures were functional outcome and aphasia at 12
weeks. Results in aphasic patients have not previously been re-
ported. Analysis was planned both in all patients (n= 927) and
an early treatment subgroup (n = 460) treated within 6 hours of
stroke onset. This period was subsequently redefined as 7
hours. Intention-to-treat analyses in the total population
showed a significant (P= 0.04) increase compared with placebo
in the number of patients recovered from aphasia but no signi-
ficant neurologic or functional improvement. Post hoc analysis
in the early treatment subgroup showed improved neurologic
outcome (P = 0.07). better function (P = 0.02) and a greater re-
covery rate from aphasia (P=0.02). Additional analysis in this
early treatment subgroup confined to 360 patients with moder-
ate and severe stroke showed significant improvement in all 3
outcomes. There was no significant difference in mortality be-
tween treatment groups after 12 weeks. There were fewer
deaths in piracetam-treated patients in those patlenb In the in-
tention-to-treat population admitted with primary hernorrhag-
ic stroke.
Pharmacopsychiat. 1999; 32 (Supplement): 2 5 - 3 2
O Georg Thieme Verlag Stuttgart . New York
ISSN 0176-3679
25
Introduction
Downloaded by: National University of Singapore. Copyrighted material.
The PASS study confirmed the improvement in aphasia seen in
pilot studies with piracetam and suggested that patients treat-
ed within 7 hours ofstroke onset. particularly those with mod-
erate and severe stroke, showed improvement i n neurologic
outcome and better function. A randomized double-blind trial
which aims to confirm these findings is i n progress.
Piracetam is the prototype nootropic agent It has been shown
to possess pharmacologic properties which suggest that i t
could benefit patients with acute aroke. In addition to a well-
recognised neuroprotective role (Giurgea et al., 1970; Giurgea,
1976), have reported hemorrheologic (Nalbandian et al., 1983;
Grotemeyer et al., 1986; Moriau et al.. 1993) and. more recent-
ly. in vivo antithrombotic effects (Stockmans et al., 1998) with
piracetam.
Piracetam has a unique mode of action which is still not encire-
ly clear although recent advances have contributed much to
our understanding. It acts on the cell membrane (Woelk,
1979; Miiller et al.. 1994) to which piracetarn binds at the level
of the polar heads of phospholipids (Peuvot et a].. 1995). It has
been shown to enhance the decreased fluidity of the neuronal
membrane found i n the aged mouse, rat and human brain but
not to alter normal brain membrane fluidity in young mice
(Miiller et al.. 1994: Miiller et al., 1997). These changes are
closely correlated with increases in muscarinic and NMDA re-
ceptor populations and functions.
Restoration of decreased neuronal membrane fluidity may ex-
plain improvement in various membrane-bound functions re-
ported after piracetam administration. including secondary
messenger activity (Weth. 1982: Canonico et al.. 1991). ATP
production (Benzi et al.. 1985) and neurotransmission (Pedata
et al.. 1984; Bering and Miiller, 1985: Copani et al., 1992: Cohen
and Miiller, 1993; Miiller et al.. 1994). The facts that changes in
membrane fluidity were confined to aged mice and that im-
provement in membrane-bound function was seen only in
cells with an underlying abnormality is consistent with obser-
vations that clinical benefit from piracetam generally occurs
when cell function i s compromised. especially i n aging and
disorders associated with hypoxia. By contrast. in accord with
the absence of effect on normal cell membranes seen in young
mice, piracetam is without effect in normal subjects.
26 Pharmacopsychiat. 1999; 32 (Supplement)
That these effects at cell membrane level are not confined to
the neuron but involve other cell types has become apparent
from the ability of piracetam to normalize pathologic platelet
aggregation (Grotemeyer et dl.. 1986) and to increase erythro-
cyte deformability (Nalbandian e t al.. 1983).
Acute Stroke
The rationale for the use of piracetam in acute ischemic stroke
is based on its combination of neuroprotective, hemorrheolog-
ic and antithrombotic properties. Piracetam has been shown to
improve the microcirculation a t the periphery of acute infarc-
tions by increasing compromised regional blood flow (Herr-
schaft. 1978: Heiss et al.. 1983; Depresseux et al.. 1986: Platt
et al.. 1992) and impaired glucose metabolism (Depresseux e t
al., 1986) in these areas. HerrschaR(1988) also found that pira-
cetam improved quantitative EEG abnormalities after acute
stroke.
The results of three small, double-blind, placebo-controlled pi-
lot studies with piracetam in acute stroke (Table I ) indicated
improved outcome (Creytens. 1980; Herrschaft. 1988; Platt et
al., 1992). In these trials, treatment was started within 1 - 5
days of stroke onset, initially with intravenous piracetam
(NootropiI@,UCB Pharma) in a daily dose of 1 2 g for 12-14
days and then with oral piracetam 4.8 gdaily for the remainder
of the 4-week treatment. One study (Creytens. 1980) utilised
an initial daily dose of 6 g intramuscular piracetam for one
week.
Despite differences in methods of assessment, significant im-
provement in neurologic outcome occurred with piracetam
relative to placebo in all 4 studies. Creytens (1980) reported a
significant increase in the number of patients improved. In the
other three trials. significant improvement with piracetam
was found in level of consciousness and. in aphasic patients.
speech. Both Herrschaft (1988) and Platt et al. (1992) reported
significant improvement in motor function (Table 1).
The consistently positive findings in these placebo-controlled
trials contributed importantly both to the decision to under-
take the large Piracetam in Acute Stroke Study (PASS) and to
its design.
Table 1 Summary of pilot studies in acute stroke
-- - -
Study No of pts Daily dose and Time from
duration of therapy stroke to
(days) treatment
Creytens (1 980) 50 6gfor7d < I day
4.8 g for 30 d
Herrschaft (1988) 44 12gfor14d < 5 days
4.8 g for 14 d
Platt et al (1 992) 56 l2gfor14d < 3 days
4.8 g for 14 d
I.-M. Orgoqozo
Piracetam in Acute Stroke Study (PASS)
PASS was a multicenter, randomized. double-blind. placebo-
controlled study which aimed to determine whether pirace-
tam improved outcome when given to a large patient popula-
tion within 12 hours of the onset of acute supratentorial
ischemic stroke (De Deyn e t al.. 1997).
Methods
A total of 927 patients, aged 40-85 years, received one intra-
venous bolus injection of placebo o r 12 g piracetarn. 12 g daily
for 4 weeks and 4.8 g daily for a further 8 weeks. The primary
measure of outcome was neurologic starus a t 4 weeks measur-
ed by the Middle Cerebral Artery (MCA) scale (Orgogozo and
Dartigues. 1986). Functional capacity in activities of daily liv-
ing a t 12 weeks assessed by the Barthel Index (Wade and Lang-
ton-Hewer, 1987) and, in the subgroup of affected patients,
aphasia evaluated using the Frenchay Aphasia Screening Test
Downloaded by: National University of Singapore. Copyrighted material.
(Enderby et al., 1987) were important secondary outcomes.
Computed tomography (a) was performed within 24 hours
of admission but not necessarily before treatment.
Determination of study power, based on a predefined clinically
relevant improvement in neurologic outcome and tested dur-
ing the pilot phase of the trial, indicated that 250 patients in
each treatment group surviving for 4 weelis would detect such
improvement with a power of 80%.
Intention-to-treat analyses were performed in all patients
(n = 927) and in a subgroup treated within 7 hours of stroke
onset (n = 460). The early rreatrnent subgroup was t o consist
of patients treated within 6 hours of onset but for several rea-
sons the steering committee extended this period to 7 hours.
This increased the power of this subgroup analysis (De Deyn
et al.. 1997).
Results (Table 2)
In the total population ( n = 927) neurologic outcome a t 4
weeks and functional outcome a t 12 weeks were similar in
both piracetam and placebo groups. At 12 weeks significantly
-
Chieroutcome Results (%) p-value
parameter
Piracetam placebo
% of patients with neurologic
improvement
% of independent patients
% of patients with neurologic
improvement
- con~ciou~ness
- motor function
- sensory function
- speech
% of patients with neurologic
improvement
- con~tiou~nes~
- motor function
- sensory function
- speech
Piracetam in the Treatment of Acute Stroke Pharmacopsychiat. 1999; 32 (Supplement) w'X
Table 2 Summary of chief features of the Piracetam in Acute Stroke Study

Study No of pts Daily dose and Time from outcome Results p-value
duration of therapy stroke to parameter
(weeks) treatment Piracetam placebo

De Deyn et a l l 9 9 7 927 12 g iv bolus < 12 hours Orgogozo score (median) 55 50 ns

12 g daily 4w Barthel score (median) 65 60 ns
4.8 g daily 8 w 'FAST (% of pts) 33 23 0.04
Mortality (%) 24 19 ns

< 7 hours Orgogozo score 60 50 0.07

(early treat- Barthel score 70 57.5 0.02
ment 'FAST (% of pts) 36 21 0.02
subgroup) Mortality (%) 21 22 ns

Orgogozo score 60 50 0.02

< 7 hours Barthel score 50 25 0.01
(early treat- Mortality (%) 25 26 ns
ment subgroup
with moderate
and severe

Downloaded by: National University of Singapore. Copyrighted material.

stroke:
initial Orgogozo
score < 55

'FAST = Frenchay Aphasia Screening Test

65- .T

C_____/.--

-Piracetam

B '
--- Placebo

El PLACEBO M PIRACETAM
Fig.1 Percentage of aphasic patients in total population (n = 373)
with complete recovery after 12 weeks.

more patients on active treatment had recovered from aphasia

(piracetam 59/180,33%;placebo 45/193,23%;P = 0.04) (Fig.1).

Post hoc analyses in the early treatment subgroup (11-460)

showed differences in neurologic and functional outcome in
favor of piracetam. The mean score for the Orgogozo scale after
4 weeks was 5.5 points higher in the piracetam (60.4) than in
the placebo group (54.9) (P = 0.07) (Fig. 2). The median Orgo-
gozo scale score at 4 weeks was also higher in the piracetam
group (piracetam 60, placebo SO; P = 0.07). The mean and me-
dian Barthel Index scores at 12 weeks were also significantly ii i s
20Ji i9 57 84
higher in the active group (mean: piracetam 58.6, placebo Days after start of treatment
49.4. P = 0.02; median: piracetam 65, placebo 50, P = 0.02) Fig.2 Early treatment subgroup. Mean scores until 12 weeks' treat-
(Ag. 2). At 12 weeks more patients in the piracetam treated ment from baseline for the Orgogozo scale (top) and from 4 days for
group had recovered completely and fewer patients remained the Barthel Index (bottom). Data are taken from De Deyn et al 1997.
dependent (Fig.3A). The proportion of patients recovering
from aphasia was greater than in the total population (pirace-
tam 3519637%;placebo 21/101,21%;P = 0.02).
28 Pharmacopsych~at.1999; 32 (Supplement) 1.-M. Orgogozo

Rg.3A Early treatment subgroup. Percent-

Piracetam (%) age of patients in both treatment groups in
each of the 6 Barthel index dependency
/ / I / I classes after 12 weeks.

q 65-1 00 : autonomous, bul with neurological deflclt

q 60-80 :home care
@ I :lnstltutlonal care
40-55
<40 : Intensive care

fig. 3 B Early treatment group: patients

w ~ t hmoderate and severe stroke (initial Or-
qoqozo scale score < 55). Percentage of pa-

Downloaded by: National University of Singapore. Copyrighted material.

/ / I I cents in both treatment groups i n each of
the 6 Barthel index dependen& classes after
12 weeks.

085-100 : autonomous, but with neurological deflclt

q 60-80 : home care
B40-55 : lnstltutlonalcare
H c40 : lntenslve care

Flg.4 Early treatment group: patients with

moderate and severe stroke (initial Orgogozo
scale score < 55). Time required for complete
recovery in both treatment groups.

WEEKS

When outcome in the early treatment subgroup was related to
the initial severity of stroke. differences in favor of piracetam
were confined to patients with mild and moderate neurologic
impairment. There was significant improvement in all out-
comes in piracetam-treated patients. At 4 weeks, the mean Or-
gogozo scale score in the active group exceeded that in the pla-
cebo group by more than 7 points ( P < 0.02) and, for functional
outcome after 12 weeks, t h e mean Barthel Index in the pirace-
tam group exceeded that in t h e placebo group by more than I1
points (P < 0.02). Complete recovery occurred in 15.8%of pira-
cetam-treated patients compared with 8.2%on placebo; that
is, 2 patients in 12 taking piracetam recovered completely
compared with one patient in 12 on placebo (Fig.3B). At all
time points more patients in the piracetam group had recov-
ered completely (Fig.4).
When cumulative mean analyses were performed a t hourly in-
tervals after onset in patients treated up to 12 hours after
Piracetam in the Treatment of Acute Stroke Pharmacopsychiat. 1999; 32 (Supplement)

flq. 5 Cumulative differences between pira-

cetam and placebo in changes of Orgogozo
scale scores in relation to time to start of
treatment (h) after stroke onset.

.---.PLACEBO
- PIRACETAM

Downloaded by: National University of Singapore. Copyrighted material.

1 5 1
4 <3 <4 4 <6 <7 <8 e9 <lo ell el2
ONSET OF TREATMENT AFTER STROKE (HOURS)

stroke, it was found that differences favoring piracetam were Discussion

consistently present between 5 and 9 hours after onset. When
treatment began more than 9 hours after stroke. benefit from Stroke is third in frequency as a cause of death in developed
piracetam decreased (Fig. 5). countries. It is predominantly a disease of the elderly with
those over 65 years of age accounting for 75%of all strokes. Ap-
There was no significant difference in mortality between treat- proximately 30%remain disabled (Dunabin, 1992) so that the
ment groups after I2 weeks - piracetam 23.9%, placebo 19.2% economic costs of stroke are high.
( P = 0.15). Of 31 patients with primary hemorrhagic stroke ini-
tially included in the study and thus in the analysis of the in- A variety of pharmacological approaches to the treatment of
tention-to-treat population, 3 of 15 patients receiving pirace- stroke have been explored focusing mainly on improving cere-
tam died, compared with 6 of 16 receiving placebo although bral reperfusion or on neuroprotection. However, these have so
the initial stroke in these patients was more severe in the pira- far generally been ineffective or compromised either by lackof
cetam group (mean baseline Orgogozo score: piracetam 29, consistent clinical benefit or the presence of unacceptable ad-
placebo 38). Cljnical improvement in the survivors was also verse events. Only one study with r-tissue plasminogen activa-
greater in piracetam-treated patients (Table 3). tor (NINDS and Stroke rt-PA Study group. 1995) has so far
shown significantly improved function without an effect on
mortality. No neuroprotective agent has shown consistent evi-
Table 3 Patients with primary hemorrhagic stroke
dence of efficacy in acute ischemic stroke.
Placebo Piracetam
(n = 463) (n = 464) Because there has been no effective drug therapy for routine
use, acute stroke was not until recently considered as a medi-
Patients with evidence of cerebral 16 15 cal emergency. However, despite the lack of safe and effective
hemorrhage on initial CTscan drug therapy, it has become clear that admission to specialised
Orgogozo scale score. Mean (SD) stroke units early after the event, with management by a mul-
baseline 38.4 (14.3) 28.7 (1 1.1) tidisciplinary team. increases the accuracy of diagnosis, im-
4 weeks 40.3 (26.4) 29.3 (12.8) proves outcome and reduces hospital stay (Langhorne et al..
Mortality 1993: Indredavik et al., 1991; Adams et al., 1994; Mitchell,
Patients dead. N (%) 1996).
4 weeks 5 (3 1.3) 3 (20.0)
12 weeks 6 (37.5) 3 (20.01 It is in this context that the results of existing studies with pi-
racetam should be considered. In four double-blind, placebo-
controlled trials in acute stroke in small homogenous popula-
In summary, piracetam did not influence neurologic or func- tions which included in all 215 patients, piracetam was report-
tional outcome in patients treated within 12 hours of the onset ed to improve consciousness, motor weakness and aphasia.
of acute ischemic stroke but was of significant benefit in apha-
sic patients. Post hoc analyses showed that, when given within Based on increasing understanding of the mode of action of pi-
7 hours of onset, piracetam may also provide neurologic and racetam and the encouraging results of these preliminary tri-
functional benefit, particularly in patients with stroke of mod- als, the Piracetam in Acute Stroke Study (PASS) was undertak-
erate to severe degree. en to test the hypothesis that, compared with placebo, pirace-
30 Pha~macopsychiat.1999; 32 (Supplement)
tam improves neurologic status when given within 12 hours of
the onset of stroke.
The trial did not show a statistically significant effect of pirace-
tam on the primary end point, neurologic outcome after 4
weeks or functional disability at 12 weeks, a major secondary
outcome. Treatment with piracetam was however associated
with recovery from aphasia in significantly more patients than
placebo after 12 weeks. a secondary end point of the study.
Considerations of space did not permit adequate presentation
of these results in the initial report by De Deyn et al.. (1997).
Initiation of treatment as soon as possible after t h e onset of
stroke is essential to success in limiting potentially reversible
ischemic damage and optimizing the chances of recovery. Ani-
mal data suggest that time windows of less than 3, or at most 6
hours are critical (Astrup et al., 1981; Weinstein et al., 1986)
but this is uncertain in man (Baron et al.. 1995)and the validity
of arbitrary periods of 6, and even 3, hours have not been con-
sistently confirmed in human stroke. PASS included patients
treated within 12 hours of onset and also required an analysis
in an early treatment subgroup of patients treated until 6
hours, a period subsequently redefined as less than 7 hours.
The methodology and chief results have recently been report-
ed (De Deyn et a]., 1997). The outcome in aphasic patients is
briefly summarized and will be reported separately in more
detail.
In the total population, significant benefit from piracetam oc-
curred only jn aphasia. In the early treatment subgroup, im-
provement in neurologic outcome approaching statistical sig-
nificance was however also seen at 4 weeks in piracetam-
treated patients together with significant functional recovery
after 12 weeks.
When neurologic scores were analysed on a cumulative basis
in patients treated a t hourly intervals up to 12 hours after
stroke, benefit from piracetam was apparent as long as 9 hours
after onset. This suggests that outcome in the early treatment
subgroup would have been similar whether this population
consisted of patients treated after 6. 7, 8 o r 9 hours and that
the positive results in the early treatment subgroup are proba-
bly valid.
Analysis in the early treatment subgroup confined to patients
with moderate to severe strokeshowed clear benefit with pjra-
cetam. As most patients with mild neurologic impairment af-
ter a stroke recover spontaneously. this creates a ceiling effect
in responses measured by neurologic scales which makes it
difficult to detect small differences due to treatment (Mohr et
al., 1994). This probably explains the similar outcomes be-
tween active and placebo groups in patients in whom stroke
was mild and the ability to demonstrate probable benefit in
moderate and severe stroke.
Calculation of study power was based o n neurologic outcome
and retrospective analysis showed this to be inadequate with a
power of only 44% to show the required improvement.
Whether the further finding in the early treatment subgroup
that improvement in functional disability was greatest a t 12
weeks, when the difference from placebo reached statistical
significance, indicates that piracetam assists rehabilitation is
1.-M. Orgogozo
speculative. This possibility deserves consideration because of
the improvement in aphasia reported with piracetam.
Benefit in aphasic patients has been reported in other control-
led trials with piracetam in which speech was assessed, in-
cluding the pilot studies in acute stroke reviewed in this paper
(Herrschaft, 1988; Platt e t al., 1992). In addition in two double-
blind studies against ptacebo in patients with subacute o r
chronic aphasia receiving speech therapy, using common
methodology (the Aachen Aphasia Test) to assess speech, there
was significant improvement with piracetam (Enderby et al.,
1994; Huber et al.. 19971.
This finding in PASS of improvement in aphasia without
change in other parameters raises the possibility that aphasia
may be more responsive to drug effect than neurologicor func-
tional impairment.
Motor impairment can be caused either by a large cortical le-
Downloaded by: National University of Singapore. Copyrighted material.
sion or a small lacunar infarction involving white matter. In
aphasia, by contrast, there is a closer correlation between the
size and site of the lesion and the type and severity of the dis-
order. An alternative explanation might be that, as language is
a complex function, recovery probably involves recruitment
and activation of previously silent areas in both homolateral
and contralateral hemispheres (Weiller e t al.. 1995). Piracetam
has been shown to facilitate and enhance information transfer
between the two cerebral hemispheres in both animal models
(Buresova and Bures, 1976; Giurgea and Moyersoons. 1979)
and man (Dimond, 1975) and this property may be relevant in
the activation of such silent areas.
Conclusions
Pilot studies in patients with acute stroke of moderate to se-
vere degree. suggested that piracetam was associated with sig-
nificant improvement in motor weakness, level of conscious-
ness and aphasia.
The improvement in aphasia was confirmed in PASS. There was
however no statistically significant improvement in motor im-
pairment or function in the total study population which con-
sisted of patients covering a wide spectrum of stroke severity.
In patients treated within 7 hours of stroke onset, particularly
those with moderate to severe stroke, retrospective analysis
showed improved neurologic outcome and better function
with piracetam. A prospective randomized, double-blind, pla-
cebo-controlled trial in such patients (PASS 11). which aims to
confirm these findings, is in progress.
References
Adams Jr HP, Brott TC. Crowell RM. Furlan AJ. Comez CR, Crotta J,
Helgason CM. Marler JR. Woolson RF, Zivin JA, Feinberg W. May-
berg M: Guidelines for the mangement of patients with acute
ischemic stroke: a statement for healthcare professionals from a
special writing group of the Stroke Council. American Heart As-
sociation. Stroke 1994; 25: 1901-1914.
Astrup J. Siesgo El<. Symon L: Thresholds in cerebral ischemia; the
ischemic penumbra. Stroke 1981; 12: 723-725.
Baron JC, von Kumer R, del Zoppo GJ: Treatment of acute ischemic
srroke: challenging the concept of a rigid and universal time
window. Stroke 1995; 26: 2219-2221.
Piracetam in the Treatment of Acute Stroke
Benzi G.Pastoris 0. Villa R. Gruffrida R: Influence of aging and exog-
enous substances on cerebral energy metabolism in post-hypo-
glycemic recovery. Biochem Pharmacol1985: 34: 1477-1483.
Bering B. Miiller W: Interaction of piracetam with several neuro-
transmitter receptors in central nervous system - Relative spe-
cificity for 3H-glutamate sites. Arzneimittelforschung 1985: 35:
1350- 1252.
Buresova 0. Bures J: Piracetam-induced facilitation of interhemi-
spheric transfer of visual information in rats. Psychopharmacol
(Berlin) 1976; 46: 93 - 102.
Canonico PL. Aronica E, Aleppo G. Casabona G. Copani A. Favit A.
Nicoletti E Scapagnini U: Repeated injections of piracetam im-
prove spatial learning and increase the stimulation of inositol
phospholipid hydrolysis by excitatory amino acids in aged rats.
Funct Neurol 1991; G(2): 107 - 111.
Cohen S, Miiller W: Effects of piracetam on N-Methyl-D-Aspartate
receptor properties in the aged mouse brain. Pharmacology
1993: 47: 217 - 222.
Copani A. Genazzani M,Aleppo G. Casabona G, Canonico PL. Sca-
pagnini U, Nicoletti F: Nootropic drugs positively modulate al-
pha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-sen-
sitive glutamate receptors in neuronal cultures. J Neumchem
1992; 58(4): 1199 - 1204.
Creytens G: Nouveautes dans le traitement de la pathologie cerC-
brale. Acta Therapeutica 1980; 6: 33-52.
De Deyn P, De Reuck J, Orgogozo JM, Vlietinck R, Deberdt W: Treat-
ment of acute ischemic stroke wirli piracetam. Stroke 1997: 28:
2347 -2352.
DepresseuxJ. Salmon E, Sadzot B, Cornette M. Franck G: Evaluation
of rhe effect of piracetam on CBF and CMROl in acute stroke pa-
tients, using PET and lSOxygen (abstract). In: Bes A (ed): Senile
Dcmentias. Proceedings of an international symposium organ-
ised by SIR International 1986; Paris. Libby Eurotext. Paris
(1986).
Dimond SJ: Use of a nootropic substance to increase the capacity for
verbal learning and memory in normal man. 3rd Congress of the
International College of Psychosomatic Medicine (1975).
Dunabin M: Cost-effective intervention in stroke. Pharmaco-eco-
nomics 1992; 2(6): 468-499.
Enderby P, Wood VA, Wade DT, Hewer RL: The Frenchay Aphasia
Screening Test: a short simple test for aphasia suitable for non-
specialists. lnt Rehabil Med 1987: 8: 166-170.
Enderby P. Broecloc J, Hospers W, Schildemans F, Deberdt W: Effect
of piracetam on recovery and rehabilitation after stroke. A dou-
ble-blind. placebo-controlled study. Clin Neuropharmacol 1994:
17(4):320 -331.
Giurgea C. Mouravieff-Lesuisse F, Leemans R: CorrPlations Plectro-
pharmacologiques au cours de I'anoxic oxypreve chez le lapin
en repiration libre ou atrificielle. Rev Neurol (Paris) 1970: 122:
484-486.
Giurgea C: Piracetam: nootropic pharmacology of neurointegrative
activity. Current Developments in Psychopharmacology. 319
(1976) 222- 273.
Giurgea C, Moyenoons FE: The pharmacology of callosal transmis-
sion: a general survey. In: Steele, E (ed) Structure and Function of
Cerebral Commisures. Russell: Macmillan Press (1979) pp 283 -
298.
Groterneyer I<, Hofferberth B. Hirschberg M: Normalisierung hyper-
reaktiver Thrombozyten bei Patienten rnit TIA's unter Pirace-
ram? Nervenarzt 1986: 57: 180-183.
Grotta J: Post-stroke management concerns and outcomes. Geriat-
rics 1988; 43: 40-47.
Heiss W, llsen H. Wagner R, Pawlik C.Wienhard K: Remote func-
tional depression of glucose metabolism in stroke and its altera-
tion by activating drugs. In: Heiss W, Phelps N (eds): Positron
Emission Tomography of the Brain. Berlin. Springer-Verlag. Ber-
lin, 1993: 162 - 168.
Herrschaft H: Die Wirkung von Piracetam auf die Gehirndurchblu-
rung des Menschen. Quantitative Regionale Hirndurchblutungs-
messungen bei der akuten zerebralen Ischamie. Med Klin 1978;
73: 195-202.
Herrschaft H: Die Wirksamkeir von Piracetam bei der akuten zere-
bralen lscharnie des Menschen. Klinisch kontrollierte Doppel-
blindstudie Piracetam/lO% Dextran 40 versus 10%Dextran 401
placebo. Med I(lin 1988; 83: 667-677.
Huber W. Willmes I<, Poeck R, Van Vleymen B, Deberdt W: Pitace-
tam in aphasia: a double-blind study. Arch Phys Med Rehabil
1997: 72: 245 - 250.
lndredavik B. Bakke F, Solberg R, Rikseth R, Hasheirn LL. Holme I:
Benefic of a stroke unit: a randomized controlled trial. Stroke
1991; 22: 1026- 1031.
Langhorne P. Williams BO. Cilchrist W. Howie K: Do stroke units
save lives? Lancet 1993: 342: 395 -398.
Mitchell J, Ballard D. Whisnant J. Matchar D: What role do neurolo-
gists play in determining the costs and outcome of stroke pa-
tients? Stroke 1996: 27: 1937- 1943.
Mohr J, Orgogozo JM. Harrison M. Hennerici M. Wahlgren N. Gel-
Downloaded by: National University of Singapore. Copyrighted material.
mers J, Martinez-Vila E. Dycka J, Tettenborn D: Meta-analysis of
the oral nimodipine trials in acute ischemic stroke. Cerebrovasc
Dis 1994; 4: 177-210.
Moriau M, Crasborn L Lavenne-Pardonge E. von Frenckell R. Col-De-
beys CH: Platelet anti-aggregant and rheological properties of pi-
racetam. Arzneimittelforschung 1993: 431(2): 110-118.
Muller WE, Hartmann H, Koch S, Scheuer K, Stoll S: Neurotransmis-
sion in aging - therapeutic aspects. In: Racagni N, Brunelli N,
Langer SZ (eds): Recent advances in the treatment of neurodege-
nerative disorders and cognitive dysfunction. Int Acad Biomed
Drug Res (1994) pp 166 - 173.
Miiller WE. Koch 5. Scheuer K, Rostock 4 Bartsch R: Effects of pira-
cetarn on membrane fluidity in the aged mouse. rat and human
brain. Biochem Pharmacol 1997: 53: 135- 140.
Nalbandian R, Henry R. Burek C. Diglio C, Goldman A.Taylor G. Hoff-
man W: Diminished adherence of sickle erythrocytes to cultured
vascular endothelium by piracetam. Am J Hematol 1983: 15:
147 - 151.
National Institute of Neurological Disorders and Stroke rt-PA Stroke
Study Group. Tissue plasminogen activator for acute ischemic
stroke. N Engl J Med 1995: 333: 1581-5187.
OrgogozoJM. Dartigues J: Clinical trials in brain infarction. In: Bat-
tistini N. Fiorani P, Courbier R. Plum F. Fieschi C (eds): Acute Brain
Ischemia: Medical and Surgical Therapy. Raven Press, New York
(Serono Symposia Publications) 1986: 32: 201 -208.
Pedata F. Moroni F. Pepeu G: Effect of nootropic agents on brain
cholinergic mechanisms. Clin Neuropharmacol 1984: 7: 772-
773.
Peuvot J. Schanck A, Deleers M, Brasseur R: Piracetam-induced
changes to membrane physical properties: a combined approach
by 31 P nuclear magnetic resonance and conformational analysis.
Biochem Pharmacol 1995: 50: 1129- 1134.
Platt D. Horn J. Summa 1-D, Schmitt-Ruth R. Reinlein B. Kauntz J,
Kronert E: Zur Wirksamkeit von Piracetam bei geriatrischen Pa-
tienten mit akuter zerebraler lschamie: eine klinisch kontrol-
lierte Doppelblindstudie. Medwelt 1992: 43: 181 -190.
Stockmans F, Deberdt W, Nystrom A. Nystrom E, StassenJM,Vermy-
len J, Deckmijn H: Inhibitory effect of piracetam on platelet-rich
thrombus formation in an animal model. Thromb Haemostasis
7911 (1998) 222 - 227.
Wade D. Langton-Hewer R: Functional abilities after stroke meas-
urement. natural history and prognosis. J Neurol Neumsurg
Psych 1987: 50: 177- 182 .
Weiller C. lsensee C. Rijntjes M. Huber W. Miiller S. Bier D. Dutschka
K. Woods RP. Noth J, Diener HC: Recovery from Wernicke's apha-
sia: a positron emission tomographic study. Ann Neurol 1995;
37: 723 -732.
Pharmacopsychiat. (Supplement) 1.-M. Orgogozo

Weinstein PR, Anderson GG, Telles DA: Neurological deficit and ce- Corresponding Author
rebral infarction after temporary middle cerebral artery occlu-
sion in unanesthetized cats. Stroke 1986: 17: 318-324. Professor J. M. Orgogozo
Weth G:Influence of piracetam on brain and gut tissue concentra- Service de Neurologie
tion of CAMP. [n: Platt D (ed): Piracetam in der Geriatric. FK Hapita1 Pellegrin
Schattauer Verlag (1982) pp 11- 22. Place Amelie Raba-Leon
Woelk H: Effects of piracetam on the incorporation of 32Pinto the F-33076 Bordeaux
phospholipids of neurons and glial cells isolated from rabbit ce- France
rebral cortex. Pharmacopsychiat 1979; 12: 251 -256.

Downloaded by: National University of Singapore. Copyrighted material.