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Dose-dependent effects of Cerebrolysin on EEG and short-term memory of healthy volunteers during control and hyperventilation induced cerebral ischemia

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Cerebrolysin®, a peptidergic nootropic drug, was to be effective on learning and other cognitive functions in animal experiments as well as in clinical studies. Hyperventilation (HV) as a model of brain ischemia induces slowing of the EEG and cognitive impairment. The aim of this study was to examine the potential dose-dependent effects of Cerebrolysin® on HV related EEG changes and short term memory during chronic (10 days) application and the time dependency of these effects. In this single centre, double blind, randomized, placebo-controlled, parallel group study 48 healthy males were enrolled and received either 100ml placebo (NaCl) or Cerebrolysin® (10 ml or 30 ml or 50 ml) in a volume of 100 ml (NaCl) for 10 days. EEG at baseline and during HV as well as the cognitive performance was evaluated at Day 1 (baseline, 15 min p.i., 2h p.i., 4h p.i., 8h p.i., 24h p.i.), Day 10 (baseline, 15min p.i., 2h p.i.) and at day 11 (24 h. after the last infusion). The main effects found during the study can be summarized as follows: At baseline we found an increase of the EEG power ratio (PR) for the grouptrated with 10 ml Cerebrolysin®. The effect was most pronounced at the parietal cortex. The effect started after 15 min, was most expressed at 2 h and was kept until 8 h. During HV we found a relative PR decrease of the group (10 ml Cerebrolysin®) at 2 hours. For short term memory, there is a trend towards less effective word recall for the baseline situation during the first 4 hours for the placebo. This effect was not observed in the Cerebrolysin® treated groups. If chronic effects are concerned, the PR increased over the parietal regions at 24 h for the groups treated with 10 and 30 ml Cerebrolysin®. The effect remains at day 10 and 11. But at 10 and 11 days there was also a trend for a relative increase of the PR in the group treated with 50 ml Cerebrolysin®. Signs of overdosage occurred with the highest concentrations of Cerebrolysin®. The events were only mild and caused no harm to the volunteers. The highest concentration caused a small but significant reduction of blood pressure. The effects could be interpreted as those of an atypical nootropic with anti-ischemic properties. In this single centre, double blind, randomized, placebo-controlled, parallel group study 48 healthy males were enrolled and received either 100ml placebo (NaCl) or Cerebrolysin® (10ml or 30ml or 50ml) in a volume of 100mi (NaCI) for 10 days. EEG at baseline and during HV as well as the cognitive performance was evaluated at Day 1 (baseline, 15min pj., 2h pj., 4h pj., 8h pj., 24h pj.), Day 10 (baseline, 15min pj., 2h pj.) and at day 11 (24 h. after the last infusion). The main effects found during the study can be summarized as follows: At baseline we found an increase of the EEG power ratio (PR) for the grouptrated with 10ml Cerebrolysin®. The effect was most pronounced at the parietal cortex. The effect started after 15 min, was most expressed at 2 hand was kept until 8h. During HV we found a relative PR decrease of the group (lOml Cerebrolysin®) at 2 hours. For short term memory, there is a trend towards less effective word recall for the baseline situation during the first 4 hours for the placebo. This effect was not observed in the Cerebrolysin® treated groups. If chronic effects are concerned, the PR increased over the parietal regions at 24h for the groups treated with 10 and 30ml Cerebrolysin®. The effect remains at day 10 and 11. But at 10 and 11 days there was also a trend for a relative increase of the PR in the group treated with 50ml Cerebrolysin®. Signs of overdosage occurred with the highest concentrations of Cerebrolysin®. The events were only mild and caused no harm to the volunteers. The highest concentration caused a small but significant reduction of blood pressure. The effects could be interpreted as those of an atypical nootropic with anti-ischemic properties.
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Dose-dependent effects
of
Cerebrolysin® on
EEG
and short term
memory
of
healthy volunteers during control
and
hyperventilation
induced cerebral ischemia
M. Funke!, J. Fiehler!, I. Mewes!, M. EiseJt1, I. Rother!, and M. Windisch2
lInstitut of Pathological Physiology, Friedrich-Schiller-University, Jena,
Federal Republic of Germany
2 EBEWE, Unterach, Austria
Summary. Cerebrolysin®, a peptidergic nootropic drug, was to be effective
on learning and
other
cognitive functions in animal experiments as well as in
clinical studies. Hyperventilation (HV) as a model of brain ischemia induces
slowing of the
EEG
and cognitive impairment. The aim of this study was to
examine the potential dose-dependent effects of Cerebrolysin® on
HV
related
EEG
changes and short term memory during chronic (10 days) application
and the time dependency of these effects.
In this single centre, double blind, randomized, placebo-controlled, paral-
lel group study
48
healthy males were enrolled and received either 100ml
placebo (NaCl)
or
Cerebrolysin® (10ml
or
30ml
or
50ml) in a volume of
100mi (NaCl) for
10
days.
EEG
at baseline and during
HV
as well
as
the
cognitive performance was evaluated at
Day
1 (baseline, 15min
pj.,
2h
pj.,
4h
pj.,
8h
pj.,
24h
pj.),
Day
10 (baseline, 15min
pj.,
2h
pj.)
and at day
11
(24h. after the last infusion).
The main effects found during the study can be summarized as follows:
At
baseline we found an increase
of
the
EEG
power ratio (PR) for the
grouptrated with 10ml Cerebrolysin®. The effect was most pronounced at the
parietal cortex. The effect started after
15
min, was most expressed at 2
hand
was kept until 8
h.
During
HV
we found a relative
PR
decrease of the group
(lOml Cerebrolysin®) at 2 hours.
For
short term memory, there
is
a trend
towards less effective word recall for the baseline situation during the first 4
hours for the placebo. This effect was not observed in the Cerebrolysin®
treated groups.
If
chronic effects are concerned, the
PR
increased over the
parietal regions at
24h
for the groups treated with 10 and 30ml Cerebrolysin®.
The effect remains at day 10 and
11.
But
at
10
and
11
days there was also a
trend for a relative increase of the
PR
in the group treated with 50ml
Cerebrolysin®. Signs of overdosage occurred with the highest concentrations
of Cerebrolysin®. The events were only mild and caused no harm to the
volunteers. The highest concentration caused a small but significant reduction
of blood pressure. The effects could be interpreted as those of an atypical
nootropic with anti-ischemic properties.
K. Jellinger et al. (eds.), Ageing and Dementia
© Springer-Verlag Wien 1998
386
M.
Funke et
al.
Introduction
Cerebrolysin® (Cer)
is
a peptidergic nootropic drug, which has been used for
the treatment of neurodegenerative
as
well
as
vascular dementia, sequelly of
stroke and brain trauma for many years. Because of a complex composition of
different low molecular weight biologically active peptides, the drug
is
acting
in a multimodal way.
It
has been shown that Cer
is
able to influence oxidative
neuronal metabolism (Windisch and Piswanger, 1985a), it
is
modulating syn-
aptic transmission (Baskys and Wojtovicz, 1994) and it
is
additionally resem-
bling neurotrophic stimulation similar to naturally ocurring growth factors
(Satou et
aI.,
1994). Because of this growth promoting action, the drug
is
able
to induce sprouting reactions, most likely increasing overall neuronal plastic-
ity (Wenzel et
aI.,
1977;
Windisch et
aI.,
1994).
It
can be assumed that in this
way the drug
is
inducing long-term adaptations under chronic treatment, but
investigations from Baskys and Wojtovicz (1994) also demonstrated immedi-
ate effects on synaptic plasticity, inducing a biphasic modulation
of
synaptic
transmission with a short inhibition and a long-lasting enhancement of synap-
tic activity in
CAl
region of rat hippocampus. These effects can be attributed
to interaction on presynaptic adenosine receptors (Xiong et
aI.,
1995) as well
as modulation of presynaptic GABA-B receptors (Xiong et
aI.,
1996). Prob-
ably as a result of long and short term influence on neuronal plasticity, the
drug
is
able to improve learning and memory of young (Paier et
aI.,
1992)
and 24-month old memory impaired rats (Paier et
aI.,
1996). Corresponding
findings, documenting amelioration of cognitive deficits after fimbria fornix
transsection, wich
is
leading to degeneration of cholinergic neurons in the
medial septum, have been reported by Francis-Turner et
ai.
(1996), where
they compared the efficacy of intraventricular administered naturally
occuring nerve growth factor (NGF) with the activity of peripherally (intrap-
eritoneally) injected Cerebrolysin®.
In this investigation, Cer
was
more effective in preventing lesion-
dependent memory deficits than NGF. The drug also improved acquisition of
new information, in contrast NGF treatment failed to influence the dis-
turbed learning function.
Similar results have also been demonstrated in clinical trials where Cer
significantly improved memory of patients, suffering from mild to moderate
forms of vascular dementia (Vereshagin et
aI.,
1991)
as
well as in an investiga-
tion about the effects of the drug in patients, suffering from Alzheimer's
disease, where a rapid onset and long-lasting improvement of memory, activi-
ties of daily living and overall function, has been reported (Ruther et
aI.,
1994).
It
cannot be assumed that drugs acting on a nootropic basis may improve
normal function to a "supernormal" one. Thus, a standardised, clinically
relevant and reproducable model of disturbed cerebral function hase to
be used. The effect of hypoxic ischaemia (Saletu et
aI.,
1988)
is
not
pathophysiologicaly relevant because general hypoxia
is
rather related to
accidental injuries
or
pulmonary disease than to diseases of the CNS such as
dementia
or
stroke. The same can be assumed for drug induced deficits
(Kugler et aI., 1990).
Dose-dependent effects of Cerebrolysin® on
EEG
387
Hyperventilation (HV) reduces cerebral blood
flow
by up to 50-60 per
cent (Bednarczyk et al., 1990).
It
models resembles nicely an ischaemic situa-
tion as given in stroke and at least partially in vascular dementia. This serves
as the basis for a model of brain ischemia and
is
widely used in routine
EEG
and pharmaco-EEG approaches (Kraaier et al., 1989).
HV
induces slowing
of
the
EEG
resulting in an increase of delta and theta activities compared to
a decrease or unchanged alpha and beta activities. This can be quantified
by time series analysis like the Fourier transformation.
EEG
and especially
quantitative
EEG
analysis
(qEEG)
are widely used in psychopharmalogical
studies (Saletu, 1988).
The cognitive deficit related to
HV
can be described via the impairment of
short term memory evaluated by a Brown-Petersen Paradigma (Kessler et al.,
1987).
A previous study using a cross-over design for the treatment with Cer
0.03ml/kg, O.lml/kg, O.3mllkg, loOmllkg body weight and placebo in
20
healthy volunteers showed that acute single Cer infusions are not able to
normalize
HV
induced abnnormalities. In contrast, higher concentrations
lead to a decrease of power ratio. The effects were dose-dependent with an
increase of vigilance for Cer
0.1
mllkg body weight. Higher concentrations
(0.3ml/kg body weight and loOmllkg body weight) showed a more sedative
like effect.
It
has to be considered that a time dependence superimposes the
dose-dependent effects.
The aim of this study was to examine the potential dose-dependent effects
of Cer on
HV
related
EEG
changes and short term memory during chronic
(10 days) application and the time dependency of acute effects after infusion.
Material and methods
Subjects and schedule
of
examination
The protocol of this single centre, double blind, randomized, placebo-controlled, parallel
group study was approved by the ethics committee of the Friedrich-Schiller University.
Signed informed consent was obtained before enrolment of each individual.
Forty-eight healthy males (age
20
to
40
years, normal clinical and neurological
status, no major diseases in case history) were enrolled in the study. Prior to the study
each volunteer underwent an extensive physical examination, including laboratory
screening and neurological status. Besides the good health status, good memory
was tested by the California Verbal Learning Test using subtest 1-4
(2::40
correct
answers) and a short delay free recall subtest
(2::7
correct answers) for qualifying for the
study.
Cer
is
a porcine brain derived peptid preparation, produced by standardized enzy-
matic brakedown of lipid free brain proteins.
It
consists of approximately 25% of low
molecular weight peptides, based on the total nitrogen content, stabilized with amino
acids.
For
10
days the volunteers received either 100ml Placebo (NaCl, group PL) or lOml
(group C 10)
or
30ml (group C 30) or 50ml (group C 50) Cerebrolysin® filled up to
a volume of 100ml with NaCl solution. Randomisation to the treatment schedule
was done by the sponsor using an IBM random generator and using random blocks of
16
each.
388
M.
Funke et
al.
EEG
at baseline and during
HV
as
well
as
the cognitive performance
was
evaluated
at Day 1 (baseline,
15
min
pj.,
2
hpj.,
4
hpj.,
8
hpj.,
24
hpj.),
Day
10
(baseline,
15
min
p.i.,
2h
pj.)
and at day
11
(24h. after the last infusion).
EEG. The
EEG
was
recorded
by
a BRAIN-Star
EEG
recording System (Schwind-
Medizintechnik Erlangen). Additionally, 2 channel EOG, the ECG and ventilation were
recorded for artifact detection.
I reference I
EEG Psych o H
+ Psycho
/
//
/
I I I 1, 1
-00:20 ·00:10 00 :00 00:10 -00:20 00:30 24:00
Time in min.
rrn \ .
24:00 p.l.
00:00 02:00 p.i 04:00 p.i. 08:00 p.i.
Time in min.
HV
Hyperventilation
I day
11
I
EEG P
syc
ho
HV·
+
Psycho
f
((«:~\~"
I
-00:20
·00
:1
0 00:00 00
:1
0 -00:20 00:30 24:00
Time in min.
00:00 02 :00 p. i 04 :00 p.i. 06:00 p.i. 08:00 p.
i.
\ -
24
:00 p.l.
Time in min.
HV -Hyperventilation
Fig.
1.
Schedule of examination, upper part for day
land
2,
lower part for day
10
and
11
Dose-dependent effects
of
Cerebrolysin®
on
EEG
389
9 silver/silver chloride electrodes were attached according to the positions
of
the
international 10/20 system (F3, F4, C3, C4, P3, P4,
01,
02,
Cz).
The
skin was pretreated
to achieve resistance
of
1-5kOhm.
EEG
was recorded with
an
linked mastoid reference,
a time constant
of
0.3
seconds, and
an
upper cut off frequency
of
70 Hz. Artifacts due to
eye blinks, sweating, movements
or
muscle activity were reduced by a
proper
instruction
of
the volunteers.
The
following bipolar
EEG
derivations were used for the analysis:
1.
F3-C3
5.
F4-C4
2.
C3-Cz
6.
C4-Cz
3.
C3-P3
7.
C4-P4
4.
P3-01
8.
P4-02
The
EEG
was digitized with a sampling
rate
of
256 seconds.
After
careful inspection for
artefact free epochs, intervals
of
2 seconds containing 512
data
points were selected.
These intervals underwent Fast Fourier Transformation.The spectral power within the
traditional frequency bands were summarised: delta (1.5
Hz-4
Hz),
theta
(4Hz-8Hz),
alpha
(8Hz-13Hz)
and
beta
(13Hz-20Hz).
The
power ratio
(PR)
as defined by the ratio
of
(delta + theta)/(alpha + beta) was
used for the analysis.
An
increase
of
the
PR
indicates
EEG
slowing
an
decrease
of
PR
indicates
EEG
desynchronisation.
Hyperventilation.
The
subject was connected with
an
infra-red gas analyser
NORMOKAP
CD
200 (Hoyer, Germany) to record the end-tidal
pC0
2 continuously.
The
investigator instructed the volunteer how
to
breath
to achieve a
pC0
2
of
at
least
2.0kPa.
The
subject started to hyperventilate under the experimeters continuous control
of
instantaneous
pC0
2
When
achieved a
pC0
2
of
2.0kPa (after about 2min) the hyper-
ventilation was continued for additional 3 min and the simultaneous registration
of
the
EEG
was started.
Cognitive test.
For
cognitive testing
of
short-term memory five runs
of
a Brown
Petersen Paradigm (Kessler
et
ai., 1987) were used.
For
one
run
six nouns with 1-3
syllable were presented by audiotape. These nouns were standardized with respect to
imaginary, concreteness and meaningfulness (Baschek
et
ai., 1977). This was followed by
20sec
of
calculation
-7:
+5;
-7;
+5
etc. starting with a number greater 100.
Then
the
volunteer was asked for the nouns presented first
The
number
of
correctly remembered words (maximum 30) as well as the number
of
calculation steps were documented.
Data processing
and
statistics
The
baseline
EEG
and the
HV
induced
EEG
reactions were related to the value
of
the
reference situation before the first infusion, expressed as relative
PR
changes in %.
The
relativ
PR
changes were calculated for the following situations:
acute effects (day 1)
-1I4h (15 min) p.i.
-
2h
-
4h
-
8h
chronic effects
-day 2 (before the 2nd infusion, corresponds to the
24
h acute effect at day 1)
-day 10 (before 10th infusion)
-day
11
(24h after the 10
th
infusion)
For
the Brown-Petersen-Paradigm absolute changes compared to the reference values
were used
to
test for treatment differences.
Efficacy criteria were compared using a unifactorial analysis
of
variance
(ANOVA)
data. Test for overall differences between treatment groups (degrees
of
freedom 3) was
390
M.
Funke et
al.
done at a significance level of
0.1
to indicate trends. Testing for differences between the
single groups was done using the least significant difference (LSD) method at a level of
p < 0.05.
Results
Acute effects
Baseline.
If
all electrodes
are
considered we found a
trend
of
increasing
PR
for
the
group
C 10
at
15 min. This
trend
became
significant
after
2 h. Significance
was lost
at
4
to
8 h,
but
still we found a nonsignificant increase
of
the
PR.
The
trend
of
an
increase
of
the
PR
started
after
15
min
over
the
parietal
cortex
and
was
most
pronounced
at
2 h
over
the
parietal
cortex. A significant
increase
of
the
PR
was found in C3-P3,
P3-01,
C4-P4
and
P4-02.
This in-
crease
remained
significant
even
after
8
hours
at
C4-P4
and
a
trend
was still
seen
after
8h
at
P4-02
(Fig. 2).
For
the
baseline situation (Fig. 3)
there
was a
trend
towards
less effective
word
recall during
the
first 4
hours
for
the
placebo
group. This effect was
not
found
in all groups
treated
with Cer.
No
dosage difference could
be
found.
HV.
In
contrast
to
the
observed
baseline results, in
the
group
treated
with
10ml
Cerebrolysin®
decreased
the
relative change
of
the
PR
during hyperven-
tilation
after
an
general
increase
of
the
PR
at
15
min
(Fig. 4). This effect was
also
most
prominent
over
the
parietal
cortex with a significant
maximum
of
60
40
.....
::.e
:....
20
0
:;:I
III
...
...
GI
~
0
0
Q.
<l
-20
-40
Acute
effects
on
baseline
EEG
(P4-02)
15'
2h
4h
time (h)
8h
OPL
.C10
~C30
.CSO
Fig.
2.
Time dependence of acute effects on baseline
EEG
(Mean ± SEM, *p
;:::
0.05) of
the P4-02 derivation (PL placebo group, C
10,
C
30,
C 50 Cerebrolysin® groups)
Dose-dependent
effects
of
Cerebrolysin®
on
EEG
Acute effect on baseline cognitive test
4~
______
~_._.
. .
________
_
31
2
-4
"_
1/4
h
* *
-------------
2h
4h
time (h)
8h
24h
391
I
io-Pil
.•
C101
ElC30j
.cso.
Fig. 3. Time
dependence
of
acute effects
on
baseline cognitive test
(Mean
± SEM, *p
;:::
0.05,
PL
placebo group, C
10,
C
30,
C 50 Cerebrolysin® groups)
140
100
.-
60
~
~
0
~
20
I!
..
III
~
-20
0
a.
<l
-60
-100
-140
Acute effects on hyperventilation EEG
(P4-02)
15'
2h
time (h) 4h 8h
IOPL
-
IIII
C10
i
El
C30
..
CSO
Fig. 4. Time
dependence
of
acute effects
on
hyperventilation
EEG
(Mean
± SEM, *p
;:::
0.05)
of
the P4-02 derivation (PL placebo group, C
10,
C
30,
C 50 Cerebrolysin® groups)
392
M.
Funke et
al.
the effect at 2h. The effect was also seen to a smaller, nonsignificant extent for
the group treated with 30ml Cer.
Chronic effects
Baseline. There was already a relative increase of the
PR
over the parietal
regions at
24h
(day 1) for the groups C
10
and C
30.
The effect remained
constant at the days
10
and
11,
but there was also a trend for a relative increase
of the
PR
in the group C
50
(Fig. 5).
There was a trend towards better performance for all treated groups at
10th and 11th day for the cognitive word test (Fig. 6).
HV.
At
24h
the
PR
decreased significantly for both centro-parietal deriva-
tions. The effect was found for all concentrations, but was most pronounced
for the group C
30
(Fig. 7). The effect could not been reproduced after 10 or
11
days.
No effect of treatment was found for the Brown-Petersen paradigm.
Tolerability.
At
day 1 after
15
minutes an increase in the systolic blood
pressure of 2.50 ± 3.17mmHg (Mean ± SEM) for the group treated with
50ml Cerebrolysin was found. There were no changes in blood pressure
immediately
after
the infusion. This was valid
as
well for the days 2-9.
At
the
10th day we found a significant decrease of the systolic blood pressure of 8.64
± 3.10mmHg (Mean ± SEM, P
:2:
0.05) at 15min after the infusion for the
group treated with the highest dose of Cer which still could be found 24h
pj.
There was no effect on the heart rate.
60
40
-
~
~
20
0
~
I!
...
; 0
0
a.
<I
-20
-40
Chronic effects
on
baseline EEG (C4-P4)
day 1
*
day 10
time (days)
day11
oPI
IIII
C10
m
C30
IIIC50
Fig. 5. Time dependence of chronic effects on baseline
EEG
(Mean ± SEM,
*p
2::
0.05)
of the C4-P4 derivation (PL placebo group, C
10,
C
30,
C 50 Cerebrolysin® groups)
6
5
4
..
l!
~
~
3
~
I 2
'0
~
1
I!!
;!!
c 0
-1
-2
day
1
Dose-dependent effects of Cerebrolysin® on
EEG
Chronic effect on baseline cognitive test
day
10
lime
(days)
day
11
393
Fig.
6.
Time dependence of chronic effects on baseline cognitive test (Mean ± SEM,
*p
2::
0.05,
PL
placebo group, C
10,
C
30,
C 50 Cerebrolysin® groups)
Withdrawals/adverse events (AE). There were no Cer related drop
outs.
At
about 2 min after starting the first infusion one placebo volunteer
developed hypotension with loss of consciouness which was felt to be
potentially drug related and led to withdrawal.
Another
volunteer suffered
Chronic effects on hyperventilation EEG (C4-P4)
140
100
......
60
~
0
;;
20
I!
..
GI
~
-20
0
CI.
oPI
<I
-60 II C10
eC30
-100
III
C50
-140
day 1 day 10
time {days)
day11
Fig.
7.
Time dependence
of
chronic effects on hyperventilation
EEG
(Mean ± SEM,
*p
2::
0.05) of the C4-P4 derivation
(PL
placebo group, C
10,
C
30,
C 50 Cerebrolysin®
groups)
394 M. Funke et al.
Table 1. Adverse events possibly drug related as reported
during the study
Group
Code day Adverse event
Placebo
P02
1 loss of consciouness
lOml
P08
1 dizziness
P 30 2
hot
flushing
at
injection side
P 34 4 sleep disturbances
30ml
P22
2 sleep disturbances
50ml P
05
2 hed ache
P21
4 flushing, back of head
P 36 8 warm feelings in
GI
tract
9 warm feelings in
GI
tract
10 warm feelings in renal region
P44
1 taste sensation
2 taste sensation
5 taste sensation
6 taste sensation
7 taste sensation
8 taste sensation
9 taste sensation
10
taste sensation
a pneumonia not considered to be drug related and was withdrawn
as
well.
Adverse events (Table 1) at least possibly related to the studied drug were
reported for one placebo subject (see withdrawal); for 3 subjects in the group
C
10
(single events) and one subject in the group C
30
(1
event). In the group
C
50
four subjects reported
AE
possibly related to study drug. In two of the
subjects the events recurred during the course of treatment consistantly. The
possibly drug related events were mild and transient and did not caused harm
to the volunteers.
Dicussion and conclusion
Traditional psychotropic drugs like neuroleptics, antidepressants, anxiolytics
and psycho stimulants can be discriminated by their effects on the human
EEG. For neuroleptics an increase of delta/theta activity with an decrease of
beta activity can be found. The effect
is
similar to antidepressants with
the same increase of the slow frequencies, but with a decrease of alpha
rather than beta activity. Anxiolytics show a slight decrease of delta/theta
activity combined with an increase of beta activity. Psychostimulants like
dextroamphetamine, methylphenidate shows a week increase of alpha activity
only. The direct
EEG
effects are less expressed for this classical type of
psychotropic drugs (for review see Hermann et al., 1978).
Dose-dependent effects of Cerebrolysin®
on
EEG
395
In this study, Cer caused an increase of delta/theta activity with loss of the
fast frequencies resulting in an increase of the
PR
relative to placebo in the
baseline
EEG
for the group C
10.
The effect started frontally after 15min,
but was most pronounced parietally at 2h. The effect was kept
until8h
after
infusion.
For
the group C 50 we found an increase of the
EEG
spectral power
for all frequency bands.
The effects for the group C 10 are different to those found for typical
nootropic drugs like pyritinol (Saletu et al., 1988), phosphatidylserine
(Rosadini
et
al., 1990)
or
aniracetam (Kraaier
et
al., 1989) where a decrease of
EEG
slow wave activity
or
no effects were reported for the spontaneous
EEG
in healthy volunteers. The effects shown for group treatet with lOml Cer are
similar to those shown for typical neuroleptics and antidepressants (Hermann
et
al., 1978), but were recently shown as well for atypical neuroprotective
drugs like caroverine (calcium channel blocker, antiglutaminergic; Saletu
et
al., 1995a).
For the Brown-Peterson paradigm there
is
a trend towards less effective
word recall during the first 4 hours for the placebo group for the baseline
situation. This might be related to an increase of tiredness during the 8 hours
lasting session. This effect was prohibited by all Cer concentrations with no
difference between dosages.
These effects combined with an increase of spectral power of the
slow
EEG
frequencies were shown
as
well for caroverine (Saletu,
1995
a), but
also other psychotropic compounds like the non-tricyclic antidepressant
venlafaxine (Saletu, 1992).
During hyperventilation Cer (group C 10) decreased the relative change of
the
PR
during hyperventilation over the parietal cortex with a clear maximum
of the effect at 2
h.
These effects on the
PR
are mostly due to a relative
increase of the alpha-, beta activity in the group C
10.
These effects are consist ant with effects shown in the human hypoxia
model by Saletu et al., for typical nootropic drugs like pyritinol (Saletu, 1988),
piracetam (Saletu
et
al., 1995b) and nicergolin (Saletu
et
al., 1990) but
also for the neuroprotectant caroverine (Saletu, 1996).
The
same effects
were described in the
HV
(ischemia) model of Kraaier
et
al. for nootropics
(aniracetam,
3-0H
aniracetam: Kraaier
et
al., 1989) and the Ca-antagonist
nimodipine (Kraaier et al., 1991).
In this small sample size no effect was found for the
HV
induced decrease
of word recall.
If
chronic treament effects are concerned, an increase of the
PR
in the
parietal regions was found already after
24h
for the groups trated with 10 and
30ml Cer. The effect remains after 10 and
11
days. But at 10 and
11
days there
is
also a trend for a relative increase of the
PR
in the group C
50.
At
baseline, there
is
a trend towards better performance in the short term
memory test for all treatment groups after 10 and
11
days.
For
HV
induced effects the
PR
decreased significantly for both centro-
parietal leads for all dosages at day
1.
This effect could not
been
reproduced
at day
10
and
11.
The short term memory showed no effect of the Cer
treatment on
HV
related changes. The reduction of
HV
induced
EEG
slow
396 M. Funke et al.
wave activity at day 1 and after
24
h
is
consist ant with an antiischemicl
antihypoxic effect. This corresponds to the findings
of
Iakhno et
aL
(1996)
on
effects in patients suffering from vascular dementia. Since the effect was not
seen at day 10 and
11,
it remains open whether this indicates a conditioning
effect on the
HV
induced reaction by the infusion series (that hardly could
be
influenced in healthy volunteers)
or
loss of effectivness of Cer on the
HV
induced changes.
Signs
of
overdosage (adverse events, drop in systolic blood pressure)
occurred with the highest concentrations
of
Cer especially towards the end
of the infusion series. The events were only mild and caused no harm
to
the
volunteers.
But
due to the different effects on the
EEG
as for the highest
concentration
(SOml
Cer) as compared to the lower dosages, these effects
could be considered as a mixture
of
direct psychotropic effects and signs
of
overdosage.
In summary, Cer showed psychotropic activity for the concentration range
tested. The effects for the group C
10
(acute and chronic) as well as the group
C
30
(chronic) differ from those of typical nootropics but are consist ant with
other drugs like neuroprotectants with antiglutaminergic, calcium antagonis-
tic properties
or
non tricyclic antidepressants. The dominant findings are an
paradoxical increase of the
EEG
power ratio indicating
EEG
slowing to-
gether with an trend to an improvement in vigilance. The method
of
the study
does not allow to characterize the specific neuropharmacologic profile of the
drug.
The reduction of
HV
induced
EEG
slow wave activity at day 1 and after
24h
is
consist ant with an antiischemic/antihypoxic effect.
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Authors' address: Dr.
M.
Funke, Institute of Pathological Physiology, Friedrich-
Schiller-University, Philosophenweg 3, D-07740 Jena, Federal Republic of Germany
... Он стимулирует процессы нейрогенеза и нейропластичности, способствует дифференциации нейронов, росту дендритов, восстановлению шипиков и синапсов, разрастанию и ветвлению аксонов нервных клеток. Церебролизин активизирует нейрорегенерацию при нейродегенеративных заболеваниях [10], травматических [11,12] и сосудистых [13] поражениях головного мозга в разных возрастных группах, улучшает нарушенные когнитивные функции, в том числе память и внимание, у здоровых [13,14], повышает настроение пациентов при разных формах нервно-психической патологии, сопровождающихся депрессивными расстройствами [3, 6, 9-12, 15, 16]. Одним из показаний к применению церебролизина (в составе комплексной терапии) является эндогенная депрессия в случаях недоста-точной эффективности антидепрессантов или фармакорезистентности [15,16]. ...
... Он стимулирует процессы нейрогенеза и нейропластичности, способствует дифференциации нейронов, росту дендритов, восстановлению шипиков и синапсов, разрастанию и ветвлению аксонов нервных клеток. Церебролизин активизирует нейрорегенерацию при нейродегенеративных заболеваниях [10], травматических [11,12] и сосудистых [13] поражениях головного мозга в разных возрастных группах, улучшает нарушенные когнитивные функции, в том числе память и внимание, у здоровых [13,14], повышает настроение пациентов при разных формах нервно-психической патологии, сопровождающихся депрессивными расстройствами [3, 6, 9-12, 15, 16]. Одним из показаний к применению церебролизина (в составе комплексной терапии) является эндогенная депрессия в случаях недоста-точной эффективности антидепрессантов или фармакорезистентности [15,16]. ...
... Аналогичное увеличение выраженности и нормализация частотной структуры теменно-затылочного α-ритма при терапии церебролизином ранее отмечались при улучшении когнитивных функций у здоровых пожилых людей [13,14], терапии отдаленных астенодепрессивных последствий черепно-мозговой травмы у подростков [11,12], а также в процессе лечения синдрома Ретта у детей [20]. Таким образом, количественные данные ЭЭГ подтверждают, что церебролизин заметно улучшает функциональное состояние головного мозга как при изолированном применении, так и в комбинации с антидепрессантами при лечении депрессии. ...
... Он стимулирует процессы нейрогенеза и нейропластичности, способствует дифференциации нейронов, росту дендритов, восстановлению шипиков и синапсов, разрастанию и ветвлению аксонов нервных клеток. Церебролизин активизирует нейрорегенерацию при нейродегенеративных заболеваниях [10], травматических [11,12] и сосудистых [13] поражениях головного мозга в разных возрастных группах, улучшает нарушенные когнитивные функции, в том числе память и внимание, у здоровых [13,14], повышает настроение пациентов при разных формах нервно-психической патологии, сопровождающихся депрессивными расстройствами [3, 6, 9-12, 15, 16]. Одним из показаний к применению церебролизина (в составе комплексной терапии) является эндогенная депрессия в случаях недоста-точной эффективности антидепрессантов или фармакорезистентности [15,16]. ...
... Он стимулирует процессы нейрогенеза и нейропластичности, способствует дифференциации нейронов, росту дендритов, восстановлению шипиков и синапсов, разрастанию и ветвлению аксонов нервных клеток. Церебролизин активизирует нейрорегенерацию при нейродегенеративных заболеваниях [10], травматических [11,12] и сосудистых [13] поражениях головного мозга в разных возрастных группах, улучшает нарушенные когнитивные функции, в том числе память и внимание, у здоровых [13,14], повышает настроение пациентов при разных формах нервно-психической патологии, сопровождающихся депрессивными расстройствами [3, 6, 9-12, 15, 16]. Одним из показаний к применению церебролизина (в составе комплексной терапии) является эндогенная депрессия в случаях недоста-точной эффективности антидепрессантов или фармакорезистентности [15,16]. ...
... Аналогичное увеличение выраженности и нормализация частотной структуры теменно-затылочного α-ритма при терапии церебролизином ранее отмечались при улучшении когнитивных функций у здоровых пожилых людей [13,14], терапии отдаленных астенодепрессивных последствий черепно-мозговой травмы у подростков [11,12], а также в процессе лечения синдрома Ретта у детей [20]. Таким образом, количественные данные ЭЭГ подтверждают, что церебролизин заметно улучшает функциональное состояние головного мозга как при изолированном применении, так и в комбинации с антидепрессантами при лечении депрессии. ...
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Objective. To perform a comparative analysis of changes in the functional status of the brain by quantitative electroencephalography (EEG) during combined antidepressant treatment (venlafaxine and Cerebrolysin) and monotherapy (venlafaxine) of elderly patients with depression. Materials and methods. A total of 40 patients aged 60–79 (mean 67.1 ± 5.7) years took part in the study and were randomized to two groups. Patients of group 1 received venlafaxine at a dose of 75–150 mg/day for four weeks. Patients of group 2 received venlafaxine for four weeks along with Cerebrolysin (20 i.v. drip infusions of 20.0 ml in 100 ml of isotonic NaCl solution). Results and discussion. Both groups of patients noted signifi cant improvements in status by the end of treatment courses in terms of clinical assessment and the HAMD-17, CGI-S, CGI-I, and MMSE scales. Quantitative EEG studies showed that combined therapy with venlafaxine and Cerebrolysin in patients of group 2 led to more marked improvements in the functional state of the brain (increases in spectral power and normalization of the frequency of the parietal-occipital α rhythm) than seen in patients of group 1, who received monotherapy with venlafaxine.
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... Using standardised and validated assessment scales, Ladurner et al. (17) reported significant improvement of motor functions, clinical global state, cognitive performance and activities of daily living in patients treated with Cerebrolysin in comparison with controls receiving standard care. These findings were supported by the results of several other small feasibility studies including electrophysiological monitoring (18). All previous data also supported a high safety profile with an extended time window and application of the drug over several weeks. ...
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Cerebrolysin has exhibited neuroprotective as well as neurotrophic properties in various animal models of cerebral ischaemia and has shown clinical efficacy and good safety in several small controlled clinical studies in ischaemic stroke. Therefore, a large double-blind placebo-controlled randomized clinical trial was launched in Asia to prove the validity of this treatment strategy. In the more than 50 participating centres patients with acute ischemic hemispheric stroke are randomized within 12 hours of symptoms onset to treatment (30 ml Cerebrolysin diluted in physiologic saline) or placebo (saline) given as intravenous infusion once daily added to standard care for 10 days. The patients are followed with regular visits for 90 days. Efficacy is evaluated on day 90 by three outcome scales - modified Rankin Scale, Barthel Index and NIH Stroke Scale - combined to single global directional test. Additionally, adverse events are documented to prove safety. In this study a total of 1060 patients will be included and analysis of data will be completed in 2010. If positive, this trial will add an effective strategy to the treatment of acute ischaemic stroke.
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Objective: To compare the changes in brain functional state in combined antidepressive treatment (venlafaxine plus cerebrolysin) vs. monotherapy with the same antidepressant in elderly depressive patients using quantitative EEG methods. Material and methods: Forty patients, aged 60-79 years, mean 67.1±5.7) were randomized to two groups. Patients of group 1 were treated with venlafaxine (4 weeks, in dose of 75-150 mg/day). Patients of group 2 were additionally treated with cerebrolysin (totally 20 i/v infusions during 4 weeks, 20.0 ml in 100 ml isotonic NaCl solution). Results and conclusion: The significant improvement of clinical conditions was shown by the end of the treatment course using both clinical assessments and HAMD-17, CGI-S, CGI-I and MMSE scores in both groups. The combined treatment with venlafaxine and cerebrolysin in patients of group 2 led to more pronounced improvement of their brain functional state (seen as an increase of spectral power and normalization of frequency alpha band of parietal-occipital EEG) in comparison with patients of group 2 treated by the same antidepressant alone.
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This is to review current clinical and experimental studies giving data about safety and efficacy of cerebrolysin (cere) in the therapy of mental and neurological disorders. Cere is a mixture of peptides and aminoacids of animal origin, which is used in the therapy of organic, metabolic and neurodegenerative brain diseases. Cere shows neurotrophic activity, which results from it’s neuroprotective and neuroregenerative effects. Presented clinical studies concern Alzheimer disease (AD), vascular dementia (VaD), stroke, traumatic brain injury (TBI), and two studies containing small groups of patients with Asperger syndrome, childhood autism and progressive supranuclear palsy. Here presented experimental studies suggest possible mechanisms of the drug’s action. Key words: cerebrolysin, efficacy, safety
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Cerebrolysin is a neuropeptide preparation mimicking the action of endogenous neurotrophic factors. Positive effects of Cerebrolysin on β-amyloid- and tau-related pathologies, neuroinflammation, neurotrophic factors, oxidative stress, excitotoxicity, neurotransmission, brain metabolism, neuroplasticity, neuronal apoptosis and degeneration, neurogenesis and cognition were demonstrated in experimental conditions. These pleiotropic effects of Cerebrolysin on Alzheimer's disease-related pathogenic events are consistent with a neurotrophic-like mode of action, and seems to involve the activation of the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3 β intracellular signaling pathway. The clinical efficacy of Cerebrolysin in Alzheimer's disease was evaluated in several randomized, double-blind, clinical trials, showing consistent benefits on global clinical function and cognition, improvements in behavior at high doses, and minor effects on daily living activities in patients with mild to moderate Alzheimer's disease, as well as in subgroups of moderate to moderately severe patients. In addition, the clinical benefits of Cerebrolysin were largely maintained for several months after ending treatment, a finding that supports its discontinuous administration. Cerebrolysin was generally well tolerated and did not induce significant adverse events in Alzheimer's patients. Although long-term studies are needed, the data available suggest that Cerebrolysin is effective as monotherapy and constitutes a promising option for combined therapy in Alzheimer's disease.
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GABAB receptors form the basis of a powerful and versatile inhibitory system in the mammalian brain. Presynaptic and postsynaptic actions of GABAB receptors have been described in various brain regions, including the hippocampus. We report here on a novel pharmacological agent, presumably a peptide, which inhibits synaptic transmission in the CA1 area of the rat hippocampus via GABAB receptors. The agent is a component of a nootropic drug, CerebrolysinTM, obtained from pig's brain extract. In contrast to other, presently known agonists, such as baclofen or GABA, CerebrolysinTM acts preferentially on presynaptic GABAB receptors and has no detectable postsynaptic inhibitory effects. Additional, postsynaptic depolarizing action of the drug resulting in increased excitability is pharmacologically distinct from the GABAB response and partially masked by the inhibition. The presynaptic GABAB agonist may add to clinical effects of CerebrolysinTM in treatment of brain injuries. Moreover, it promises to be a useful experimental agent in further studies of many possible functional roles of GABAB receptors.
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1. In a double-blind, placebo-controlled study the effects of venlafaxine--a novel nontricyclic compound inhibiting neuronal uptake of serotonin, noradrenaline and to a lesser extent dopamine--were investigated utilizing EEG brain mapping, psychometric and psychophysiological measures. 2. Sixteen healthy volunteers (eight males, eight females) aged 21-36 years received randomized and at weekly intervals single oral doses of placebo, 12.5 mg, 25 mg and 50 mg venlafaxine. EEG recordings, psychometric and psychophysiological tests, and evaluation of pulse, blood pressure and side-effects were carried out at 0, 2, 4, 6, and 8 h. 3. EEG brain mapping demonstrated that venlafaxine exerted a significant action on human brain function as compared with placebo at all three doses, characterized mostly by attenuation of absolute power, increase of relative delta/theta and beta, and decrease of alpha power, as well as by an acceleration of the total centroid fronto-temporally and by its slowing centrally and parietally. These findings are similar to antidepressants such as imipramine. Topographically, drug-induced alterations were most pronounced over both fronto-temporal and the right temporal to temporo-occipital regions. 4. Psychometric and psychophysiological investigations demonstrated significant dose-dependent psychotropic properties of the drug. Multivariate statistics exhibited an improvement of both the noopsyche (e.g. attention, concentration, attention variability, memory, fine motor activity, reaction time performance) and thymopsyche (e.g. drive, wakefulness)) but also significant psychophysiological activation (e.g. in c.f.f., pupillary and skin conductance measures). 5. Time-efficiency calculations showed significant central effects from the 2nd hour onwards, with increasing differences between placebo and treatment up to the 8th hour. Nausea was the most frequent complaint and appeared dose dependent.
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The acute efficacy of single oral dosages of 20 psychotropic drugs, 5 neuroleptics, 5 anxiolytics, 5 antidepressants and 5 psychostimulants plus 5 placebos has been tested in 5 basic studies simultaneously designed and performed and involving 75 healthy male volunteers. Each study was done in a Latin square double-blind design with 15 subjects, each receiving one placebo and one compound of each of the four clinical therapeutic psychotropic drug classes. Three 5-minute EEG recordings (pre, 1 hr. and 3 hr. post drug intake) are taken to represent the drug effects. The differences in drug efficacy were tested by multivariate analysis of variance using 3 × 7 power spectrum estimates selected from these 3 EEG recordings. 14 of the 20 substances could be distinguished from placebo at a 5%, 16 at a 10% level. In order to demonstrate the results visually, examples of the mean relative power estimates as well as the standard q-score profiles of the 7 variables at three times are given. All 7 variables selected contribute to the differences between the drugs. However, some variables seem to be more specific for a defined drug class than others:υ = 5.5 – 8.5 Hz for the neuroleptics, β1F = 12.0 – 18.0 Hz for the anxiolytics, α1F = 8.5 – 10.5 Hz for the psychostimulants and a combination of δF = 1.5 – 3.5 Hz, lF and α1F for the antidepressants.
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This study examined the neurotrophic-like effects of FPF-1070 (Fujimoto-diagnostic, INC.), produced by enzymatic hydrolysis of pig brain protein on the cultured neurons from the chicken embryonic dorsal root ganglia. Cell suspension (1 ml), adjusted to 3 x 103 cells/ml, was added to each well of 24-well multi well plates for tissue culture which was then cultured in a CO2 incubator. FPF-1070, nerve growth factor (NGF) or phosphate-buffered saline, pH 7.4 (PBS) was added to the culture medium. The culture plates were observed with a phase contrast microscope 12, 24, 48 and 96 hours after the start of the culture followed by fixation with 3% formaldehyde and the indirect method of immunohistochemical staining using the anti-neurofilament monoclonal antibody as the first antibody. The number of neurons with extended nerve fibers was counted in each well 96 hours after the start of culture. Neurons with extended nerve fibers were observed in the cultures with FPF-1070 and NGF although no such neurons were noted in the cultures with PBS. Nerve fiber elongation was first detected 12 hours after the start of the culture with NGF and 12 hours later in the culture with FPF-1070. The culture with FPF-1070 showed smaller clumps of neurons which had nerve fibers smaller in number and thinner than the culture with NGF. The number of neurons with extended nerve fibers was significantly smaller in the culture with FPF-1070 than in that with NGF. These findings revealed FPF-1070 have the neurotrophic-like effects to the neurons although its effects on survival, sustenance and fiber elongation of neurons was not as strong as those of NGF.
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By means of electron microscopic and quantitative methods a synthetic mixture of amino acids and the brain hydrolysat 'Cerebrolysin' were tested on the explantate cultures of the hippocampus in vitro (explants of the hippocampus of 18 days old fetal rats; age of explants 3 and 13 days in vitro). The influence of these drugs on the in vitro differentiation of the free and membrane-bound ribosomes and polysomes within the neurons and on the synaptogenesis at the explants was investigated. The drugs in vitro significantly stimulate the differentiation and the maturation of the neurons compared to the controls. After the application of the amino acids and 'Cerebrolysin' the total of ribosomes significantly was increased upon 3 days by 40% resp. 30% and after 13 days by 30%. In the effect no significant distinction consists between the two drugs; the synthetic mixture of amino acids particularly effects an increase of the free and membrane-bound ribosomes, whereas 'Cerebrolysin' specially increases the membrane-bound ribosomes and the polysomes. The synaptogenesis at the cultivated explants of the hippocampus begins on the third day in vitro. Besides the desmosome-like contacts axo-somatic, axo-dendritic and axo-spinodendritic synapses were seen.
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The effects of two subcutaneously injected peptide solutions CERE (100 mg/kg b. wt.) and E021 (1 mg/kg b. wt.) and of 0.9% saline on passive avoidance reaction (PAR) of young rats were examined. Animals were trained and tested in a step-through avoidance task using a footshock of 0.5 mA or 1 mA. Step-through latencies were observed up to 200 s and from these data the percentage of good learners (latency = 200 s) and bad learners (latency < 200 s) was calculated. Two experimental schedules were performed (n > 6). In Expt. 1 rat pups were chronically treated with the substances within the first 7 days after birth. In Expt. 2 the 7 days of treatment started in the 4th postnatal week. In both experiments PAR acquisition was trained on the 28th day after birth (learning trial), PAR extinction testing started on the 29th day (retention trials). After applying a 0.5-mA footshock, rat pups treated with E021 within the first 7 days of life (Expt. 1) displayed significantly slower PAR extinction when compared to saline- and CERE-treated rats. In the 1 mA groups, significant differences in step-through latencies were measured between 0.9% saline- and E021-pretreated animals on retention day 11 and between saline and CERE on retention days 9 and 13. E021-treated rats of Expt. 2, receiving a footshock intensity of 0.5 mA, showed significant lower step-through latencies when compared to E021-treated rats of Expt. 1. In Expt. 2 no significant differences between treatment groups were observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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The randomized double-blind placebo-controlled study of the effectiveness of cerebrolysin in a mild form of multi-infarct dementia was carried out. Sixty patients were divided in two equal groups differing significantly at the beginning of the study by none of the compared parameters. They received for 28 days daily drop intravenous doses of cerebrolysin (15 ml of the drug in 200 ml of a 0.85% NaCl solution: 10 ml in the morning and 5 ml in the evening) or placebo in the same amount of the solution. The control of the therapy effectiveness was instituted clinically (by means of a special scale), electroencephalographically, and using the psychological test of Arnold-Kohlmann and the test for response time. The study found a significant improvement of the memory (p-0.01), abstract thinking and time of reaction in the patients on cerebrolysin, confirmed also by the EEG-mapping. It is believed advisable to use the drug cerebrolysin in mild forms of multi-infarct dementia.
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The anti-ischaemic properties of nimodipine 30 mg and 60 mg t.i.d. for 4 days has been tested in a double-blind, placebo-controlled, cross-over study based on the use of hyperventilation to reduce flow velocity in cerebral arteries. Whether the anti-ischaemic properties were due to a vasodilatator action on cerebral blood vessels or to an anti-ischaemic effect on cerebral neurons was studied. There was a slight cardiovascular effect, without any significant change in the EEG at rest. During standardized hyperventilation, there was no difference in the reduction in the blood flow velocity in the nimodipine and placebo groups (namely 56%, 56% and 59%). Both doses of nimodipine, however, significantly attenuated the hyperventilation-induced increase in slow EEG activity in the 1.5-6.0 Hz range. It is concluded that the anti-ischaemic properties of nimodipine are due to an effect on the central nervous system rather than to an effect on cerebral blood flow.
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In a double-blind, placebo-controlled trial human brain function and mental performance as well as the antihypoxidotic properties of nicergoline were studied utilizing blood gas analysis, EEG brain mapping and psychometry. Hypoxic hypoxidosis was experimentally induced by a fixed gas combination of 9.8% oxygen (O2) and 90.2% nitrogen (N2) equivalent to 6,000 m altitude, which was inhaled for 23 min under normobaric conditions by 16 healthy volunteers. They received randomized after an adaptation session placebo, 10 mg, 30 mg and 60 mg nicergoline (NIC). Evaluation of blood gases, brain mapping and psychometry was carried out at 0, 2, 4, 6, 8 hrs oral drug administration. Blood gas analysis demonstrated a drop in PO2 from 95 to 35 and 34 mm Hg in the 14 and 23 min of inhalation, respectively. PCO2 decreased too (38 to 34 and 34 mm Hg), while pH increased (7.39 to 7.44 and 7.44). Base excess increased (−0.6 to 0.6 and 0.4) while standard bicarbonate decreased (24.4 to 24.1 and 23.8 mmol/l). Thus, blood gases remained stable between the 14 and 23 min of hypoxia during which time the neurophysiological and behavioral evaluations were carried out. EEG brain mapping exhibited an increase in delta/theta activity mostly over the parietal, temporal and central regions (left more than right), while alpha activity decreased (mostly over the parietal, central, frontal, frontotemporal and temporo-occipital regions). 30 and 60 mg NIC attenuated this deterioration of vigilance. At the behavioral level, hypoxic hypoxidosis induced a deterioration of the noo- and thymospsyche which was mitigated by NIC. Based on 13 psychometric variables, the hypoxia-induced performance decrement was on the overall (2nd–8th hr) 43% after placebo as compared with pretreatment normoxic values, while only 29, 24 and 31% after 10, 30 and 60 mg nicergoline, respectively. The difference between placebo and the optimal dosage of nicergoline 30 mg reached the level of statistical significance (p