Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders


Malykh, A.G.; Sadaie, M.Reza.

Drugs 70(3): 287-312

2010


There is an increasing interest in nootropic drugs for the treatment of CNS disorders. Since the last meta-analysis of the clinical efficacy of piracetam, more information has accumulated. The primary objective of this systematic survey is to evaluate the clinical outcomes as well as the scientific literature relating to the pharmacology, pharmacokinetics/pharmacodynamics, mechanism of action, dosing, toxicology and adverse effects of marketed and investigational drugs. The major focus of the literature search was on articles demonstrating evidence-based clinical investigations during the past 10 years for the following therapeutic categories of CNS disorders: (i) cognition/memory; (ii) epilepsy and seizure; (iii) neurodegenerative diseases; (iv) stroke/ischaemia; and (v) stress and anxiety. In this article, piracetam-like compounds are divided into three subgroups based on their chemical structures, known efficacy and intended clinical uses. Subgroup 1 drugs include piracetam, oxiracetam, aniracetam, pramiracetam and phenylpiracetam, which have been used in humans and some of which are available as dietary supplements. Of these, oxiracetam and aniracetam are no longer in clinical use. Pramiracetam reportedly improved cognitive deficits associated with traumatic brain injuries. Although piracetam exhibited no long-term benefits for the treatment of mild cognitive impairments, recent studies demonstrated its neuroprotective effect when used during coronary bypass surgery. It was also effective in the treatment of cognitive disorders of cerebrovascular and traumatic origins; however, its overall effect on lowering depression and anxiety was higher than improving memory. As add-on therapy, it appears to benefit individuals with myoclonus epilepsy and tardive dyskinesia. Phenylpiracetam is more potent than piracetam and is used for a wider range of indications. In combination with a vasodilator drug, piracetam appeared to have an additive beneficial effect on various cognitive disabilities. Subgroup 2 drugs include levetiracetam, seletracetam and brivaracetam, which demonstrate antiepileptic activity, although their cognitive effects are unclear. Subgroup 3 includes piracetam derivatives with unknown clinical efficacies, and of these nefiracetam failed to improve cognition in post-stroke patients and rolipram is currently in clinical trials as an antidepressant. The remaining compounds of this subgroup are at various preclinical stages of research. The modes of action of piracetam and most of its derivatives remain an enigma. Differential effects on subtypes of glutamate receptors, but not the GABAergic actions, have been implicated. Piracetam seems to activate calcium influx into neuronal cells; however, this function is questionable in the light of findings that a persistent calcium inflow may have deleterious impact on neuronal cells. Although subgroup 2 compounds act via binding to another neuronal receptor (synaptic vesicle 2A), some of the subgroup 3 compounds, such as nefiracetam, are similar to those of subgroup 1. Based on calculations of the efficacy rates, our assessments indicate notable improvements in clinical outcomes with some of these agents.

REVIEW
ARTICLE
Drugs
2010;
70
(3):
287-312
0012-6667/10/0003-0287/555.55/0
©
2010
Adls
Data
Information
By.
All
rights
reserved.
Piracetam
and
Piracetam-Like
Drugs
From
Basic
Science
to
Novel
Clinical
Applications
to
CNS
Disorders
Andrei
G.
Malykh
and
M.
Reza
Sadaie
NovoMed
Consulting,
Silver
Spring,
Maryland,
USA
Contents
Abstract
287
1.
Therapeutic
Applications
and
Publications
289
2.
Marketed
Products
290
3.
Mechanisms
of
Action
290
4.
Pharmacology
and
Classification
294
4.1
Subgroup
1:
Cognitive
Enhancers
294
4.1.1
Piracetam
294
4.1.2
Oxiracetam
298
4.1.3
Pramiracetam
298
4.1.4
Aniracetam
299
4.1.5
Phenylpiracetam
299
4.2
Subgroup
2:
Antiepileptic/Anticonvulsive
Drugs
302
4.2.1
Levetiracetam
302
4.2.2
Brivaracetam
and
Seletracetam
303
4.3
Subgroup
3:
Compounds
with
Unknown
Efficacy
303
4.3.1
Nefiracetam
303
4.3.2
Nebracetam
303
4.3.3
Rolipram
303
4.3.4
Fasoracetam
304
4.3.5
Coluracetam
304
4.3.6
Rolziracetam
304
4.3.7
Dimiracetam
304
5.
Discussion
304
6.
Conclusion
307
Abstract
There
is
an
increasing
interest
in
nootropic
drugs
for
the
treatment
of
CNS
disorders.
Since
the
last
meta-analysis
of
the
clinical
efficacy
of
piracetam,
more
information
has
accumulated.
The
primary
objective
of
this
systematic
survey
is
to
evaluate
the
clinical
outcomes
as
well
as
the
scientific
literature
relating
to
the
pharmacology,
pharmacokinetics/pharmacodynamics,
mechanism
of
action,
dosing,
toxicology
and
adverse
effects
of
marketed
and
investigational
drugs.
The
major
focus
of
the
literature
search
was
on
articles
demonstrating
evidence-
based
clinical
investigations
during
the
past
10
years
for
the
following
ther-
apeutic
categories
of
CNS
disorders:
(i)
cognition/memory;
(ii)
epilepsy
and
seizure;
(iii)
neurodegenerative
diseases;
(iv)
stroke/ischaemia;
and
(v)
stress
and
anxiety.
288
Malykh
&
Sadaie
In
this
article,
piracetam-like
compounds
are
divided
into
three
subgroups
based
on
their
chemical
structures,
known
efficacy
and
intended
clinical
uses.
Subgroup
1
drugs
include
piracetam,
oxiracetam,
aniracetam,
pramiracetam
and
phenylpiracetam,
which
have
been
used
in
humans
and
some
of
which
are
available
as
dietary
supplements.
Of
these,
oxiracetam
and
aniracetam
are
no
longer
in
clinical
use.
Pramiracetam
reportedly
improved
cognitive
deficits
as-
sociated
with
traumatic
brain
injuries.
Although
piracetam
exhibited
no
long-
term
benefits
for
the
treatment
of
mild
cognitive
impairments,
recent
studies
demonstrated
its
neuroprotective
effect
when
used
during
coronary
bypass
surgery.
It
was
also
effective
in
the
treatment
of
cognitive
disorders
of
cere-
brovascular
and
traumatic
origins;
however,
its
overall
effect
on
lowering
de-
pression
and
anxiety
was
higher
than
improving
memory.
As
add-on
therapy,
it
appears
to
benefit
individuals
with
myoclonus
epilepsy
and
tardive
dyskinesia.
Phenylpiracetam
is
more
potent
than
piracetam
and
is
used
for
a
wider
range
of
indications.
In
combination
with
a
vasodilator
drug,
piracetam
appeared
to
have
an
additive
beneficial
effect
on
various
cognitive
disabilities.
Subgroup
2
drugs
include
levetiracetam,
seletracetam
and
brivaracetam,
which
demonstrate
antiepileptic
activity,
although
their
cognitive
effects
are
unclear.
Subgroup
3
includes
piracetam
derivatives
with
unknown
clinical
efficacies,
and
of
these
nefiracetam
failed
to
improve
cognition
in
post-stroke
patients
and
rolipram
is
currently
in
clinical
trials
as
an
antidepressant.
The
remaining
compounds
of
this
subgroup
are
at
various
preclinical
stages
of
research.
The
modes
of
action
of
piracetam
and
most
of
its
derivatives
remain
an
enigma.
Differential
effects
on
subtypes
of
glutamate
receptors,
but
not
the
GABAergic
actions,
have
been
implicated.
Piracetam
seems
to
activate
cal-
cium
influx
into
neuronal
cells;
however,
this
function
is
questionable
in
the
light
of
findings
that
a
persistent
calcium
inflow
may
have
deleterious
impact
on
neuronal
cells.
Although
subgroup
2
compounds
act
via
binding
to
another
neuronal
receptor
(synaptic
vesicle
2A),
some
of
the
subgroup
3
compounds,
such
as
nefiracetam,
are
similar
to
those
of
subgroup
1.
Based
on
calculations
of
the
efficacy
rates,
our
assessments
indicate
notable
improvements
in
clinical
outcomes
with
some
of
these
agents.
Piracetam
(pyrrolidone
acetamide)
and
related
small
molecule
ligands
share
a
five-carbon
oxo-
pyrrolidone
ring,
also
referred
to
as
racetams,
belong
to
the
class
of
nootropic
compounds
in
a
broader
definition.
The
term
`nootrope'
(from
the
Greek
words
noos
for
mind
and
tropein
for
to-
wards)
was
proposed
initially
when
a
positive
ef-
fect
of
piracetam
on
cognitive
improvement
was
demonstrated.
[1]
Piracetam
and
piracetam-like
drugs
are
modulators
of
cerebral
functions.
These
agents
are
also
used
in
efforts
to
restore
memory
and
brain
performance
in
patients
with
encephalopathies
of
various
aetiologies,
includ-
ing
cranial
traumas,
inflammation
and
stroke/
ischaemia
complications
after
bypass
surgery,
while
some
derivatives
are
indicated
for
neuro-
logical
disorders
such
as
seizures
and
neuromus-
cular
convulsions.
The
need
for
new
medications
for
age-related
CNS
problems
will
increase
in
the
near
future
as
the
generation
of
baby
boomers
approach
retirement
age.
Memory
loss
is
one
of
the
major
factors
affecting
the
everyday
living
activities
of
the
elderly
population.
Since
the
discovery
of
piracetam
in
the
late
1960s,
more
than
a
dozen
lead
piracetam-like
substances
have
been
synthesized
and
proposed
for
treatment
of
cog-
nitive
impairment
and
CNS
disorders.
©
2010
Adis
Data
Information
By.
All
rights
reserved.
Drugs
2010;
70
(3)
Piracetam
and
Related
Drugs
for
CNS
Disorders
289
The
aim
of
this
review
is
to
summarize
the
(i)
status
of
marketed
piracetam-like
drugs;
(ii)
data
on
the
known
chemical
structures
and
their
crucial
pharmacological
properties;
and
(iii)
current
trend
and
validity
of
clinical
ob-
servations
regarding
the
effects
of
piracetam-like
compounds
on
brain
performance
and
cognition.
The
major
questions
addressed
in
this
article
are:
(i)
what
is
the
literature
trend
toward
lead
clinical
candidate
compounds
in
terms
of
potency
and
target
specificity?;
(ii)
do
improvements
in
design
of
new-generation
chemical
entities
translate
to
improved
clinical
efficacy?;
and
(iii)
do
the
ex-
panded
indications
for
the
first-generation
com-
pounds
exhibit
any
meaningful
patient
benefits?
To
determine
the
major
trends
in
this
field,
we
have
surveyed
the
strength
of
associations
between
known
mechanisms
of
drug
action,
findings
in
animal
test
systems
and
their
re-
levance
to
clinical
trial
outcomes.
We
have
compiled,
tabulated
and
analysed
clinical
find-
ings,
and
discuss
the
advantages
and
limitations
of
old-
and
new-generation
piracetam-like
com-
pounds,
and
potential
relevant
areas
that
require
further
research.
1.
Therapeutic
Applications
and
Publications
Numerous
broad
clinical
applications
are
at-
tributed
to
piracetam,
(2)
many
of
which
are
based
on
open-label
and/or
non-controlled
studies
in
animals
and
humans.
Piracetam
and
its
analogues
have
been
used
for
various
therapeutic
interven-
tions
relating
to
the
CNS,
including
(i)
cognition/
memory;
(ii)
epilepsy
and
seizure;
(iii)
neurode-
generative
diseases;
(iv)
stroke/ischaemia;
and
(v)
stress
and
anxiety.
Piracetam-related
compounds
have
been
extensively
researched
and
large
numbers
of
publications
reported
in
the
past
3
decades.
From
more
than
a
dozen
new
products,
eight
have
en-
tered
clinical
investigations
for
various
CNS
in-
dications
in
recent
years.
We
searched
the
US
national
clinical
trials
databank,
(3)
PubMed
and
the
Internet.
The
search
criteria
for
clinical
data
in
PubMed
were
'clinical
trial'
and
the
tag
term
`title/abstract'.
The
total
number
of
clinical
pub-
lications
representing
all
compounds
exceeds
300.
While
most
papers
on
piracetam
were
published
more
than
10
years
ago,
the
highest
number
in
the
past
3
years
concern
levetiracetam.
To
highlight
these
trends
better,
we
tabulated
the
search
results
to
indicate
the
numbers,
sequence
and
continuity.
Table
I
shows
both
ascending
and
descending
number
of
articles
for
the
indicated
periods.
Two
reviews
describe
meta-analyses:
one
on
efficacy
of
piracetam
in
cognitive
impairment,H
and
the
other
on
piracetam
and
piracetam-like
compounds
in
experimental
stroke
in
animals.[
51
The
PubMed
search
for
phenylpiracetam,
only
with
its
trade
name
(Phenotropil
®
),
retrieved
Table
I.
Number
of
clinical
trial
publications
on
piracetam-related
ligands
a
Products
3y 3y
5y
>10
y
(2007-2009)
(2004-2006)
(1999-2003)
(prior
to
1999)
Levetiracetam
98
70
35
2
Piracetam
10
3
18
118
Phenylpiracetam
5
3
Brivaracetam
3
Nefiracetam
2
Fasoracetam
Oxiracetam
22
Rolipram
10
Pramiracetam
4
Aniracetam
6
Nebracetam
3
a
PubMed
was
searched
with
the
indicated
time
limits
and
keywords,
including
the
product
names
and
other
used
names
phenotropil,
phenotropyl,
WEB
1881
FU,
NS
105,
LAM
105
and
MKC-231
(last
accessed
on
23
January
2010).
©
2010
Adis
Data
Information
By.
All
rights
reserved.
Drugs
2010;
70
(3)
290
Malykh
&
Sadaie
eight
articles,
of
which
six
were
clinical
trials
in
patient
with
neurological
disorders.
Several
se-
lected
publications
on
phenylpiracetam
that
we
cite
here
are
from
Russian
journals,
which
are
not
in
PubMed.
We
reviewed,
without
a
selection
bias,
key
and
core
articles
that
demonstrate
evidence-
based
clinical
investigations
and
other
available
information
on
marketed
products,
clinical
find-
ings,
non-clinical
biochemical
and
pharmacologi-
cal
data,
and
promising
piracetam-like
drugs
with
unknown
benefit-risk
profiles.
2.
Marketed
Products
There
are
six
relevant
medications
on
the
mar-
ket
worldwide
(table
II).
Piracetam
and
levetir-
acetam
were
developed by
UCB
Pharma,
Belgium;
oxiracetam
by
ISF,
Italy;
aniracetam
by
Roche
Pharmaceuticals,
Switzerland;
pramiracetam
by
Warner-Lambert,
USA;
161
and
phenylpiracetam
by
the
Medical-Biological
Institute
of
the
Russian
Academy
of
Sciences
(manufactured
by
Valenta
Pharmaceuticals,
Russia).
The
product
insert
(In-
ternational
Anti-Aging
Systems,
UK)
states
that
oxiracetam
is
for
"mental
syndromes
caused
by
cerebral
insufficiency,
disturbances
in
mental
per-
formance
in
the
elderly,
and
no
adverse
interac-
tions
have
been
noted",
but
it
is
unavailable
from
this
supplier.
In
2003,
the
State
Pharmacological
Committee
of
Russia
approved
phenylpiracetam
as
a
prescription
drug
for
cerebrovascular
defi-
ciency,
depression,
apathy,
attention
and
memory
decline,
and
it
is
recommended
for
cosmonauts
for
increasing
physical
and
mental/cognitive
activities
in
space.
(
Levetiracetam
was
initially
approved
in
the
US
in
1999
as
adjunctive
therapy
for
partial
onset
seizures
in
adults
and
children
aged
years,
and
for
adults
and
adolescents
with
myoclonic
epilepsy.
The
European
Medicines
Agency
recently
approved
it
as
monotherapy
for
partial
seizures
and
as
adjunctive
therapy
for
tonic-clonic
seizures.
With
the
exception
of
levetiracetam,
these
products
are
not
registered
as
ethical
medications
in
the
US.
3.
Mechanisms
of
Action
The
pharmacology
of
piracetam-related
drugs
has
been
less
explored
than
the
clinical
applications
Table
II.
Marketed
piracetam-like
drug
products
and
dietary
supplements
a
Active
compound
Trade
name
Indication(s)
Availability
Adverse
effects
R„
non-R„
Piracetam
Nootropil®
Neurocognitive
impairments,
Tablet/injectable
NootropTM
memory
decline,
cortical
(EU)
NootropylTM
myoclonus
Piracetam
+cinnarizine
Fezam®
Cerebral
circulation
disorders
Capsule
(Bulgaria,
Russia)
Capsule
Sleep
disturbance,
diarrhoea
(uncommon)
Irritation,
dyspepsia,
headache
Oxiracetam
Neuromet
®
Aging
mental
impairments
Aniracetam
Ampamet®
Memory
decline,
Draganon
®
neurodegenerative
disorders
Sarpul
®
Pramiracetam
Neupramir®
Aging
mental
impairments,
Pramistar®
anxiety
Phenylpiracetam
Phenotropil®
Mental
function
impairment
CNS,
neurotic
disorders
Levetiracetam
Keppra
®
Epilepsy
Capsule
Psychomotor
excitability,
sleep
disorders
Tablet
Agitation,
anxiety,
restlessness,
insomnia
Tablet
Insomnia,
dysphoria,
gastralgia,
heartburn
Tablet
(Russia)
Sleep
disturbance
Tablet/injectable
Somnolence,
fatigue,
(EU,
USA)
coordination
difficulties,
behavioural
abnormalities
a
Ft„
and
non-R„
dose
forms
of
the
marketed
piracetam-like
compounds,
their
indications/claimed
therapeutic
areas,
and
probable,
common
and/or
generally
mild
adverse
effects
are
summarized
from
information
provided
in
manufacturers'
package
inserts/product
labels.
Non-R„
forms
are
available
from
online
sources.
Non-R„=
non-prescription;
1
,
1„=
prescription.
©
2010
Adis
Data
Information
By.
All
rights
reserved.
Drugs
2010;
70
(3)
Piracetam
and
Related
Drugs
for
CNS
Disorders
291
of
these
drugs
and
remains
to
be
elucidated.
These
compounds
interact
with
target
receptors
in
brain
and
modulate
the
excitatory
and/or
inhibitory
processes
of
neurotransmitters,
neuro-
hormones
and/or
post-synaptic
signals.
The
ef-
fect(s)
on
signal
trafficking
can
have
an
impact
on
cognition
and
neurological
behaviours.
Several
groups
have
suggested
the
roles
of
piracetam
in
energy
metabolism,
including
(i)
increased
oxy-
gen
utilization
in
the
brain,
and
permeability
of
cell
and
mitochondrial
membranes
to
inter-
mediaries
of
the
Krebs
cycle;
[8,91
and
(ii)
synthesis
of
cytochrome
b5.
[1
°
1
These
actions
are
possibly
downstream
consequences
of
piracetam
on
ion
channels
and/or
ion
transporters
in
neurons
(see
later
this
section).
The
similarity
of
its
chemical
structure
to
a
cyclic
derivative
of
GABA
suggests
that
pir-
acetam
probably
has
a
GABA-mimetic
action.L
1
To
date,
this
mechanism
remains
unclear.
Others
have
proposed
that
it
functions
as
an
antioxidant/
neurotonic
[12,131
and
increases
the
density
of
ace-
tylcholine
receptor.
[141
Comparative
and
com-
pelling
data
for
these
potential
functions
are
unavailable.
It
is
also
unclear
how
piracetam
exerts
its
broad
clinical
benefits
through
these
actions.
Because
of
differences
among
piracetam
derivatives
(table
III,
figure
1),
it
is
unlikely
that
all
these
drugs
will
operate
in
a
similar
manner,
use
the
same
cell
type(s)
or
drug
target(s),
or
both.
For
that
matter,
their
pharmacokinetics,
degradation
kinetics,
fate
of
metabolites,
and
even
ADMET
(adsorption,
distribution,
meta-
bolism,
excretion
and
toxicity)
properties,
can
vary.
These
variations
can
be
quite
profound
when
the
studies
use
different
test
systems.
It
is
reasonable
to
expect
that
the
compounds
with
'minimal'
changes
in
their
chemical
struc-
tures
share
the
same
mechanism
of
action,
such
as
binding
to
or
modulating
a
selective
subset
of
neurotransmitter
receptors.
The
following
hypotheses
focus
on
modulation
of
ionotropic,
ligand-gated
and/or
voltage-dependent
ion
chan-
nels,
such
as
[Na+/Ca
2
+
1
]/K+
exchanger
pumps
in
neuronal
cell
membranes
or
neuromuscular
junctions.
The
subgroup
1
agents
piracetam,
oxiracetam
and
aniracetam
(table
III,
figure
1)
activate
cframino-3-hydroxy-5-methylisoxazole-4-propionate
(AMPA)-type
glutamate
receptors
but
not
kainate
or
NMDA
receptors
in
neuronal
cultures.
This
action
increases
the
density
of
receptor
binding
sites
for
AMPA
and
calcium
uptake,
[381
pre-
sumably
resulting
in
elevation
of
intracellular
cal-
cium
([Ca
2
1).
Pramiracetam
increases
the
rate
of
sodium-dependent
high-affinity
choline
uptake
in
rat
hippocampal
synaptosomes
in
vitro,
suggesting
that
its
effect
on
cognitive
functions
might
occur
via
acceleration
of
cholinergic
neuronal
impulse
flow
in
the
septal-hippocampal
region.
[391
The
af-
finity
of
phenylpiracetam
to
the
nicotinitic
acet-
ylcholine
(nACh)
receptor,
but
not
the
glutamate
NMDA
subtype,
was
demonstrated
in
ligand-
binding
experiments
in
vitro.
However,
injection
of
this
drug
(100
mg/kg,
intraperitoneally)
to
rats
in-
creases
the
numbers
of
both
nACh
and
NMDA
receptors,
but
decreases
serotonin
and
dopamine
receptors
in
the
brain
tissue.
[401
For
subgroup
2
drugs
(table
III,
figure
1),
more
recent
data
assert
that
levetiracetam
prob-
ably
acts
through
an
alternative
mechanism
for
its
antiepileptic
activity.
At
a
therapeutic
dose
range,
it
was
initially
shown
to
decrease
incoming
ions
in
AMPA-
and
kainite-induced
currents
in
cultured
cortical
neurons.
[411
In
contrast
to
sub-
group
1
compounds,
levetiracetam
apparently
inhibits
neuronal
Ca
2
+
ion
channels
that
are
possibly
important
to
its
antiepileptic
effect.
[41-431
In
a
different
experimental
setting
using
a
seizure
model
in
mice,
it
was
later
demonstrated
to
bind
to
synaptic
vesicle
2A
(SV2A)
protein
in
brain
membranes
and
fibroblasts.
[
"
]
The
data
corre-
lated
with
the
clinical
application
of
levetir-
acetam
as
an
antiepileptic
drug
(AED).[
44
'
Brivaracetam
and
seletracetam,
the
newer-gen-
eration
chemical
entities
after
levetiracetam,
bind
to
SV2A
with
a
higher
affinity
and
are
currently
being
evaluated
clinically
for
their
antiepileptic
properties.
[23,241
It
is
unclear
whether
subgroup
2
drugs
affect
other
physiological
(nonpatho-
logical)
roles
of
SV2A
and/or
disturb
the
normal
homeostasis
of
calcium
in
different
regions
of
brain.
It
is
unlikely
that
only
one
mechanism
of
action
is
operative
in
vivo,
allowing
a
selective
pharmacological
advantage
to
these
drugs
con-
sidering
the
closeness
of
their
molecular
structures
©
2010
Adis
Data
Information
By.
All
rights
reserved.
Drugs
2010;
70
(3)
©
2
01
0
A
di
s
D
at
a
I
nf
orm
ati
on
By
.
All
ri
ght
s
r
eserv
ed
.
OL
:Om
s
bniCI
Table
Ill.
Pharmacological
properties
of
piracetam-like
compounds
amp
lis
9
1p1
fi1
vw
Category
Active
compound
IUPAC
name
Potency
a
(dosage)
Bioavailability
Half-life
°
References
(%)
b
Subgroup
1:
cognitive
enhancers
Piracetam
2-oxo-1-pyrrolidineacetamide
Low:
50
to
>300 mg/kg/d
(up
to
37
g/d)
-100
4-5
h
6
c
Oxiracetam
2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetamide
Medium:
25-40
mg/kg/d
-75
3-6
h
6,15
(up
to
2.4
g/d)
Pramiracetam
N42-(dipropan-2-ylamino)ethy1]-2-
Medium:
10-20
mg/kg/d
-100
2-8
h
6,16,17
(2-oxopyrrolidin-1-yl)acetamide
(1.2
g/d)
Aniracetam
1-[(4-methoxybenzoyl)]-2-pyrrolidinone
Medium:
-11
1-2.5h
6,18
12-25
mg/kg/d
(1.5
g/d)
Phenylpiracetam
2-(4-phenyl-2-oxopyrrolidin-1-yl)acetamide
High:
2.5-5
mg/kg/d
-100
3-5
h
19,20
c
(up
to
0.75
g/d)
Subgroup
2:
antiepileptic
drugs
Levetiracetam
(2S)-2-(2-oxopyrrolidin-1-yl)butanamide
Medium:
20-60
mg/kg/d
(up
to
3
g/d)
-100
6-8
h
6
c
Brivaracetam
(2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-111]
butanamide
Medium:
10-25
mg/kg/d
(up
to
1.4
g/d)
-90
7-8
h
21,22
Seletracetam
(2S)-2-[(4R)-4-(2,2-difluoroetheny1)-2-oxo-
pyrrolidin-1-yl]butanamide
High:
0.03-10
mg/kg/d
(up
to
O.
6
g/d)
>90
8h
23,24
Subgroup
3:
unknown
clinical
efficacy
Nefiracetam
N-(2,6-dimethylphenyl)-2-(2-oxopyrrolidin-1-
yl)acetamide
Medium:
10-15
mg/kg/d
(up
to
0.9
g/d)
NA
3-5
h
25,26
Nebracetam
4-(aminomethyl)-1-benzyl-pyrrolidin-2-one
Medium:
200-800
mg/d
NA NA
27,28
Rolipram
4-(3-cyclopentyloxy-4-methoxy-phenyl)pyrrolidin-
High:
0.75-3.0
mg/d
>70
2h
29,30
2-one
Fasoracetam
(5R)-5-(piperidine-1-carbonyl)
pyrrolidin-2-one
High:
100
mg/d)
79-97
4-6.5
h
31,32
(NS-105)
Coluracetam
(MKC-231)
N-(2,3-dimethy1-5,6,7,8-
tetrahydrofuro[2,3-b]
quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamide
NA
NA NA
33,34
Rolziracetam
2,6,7,8-tetrahydro-1H-pyrrolizine-3,5-dione
NA
-90
<25
min
35
Dimiracetam
dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-
diones
NA
NA NA
36,37
a
To
compare
the
potencies
for
each
drug,
we
calculated
the
daily
treatment
dose
(assuming
that
the
average
weight
of
a
patient
is
60
kg)
and
defined
the
values
as
low
(>50
mg/kg/d),
medium
(10-50
mg/kg/d)
and
high
(<10
mg/kg/d).
b
Selected
pharmacokinetic
outcome
measures,
bioavailability
and
half-life
in
plasma
represent
the
values
derived
from
pharmacokinetic
examinations
on
humans,
except
those
of
aniracetam
and
rolziracetam,
which
were
tested
on
rodents.
c
Pharmacokinetic
and
dose
values
described
in
product
insert
as
well
as
reference.
IUPAC=
International
Union
of
Pure
and
Applied
Chemistry;
NA=
not
available.
Piracetam
and
Related
Drugs
for
CNS
Disorders
293
a
0
0
0
NH
2
NH
2
H
OH
Piracetam
Oxiracetam
Pramiracetam
Aniracetam
0
N
NH
2
Phenylpiracetam
b
0
0
0
C
H3
1
NH
2
NH2
NH
2
O
Levetiracetam
Brivaracetam
Seletracetam
0
0
H
NH
2
Nebracetam
Nebracetam
Rolipram
Fasoracetam
(NS-105)
0
H
Coluracetam
Rolziracetam
Dimiracetam
(MKC-231)
Fig.
1.
Chemical
structures
and
pharmacological
properties
of
piracetam-like
compounds:
(a)
subgroup
1
cognitive
enhancers;
(b)
subgroup
2
antiepileptic
drugs;
and
(c)
subgroup
3
unknown
clinical
efficacy.
©
2010
Adis
Data
Information
By.
All
rights
reserved.
Drugs
2010;
70
(3)
294
Malykh
&
Sadaie
to
subgroup
1
and/or
their
pharmacodynamic
attributes.
This
contention
applies
particularly
to
subgroup
3
compounds,
which
indicate
more
ex-
tensive
differences
in
their
chemical
structures
than
most
other
derivatives
(table
III,
figure
1).
In
contrast
to
subgroup
1
and
2
compounds,
the
subgroup
3
compound
nefiracetam
appears
to
potentiate
NMDA
receptors.
In
cultured
cor-
tical
neurons
of
rats,
this
action
occurs
indirectly
via
activation
of
protein
kinase
C
(PKC)
and
phosphorylation
of
one
of
the
subunits
of
the
heterotetramer
NMDA
receptor
(NR1).
This
in
turn
enhances
binding
of
glycine
to
NMDA,
and
removes
the
suppression
of
voltage-dependent
currents
caused
by
Mg'
ions.K
51
Expelling
Mg"
ions
can
open
up
the
gate
and
allow
Ca'
to
flow
into
the
cytosol.
This
depolarization
can
cause
a
net
positive
and/or
negative
effect,
as
discussed
previously.
Furthermore,
previous
contradictory
results
regarding
nefiracetam
potentiation
of
a4[32-
type
nACh
receptors
at
various
sites
are
possibly
reconciled,
considering
that
different
PKC
iso-
zymes
were
involved
in
different
tissues.
[41
On
the
other
hand,
nebracetam
supposedly
interacts
largely
with
the
ligand-gated
NMDA
re-
ceptor.
This
enables
the
drug
to
inhibit
the
(po-
tentially
lethal)
excessive
[Ca
2
+]i
through
NMDA
channels,
and
to
a
lesser
extent
via
the
voltage-
gated
channels.
[46,471
Fasoracetam
modulates
meta-
botropic
glutamate
receptor
(mGluR)
subclasses
that
are
(positively
and
negatively)
coupled
to
the
G-protein
receptor
complex,
thereby
stimulating
(or
inhibiting)
adenylate
cyclase
or
cyclic
adeno-
sine
monophosphate
(cAMP)
formation,
which
is
implicated
in
a
variety
of
signal
transduction
processes
such
as
learning
and
memory.
Its
an-
tagonist
role
was
most
evident
in
mitigating
the
deficits
in
learning
and
memory
induced
by
one
of
the
most
potent
GABA
B
-mimetic
drugs,
baclofen,
in
rats.
[48,491
Furthermore,
repeat
dose
administration
of
fasoracetam
upregulated
GA-
BA
B
receptors
and
that
was
linked
to
its
promis-
ing
antidepressant
action
in
rats.
[501
Coluracetam
appears
to
function
very
differently,
i.e.
through
trafficking
of
high-affinity
choline
transporters
[511
and
enhancing
choline
uptake
in
hippocampal
synaptosomes,
thus
facilitating
the
synthesis,
re-
lease
and
availability
of
acetylcholine.
[521
The
inter-relationships
between
these
diverse
complex
processes
would
be
challenging
to
dissect.
These
distinct
and
overlapping
mechanisms
may
trans-
late
to
additive,
synergistic
or
antagonistic
effects
if
more
than
one
of
these
drugs
is
administered
at
a
given
time.
4.
Pharmacology
and
Classification
For
clarity
in
reviewing
and
analysing
the
data,
we
have
separated
the
lead
compounds
into
three
subgroups.
Subgroups
1
and
2
are
based
partly
on
the
similarity
of
their
molecular
struc-
tures
and
partly
on
their
therapeutic
attributes.
Subgroup
3
represents
both
old
and
new
mole-
cular
entities
with
more
diverse
structures
and
unknown
efficacies.
Table
III
and
figure
1
show
this
classification,
as
well
as
key
pharmacokinetic
properties
for
each
compound.
Major
findings
on
pharmacological
properties
and
stages
of
devel-
opment
for
each
subgroup
are
described
in
the
following
sections.
4.1
Subgroup
1:
Cognitive
Enhancers
4.1.1
Piracetam
Piracetam
was
first
approved
in
Europe
in
the
early
1970s
for
treatment
of
vertigo
and
age-
related
disorders.
It
is
a
non-potent
drug
(table
III
and
figure
1);
recent
and
ongoing
trials
have
used
escalating
or
various
high
doses
depending
upon
the
indication
[6,531
(table
IV).
Adverse
effects,
al-
though
rare,
mild
and
transitory,
include
anxiety,
insomnia,
drowsiness
and
agitation.K
531
Effect
on
Memory,
Cognition,
Attention,
Depression
In
the
past
decade,
more
than
20
review
arti-
cles
have
been
published
showing
the
results
of
clinical
trials
and
the
use
of
piracetam
in
a
variety
of
neurological
disorders.
A
meta-analysis
of
19
double-blind
placebo-controlled
trials
per-
formed
between
1972
and
2001
on
piracetam
use
in
age-related
mental
impairments
confirmed
that
individuals
receiving
piracetam
improved
by
60.9%
compared
with
32.5%
in placebo,
with
a
combined
number
needed
to
treat
of
4.1,
i.e.
ap-
proximately
four
people
had
to
receive
piracetam
to
benefit
one
individual.
[41
Since
then,
several
©
2010
Adis
Data
Information
By.
All
rights
reserved.
Drugs
2010;
70
(3)
©
2
01
0
A
di
s
D
at
a
I
nf
orm
ati
on
By
.
All
ri
ght
s
r
eserv
ed
.
CO
OL
:Om
s
bniCI
Table
IV.
Piracetam
in
clinical
development
s
Sponsor/study
site
Intent
to
treat
Study
design
No.
of
pts
(age
in
y)
Dosage
Trial
duration
Outcome
measures
Efficacy
summary
(%
improvement
rate
[APIR])
Adverse
event
References
CD
Piracetam
CD
Medical
University,
Berlin,
Germany
Cognition/memory
deficits
after
bypass
surgery
rdbpc
120
Bolus
12g
preoperative
infusion
3d
Syndrome
Kurztest
and
Alzheimer's
disease
assessment
46±22
None
54
0
Humboldt
University,
Germany
Cognition/memory
rdbpc
64
(40-80,
Bolus
12
g
3d
Short-term
55
±20
None
55
2
deficits
after
bypass
surgery
mean
63)
preoperative
infusion
memory
and
attention
tests
0
CD
University
of
Targu,
Romania;
Cognition/memory
rdbpc
98
(11
65,
T
6
wk
Psychological
29
±19
None
56
University
of
Debrecen,
Hungary
deficits
after
bypass
surgery
mean
56)
12-24g/d,
IV
then
PO
tests,
cranial
CT
scans
Russian
State
Medical
University,
Cognition/memory
Open-
70
(45-75,
(2)
8
wk
MMSE
13±5
Headache
57
Moscow,
Russia
in
cerebrovascular
disorders
label,
parallel
mean
62)
1.2
g/d,
2.4
g/d,
PO
Depression
62
±20
(15.7%)
Research
Institute
of
Cognition/memory
rac
53
(18-60)
(2)->
56d
MMSE
7±3
High
blood
58
Pharmacology,
Moscow,
Russia
in
cerebrovascular
disorders
and
TBI
1.2
g/d,
PO
CCSE
8±2
pressure
(18%)
Russian
State
Medical
University,
Moscow,
Russia
Cognition/memory
deficits
(after
TBI)
rpc
42
(12-18)
(3)-.
1.2
g/d,
2.4
g/d,
PO
1
mo
Memory
and
coordination
tests
50±11
None
59
UCB
Pharma,
Belgium
Mild
cognitive
rdbpc
675
(50-89,
(3)-.
12mo
Cognitive
None
None
60,61
impairment
mean
68)
4.8
g/d,
9.6
g/d,
PO
scores,
safety
McGill
University,
Montreal,
QC,
Myoclonus
Open-
11
(17-36,
T
18
mo
MII,
seizure
30±13
Drowsiness
53
Canada
epilepsy
label
mean
24.5)
3.2-20
g/d,
PO
frequency
Continued
next
page
(11
©
2
01
0
A
di
s
D
at
a
I
nf
orm
ati
on
By
.
All
ri
ght
s
r
eserv
ed
.
OL
:Om
s
bniCI
Table
IV.
Contd
Sponsor/study
site
Intent
to
treat
Study
No.
of
pts
Dosage
Trial
Outcome
Efficacy
Adverse
References
design
(age
in
y)
duration
measures
summary
(%
event
improvement
rate
[APIR])
Beersheva
Mental
Health
Center,
Tardive
dyskinesia
rdbpc
40
(24-69,
(2)-.
4
wk
Extrapyramidal
38
±
6
None
62,63
Israel
crossover
mean
47)
4.8
g/d
symptom
rating
Marmara
University,
Turkey
Ataxia
Open-
8
(mean
43.4)
f
14d
!CARS
(such
as
29
±
19
None
64
label
30-60
g/d
posture
and
gait
infusion
tests)
Max-Plank-Institute,
Dresden,
Aphasia
rpc
24
(mean
57)
(2)-.
6
wk
Language
20
±
8
None
65
Germany
2
x
2.4
g/d,
PO
performance
NIDA,
Bethesda,
MD,
USA;
Cocaine-related
rdbpc
44
(2)-.
10
wk
Anxiety,
None
None
66-68
University
of
Pennsylvania,
PA,
disorders
4.8
g/d,
PO
withdrawal
USA
symptoms
Piracetam
+cinnarizine
State
Medical
University,
Moscow,
CFS
after
Open-
29
MS
(2)-.
1
mo
Depression,
25
±
8
Sleep
69
Russia
encephalopathy
label,
21
non-MS
2.4
g/d,
PO
psychometric
15
±
10
disturbance
(MS
and
TBI)
parallel
encephalopathies
questionnaires
(12%)
(20-57)
amp
lis
9
1p1
fi1
vw
Piracetam
+risperidone
Tehran
University,
Iran
Autism
rdbpc
40
(3-11)
t
10
wk
Psychometric
41
±11
200-800
mg/d,
ABC-C
PO
questionnaires
Morning
70
drowsiness
a
The
information
summarized
here
was
derived
partly
from
the
data
submitted
to
the
ClinicalTrials.gov
databank
(accessed
1
May
2009)
and
partly
from
articles
entered
in
PubMed
after
the
last
meta-analysis
in
2002.
[4]
To
simplify
presentations
of
the
reported
statistically
significant
data
(test
score
numbers)
for
the
efficacies,
we
calculated
the
total
differences
between
test
treatments
and
controls
from
baselines,
and
summarized
as
approximate
percentage
composite
mean
values
or
attributable
percentage
improvement
rate.rili
'None'
denotes
that
there
was
no
increase
in
the
frequency
or
severity
of
adverse
effects
at
the
highest
dose
tested,
which
refers
to
the
no
observable
adverse
effect
level
dose.
ABC-C
=Aberrant
Behavior
Checklist-Community;
APIR
=
attributable
percentage
improvement
rate
(see
Appendix);
CCSE=
cognitive
capacity
screening
examination;
CFS=
chronic
fatigue
syndrome;
!CARS=
International
Cooperative
Ataxia
Rating
Scale;
IV=
intravenous
injection;
MII
=
Motor
Impairment
Index;
MMSE=
Mini
Mental
State
Examination;
MS=
multiple
sclerosis;
NIDA=
National
Institute
on
Drug
Abuse;
PO=
oral;
rac=
randomized,
active
controlled;
rdbpc=
randomized,
double-blind,
placebo-controlled;
rpc=
randomized,
placebo-controlled;
TBI
=
traumatic
brain
injury;
t
indicates
escalating
dose;
indicates
escalating
and
de-escalating
doses;
(2)->,
(3)->
indicates
parallel
fixed
doses.
Piracetam
and
Related
Drugs
for
CNS
Disorders
297
new
trials
have
been
performed
(table
IV).
Piracetam
benefited
most
of
the
patients
with
cerebral
ischaemia-induced
short-term
memory/
cognitive
deterioration
after
heart
bypass
surgery.
[551
New
data
confirm
a
neuroprotective
effect
of
piracetam
for
this
intended
use.
[541
Con-
sistent
with
this,
an
earlier
study
indicated
that
of
numerous
different
tests
related
to
visuomotor
examinations,
only
the
ability
to
recognize
and
shift
numbers
and
letters
(so-called
'trail-
making')
was
considerably
improved,
[561
but
the
outcome
was
fairly
variable
(table
IV).
These
independent
cohort
studies
suggested
that
pir-
acetam
is
neuroprotective.
It
is
noteworthy
that,
although
piracetam
treatment
of
patients
with
chronic
cerebrovascu-
lar
disorders
showed
only
a
modest
improvement
in
memory,
it
considerably
mitigated
depres-
sion.
[571
Such
improvement
rates
in
a
wide
range
of
age
groups
with
diverse
origins
of
cerebrova-
scular
disorders
were
comparable.
[581
However,
in
traumatic
brain
injury
of
adolescents
the
re-
sponse
rates
to
memory
and
attention
were
increased
to
approximately
60%
[59]
(table
IV).
These
investigations
suggest
that
piracetam
is
more
effective
in
the
latter
cohorts.
Piracetam
and
its
vasodilator
partner
drug
cinnarizine
(a
calcium
channel
antagonist),
as
a
combined
product
(Fezam®),
modestly
improved
various
cognitive
abilities,
such
as
activity/mood,
in
patients
with
multiple
sclerosis
(MS)
with
presumably
'ongoing'
encephalopathies.
How-
ever,
it
appears
that
it
benefited
non-MS
patients
with
cerebral
(post-traumatic)
chronic
lesions
to
a
lesser
extent.
The
most
observed
adverse
event
(AE)
was
a
mild
sleep
disturbance
[691
(table
IV).
Although
the
trial
favoured
MS
patients,
the
subjectivity
of
(patient-reported)
outcome
mea-
sures
complicates
evaluations
of
these
small
cohort
studies.
Based
on
the
rationale
that
glutamatergic
de-
ficiency
may
be
an
underlying
cause
of
autism,
an
investigational
use
of
piracetam
as
add-on
ther-
apy
to
the
antipsychotic
risperidone
in
autistic
children
resulted
in
noticeably
improved
unusual
behaviours,
and
was
more
effective
than
risper-
idone
monotherapy,
without
apparently
increas-
ing
AEs[
701
(table
IV).
The
positive
trend
began
on
week
2
and
continued
until
the
trial
end
on
week
10,
but
the
highest
difference
was
only
one
standard
deviation
apart.
A
large
trial
would
be
useful
to
determine
the
extent
of
its
long-term
benefit.
Piracetam
use
for
several
other
expanded
indications
failed
to
demonstrate
a
beneficial
ef-
fect,
including
older
people
with
mild
cognitive
impairment
(MCI)
who
were
suspected
of
devel-
oping
dementia,
[601
electroconvulsive
therapy-in-
duced
cognitive
disturbances
in
schizophrenic
patients
or
patients
with
depressive
illness.
[721
Moreover,
it
neither
benefited
cognitive
func-
tions
in
children
with
Down's
syndrome[
731
nor
in
abstinent
people
with
cocaine
addiction,
al-
though
it
surprisingly
augmented
cocaine-
dependency
[661
for
reasons
unknown.
Epilepsy,
Convulsion,
Seizure
Piracetam
as
add-on
therapy
to
valproate
or
a
combination
of
these
with
clonazepam
sig-
nificantly
improved
the
motor
impairment
index
in
patients
with
myoclonus
epilepsy
[531
(table
IV).
In
this
structured
protocol,
an
escalating
dose
was
administered
to
the
same
treatment
group,
starting
with
a
low
dose
with
step
increases
every
4
days.
This
could
arguably
tolerise
the
patients
to
the
drug
uptake
and/or
turnover,
hence
com-
promising
outcome
measures.
In
tardive
dyski-
nesia,
which
can
occur
as
an
adverse
effect
of
conventional
antipsychotic
drugs
such
as
chlor-
promazine,
approximately
67%
of
patients
re-
ceiving
piracetam
responded
favourably
with
a
peak
efficacy
on
week
4
compared
with
24%
on
placebo
(table
IV);
however,
improved
symptoms
worsened
after
discontinuation
of
therapy.
[62]
The
investigators
stated
that
large
well
controlled
trials
are
needed
to
determine
the
effectiveness
of
piracetam
in
this
indication.
Neurodegenerative
Disorders:
Ataxia
Piracetam
modestly
benefited
posture
and
gait
disturbances,
but
not
kinetic
functions,
speech
and
oculomotor
disorders
of
patients
with
her-
editary
ataxia
[641
(table
IV).
The
drug
was
safe,
but
the
study
is
too
small
to
determine
its
real
benefit-risk
profile
in
ataxia.
It
also
remains
to
be
determined
whether
piracetam,
or
its
derivative,
would
be
effective
in
a
non-hereditary
ataxia.
©
2010
Adis
Data
Information
By.
All
rights
reserved.
Drugs
2010;
70
(3)
298
Malykh
&
Sadaie
Stroke/Ischaemia
A
meta-analysis
of
studies
in
models
of
stro-
ke/cerebral
ischaemia
in
rats
supports
the
poten-
tial
effectiveness
of
piracetam.
151
The
reviewers
cautioned
that
the
results
were
published
at
least
10
years
after
clinical
trials
and
that
the
numbers
of
reliable
studies
are
too
small
(six
articles)
to
draw
a
robust
conclusion,
and
reiterated
that
piracetam,
but
not
oxiracetam
and
levetiracetam,
decreased
infarct
volumes
by
almost
50%.J
51
They
also
noted
that
these
data
are
consistent
with
a
post
hoc
clinical
finding
"if
given
soon
after
stroke
onset,
piracetam
might
have
a
beneficial
effect"
and
"the
failure
of
clinical
trials
with
pir-
acetam
cannot
therefore
be
taken
as
a
failure
animal
modelling
of
stroke".
[51
A
previous
Co-
chrane
Review
pointed
out
that
piracetam
is
in-
effective
in
patients
with
presumed
ischaemic
stroke,
although
other
potential
beneficial
effects
of
piracetam
remain
unclear
because
of
in-
sufficient
well
controlled
studies.
[741
The
strength
of
data
derived
from
stroke
modelling
in
rats
and
their
relevance
to
humans
are
questionable.
The
negative
outcome
of
clinical
trials
was
based
on
survival
rate
assessment
as
the
endpoint,
not
the
infarct
size
as
surrogate.
Consistent
with
this,
piracetam
facilitated
recovery
of
verbal
skills
in
stroke
patients
with
aphasia
(confirmed
by
neu-
roimaging
tests),
but
it
failed
to
improve
visuos-
patial
and
recognition
memory,
and
cognitive
functions
such
as
reasoning
[651
(table
IV).
Con-
firmatory
results
from
large
investigations
are
unavailable.
Vision
Piracetam
also
improved
colour
discrimination
in
patients
(aged
19-24
years)
who
suffered
from
traumatic
brain
injuries
of
different
severity.
In
this
double-blind
trial,
patients
were
divided
into
three
arms:
(i)
ten
people
with
mild
concussion;
(ii)
eight
with
minor
concussion
(both
arms
received
pir-
acetam);
and
(iii)
four
with
mixed
levels
of
con-
cussion,
who
received
placebo.
Functional
activity
of
the
retina
was
evaluated
by
measurement
of
brightness
sensitivity
thresholds
(BST)
to
four
colours
(blue,
green,
red
and
white;
achromatic).
BST
scores
significantly
decreased
in
the
test
drug
arms
(blue
36%
and
25%;
green
20%
and
17%;
red
18%
and
16%;
and
white
31%
and
24%,
respec-
tively)
but
not
in
placebo,
suggesting
colour
dis-
crimination
progress.
[751
The
investigators
believed
that
piracetam
improved
retinal
microcirculation
and
presumably
acted
as
a
GABA-mimetic
drug,
since
GABA
is
also
present
in
the
retina.
Using
Fezam®
for
treatment
of
senile
macular
degenera-
tion,
the
visual
acuity
improved
significantly,
though
quite
variably
(50
±
30%),
in
76%
of
the
eyes,
and
this
was
attributed
to
the
vasoactive
action
of
cinnarizine
and
the
neurotonic
effect
of
piracetam.
[761
4.1.2
Oxiracetam
With
a
hydroxyl
group
substitution
in
its
ox-
opyrrolidone
nucleus,
oxiracetam
exhibits
a
favourable
pharmacokinetic
profile
and
oral
bioavailability
[151
(table
III,
figure
1).
It
dose-
dependently
mitigated
the
scopolamine-induced
deterioration
of
neuropsychological
performance
(e.g.
semantic
memory,
word
recall
tests,
reading)
in
a
double-blind
trial
on
12
healthy
volunteers.
1771
Consistent
with
this,
its
use
for
2-6
months
in
people
aged
>65
years
improved
certain
of
their
cognitive
deficits
of
nonspecific
aetiology.
[781
However,
it
failed
to
benefit
patients
with
Alzheimer's
disease
(AD),
although
the
length
of
treatment
was
only
1
month.
[791
No
AEs
were
noted.
4.1.3
Pramiracetam
Prepared
by
substitution
of
the
amide
of
pir-
acetam
with
the
dipropan-2-ylaminoethyl
group,
pramiracetam
exhibits
a
remarkable
oral
bioa-
vailability
and
a
variable
half-life[
16,171
(table
III,
figure
1).
It
is
more
potent
and
is
thus
used
in
lower
doses
than
piracetam.
[801
The
only
trial
conducted
in
the
US
was
in
four
young
men
who
had
cognitive
problems
after
head
injury
and
anoxia.
It
significantly
improved
some
memory
activities,
especially
delayed
recall
(30-50%)
dur-
ing
18
months
of
therapy
and
1
month
of
follow-
up.
[811
However,
there
was
a
large
variability
in
test
results.
Later,
Italian
researchers
demon-
strated
the
reduction
of
scopolamine-induced
amnestic
effects
in
healthy
volunteers,
i.e.
two
of
five
cognitive
parameters
(including
tests
for
©
2010
Adis
Data
Information
By.
All
rights
reserved.
Drugs
2010;
70
(3)
Piracetam
and
Related
Drugs
for
CNS
Disorders
299
immediate
and
delayed
verbal
recall)
were
ap-
proximately
50%
better
than
those
receiving
pla-
cebo
when
tested
1
and
3
hours
after
scopolamine
injection.
[821
Two
small
trials
were
conducted
in
the
Ukraine:
one
in
patients
with
cerebrovascular
disease
[831
and
another
in
patients
with
concus-
sion.
[841
The
first
trial
claims
that
visual
and
ver-
bal
memories
moderately
improved
in
younger
patients
with
chronic
cerebrovascular
and
post-
stroke
cognitive
symptoms,
and
to
a
lesser
degree
in
older
patients.
The
data
in
the
second
trial
shows
that
pramiracetam
was
more
effective
than
piracetam
in
restoring
memory
loss/disorientation
in
patients
with
mild
craniocereberal
traumas
[841
(table
V).
4.1.4
Aniracetam
An
N-side
chain
modified
derivative,
anir-
acetam
has
low
bioavailability
in
plasma
and
is
eliminated
rapidly
in
animals
[1
°
21
(table
III,
figure
1).
Considering
issues
in
treating
elderly
people
with
renal
dysfunction,
its
pharmacoki-
netics
and
the
fate
of
metabolites
were
evaluated
in
six
women
(mean
age
84.5
years)
with
cere-
brovascular
disease.
The
half-life
of
its
major
metabolites
(anisic
acid,
p-methoxyhippuric
acid,
2-pyrrolidone
and
succinimide)
increased
4-
to
7-fold
compared
with
those
in
young
heal-
thy
volunteers
(0.79-1.58
hours).
No
adverse
ef-
fects
were
noted.
[181
It
improved
psychometric
parameters
up
to
30%
in
aged
MCI
patients
compared
with
placebo,
with
mild
AEs
appar-
ently
unrelated
to
aniracetam.
[1
°
31
In
another
small
trial
involving
elderly
patients
with
slight
to
moderate
vascular
cerebral
pathologies,
it
was
reportedly
useful.
[1
°
41
However,
aniracetam
was
not
efficacious
in
people
with
memory/cognitive
impairments
associated
with
chronic
exposure
to
hazardous
organic
solvents.
[1
°
51
4.1.5
Phenylpiracetam
A
phenyl
derivative
of
piracetam,
phenotropil
or
phenotropyl
is
absorbed
fast
and
exhibits
high
oral
bioavailability
(Phenotropil®,
product
insert).
Studies
on
rodents
(100
mg/kg,
intramuscular,
oral)
showed
absorption
time
of
<1
hour
and
half-life
of
2.5-3
hours,
[19,2
°
1
but
its
pharmaco-
kinetic
profiles
in
humans
are
unpublished.
It
demonstrates
multitherapeutic
potential,
some
in
common
with
subgroup
2
AEDs.
Memory,
Cognition,
Attention,
Depression
Phenylpiracetam
is
reportedly
beneficial
to
people
who
develop
cognitive
deficits
and/or
de-
pression
after
encephalopathy
and
brain
injures
(table
V).
It
increased
quality
of
life
in
patients
with
encephalopathy
after
acute
lesions
(30
peo-
ple),
brain
traumas
(33
people)
and
gliomas
surgery
(36
people).
The
average
minimental
state
examination
(MMSE)
scores
(a
standard
30-point
questionnaire
used
to
assess
cognition)
from
baseline
improved
in
all
groups.
In
the
end,
anxiety
improved
and
depression
declined
sub-
stantially,
and
that
resulted
in
less
discomfort
and
better
ability
to
execute
everyday
activities.
[851
Recovery
of
memory,
attention
and
sensomotor
disturbances
were
indistinguishable
for
similar
treatments
in
mild
cranial
brain
traumas.
The
differences
noted
favoured
phenylpiracetam
over
piracetam
because
of
faster
alleviation
of
head-
aches
and
a
general
fatigue
after
7
and
14
days.
[861
Phenylpiracetam
was
favoured
in
the
treatment
of
chronic
vascular
encephalopathy
as
it
im-
proved
the
cognitive
performance
in
all
tests,
whereas
only
two
of
the
eight
test
scores
increased
in
the
piracetam
arm.
[871
It
also
improved
both
asthenia
and
depression
scores,
albeit
to
a
lesser
extent
in
MS
patients.
[881
In
a
comparative
trial,
asthenia
and
chronic
fatigue
syndrome
(CFS)
patients
were
treated
with
phenylpiracetam
(68
people),
piracetam
(65
people)
and
placebo
(47
people).
The
scores
of
the
ten-word
memory
test
and
attention
switching
tests
for
the
phenylpiracetam
improved
relative
to
those
of
piracetam
and
placebo.
Overall,
83%
of
asthenic
and
87%
of
CFS
patients
responded
well
to
phenylpiracetam
versus
48%
and
55%,
respectively,
to
piracetam.
[891
In
agree-
ment
with
this,
phenylpiracetam
markedly
in-
creased
the
problem-solving
skills
of
adolescents
with
asthenia
who
were
A-players,
B-players
and
C-players
(i.e.
the
number
of
individuals
able
to
respond
to
the
memory
and
attention
tests
after
the
first,
second
and
third
attempts)
from
11%,
15%,
73%
before
to
23%,
40%,
37%
after
treat-
ment,
respectively.
It
was
superior
to
piracetam
©
2010
Adis
Data
Information
By.
All
rights
reserved.
Drugs
2010;
70
(3)
©
2
01
0
A
di
s
D
at
a
I
nf
orm
ati
on
By
.
All
ri
ght
s
r
eserv
ed
.
OL
:Om
s
bniCI
Table
V.
Piracetam-like
compounds
in
clinical
development
amp
lis
9
1p1
fi1
vw
Sponsor/study
site
Intent
to
treat
Study
design
No.
of
pts
(age
in
y)
Dosage
(mg/d,
oral)
Trial
duration
Outcome
measures
Efficacy
summary
(%
improvement
rate)
Adverse
event
References
Pram
iracetam
Army
Central
Hospital,
Kiev,
Cognition/memory
Active
65
(2)-.
1
mo
Amnesia
and
Tx
86
NA
84
Ukraine
deficits
(after
TBI)
(piracetam)
(16-60,
600
orientation
Cx
60
controlled
mean
31)
Phenylpiracetam
Omsk
State
Medical
Academy,
Encephalopathy
Open-label
99
200
1
mo
MMSE
Tx
45
±
16
None
85
Russia
(gliomas
to
acute
lesions)
(40-60)
Anxiety
Depression
50±
5
38±
4
Navy
Hospital,
Vladivostok,
Russia
Encephalopathy
Active
56
(2)-.
1
mo
Asthenia,
ND
None
86
(after
TBI)
controlled
(20-30)
100
headache
Nizhny
Novgorod
State
Medical
Encephalopathy
Active
51
(2)-.
1
mo
Neurological
Tx
32
±
11
None
87
Academy,
Russia
(vascular)
controlled
(mean
200
and
Cx
25
±
11
57.2)
psychological
Multiple
Sclerosis
Center
of
Novosibirsk,
Russia
Multiple
sclerosis
Open-label
39
200
1
mo
Asthenia
Anxiety
11
20
Sleep
disturbance
88
Depression
21
National
Research
Center
for
Social
Asthenia/fatigue
Active
and
180
(3)-.
1
mo
Memory
Tx
88
±
52
None
89
and
Forensic
Psychiatry,
Moscow,
syndrome
placebo
(21-40,
100-200
(10-word
test)
Cx
37
±
19
Russia
controlled
mean
25
PL
16
±
13
Clinic
No.
28,
Volgograd,
Russia
Asthenia
Active
39
(2)-.
1
mo
Problem
ND
None
90
controlled
(14-19,
100
solving
mean
15)
Ural
State
Medical
Academy,
Epilepsy
rpc
61
(2)-.
2
mo
Seizure:
Tx
None
91
Chelyabinsk,
Russia
(mean
100
Total
no.
46±1
29.7)
Frequency
46±3
Continued
next
page
©
2
01
0
A
di
s
D
at
a
I
nf
orm
ati
on
By
.
All
ri
ght
s
r
eserv
ed
.
CO
OL
:Om
s
bniCI
Table
V.
Contd
Sponsor/study
site
Intent
to
treat
Study
design
No.
of
pts
Dosage
Trial
Outcome
Efficacy
summary
Adverse
References
(age
in
y)
(mg/d,
oral)
duration
measures
(%
improvement
rate)
event
CD
Gorbunov
Hospital,
Kemerovo,
Epilepsy
rpc
40
(2)-.
1
mo
MMSE
12
None
92
Russia
(17-20)
100
CD
Tver
State
Medical
Academy,
Cerebral
stroke
Open-label
20
100
1
mo
Ab
titres:
Tx
None
93
Russia
(31-67,
MMP
34
±
4
mean
52)
PHL
7.5
±
0.6
0
2
Regional
Neurologic
Department,
Moscow,
Russia
Cerebral
stroke
(ischaemic)
Open-label
120
(3)-.
100,
200
1
mo
MMSE
Barthel
index
Tx
10±
0.4
6
±
0.4
Nausea
(3%)
94
0
Stroke
scale
9.1
CD
Orel
State
University,
Russia
Glaucoma
Open-label
26
100
1
mo
Vision
acuity
Tx
16
±
8
None
95
Nefiracetam
Daiichi
Sankyo,
Tokyo,
Japan;
Poststroke
rdbpc
159
(3)-.
12
wk
Depression
None None
96
Prestwick
Clinical,
Washington,
DC,
depression
(mean
600,
900
Apathy
Tx
34
97
USA
66.8)
PL
5
NINDS
Alzheimer's
Open-label
50
NA
20
wk
NA
NA NA
98
disease
(50-90)
Rolipram
NIMH
Major
depressive
rdbpc
50
NA
3y
Depression,
NA NA
99
disorder
(18-65)
PDE4
test
NINDS
Multiple
sclerosis
Open-label
6
7.5-9
8
mo
MRI
None
Poor
100,101
(18-65)
tolerability
Ab=
antibody;
Cx
=
control;
MMP=
main
myelin
protein;
MMSE=
Mini
Mental
State
Examination;
MRI
=
magnetic
resonance
imaging;
NA=
not
available;
ND=
not
done
(test
scores
lacking);
NINDS
=
National
Institute
of
Neurological
Disorders
and
Stroke;
NIMH
=National
Institute
of
Mental
Health;
PDE4=
phosphodiesterase
type
4;
PHL
=phospholipids;
PL
=
placebo;
rdbpc=
randomized,
double-blind,
placebo-controlled;
rpc=
randomized,
placebo
controlled;
TBI
=traumatic
brain
injury;
Tx=
test
agent;
(2)->,
(3)->
indicates
parallel
fixed
doses.
302
Malykh
&
Sadaie
(400
mg/day)
in
combination
with
multivitamins
and
physiotherapy.
[901
It
is
unclear
whether
any
particular
patient(s)
was
unresponsive
to
or
re-
lapsed
after
therapy.
Convulsion/Epilepsy,
Seizure
Phenylpiracetam
exhibited
an
antiepileptic
action
in
rodents.
Its
effective
dose
(300
mg/kg)
decreased
the
metrazol
(a
drug
used
as
a
circula-
tory
and
respiratory
stimulant)-induced
seizure
by
50%.
[1061
Phenylpiracetam
was
administered
to
patients
in
addition
to
one
standard
AED
(including
valproyl
amide,
carbamazepine,
la-
motrigine,
topiramate
or
a
barbiturate,
or
struc-
tured
polytherapy
with
more
than
one
of
these
drugs).
It
substantially
mitigated
the
number
and
frequency
of
seizures
of
patients
receiving
AED
only
and
the
number
of
individuals
with
a
de-
synchronous
EEG
profile
decreased
from
eight
to
three,
while
the
number
of
individuals
with
seizure
remissions
increased
modestly.
[911
Con-
sistent
with
this,
cognitive
functions
in
epileptic
patients
based
on
an
MMSE
test
improved
to
only
a
small
extent.
[921
These
trials
favoured
phenylpiracetam
as
add-on
medication
for
epi-
lepsy
(table
V).
Cerebral
Stroke/Ischaemia
Because
the
immune
system
has
a
crucial
role
in
the
pathogenesis
of
ischaemia-stroke,
titres
of
antibodies
against
the
main
myelin
protein
and
phospholipids
were
measured
in
patients
with
acute
cerebral
stroke
treated
with
phenylpir-
acetam.
The
titres
of
both
antibodies
decreased,
suggesting
possible
reduction
of
ongoing
demye-
lination
[931
(table
V).
In
a
two-arm
parallel
trial
with
patients
receiving
one
tablet
(80
people)
and
two
tablets
(40
people)
a
day,
both
MMSE
and
severity
of
stroke
scores
improved
significantly,
while
only
showing
a
trend
toward
improvement
in
daily
living
activities
(Barthel
test).
[941
A
post
hoc
analysis
for
a
subset
of
these
data
might
be
useful,
but
overall
the
therapy
appears
modestly
beneficial
(table
V).
Vision/Glaucoma
The
cause
of
blindness
in
glaucoma
is
optical
neuropathy
and
ganglia
cell
apoptosis.
Use
of
a
neuroprotective
agent
in
delaying
or
preventing
ganglial
cell
death
was
the
rationale
of
a
recent
trial.
Phenylpiracetam
was
given
to
patients
with
unstable
open-angle
glaucomas
after
the
eye
pressures
were
normalized
using
ocular
hypo-
tensive
therapy
and
laser
trabeculoplasty.
The
average
number
of
blind
spots
or
islands
of
loss
or
impairment
of
visual
acuity
decreased,
and
glaucoma
stabilized
in
80%
of
patients
at
6-month
follow-up
[951
(table
V).
It
is
premature
to
conclude
whether
the
trial
favours
phenylpir-
acetam
because
of
the
lack
of
a
prospective
placebo
control
and
possible
variables
such
as
patient
heterogeneity
at
the
trial
entry
point.
4.2
Subgroup
2:
Antiepileptic/Anticonvulsive
Drugs
This
subgroup
is
discussed
briefly
in
the
fol-
lowing
sections
because
of
their
approved
and
purported
activities
as
AEDs.
These
drugs
have
been
reviewed
recently
by
others
(e.g.
Bialer
et
al.,
[1
°
71
Rogawski
[1
°
81
and
Pollard
[1
°
91
)
and
will
be
topics
of
reviews
in
the
future.
4.2.1
Levetiracetam
Levetiracetam
is
a
second-generation
homo-
logue
of
piracetam
with
an
a-ethyl
side-chain
sub-
stitution
that
has
a
favourable
pharmacokinetic
and
safety
profile,
[11
°
1
and
is
the
only
approved
drug
in
this
subgroup
(table
III,
figure
1).
Other
recent
reviews
have
called
into
question
the
safety
of
levetiracetam
because
of
its
potential
ad-
verse
effects
on
bone
strength
and
formation,[]]]"
as
well
as
behaviour
or
mood.
[1121
However,
it
im-
proved
memory
and
cognitive
functions
in
patients
with
refractory
partial
seizures
[1131
and
language
dysfunctions
in
children
with
benign
sporadic
seizures,
[1141
in
a
small
controlled
trial
and
an
open-label
study,
respectively.
A
retrospective
analysis
[]151
and
non-controlled
trials
in
both
non-
epileptic
[1161
and
epileptic
[1171
patients
with
anxiety
and/or
depression
suggested
that
levetiracetam
is
effective
to
some
extent.
These
results
could
sug-
gest
that
levetiracetam
is
a
pluripotent
compound,
which
means
it
is
stimulatory
to
certain
behaviours
and
inhibitory
to
other
functions.
However,
its
beneficial
effect
(as
a
monotherapy)
for
other
indications
such
as
autism
is
controversial.
In
©
2010
Adis
Data
Information
By.
All
rights
reserved.
Drugs
2010;
70
(3)
Piracetam
and
Related
Drugs
for
CNS
Disorders
303
constrast
to
a
previous
report,
it
did
not
inhibit
behavioural
disturbances
in
autistic
children.
[1181
As
a
monotherapy,
it
was
ineffective
for
treatment
of
corticosteroid-induced
mood
and
cognitive
im-
pairment.[
1191
Whether
levetiracetam
would
work
better
than
piracetam
if
given
as
a
complementary
medication,
similar
to
the
piracetam
with
risper-
idone
protocol,
[661
is
unknown.
4.2.2
Brivaracetam
and
Seletracetam
The
4-n-propyl
homologue
brivaracetam
and
the
difluoroethenyled
derivative
seletracetam
(next-generation
drugs
to
levetiracetam)
have
more
recently
been
attributed
with
potentially
superior
antiepileptic
activities
based
on
in
vitro
drug
screening
and
animal
tests.
[42,43,1
°
71
The
higher
potency
and
apparently
common
mechanisms
of
action
demonstrated
for
both
brivaracetam
and
seletracetam
are
partially
consistent
with
clinical
results.
Both
exhibited
promising,
although
less
than
anticipated
benefits
in
phase
II
trials.
[1
°
8,12
°
1
Brivaracetam
was
safe
in
healthy
volunteers.
It
is
readily
absorbed
after
oral
administration,
reaching
maximum
plasma
concentration
in
0.5-1
hours,
and
eliminated
with
a
half-life
of
7-8
hours.
The
most
common
AEs
(mild
to
moder-
ate)
were
somnolence
and
dizziness
(similar
to
levetiracetam),
especially
at
high
doses.
[21,221
It
produced
a
reduction
of
seizure
frequencies
in
55%
of
patients
and
the
elimination
of
seizure
in
about
8%.
[120]
Brivaracetam
as
adjunctive
ther-
apy
was
well
tolerated
in
refractory
partial-onset
seizures
in
adults
according
to
a
presentation
at
the
2007
Epilepsy
Conference,
[1211
although
it
failed
to
decrease
the
frequency
of
seizures
during
7
weeks'
treatment.
[1221
Although
both
drugs
may
be
non-inferior
if
not
superior
to
levetiracetam,
it
seems
that
there
is
a
level
of
uncertainty
in
con-
tinuing
some
trials;
development
of
brivaracetam
for
epilepsy,
Unverricht-Landborg
disease
and
nerve
pain
appears
to
be
in
progress,
but
sele-
tracetam
development
seems
to
be
on
hold.
[1
°
91
4.3
Subgroup
3:
Compounds
with
Unknown
Efficacy
4.3.1
Nefiracetam
Nefiracetam
is
being
developed
for
the
treat-
ment
of
dementia
(AD
and
vascular
type).
It
potentiated
nicotinic
acetylcholine
receptors
in
rat
cortical
neuronal
primary
culture
at
very
low
concentrations
(0.1-1
nmol/L);
thus,
it
is
highly
potent.
[250231
In
humans,
its
concentration
in
blood
peaked
in
2
hours
with
half-life
of
3-5
hours
[261
(table
III,
figure
1).
A
phase
II
trial
of
nefiracetam
for
AD
patients
is
completed,
but
the
results
are
unpublished.
In
addition,
nefir-
acetam
failed
to
demonstrate
efficacy
in
a
12-week
trial
on
cognitive
deficits
in
patients
with
major
depression
after
stroke.
[961
Subsequent
analysis
showed
noticeably
improved
apathy
in
a
subpopulation
of
the
same
individuals
(table
V).
[971
Whether
this
drug
in
combination
with
other
agents
will
be
more
effective
for
these
or
other
indications
is
unexplored.
4.3.2
Nebracetam
Nebracetam
(WEB
1881
FU)
is
a
cholinergic
agent
that
has
been
predominantly
studied
in
Japan
since
the
late
1980s.
In
animals
it
was
neuroprotective,
possibly
via
enhancing
both
cholinergic
and
limbic
noradrenergic
functions
of
the
hippocampus.
[271
Histological
evidence
in-
dicated
that
it
is
protective
against
ischaemic
delayed
neuronal
cell
death
in
the
hippocampus
of
stroke-prone
rats.
[281
Clinical
trials
in
healthy
volunteers
in
Germany
were
conducted
to
de-
termine
whether
it
affected
event-related
cerebral
potentials
[1241
and
visual
spatial
attention.
[1251
Both
investigations
revealed
no
significant
effects
on
memory
performance.
Nonetheless,
a
small
trial
in
nine
AD
patients
demonstrated
a
pro-
mising
improvement
of
dementia.
[126]
4.3.3
Rolipram
The
analogue
rolipram,
distantly
related
to
piracetam,
inhibits
phosphodiesterase
type
4
(PDE4).
It
has
a
good
bioavailability
and
short
half-life[
291
(table
III,
figure
1),
and
was
appar-
ently
safe
within
the
dose
range
of
0.75-3
mg/day
in
humans.
[301
It
was
tested
as
an
antidepressant
in
several
clinical
trials,
but
it
was
not
better
than
available
drugs
such
as
amitriptyline
[127,1281
and
imipramine.[129'
130]
Its
typical
adverse
effect
was
nausea,
which
presumably
compromised
its
use
as
an
antidepressant.
The
neuroprotective
effect
of
rolipram
was
evident
in
cultured
cells
and
in
©
2010
Adis
Data
Information
By.
All
rights
reserved.
Drugs
2010;
70
(3)
304
Malykh
&
Sadaie
animals.
Interestingly,
it
promoted
regeneration
of
axons
[1311
and
induced
phrenic
nerve
recovery
after
cervical
spinal
cord
injury
in
rats.
[1321
These
findings
support
its
potential
use
for
similar
conditions
in
humans.
However,
rolipram
failed
to
suppress
inflammation
in
the
brain
of
MS
pa-
tients
and
even
showed
increased
inflammatory
activity
(table
v).[loo,m1
Recently,
another
clin-
ical
trial
began
to
investigate
the
correlation
be-
tween
depression
and
modulation
of
cAMP-
specific
PDE4
levels
(table
V).
Additional
investi-
gation
of
the
potential
clinical
use
of
rolipram
appears
underway,
which
involves
treatment
of
memory
and
learning
deficits
after
microsphere
embolism-induced
cerebral
ischaemia.
[1331
4.3.4
Fasoracetam
Fasoracetam
(NS
105,
LAM
105)
is
a
rela-
tively
new
candidate
drug,
which
has
potential
as
a
cognitive
enhancer.
It
is
absorbed
rapidly
after
oral
administration
in
rats
(maximum
con-
centration
reached
after
0.5
hours),
distributes
intact
[1341
and
excretes
predominantly
unchanged
from
kidneys.
[311
Bioavailability
in
rats,
dogs
and
monkeys
were
97%,
90%
and
79%,
with
a
half-life
of
0.91,
2.8
and
1.3
hours,
respectively.
[311
It
takes
a
little
longer
for
this
drug
to
clear
in
elderly
people
(half-life
=
5.17
hours)
than
in
young
people
(4.45
hours),
[321
which
might
limit
its
uti-
lity,
especially
if
it
causes
prolonged
adverse
drug
interactions.
Its
safety
and
efficacy
have
not
been
determined
yet.
4.3.5
Coluracetam
Coluracetam
(MKC-23
1)
is
a
quinolin
deriva-
tive
of
piracetam
and
a
choline-uptake
enhancer
that
is
being
explored
in
Japan.
This
distinctly
no-
vel
compound
improved
an
artificially
induced
memory
impairment
loss
in
rats
P
3
'
A
daily
repeat
dosing
study
showed
a
long-lasting
effect
in
ro-
dents.
[34]
Data
related
to
its
pharmacokinetic
and
pharmatoxicological
properties
are
unpublished.
4.3.6
Rolziracetam
Rolziracetam
is
a
cyclic
imide
that
improved
performance
of
a
delayed-response
task
in
aged
Rhesus
monkeys.
[711
As
a
result,
this
drug
was
proposed
as
a
good
candidate
for
the
treatment
of
cognitive
impairment
in
humans.
However,
it
was
shown
later
that
it
is
quite
unstable
in
vivo
(half-life
<25
minutes)
and
is
eliminated
in
a
me-
tabolized
form
as
5-oxo-2-pyrrolodinepropanoic
acid
via
urinary
excretion
in
rats.
[351
This
has
possibly
slowed
down
its
development.
4.3.7
Dimiracetam
A
series
of
bicyclic
pyrrolidinone
analogues
of
piracetam
have
been
synthesized
and
tested
for
their
ability
to
reverse
scopolamine-induced
am-
nesia
in
rodents.
[361
One
such
compound
is
di-
miracetam,
which
was
10-
to
30-fold
more
potent
than
oxiracetam.
Dimiracetam
congeners
re-
portedly
had
beneficial
effects
on
peripheral
neuropathic
pain
in
rats.
[371
With
respect
to
its
effect
site,
the
activities
and
bioavailability
of
these
compounds
in
the
brain
are
unknown.
The
causes
of
peripheral
neuropathic
pain
are
gen-
erally
associated
with
damage
to
the
peripheral
tissues
outside
of
the
CNS.
There
is
no
evidence
to
suggest
that
piracetam,
or
its
derivatives,
are
effective
analgesic
medications.
5.
Discussion
Subgroup
1
and
2
compounds
are
the
most
researched
among
nootropic
drugs,
some
with
proven
efficacy
and
some
with
unsubstantiated
claims.
The
piracetam-like
compounds
with
che-
mical
structures
most
closely
related
to
pir-
acetam,
including
the
oxopyrrolidone
ring
and
its
alkylamine
branch,
resemble
certain
amino
acids
(such
as
glycine,
proline
or
hydroxyproline,
and
glutamate,
which
also
act
as
neurotransmitters).
The
oxopyrrolidone
ring
is
generally
recognized
as
safe
because
its
polymeric
cross-linked
form,
polyvinylpyrrolidone,
is
used
as
a
disintegrant
and
coating
excipient
in
tablet
manufacture.
Some
piracetam-like
compounds
indeed
exhibit
similar
modes
of
action
as
well
as
overlapping
pharmacokinetic
profiles.
These
features,
in
part,
can
explain
the
observed
high
degree
of
safety
for
piracetam
compounds.
In
contrast,
the
molecular
entities
in
subgroup
3
can
possibly
exhibit
other
undesirable
side
ef-
fects,
e.g.
the
overinduction
of
certain
first-pass
metabolic
enzymes
or
undesirable
interaction
with
non-target
sites.
Thus,
it
is
important
to
©
2010
Adis
Data
Information
By.
All
rights
reserved.
Drugs
2010;
70
(3)
Piracetam
and
Related
Drugs
for
CNS
Disorders
305
investigate
their
mechanisms
of
action
as
well
as
their
other
biochemical
properties.
Potential
drug-to-drug
interactions
in
combination
thera-
pies
are
important,
albeit
that
little
research
has
been
done
with
lead
drugs
of
the
piracetam
fa-
mily.
It
appears
that
there
is
no
general
corollary
of
evidence
between
drugs
potencies,
bioavail-
abilities,
pharmacokinetics,
and
their
safety
and
efficacy.
The
relevance
of
the
mechanisms
of
action
of
these
drugs
to
the
known
deficiencies
of
both
glutamate
receptors,
such
as
NMDA,
and
nACh
receptors
in
the
brain
of
AD
patients
are
im-
portant,
and
research
in
this
area
will
continue
to
unfold
new
insights.
At
least
some
of
the
sub-
group
3
drugs
may
be
useful
for
the
treatment
of
various
cognitive
dysfunctions
and/or
AD
pa-
tients.
However,
overstimulation
of,
for
instance,
NMDA
receptors
could
cause
toxicity
and
cell
death.
The
molecular
structures
of
subgroup
1
and
2
compounds
differ
only
very
slightly.
It
seems
perplexing
that
the
mechanisms
modulating
Ca'
currents
for
the
subgroup
1
compounds
(pir-
acetam,
oxiracetam,
aniracetam)
are
distinctly
different
from
those
of
subgroup
2
(particularly
levetiracetam),
which
results
in
the
opposite
direc-
tion
and
flow
of
Ca'
currents
in
neurons.
Although
neuromodulatory
substances
can
be
agonists
or
antagonists,
such
conflicting
functions
are
generally
dose
dependent.
Inadequate
data
exist
on
how
these
com-
pounds,
including
active
agents
outside
this
fa-
mily
of
nootrops,
impact
on
brain
performance
when
given
as
a
combined
drug
product.
To
im-
prove
the
efficacy
of
piracetam-like
drugs,
future
research
will
probably
focus
on
designing
newer
small
molecule
compounds
to
enable
a
higher
potency,
better
target
bioavailability
and
toler-
ability,
and
thus
be
suitable
for
longer-term
use.
Researchers
in
this
area
are
also
likely
to
focus
on
the
novel
prodrugs
of
piracetam
that
can
enable
sustained
delivery
and
higher
permeability,
espe-
cially
across
the
blood-brain
barrier.
To
achieve
this,
it
may
be
necessary
to
generate
rationally
designed
drugs
for
a
set
of
prespecified
target
re-
ceptors.
Alternatively,
novel
derivatives
may
be
designed
with
a
dual
property
to
affect
receptors
in
CNS
and
peripheral
neurons.
Numerous
reports
have
recently
reiterated
that
the
glutamate
receptors
are
associated
with
broad
important
functions
of
the
brain,
including
memory
and
learning,
[1351
anxiety
and
depres-
sion.
[1361
These
receptors
are
also
connected
to
pain,
[1371
and
neurodegenerative
[1381
as
well
as
neuronal
cell
repair
processes.
[1391
Notably,
the
activation
of
ionotropic
glutamate
receptors
in-
creases
[Ca
2-
1i,
which,
if
it
exceeds
normal
phy-
siological
concentrations
in
neurons,
can
in
turn
cause
toxic
injury
and
neuronal
cell
death.
[1401
An
overstimulation
and
release
of
glutamate
lets
in
calcium
and
increases
its
intracellular
deposit,
a
key
step
that
triggers
(glutamate-/[Ca
2
1-
induced)
neurotoxicity
in
both
hippocampal
and
cerebral
Purkinje
neurons
[141,1421
(reviewed
by
Mattson
[1431
).
The
excess
calcium
influx
activates
destructive
cysteine
proteases,
such
as
calpains,
through
a
variety
of
biochemical
processes,
which
leads
to
proteolysis
of
glutamate
receptor
pro-
teins,
including
AMPA[
141,1421
and
NMDA.['
441
The
ensuing
calcification,
among
other
factors,
can
then
cause
neuronal
apoptosis
or
degenera-
tion
of
'dark
cells',
and
lead
to
deleterious
side
effects.
These
actions
would
raise
a
safety
con-
cern
for
the
compounds
disturbing
the
homeo-
stasis
of
ionotropic
glutamate
receptors.
Whether
or
not
the
subgroup
1
drugs
pose
a
long-term
risk
based
on
this
possibility
has
not
been
thoroughly
explored.
It
would
be
desirable
if
a
piracetam-like
ligand
polarizes
the
glutamate
receptor
to
an
extent
that
it
reverses
the
current
and
decreases
calcium
overload
in
neurons.
This
can
have
a
beneficial
(neuroprotective)
effect,
resulting
in
inhibition
of
[Ca
2
ji-mediated
neuronal
cell
death.
Consistent
with
this,
deactivation
of
AMPA
receptors
in
cultured
neurons
of
the
hippocampus
and
cere-
bellum
decreases
intracellular
calcium
load
and
this
leads
to
neuroprotection.
[141,142]
The
key
significance
of
the
latter
model
is
that
some
of
the
crucial
roles
of
the
hippocampus
have
been
implicated
in
spatial
learning
(the
ability
to
re-
member
to
find
the
way
to
a
given
place),
'con-
struction
of
mental
images'
and
long-term
mem-
ories.
[145,146]
Importantly,
piracetam-like
drugs
can
affect
different
parts
of
brain
tissue,
from
the
cortical
motor
region
to
deep
neurons
in
the
©
2010
Adis
Data
Information
By.
All
rights
reserved.
Drugs
2010;
70
(3)
306
Malykh
&
Sadaie
hippocampus.
This
region
of
the
brain
is
com-
promised
in
aging
people
and
deteriorates
espe-
cially
in
CNS
disorders
such
as
AD.
[1471
As
the
role
of
calcium
in
neuronal
growth
and
plasticity
is
beginning
to
unfold,
a
positive
regulation
of
homeostasis
that
prevents
disturbances
in
cellular
Ca'
can
be
neuroprotective
in
people
with
MCI
and
ADJ138'
143]
However,
the
previous
reports
come
short
of
validating
the
mechanisms
of
ac-
tion
of
piracetam
nootrops
before
their
clinical
efficacies
were
established.
Glutamate
receptors
also
serve
as
biological
targets
for
non-piracetam-
like
nootropic
drugs
such
as
acetyl-L-carnitine,
which
reportedly
increased
expression
of
mGluR
(type
2
protein)
in
the
cerebral
cortex
as
well
as
spinal
cord
of
rats,
though
not
in
the
cerebellum
or
hippocampus.
[1481
In
addition,
acetyl-L-
carnitine
protected
hippocampus
from
hypoxia-
induced
neuronal
damage
and
improved
spatial
memory
deficits
in
rats,
by
reversing
the
aberrant
expression
of
the
NR1
subunit
of
the
NMDA
receptor
and
apoptotic
proteins.
[1491
Notably,
its
unacetylated
form,
L-carnitine,
protected
rat
pups
from
the
neurotoxic
adverse
effects
of
iso-
flurane
and
nitrous
oxide.
These
anaesthetic
gases,
which
are
used
in
surgical
procedures
for
human
infants
and
in
animals,
block
NMDA
or
potentiate
GABA
receptors.
[1501
Although
the
neuroprotective
effect
of
L-carnitine
is
probably
through
removal
of
toxic
fatty
acid
accumula-
tions
in
neurons,
acetyl-L-carnitine
may
also
affect
neurotransmitter
receptors.
It
will
be
of
interest
to
determine
whether
non-
piracetam
nootrops
such
as
acetyl-L-carnitine
can
synergize
with
a
piracetam-like
compound.
We
draw
this
hypothesis
from
independent
pub-
lished
papers
showing
that
acetyl-L-carnitine
increases
expression
of
type
2
metabotropic
glutamate
receptors
in
neurons
(a
mechanism
consistent
with
abilities
of
acetyl-L-carnitine
to
increase
nerve
conduction
velocity,
decrease
neuronal
loss
and
promote
nerve
regenera-
tion)
[148]
and
that
some
piracetam
compounds
interact
with
glutamate
receptors.
In
moderate
to
severe
AD
both
glutamate
and
cholinergic
re-
ceptors
are
downregulated.P
511
These
compounds
were
investigated
for
their
ability
to
improve
memory
in
AD,
and
have
been
implicated
to
be
neuroprotective
in
an
aging
brain
model
in
rats.
Whether
a
combination
of
acetyl-L-carnitine
and
a
piracetam-like
active
would
exhibit
a
synergetic
effect
remains
to
be
determined.
Meta-analysis
in
and
out
of
itself
carries
a
probability
of
error.
Failure
to
consider
the
con-
founding
variables
for
outcome
measures,
espe-
cially
in
a
large
data
pool
(in
addition
to
factors
such
as
sample
heterogeneity
across
and
within
studies
and
potential
publication
biases),
can
lead
to
overstatements
of
efficacy
or
positive
pre-
dicative
value
while
potentially
underestimating
negative
predictive
value
and
adverse
effects.
This
is
consistent
with
the
concerns
of
the
authors
of
a
recent
review
and
meta-analysis
of
piracetam
and
piracetam-like
drugs
in
stroke
models
in
ro-
dents,
[51
e.g.
inclusion
of
a
selected
few
articles
could
disproportionately
favour
the
efficacy
findings.
Interestingly,
efficacy
of
piracetam
was
the
highest
when
halothane
anaesthesia
was
used.
[51
In
this
context,
piracetam
was
neuropro-
tective
against
lesion
induction,
but
it
was
given
as
an
acute
treatment.
We
offer
a
different
ex-
planation,
which
is
that
piracetam
possibly
acted
as
an
antagonist
to
halothane,
hence
attenuating
the
neurotoxic
adverse
effect
of
this
general
an-
aesthetic
(which
has
recently
been
abandoned
for
human
use),
and
that
could
be
the
underlying
mechanism
of
piracetam
in
reducing
cerebral
in-
farctions
in
rats.
Finally,
potential
interactions
of
piracetam-like
drugs
with
the
actions
of
other
drugs
in
polytherapies
are
the
subject
of
a
sepa-
rate
review.
Overall,
the
published
data
predominantly
state
that
lead
drugs
in
clinical
use
are
generally
safe
and
effective,
although
most
outcome
mea-
sures
appear
inconclusive
and/or
too
premature
to
draw
a
definitive
conclusion.
The
compounds
that
demonstrate
no
observable
adverse
effect
level
(NOAEL)
at
high
doses
were
mostly
ex-
plored
for
broad
indications.
While
several
expanded
trials
revealed
few
beneficial
effects,
such
investigations
are
likely
to
continue
for
multiple
reasons.
Chief
among
them,
an
auxiliary
drug
can
complement
suboptimal
drugs,
and
this
would
be
cost
effective.
A
development
strategy
relying
solely
on
old
drugs
simply
because
of
their
favourable
benefit-risk
profile
can
also
be
©
2010
Adis
Data
Information
By.
All
rights
reserved.
Drugs
2010;
70
(3)
Piracetam
and
Related
Drugs
for
CNS
Disorders
307
counterproductive,
potentially
detracting
from
the
creation
of
innovative
new
drugs.
Future
re-
search
has
to
reconcile
the
remaining
issues
and
come
up
with
more
rational
designs
or
better
alternatives.
6.
Conclusion
The
current
trend
of
research
is
gearing
more
towards
testing
piracetam
and
piracetam-like
compounds
for
new
indications.
Many
trials
started
with
insufficient
prior
explorations
in
animal
models
of
human
diseases.
The
efficacies
of
these
drugs
for
most
indications
appear
pro-
mising,
although
most
trials
are
inconclusive
and
well
controlled
studies
are
required.
Their
po-
tential
neuroprotective
and
neuroregenerative
effects
are
the
least
explored.
The
low
to
moder-
ate
potencies
of
most
of
these
active
agents
and
their
lack
of
target
specificities
may
have
con-
tributed
to
some
of
their
suboptimal
efficacy.
Unlike
most
GABA-mimetic
drugs
(such
as
barbiturates,
carbamazepines
and
gabazine
[SR-
95531])
that
can
cause
the
AE
of
amnesia,
pir-
acetam
and
some
piracetam-like
drugs
are
rela-
tively
safe,
and
are
dynamic
and
flexible
enough
to
develop
for
different
indications.
Long-term
consequences
and
potential
risks
associated
with
off-label
use
of
these
drugs
are
unidentified.
Their
mechanisms
of
action
have
also
been
inade-
quately
researched.
Potential
biases
in
the
design,
disease
modelling
and
interpretation
of
outcome
measures
for
expanded
trials
are
difficult
to
rule
out,
especially
after
the
effectiveness
of
a
given
drug
is
revealed.
Improvements
to
the
design
of
newer-generation
chemical
entities
can
lead
to
better
clinical
efficacy.
Acknowledgements
The
authors
thank
Dr
Allan
Kalueff
who
is
affiliated
with
the
Department
of
Pharmacology,
Tulane
University
School
of
Medicine,
New
Orleans,
LA,
USA
and
Dr
Nasi
Samiy
who
is
with
the
Retina
Institute
of
the
Carolinas
and
The
Macular
Degeneration
Center,
Rock
Hill,
SC,
USA,
for
their
critical
reviewing
of
the
manuscript.
The
authors
have
no
financial
relationship
with
and
did
not
receive
funds
from
companies
developing
and
marketing
piracetam
and
related
products
or
their
competitors.
Appendix
Explanation
of
attributable
percentage
improve-
ment
rate
(APIR)
calculations.
The
test
scores
in
various
clinical
trials
re-
present
a
set
of
incomparable
numerical
values,
and
the
statistical
inferences
of
such
data
indicate
little
or
nothing
of
the
size
of
potential
difference
or
clinical
importance.
For
clarity,
uniformity
and
comparability
we
used
the
following
for-
mulas:
APIR%
=
(Bp
p)
(Bt
Tx)
x
100
(B1)
1))
or
(Bt
Tx)
APIR%
=
Bt
x
100
where
Bp
and
Bt
are
placebo
and
test
agent
baselines,
respectively,
P
is
placebo
and
Tx
is
the
test
agent,
to
estimate
the
percentage
improve-
ment
rates.
The
APIRs,
or
the
composite
mean
values,
were
calculated
for
the
outcome
measures
that
were
significant
(p
0.05).
For
example,
in
the
study
by
Holinski
et
al.
[54]
(table
IV),
score
values
decreased
in
both
test
and
placebo
arms,
compared
with
baseline.
The
effect
of
the
test
agent
resulted
in
lesser
decline.
The
overall
cognitive
function
score
at
baseline
was
0.06±
1.02
and
—0.06
±
0.99
in
the
test
and
place-
bo
arms.
The
outcome
measure
values
were
—0.65
±
0.93
and
—1.38±
1.1,
correspondingly.
APIR%
=
[(-0.06)
(-1.38)]
[(-0.06)
(0.65)]
x
100
=
46%
(-0.06)
(-1.38)
For
trials,
where
the
outcomes
were
compared
with
baselines,
we
used
the
second
formula
as
follows:
APIR%
=
34.6
29.5
x
100
=
15%
34.6
In
the
study
by
Batysheva
et
al.,
[571
for
example,
the
activity
test
score
was
34.6
1.34
at
baseline
and
29.5
±
1.43
after
the
treatment.
Percentage
standard
deviations
SD%)
were
calculated
based
on
three
values:
APIR
'low',
APIR
'mean'
and
APIR
'high'.
Lower
limit
value
=
test
score
mean
value
SD;
upper
limit
value
=
test
score
mean
value
+
SD.
©
2010
Adis
Data
Information
By.
All
rights
reserved.
Drugs
2010;
70
(3)
308
Malykh
&
Sadaie
References
1.
Giurgea
C.
The
`nootropic'
approach
to
the
pharmacology
of
the
integrative
activity
of
the
brain.
Cond
Reflex
1973
Apr-Jun;
8
(2):
108-15
2.
Piracetam
[online].
Available
from
URL:
http://www
.
piracetam.com
[Accessed
2010
Jan
22]
3.
US
National
Institutes
of
Health.
ClinicalTrials.gov
[on-
line].
Available
from
URL:
http://www.clinicaltrials.gov
[Accessed
2010
Jan
22]
4.
Waegemans
T,
Wilsher
CR,
Danniau
A,
et
al.
Clinical
efficacy
of
piracetam
in
cognitive
impairment:
a
meta-
analysis.
Dement
Geriatr
Cogn
Disord
2002;
13
(4):
217-24
5.
Wheble
PC,
Sena
ES,
Macleod
MR.
A
systematic
review
and
meta-analysis
of
the
efficacy
of
piracetam
and
piracetam-like
compounds
in
experimental
stroke.
Cerebrovasc
Dis
2008;
25
(1-2):
5-11
6.
Gualtieri
F,
Manetti
D,
Romanelli
MN,
et
al.
Design
and
study
of
piracetam-like
nootropics,
controversial
mem-
bers
of
the
problematic
class
of
cognition-enhancing
drugs.
Curr
Pharm
Des
2002;
8
(2):
125-38
7.
Information
letter
from
the
Institute
of
Medical-Biological
Problems
of
the
Russian
Academy
of
Sciences
[in
Rus-
sian;
online].
Available
from
URL:
http://www.pheno
tropil.ru/img/articles/popup_01264.html
[Accessed
2010
Jan
22]
8.
Nickolson
VJ,
Wolthuis
OL.
Effect
of
the
acquisition-
enhancing
drug
piracetam
on
rat
cerebral
energy
meta-
bolism:
comparison
with
naftidrofuryl
and
methamphe-
tamine.
Biochem
Pharmacol
1976
Oct
15;
25
(20):
2241-4
9.
Grau
M,
Montero
JL,
Balasch
J.
Effect
of
Piracetam
on
electrocorticogram
and
local
cerebral
glucose
utilization
in
the
rat.
Gen
Pharmacol
1987;
18
(2):
205-11
10.
Tacconi
MT,
Wurtman
RJ.
Piracetam:
physiological
dis-
position
and
mechanism
of
action.
Adv
Neurol
1986;
43:
675-85
11.
Wischer
S,
Paulus
W,
Sommer
M,
et
al.
Piracetam
affects
facilitatory
I-wave
interaction
in
the
human
motor
cortex.
Clin
Neurophysiol
2001
Feb;
112
(2):
275-9
12.
Horvath
B,
Marton
Z,
Halmosi
R,
et
al.
In
vitro
antioxidant
properties
of
pentoxifylline,
piracetam,
and
vinpocetine.
Clin
Neuropharmacol
2002
Jan-Feb;
25
(1):
37-42
13.
Pepeu
G,
Spignoli
G.
Nootropic
drugs
and
brain
choli-
nergic
mechanisms.
Prog
Neuropsychopharmacol
Biol
Psychiatry
1989;
13
Suppl.:
S77-8
14.
Pilch
H,
Muller
WE.
Piracetam
elevates
muscarinic
choli-
nergic
receptor
density
in
the
frontal
cortex
of
aged
but
not
of
young
mice.
Psychopharmacology
(Berl)
1988;
94
(1):
74-8
15.
Perucca
E,
Albrici
A,
Gatti
G,
et
al.
Pharmacokinetics
of
oxiracetam
following
intravenous
and
oral
administration
in
healthy
volunteers.
Eur
J
Drug
Metab
Pharmacokinet
1984
Jul-Sep;
9
(3):
267-74
16.
Chang
T,
Young
RM,
Goulet
JR,
et
al.
Pharmacokinetics
of
oral
pramiracetam
in
normal
volunteers.
J
Clin
Phar-
macol
1985
May-Jun;
25
(4):
291-5
17.
Auteri
A,
Blardi
P,
Celasco
G,
et
al.
Pharmacokinetics
of
pramiracetam
in
healthy
volunteers
after
oral
adminis-
tration.
Int
J
Clin
Pharmacol
Res
1992;
12
(3):
129-32
18.
Endo
H,
Tajima
T,
Yamada
H,
et
al.
Pharmacokinetic
study
of
aniracetam
in
elderly
patients
with
cerebrova-
scular
disease.
Behav
Brain
Res
1997
Feb;
83
(1-2):
243-4
19.
Spektor
SS,
Berlyand
AS.
Molecular-biological
problems
of
drug
design
and
mechanisms
of
drug
action:
experi-
mental
pharmacokinetics
of
carphedon.
Pharm
Chem
J
1996;
30
(8):
89-90
20.
Antonova
MI,
Prokopov
AA,
Berlyand AS,
et
al.
Experi-
mental
pharmacokinetic
of
Phenotropil
in
rats.
Pharm
Chem
J
2003;
37:
7-8
21.
Sargentini-Maier
ML,
Rolan
P,
Connell
J,
et
al.
The
pharmacokinetics,
CNS
pharmacodynamics
and
adverse
event
profile
of
brivaracetam
after
single
increasing
oral
doses
in
healthy
males.
Br
J
Clin
Pharmacol
2007
Jun;
63
(6):
680-8
22.
Rolan
P,
Sargentini-Maier
ML,
Pigeolet
E,
et
al.
The
pharmacokinetics,
CNS
pharmacodynamics
and
adverse
event
profile
of
brivaracetam
after
multiple
increasing
oral
doses
in
healthy
men.
Br
J
Clin
Pharmacol
2008
Jul;
66
(1):
71-5
23.
Bennett
B,
Matagne
A,
Michel
P,
et
al.
Seletracetam
(UCB
44212).
Neurotherapeutics
2007
Jan;
4
(1):
117-22
24.
Tai
KK,
Truong
DD.
Brivaracetam
is
superior
to
levetir-
acetam
in
a
rat
model
of
post-hypoxic
myoclonus.
J
Neural
Transm
2007;
114
(12):
1547-51
25.
Zhao
X,
Kuryatov
A,
Lindstrom
JM,
et
al.
Nootropic
drug
modulation
of
neuronal
nicotinic
acetylcholine
receptors
in
rat
cortical
neurons.
Mol
Pharmacol
2001
Apr;
59
(4):
674-83
26.
Fujimaki
Y,
Sudo
K,
Hakusui
H,
et
al.
Single-
and
multi-
ple-dose
pharmacokinetics
of
nefiracetam,
a
new
noo-
tropic
agent,
in
healthy
volunteers.
J
Pharm
Pharmacol
1992
Sep;
44
(9):
750-4
27.
Iwasaki
K,
Matsumoto
Y,
Fujiwara
M.
Effect
of
nebrace-
tam
on
the
disruption
of
spatial
cognition
in
rats.
Jpn
J
Pharmacol
1992
Feb;
58
(2):
117-26
28.
Nakashima
MN,
Kataoka
Y,
Yamashita
K,
et
al.
Histo-
logical
evidence
for
neuroprotective
action
of
nebracetam
on
ischemic
neuronal
injury
in
the
hippocampus
of
stroke-
prone
spontaneously
hypertensive
rats.
Jpn
J
Pharmacol
1995
Jan;
67
(1):
91-4
29.
Krause
W,
Kiihne
G,
Matthes
H.
Pharmacokinetics
of
the
antidepressant
rolipram
in
healthy
volunteers.
Xenobio-
tica
1989
Jun;
19
(6):
683-92
30.
Fleischhacker
WW,
Hinterhuber
H,
Bauer
H,
et
al.
A
multicenter
double-blind
study
of
three
different
doses
of
the
new
cAMP-phosphodiesterase
inhibitor
rolipram
in
patients
with
major
depressive
disorder.
Neuropsycho-
biology
1992;
26
(1-2):
59-64
31.
Mukai
H,
Sugimoto
T,
Ago
M,
et
al.
Pharmacokinetics
of
NS-105,
a
novel
cognition
enhancer.
1st
communication:
absorption,
metabolism
and
excretion
in
rats,
dogs
and
monkeys
after
single
administration
of
14C-NS-105.
Arzneimittelforschung
1999
Nov;
49
(11):
881-90
32.
Kumagai
Y,
Yokota
S,
Isawa
S,
et
al.
Comparison
of
pharmacokinetics
of
NS-105,
a
novel
agent
for
cere-
brovascular
disease,
in
elderly
and
young
subjects.
Int
J
Clin
Pharmacol
Res
1999;
19
(1):
1-8
33.
Bessho
T,
Takashina
K,
Tabata
R,
et
al.
Effect
of
the
novel
high
affinity
choline
uptake
enhancer
2-(2-oxopyrrolidin-
©
2010
Adis
Data
Information
By.
All
rights
reserved.
Drugs
2010;
70
(3)
Piracetam
and
Related
Drugs
for
CNS
Disorders
309
1-yl)-N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin
-4-yl)acetoamide
on
deficits
of
water
maze
learning
in
rats.
Arzneimittelforschung
1996
Apr;
46
(4):
369-73
34.
Bessho
T,
Takashina
K,
Eguchi
J,
et
al.
MKC-231,
a
cho-
line-uptake
enhancer:
(1)
long-lasting
cognitive
improve-
ment
after
repeated
administration
in
AF64A-treated
rats.
J
Neural
Transm
2008
Jul;
115
(7):
1019-25
35.
Black
A,
Chang
T.
Metabolic
disposition
of
Rolziracetam
in
laboratory
animals.
Eur
J
Drug
Metab
Pharmacokinet
1987
Apr-Jun;
12
(2):
135-43
36.
Pinza
M,
Farina
C,
Cerri
A,
et
al.
Synthesis
and
pharma-
cological
activity
of
a
series
of
dihydro-1H-pyrrolo[1,
2-a]imidazole-2,5(3H,6H)-diones,
a
novel
class
of
potent
cognition
enhancers.
J
Med
Chem
1993
Dec
24;
36
(26):
4214-20
37.
Farina
C,
Gagliardi
S,
Ghelardini
C,
et
al.
Synthesis
and
biological
evaluation
of
novel
dimiracetam
derivatives
useful
for
the
treatment
of
neuropathic
pain.
Bioorg
Med
Chem
2008
Mar
15;
16
(6):
3224-32
38.
Copani A,
Genazzani
AA,
Aleppo
G,
et
al.
Nootropic
drugs
positively
modulate
alpha-amino-3-hydroxy-5-me-
thyl-4-isoxazolepropionic
acid-sensitive
glutamate
re-
ceptors
in
neuronal
cultures.
J
Neurochem
1992
Apr;
58
(4):
1199-204
39.
Pugsley
TA,
Shih
Y-H,
Coughenour
L,
et
al.
Some
neuro-
chemical
properties
of
pramiracetam
(CI-879),
a
new
cognition-enhancing
agent.
Drug
Dev
Res
1983;
3:
407-20
40.
Kovalev
GI,
Akhapkina
VI,
Abaimov
DA,
et
al.
Pheno-
tropil
as
receptor
modulator
of
synaptic
neurotransmis-
sion
[in
Russian].
Nervnye
Bolezni
2007;
4:
22-6
41.
Carunchio
I,
Pieri
M,
Ciotti
MT,
et
al.
Modulation
of
AMPA
receptors
in
cultured
cortical
neurons
induced
by
the
antiepileptic
drug
levetiracetam.
Epilepsia
2007
Apr;
48
(4):
654-62
42.
Lukyanetz
EA,
Shkryl
VM,
Kostyuk
PG.
Selective
block-
ade
of
N-type
calcium
channels
by
levetiracetam.
Epi-
lepsia
2002
Jan;
43
(1):
9-18
43.
Pisani
A,
Bonsi
P,
Martella
G,
et
al.
Intracellular
calcium
increase
in
epileptiform
activity:
modulation
by
levetir-
acetam
and
lamotrigine.
Epilepsia
2004
Jul;
45
(7):
719-28
44.
Lynch
BA,
Lambeng
N,
Nocka
K,
et
al.
The
synaptic
ve-
sicle
protein
SV2A
is
the
binding
site
for
the
antiepileptic
drug
levetiracetam.
Proc
Natl
Acad
Sci
U
S
A
2004
Jun;
101
(26):
9861-6
45.
Moriguchi
S,
Shioda
N,
Maejima
H,
et
al.
Nefiracetam
potentiates
N-methyl-D-aspartate
(NMDA)
receptor
function
via
protein
kinase
C
activation
and
reduces
magnesium
block
of
NMDA
receptor.
Mol
Pharmacol
2007
Feb;
71
(2):
580-7
46.
Kataoka
Y,
Niwa
M,
Koizumi
S,
et
al.
Nebracetam
(WEB
1881FU)
prevents
N-methyl-D-aspartate
receptor-medi-
ated
neurotoxicity
in
rat
striatal
slices.
Jpn
J
Pharmacol
1992
Jun;
59
(2):
247-50
47.
Kataoka
Y,
Kohno
Y,
Watanabe
Y.
Inhibitory
action
of
nebracetam
on
various
stimuli-evoked
increases
in
in-
tracellular
Ca2+
concentrations
in
cultured
rat
cerebellar
granule
cells.
Jpn
J
Pharmacol
1995
Jan;
67
(1):
87-90
48.
Oka
M,
Itoh
Y,
Tatsumi
S,
et
al.
A
novel
cognition
en-
hancer
NS-105
modulates
adenylate
cyclase
activity
through
metabotropic
glutamate
receptors
in
primary
neuronal
culture.
Naunyn
Schmiedebergs
Arch
Pharma-
col
1997
Aug;
356
(2):
189-96
49.
Oka
M,
Itoh
Y,
Shimidzu
T,
et
al.
Involvement
of
meta-
botropic
glutamate
receptors
in
Gi-
and
Gs-dependent
modulation
of
adenylate
cyclase
activity
induced
by
a
novel
cognition
enhancer
NS-105
in
rat
brain.
Brain
Res
1997
Apr
18;
754
(1-2):
121-30
50.
Shimidzu
T,
Itoh
Y,
Oka
M,
et
al.
Effect
of
a
novel
cogni-
tion
enhancer
NS-105
on
learned
helplessness
in
rats:
possible
involvement
of
GABA(B)
receptor
up-regulation
after
repeated
treatment.
Eur
J
Pharmacol
1997
Nov
12;
338
(3):
225-32
51.
Takashina
K,
Bessho
T,
Mori
R,
et
al.
MKC-231,
a
choline
uptake
enhancer:
(3)
mode
of
action
of
MKC-231
in
the
enhancement
of
high-affinity
choline
uptake.
J
Neural
Transm
2008
Jul;
115
(7):
1037-46
52.
Takashina
K,
Bessho
T,
Mori
R,
et
al.
MKC-231,
a
choline
uptake
enhancer:
(2)
effect
on
synthesis
and
release
of
acetylcholine
in
AF64A-treated
rats.
J
Neural
Transm
2008
Jul;
115
(7):
1027-35
53.
Fedi
M,
Reutens
D,
Dubeau
F,
et
al.
Long-term
efficacy
and
safety
of
piracetam
in
the
treatment
of
progressive
myoclonus
epilepsy.
Arch
Neurol
2001
May;
58
(5):
781-6
54.
Holinski
S,
Claus
B,
Alaaraj
N,
et
al.
Cerebroprotective
effect
of
piracetam
in
patients
undergoing
coronary
by-
pass
burgery.
Med
Sci
Monit
2008
Nov;
14
(11):
PI53-7
55.
Uebelhack
R,
Vohs
K,
Zytowski
M,
et
al.
Effect
of
pir-
acetam
on
cognitive
performance
in
patients
undergoing
bypass
surgery.
Pharmacopsychiatry
2003
May;
36
(3):
89-93
56.
Szalma
I,
Kiss
A,
Kardos
L,
et
al.
Piracetam
prevents
cognitive
decline
in
coronary
artery
bypass:
a
randomized
trial
versus
placebo.
Ann
Thorac
Surg
2006
Oct;
82
(4):
1430-5
57.
Batysheva
TT,
Bagir
LV,
Kostenko
EV,
et
al.
Experience
of
the
out-patient
use
of
memotropil
in
the
treatment
of
cognitive
disorders
in
patients
with
chronic
progressive
cerebrovascular
disorders.
Neurosci
Behav
Physiol
2009
Feb;
39
(2):
193-7
58.
Neznamov
GG,
Teleshova
ES.
Comparative
studies
of
Noopept
and
piracetam
in
the
treatment
of
patients
with
mild
cognitive
disorders
in
organic
brain
diseases
of
vas-
cular
and
traumatic
origin.
Neurosci
Behav
Physiol
2009
Mar;
39
(3):
311-21
59.
Zavadenko
NN,
Guzilova
LS.
Sequelae
of
closed
cranio-
cerebral
trauma
and
the
efficacy
of
piracetam
in
its
treatment
in
adolescents.
Neurosci
Behav
Physiol
2009
May;
39
(4):
323-8
60.
Jelic
V,
Kivipelto
M,
Winblad
B.
Clinical
trials
in
mild
cognitive
impairment:
lessons
for
the
future.
J
Neurol
Neurosurg
Psychiatry
2006
Apr;
77
(4):
429-38
61.
UCB,
Inc.
Efficacy
and
safety
of
piracetam
taken
for
12
months
in
subjects
suffering
from
mild
cognitive
impair-
ment
(MCI)
[ClinicalTrials.gov
identifier
NCT00567060].
US
National
Institutes
of
Health,
ClinicalTrials.gov
[on-
line].
Available
from
URL:
http://www.clinicaltrials.gov
[Accessed
2010
Jan
22]
62.
Libov
I,
Miodownik
C,
Bersudsky
Y,
et
al.
Efficacy
of
piracetam
in
the
treatment
of
tardive
dyskinesia
in
schi-
zophrenic
patients:
a
randomized,
double-blind,
placebo-
©
2010
Adis
Data
Information
By.
All
rights
reserved.
Drugs
2010;
70
(3)
310
Malykh
&
Sadaie
controlled
crossover
study.
J
Clin
Psychiatry
2007
Jul;
68
(7):
1031-7
63.
Beersheva
Mental
Health
Center.
Piracetam
for
treatment
tardive
dyskinesia
[ClinicalTrials.gov
identifier
NCT001
90008].
US
National
Institutes
of
Health,
ClinicalTrials.
gov
[online].
Available
from
URL:
http://www.clinical
trials.gov
[Accessed
2010
Jan
22]
64.
Ince
Gunal
D,
Agan
K,
Afsar
N,
et
al.
The
effect
of
pir-
acetam
on
ataxia:
clinical
observations
in
a
group
of
au-
tosomal
dominant
cerebellar
ataxia
patients.
J
Clin
Pharm
Ther
2008
Apr;
33
(2):
175-8
65.
Kessler
J,
Thiel
A,
Karbe
H,
et
al.
Piracetam
improves
activated
blood
flow
and
facilitates
rehabilitation
of
post-
stroke
aphasic
patients.
Stroke
2000
Sep;
31
(9):
2112-6
66.
Kampman
K,
Majewska
MD,
Tourian
K,
et
al.
A
pilot
trial
of
piracetam
and
ginkgo
biloba
for
the
treatment
of
cocaine
dependence.
Addic
Behav
2003
Apr;
28
(3):
437-48
67.
National
Institute
on
Drug
Abuse
(NIDA).
Piracetam
for
treatment
of
cocaine
addiction
-
3
[ClinicalTrials.gov
identifier
NCT00000198].
US
National
Institutes
of
Health,
ClinicalTrials.gov
[online].
Available
from
URL:
http://www.clinicaltrials.gov
[Accessed
2010
Jan
22]
68.
National
Institute
on
Drug
Abuse
(NIDA).
Piracetam
for
treatment
of
cocaine
addiction,
phase
II
-
4
[Clinical-
Trials.gov
identifier
NCT00000199].
US
National
In-
stitutes
of
Health,
ClinicalTrials.gov
[online].
Available
from
URL:
http://www.clinicaltrials.gov
[Accessed
2010
Jan
22]
69.
Boiko
AN,
Batysheva
TT,
Matvievskaya
OV,
et
al.
Char-
acteristics
of
the
formation
of
chronic
fatigue
syndrome
and
approaches
to
its
treatment
in
young
patients
with
focal
brain
damage.
Neurosci
Behav
Physiol
2007
Mar;
37
(3):
221-8
70.
Akhondzadeh
S,
Tajdar
H,
Mohammadi
MR,
et
al.
A
double-blind
placebo
controlled
trial
of
piracetam
added
to
risperidone
in
patients
with
autistic
disorder.
Child
Psychiatry
Hum
Dev
2008
Sep;
39
(3):
237-45
71.
Butler
DE,
Leonard
JD,
Caprathe
BW,
et
al.
Amnesia-
reversal
activity
of
a
series
of
cyclic
imides.
J
Med
Chem
1987
Mar;
30
(3):
498-503
72.
Tang
WK,
Ungvari
GS,
Leung
HC.
Effect
of
piracetam
on
ECT-induced
cognitive
disturbances:
a
randomized,
pla-
cebo-controlled,
double-blind
study.
J
ECT
2002
Sep;
18
(3):
130-7
73.
Lobaugh
NJ,
Karaskov
V,
Rombough
V,
et
al.
Piracetam
therapy
does
not
enhance
cognitive
functioning
in
chil-
dren
with
Down
syndrome.
Arch
Pediatr
Adolesc
Med
2001
Apr;
155
(4):
442-8
74.
Ricci
S,
Celani
MG,
Cantisani
TA,
et
al.
Piracetam
in
acute
stroke:
a
systematic
review.
J
Neurol
2000
Apr;
247
(4):
263-6
75.
Ovanesov
KB,
Shikina
IB,
Arushanian
EB,
et
al.
Effect
of
pyracetam
on
the
color
discriminative
function
of
retina
in
patients
with
craniocerebral
trauma
[in
Russian].
Eksp
Klin
Farmakol
2003
Jul-Aug;
66
(4):
6-8
76.
Kiseleva
TN,
Lagutina
IuM,
Kravchuk
EA.
Effect
of
fezam
on
ocular
dynamics
in
patients
with
senile
macular
degeneration
[in
Russian].
Vestn
Oftalmol
2005
Jul-Aug;
121
(4):
26-8
77.
Preda
L,
Alberoni
M,
Bressi
S,
et
al.
Effects
of
acute
doses
of
oxiracetam
in
the
scopolamine
model
of
human
am-
nesia.
Psychopharmacology
(Berl)
1993;
110
(4):
421-6
78.
Rozzini
R,
Zanetti
0,
Bianchetti
A.
Treatment
of
cognitive
impairment
secondary
to
degenerative
dementia:
effec-
tiveness
of
oxiracetam
therapy.
Acta
Neurol
(Napoli)
1993
Feb;
15
(1):
44-52
79.
Green
RC,
Goldstein
FC,
Auchus
AP,
et
al.
Treatment
trial
of
oxiracetam
in
Alzheimer's
disease.
Arch
Neurol
1992
Nov;
49
(11):
1135-6
80.
Biogenesis
Laboratories.
Product
information:
pramir-
acetam
(Neupramir)
[online].
Available
from
URL:
http://
www.biogenesis.co.za/pi-pramiracetam.asp
[Accessed
2010
Jan
22]
81.
McLean
Jr
A,
Cardenas
DD,
Burgess
D,
et
al.
Placebo-
controlled
study
of
pramiracetam
in
young
males
with
memory
and
cognitive
problems
resulting
from
head
in-
jury
and
anoxia.
Brain
Inj
1991
Oct-Dec;
5
(4):
375-80
82.
Mauri
M,
Sinforiani
E,
Reverberi
F,
et
al.
Pramiracetam
effects
on
scopolamine-induced
amnesia
in
healthy
vo-
lunteers.
Arch
Gerontol
Geriatr
1994
Mar-Apr;
18
(2):
133-9
83.
Dziak
LA,
Golik
VA,
Miziakina
EV.
Experience
in
the
application
of
pramistar,
a
new
nootropic
preparation,
in
the
treatment
of
memory
disorders
in
patients
with
cere-
brovascular
pathology
[in
Russian].
Lik
Sprava
2003
Dec;
(8):
67-72
84.
Tkachev
AV.
Application
of
nootropic
agents
in
complex
treatment
of
patients
with
concussion
of
the
brain
[in
Russian].
Lik
Sprava
2007
Jul-Sep;
(5-6):
82-5
85.
Savchenko
AIu,
Zakharova
NS,
Stepanov
IN.
The
phe-
notropil
treatment
of
the
consequences
of
brain
organic
lesions
[in
Russian].
Zh
Nevrol
Psikhiatr
Im
S S
Korsa-
kova
2005;
105
(12):
22-6
86.
Kalinsky
PP,
Nazarov
VV.
Use
of
phenotropil
in
the
treatment
of
asthenic
syndrome
and
autonomic
dis-
turbances
in
the
acute
period
of
mild
cranial
brain
trauma
[in
Russian].
Zh
Nevrol
Psikhiatr
Im
S S
Korsakova
2007;
107
(2):
61-3
87.
Gustov
AA,
Smirnov
AA,
Korshunova
IuA,
et
al.
Pheno-
tropil
in
the
treatment
of
vascular
encephalopathy
[in
Russian].
Zh
Nevrol
Psikhiatr
Im
S
S
Korsakova
2006;
106
(3):
52-3
88.
Sazonov
DV,
Ryablikhina
OV,
Bulatova
EV,
et
al.
Use
of
phenotropil
in
complex
treatment
of
multiple
sclerosis
[in
Russian].
Nervnye
Bolezni
2006;
4:
18-21
89.
Akhapkina
VI,
Fedin
AI,
Avedisova
AS,
et
al.
Efficacy
of
Phenotropil
for
treatment
of
astenic
and
chronic
fatigue
syndromes
[in
Russian].
Nervnye
Bolezni
2004;
3:
28-32
90.
Zvonareva
EV.
Phenotropil
in
the
therapy
of
cognitive
disorders
in
teenagers
with
astenic
syndrome
[in
Russian].
Nervnye
Bolezni
2006;
2:
27-8
91.
Bel'skaia
GN,
Ponomareva
IV,
Lukashevich
IG,
et
al.
Complex
treatment
of
epilepsy
with
phenotropil
[in
Rus-
sian].
Zh
Nevrol
Psikhiatr
Im
S S
Korsakova
2007;
107
(8):
40-3
92.
Lybzikova
GN,
Iaglova
ZhS,
Kharlamova
IuS.
The
effi-
cacy
of
phenotropil
in
the
complex
treatment
of
epilepsy
[in
Russian].
Zh
Nevrol
Psikhiatr
Im
S S
Korsakova
2008;
108
(2):
69-70
©
2010
Adis
Data
Information
By.
All
rights
reserved.
Drugs
2010;
70
(3)
Piracetam
and
Related
Drugs
for
CNS
Disorders
311
93.
Gerasimova
MM,
Chichanovskaia
LV,
Slezkina
LA.
The
clinical
and
immunological
aspects
of
the
effects
of
phenotropil
on
consequences
of
stroke
[in
Russian].
Zh
Nevrol
Psikhiatr
Im
S S
Korsakova
2005;
105
(5):
63-4
94.
Bagir
LV,
Batysheva
TT,
Boiko
AN,
et
al.
Use
of
pheno-
tropil
for
early
treatment
of
patients
after
stroke
[in
Russian].
Concilium
Medicum
2006;
8
(8):
96-101
95.
Basinskii
SN,
Basinskii
AS.
Neuroprotective
effect
of
Fenotropil
in
unstabilized
primary
glaucoma
[in
Russian].
Russkii
Med
Zh
2007;
8
(4):
148-51
96.
Robinson
RG,
Jorge
RE,
Clarence-Smith
K.
Double-blind
randomized
treatment
of
poststroke
depression
using
ne-
firacetam.
J
Neuropsychiatry
Clin
Neurosci
2008
Spring;
20
(2):
178-84
97.
Robinson
RG,
Jorge
RE,
Clarence-Smith
K,
et
al.
Double-
blind
treatment
of
apathy
in
patients
with
poststroke
depression
using
nefiracetam.
J
Neuropsychiatry
Clin
Neurosci
2009
Spring;
21
(2):
144-51
98.
National
Institutes
of
Health
Clinical
Center
(CC).
Nefir-
acetam
in
the
treatment
of
Alzheimer's
disease
[Clinical-
Trials.gov
identifier
NCT00001933].
US
National
In-
stitutes
of
Health,
ClinicalTrials.gov
[online].
Available
from
URL:
http://www.clinicaltrials.gov
[Accessed
2010
Jan
22]
99.
National
Institutes
of
Health
Clinical
Center
(CC).
Anti-
depressant
effects
on
cAMP
specific
phosphodiesterase
(PDE4)
in
depressed
patients
[ClinicalTrials.gov
identifier
NCT00369798].
US
National
Institutes
of
Health,
Clin-
icalTrials.gov
[online].
Available
from
URL:
http://www.
clinicaltrials.gov
[Accessed
2010
Jan
22]
100.
National
Institutes
of
Health
Clinical
Center
(CC).
Roli-
pram
to
treat
multiple
sclerosis
[ClinicalTrials.gov
iden-
tifier
NCT00011375].
US
National
Institutes
of
Health,
ClinicalTrials.gov
[online].
Available
from
URL:
http://
www.clinicaltrials.gov
[Accessed
2010
Jan
22]
101.
Bielekova
B,
Richert
N,
Howard
T,
et
al.
Treatment
with
the
phosphodiesterase
type-4
inhibitor
rolipram
fails
to
inhibit
blood:
brain
barrier
disruption
in
multiple
sclero-
sis.
Mult
Scler
2009
Oct;
15
(10):
1206-14
102.
Ogiso
T,
Iwaki
M,
Tanino
T,
et
al.
Pharmacokinetics
of
aniracetam
and
its
metabolites
in
rats.
J
Pharm
Sci
1998
May;
87
(5):
594-8
103.
Senin
U,
Abate
G,
Fieschi
C,
et
al.
Aniracetam
(Ro
13-
5057)
in
the
treatment
of
senile
dementia
of
Alzheimer
type
(SDAT):
results
of
a
placebo
controlled
multicentre
clinical
study.
Eur
Neuropsychopharmacol
1991
Dec;
1
(4):
511-7
104.
Canonico
V,
Forgione
L,
Paoletti
C,
et
al.
Efficacy
and
tolerance
of
aniracetam
in
elderly
patients
with
primary
or
secondary
mental
deterioration
[in
Italian].
Riv
Neurol
1991
May-Jun;
61
(3):
92-6
105.
Somnier
FE,
Ostergaard
MS,
Boysen
G,
et
al.
Aniracetam
tested
in
chronic
psychosyndrome
after
long-term
ex-
posure
to
organic
solvents:
a
randomized,
double-blind,
placebo-controlled
cross-over
study
with
neuropsycholo-
gical
tests.
Psychopharmacology
(Berl)
1990;
101
(1):
43-6
106.
Bobkov
IuG,
Morozov
IS,
Glozman
OM,
et
al.
Pharma-
cological
characteristics
of
a
new
phenyl
analog
of
pir-
acetam-4-phenylpiracetam
[in
Russian].
Biull
Eksp
Biol
Med
1983
Apr;
95
(4):
50-3
107.
Bialer
M,
Johannessen
SI,
Kupferberg
HJ,
et
al.
Progress
report
on
new
antiepileptic
drugs:
a
summary
of
the
Eigth
Eilat
Conference
(EILAT
VIII).
Epilepsy
Res
2007
Jan;
73
(1):
1-52
108.
Rogawski
MA.
Brivaracetam:
a
rational
drug
discovery
success
story.
Br
J
Pharmacol
2008
Aug;
154
(8):
1555-7
109.
Pollard
JR.
Seletracetam,
a
small
molecule
SV2A
mod-
ulator for
the
treatment
of
epilepsy.
Curr
Opin
Investig
Drugs
2008
Jan;
9
(1):
101-7
110.
Sirsi
D,
Safdieh
JE.
The
safety
of
levetiracetam.
Expert
Opin
Drug
Saf
2007
May;
6
(3):
241-50
111.
Nissen-Meyer
LS,
Svalheim
S,
Tauboll
E,
et
al.
How
can
antiepileptic
drugs
affect
bone
mass,
structure
and
meta-
bolism?
Lessons
from
animal
studies.
Seizure
2008
Mar;
17
(2):
187-91
112.
Carreno
M.
Levetiracetam.
Drugs
Today
(Bare)
2007
Nov;
43
(11):
769-94
113.
Zhou
B,
Zhang
Q,
Tian
L,
et
al.
Effects
of
levetiracetam
as
an
add-on
therapy
on
cognitive
function
and
quality
of
life
in
patients
with
refractory
partial
seizures.
Epilepsy
Behav
2008
Feb;
12
(2):
305-10
114.
Kossoff
EH,
Los
JG,
Boatman
DF.
A
pilot
study
transi-
tioning
children
onto
levetiracetam
monotherapy
to
im-
prove
language
dysfunction
associated
with
benign
rolandic
epilepsy.
Epilepsy
Behav
2007
Dec;
11
(4):
514-7
115.
Kinrys
G,
Wygant
LE,
Pardo
TB,
et
al.
Levetiracetam
for
treatment-refractory
posttraumatic
stress
disorder.
J
Clin
Psychiatry
2006
Feb;
67
(2):
211-4
116.
Simon
NM,
Worthington
JJ,
Doyle
AC,
et
al.
An
open-
label
study
of
levetiracetam
for
the
treatment
of
social
anxiety
disorder.
J
Clin
Psychiatry
2004
Sep;
65
(9):
1219-22
117.
Mazza
M,
Martini
A,
Scoppetta
M,
et
al.
Effect
of
levetir-
acetam
on
depression
and
anxiety
in
adult
epileptic
pa-
tients.
Prog
Neuropsychopharmacol
Biol
Psychiatry
2008
Feb
15;
32
(2):
539-43
118.
Wasserman
S,
Iyengar
R,
Chaplin
WF,
et
al.
Levetiracetam
versus
placebo
in
childhood
and
adolescent
autism:
a
double-blind
placebo-controlled
study.
Int
Clin
Psycho-
pharmacol
2006
Nov;
21
(6):
363-7
119.
Brown
ES,
Frol
AB,
Khan
DA,
et
al.
Impact
of
levetir-
acetam
on
mood
and
cognition
during
prednisone
ther-
apy.
Eur
Psychiatry
2007
Oct;
22
(7):
448-52
120.
Malawska
B,
Kulig
K.
Brivaracetam:
a
new
drug
in
devel-
opment
for
epilepsy
and
neuropathic
pain.
Expert
Opin
Investig
Drugs
2008
Mar;
17
(3):
361-9
121.
French
J,
von
Rosenstiel
P.
Efficacy
and
tolerability
of
brivaracetam
as
adjunctive
treatment
for
adults
with
re-
fractory
partial-onset
seizures
[abstract].
Epilepsia
2007;
48
Suppl.
7:
78
122.
van
Paesschen
W,
von
Rosenstiel
P.
Efficacy
and
toler-
ability
of
brivaracetam
as
adjunctive
treatment
for
adults
with
refractory
partial-onset
epilepsy.
Epilepsia
2007;
48
Suppl.
7:
56-7
123.
Narahashi
T,
Moriguchi
S,
Zhao
X,
et
al.
Mechanisms
of
action
of
cognitive
enhancers
on
neuroreceptors.
Biol
Pharm
Bull
2004
Nov;
27
(11):
1701-6
124.
Miinte
TF,
Heinze
HJ,
Scholz
M,
et
al.
Effects
of
a
choli-
nergic
nootropic
(WEB
1881
FU)
on
event-related
©
2010
Adis
Data
Information
By.
All
rights
reserved.
Drugs
2010;
70
(3)
312
Malykh
&
Sadaie
potentials
recorded
in
incidental
and
intentional
memory
tasks.
Neuropsychobiology
1988;
19
(3):
158-68
125.
Miinte
TF,
Heinze
HJ,
Scholz
MB,
et
al.
Event-related
potentials
and
visual
spatial
attention:
influence
of
a
cholinergic
drug.
Neuropsychobiology
1989;
21
(2):
94-9
126.
Urakami
K,
Shimomura
T,
Ohshima
T,
et
al.
Clinical
effect
of
WEB
1881
(nebracetam
fumarate)
on
patients
with
dementia
of
the
Alzheimer
type
and
study
of
its
clinical
pharmacology.
Clin
Neuropharmacol
1993
Aug;
16
(4):
347-58
127.
Scott
AI,
Perini
AF,
Shering
PA,
et
al.
In-patient
major
depression:
is
rolipram
as
effective
as
amitriptyline?
Eur
J
Clin
Pharmacol
1991;
40
(2):
127-9
128.
Ross
CE,
Toon
S,
Rowland
M,
et
al.
A
study
to
assess
the
anticholinergic
activity
of
rolipram
in
healthy
elderly
vo-
lunteers.
Pharmacopsychiatry
1988
Sep;
21
(5):
222-5
129.
Hebenstreit
GF,
Fellerer
K,
Fichte
K,
et
al.
Rolipram
in
major
depressive
disorder:
results
of
a
double-blind
com-
parative
study
with
imipramine.
Pharmacopsychiatry
1989
Jul;
22
(4):
156-60
130.
Bertolino
A,
Crippa
D,
di
Dio
S,
et
al.
Rolipram
versus
imipramine
in
inpatients
with
major,
"minor"
or
atypical
depressive
disorder:
a
double-blind
double-dummy
study
aimed
at
testing
a
novel
therapeutic
approach.
Int
Clin
Psychopharmacol
1988
Jul;
3
(3):
245-53
131.
Nikulina
E,
Tidwell
JL,
Dai
HN,
et
al.
The
phosphodies-
terase
inhibitor
rolipram