DRUG EVALUATION
Drugs & Aging I ( 1 ) : 17-35. 1991
1I70-229X/91/OOO1-OO17/S09.50/0
© Adis International Limited. All rights reserved.
DRA1 1
Piracetam
An Overview of its Pharmacological Properties and a Review of
its Therapeutic Use in Senile Cognitive Disorders
Margaret W. Vernon and Eugene M. Sorkin
Adis International Drug Information Services, Auckland, New Zealand
Various sections of the manuscript reviewed by: A. Ennaceur, Laboratoire de Psychophysiologie, Universite Paris
7, France; S.H. Ferris, Aging and Dementia Research Center, New York University Medical Center, New York,
New York, USA; 7. Kabes, Department of Neurology and Psychiatry, Faculty Hospital, Prague, Czechoslovakia;
C McDonald, Warlingham Park Hospital, Warlingham, Surrey, England; J.S. Meyer, Cerebrovascular Research
Laboratories, Baylor College of Medicine, Houston, Texas, USA; M. Nikolova, The Chemical Pharmaceutical
Research Institute, Sofia, Bulgaria.
Contents
17
19
19
20
21
22
23
23
25
26
27
27
30
30
31
31
Summary
1. Overview of Pharmacological Properties
1.1 Protection Against Brain Aggressions
1.2 Facilitation of Memory and Learning
1.3 Facilitation of Interhemispheric Connectivity
1.4 Electrophysioiogical Studies
1.5 Effects on the Microcirculation
1.6 Effects in Healthy Volunteers
1.7. Mechanism of Action
2. Pharmacokinetic Properties
3. Therapeutic Properties in Patients with Senile Cognitive Disorders
3.1 Comparative Studies
3.2 Piracetam in Combination with Acetylcholine Precursors
4. Adverse Effects
5. Dosage and Administration
6. Place of Piracetam in.Therapy
Summary
Synopsis
Piracetam is the first of the so-called 'nootropic' drugs, a unique class of drugs which affect
mental function. In animal models and in healthy volunteers, the drug improves the efficiency of
the higher telencephalic functions of the brain involved in cognitive processes such as learning and
memory.
The pharmacology of piracetam is unusual because it protects against various physical and
chemical insults applied to the brain. It facilitates learning and memory in healthy animals and
in animals whose brain function has been compromised, and it enhances interhemispheric transfer
Drugs & Aging 1 (!) 199'
18
of information via callosal transmission. At the same time, even in relatively high dosages it is
devoid of any sedative, analeptic or autonomic activities. How piracetam exerts its effects on memory disorders is still under investigation, although among other proposed mechanisms of action it
is thought to facilitate central nervous system efficiency of cholinergic neurotransmission.
Results from trials involving elderly patients with senile cognitive disorders have been equivocal,
as have the results obtained when piracetam has been combined with acetylcholine precursors.
Piracetam seems to be almost completely devoid of adverse effects, and is extremely well tolerated.
In conclusion, opinion is divided to the benefits of piracetam in the treatment of senile
cognitive decline. Although double-blind studies in the elderly have produced mixed results, some
such trials (particularly those involving larger numbers of patients) have reported favourable findings, thus offering some reason for cautious optimism in a notoriously difficult area of therapeutics.
However, further investigations of piracetam alone and in combination therapy are required before
any absolute conclusions can be drawn.
Pharmacological Properties
Piracetam is a cyclic derivative of -aminobutyric acid (GABA), and the first representative of
what are commonly known as the 'nootropic' drugs. It has a protective effect on brain functions
against externally applied brain 'aggressions', which include hypoxia, electroconvulsive treatment
and barbiturate intoxication in experimental animals, It has been reported to facilitate learning
and memory in several animal models as well as in aged animals. In electrophysiological and
behavioural models, the drug facilitates cerebral inter- and intrahemispheric connectivity, indicating that it may enhance information transfer in the brain. Piracetam enhances microcirculation
by reducing platelet activity, enhancing red blood cell deformability and reducing adherence of
damaged erythrocytes to endothelial cells. In healthy volunteers, the drug enhances recall of learned
information, increases verbal capacity and improves mental functioning under certain conditions.
Piracetam stimulates glucose degradation in rat cortex slices, enhances 32P incorporation into
brain phospholipids and stimulates adenylate cyclase. Although structurally related to GABA, it
does not appear to have any similar GABA-like effects in animals. Its mechanism of action
appears to be via stimulation of central cholinergic activity, although a number of other neurotransmitters may also be involved.
Pharmacokinetic Studies
Piracetam is completely absorbed after oral administration: peak plasma concentrations are
reached after 30 to 40 minutes, and oral bioavailability is close to 100%. The elimination halflife of the drug in healthy volunteers is about 5 to 6 hours, but this may be increased in elderly
patients, particularly those with multiple disease states. Piracetam is excreted unchanged in the
urine, urinary excretion accounting for more than 98% of the administered dose. Distribution
studies have shown that the drug is rapidly distributed in most essential organs. It crosses the
blood-brain barrier, and is preferentially concentrated in the grey matter of the cerebrum and
cerebellum, caudate nucleus, hippocampus, lateral geniculate body and chorioid plexus. Half-life
in cerebrospinal fluid is greater than plasma half-life, indicating a tropism for brain tissue.
Therapeutic Trials
Double-blind controlled studies have produced mi -ted results with piracetam in the treatment
of learning and memory disorders of the elderly. Coriparison between different trials is difficult
because of lack of standardisation of patient groups or assessment protocols. Although some
improvements in memory and learning as a result of piracetam administration have been noted,
these have been small and inconsistent. Because memory impairment in senile dementia is highly
correlated with brain cholinergic function, trials have been carried out using piracetam and the
acetylcholine precursors lecithin and choline. Although experiments in rats have shown that piracetam plus choline has a superior effect to either agent administered alone, results in human
trials have been equivocal.
Drugs & Aging 1 (!)
1991
Piracetarn: An Overview
19
Adverse Effects
Piracetam is extremely well tolerated and generally free from adverse effects. Side effects which
have been reported occasionally include mild dizziness, insomnia and nausea, but none of t hese
have necessitated stopping therapy.
Dosage and Administration
Piracetam can be administered orally or intravenously in dosages ranging from 20 to 150 mg/
kg daily in divided doses. For long term treatment of senility, it is recommended that 2.4 to 4.8g
orally be given daily, depending on the severity of the symptoms. In patients with impaired renal
function, dosage regimens should be adjusted according to the manufacturer's recommendations.
1. Overview of Pharmacological Properties
Piracetam is a cyclic derivative of -aminobutyric acid (GABA) and is the first representative of
what are being called 'nootropic' drugs (fig. 1). The
nootropic concept is based on the role played by
the telencephalon on central nervous system (CNS)
activity, and the possibility of pharmacological intervention at this level. It is a class of drugs aimed
directly at promoting the efficiency of the essential
brain integrative activity mechanisms. The most
important features of nootropes are facilitation of
learning and memory consolidation, and their ability to increase and enhance resistance to learning
impairments and several experimental types of
brain hypoxia and cerebral drug intoxications
Fig. 1. -Aminobutyric acid
(GABA) and structurally related nootropic drugs.
(Giurgea & Moyersoons 1974). They are also devoid of the usual psychotropic effects in that they
cause neither stimulation nor sedation, and in general have no locomotor effect.
Pharmacological testing of piracetam has been
carried out in a number of species which have in
cluded cats, rats, mice, rabbits and goldfish as ex
perimental models, to measure both the facilitatory effects on learning and memory and the
influence on induced brain 'aggressions' such as
hypoxia, electroconvulsive shock and barbiturate
intoxication.
l . l Protection Against Brain Aggressions
Piracetam has been shown to have a protective
effect on certain brain functions, as measured by
EEG, against various 'aggressions' or brain traumas caused by hypoxic or toxic insults applied to
experimental animals. These insults include both
cerebral hypoxia and drug intoxication. Rats trained
in a passive avoidance test and subjected to hypoxic conditions (Sara & Lefevre 1972) behaved as
untrained animals when retested, whereas those
treated with 100 mg/kg of piracetam during the acquisition training or immediately before the retention test showed good retention and behaved as
though they had not been subjected to amnesic effects of hypoxia.
Nikolova et al. (1984) demonstrated the antihypoxic effect of piracetam in several other animal
models, including anoxic, haemic and ischaemic
hypoxias, showing that piracetam has a wide spectrum of antihypoxic effects. Similarly, brain recov-
Drugs & Aging I (1) 1991
20
ery time, or time to revert to a normal EEG after
readmission of air to hypoxic rabbits, was significantly reduced after piracetam administration
(Giurgea et al. 1970).
The antihypoxic effect of piracetam has also
been shown to be potentiated by the simultaneous
administration of epoprostenoi (prostacyclin; prostaglandin I2) via an unknown mechanism, while
piracetam and dihydroergocristine similarly produced synergistic effects in animal models of cerebral hypoxia and ischaemia (Berga et al. 1986). This
is thought to be due to complementary actions at
the level of cerebral neurons, and possibly to physicochemical and biochemical properties of the
blood.
The influence of piracetam on local depression
of cortical activity has been studied in cats by Dimov et al. (1983), who topically applied substances
known to have a depressant action on neuronal
function, Piracetam reduced the depression of cortical activity induced by potassium chloride, reduced the duration of depression with adenosine
monophosphate, and gave almost total protection
against depression induced by phenobarbital. Since
these models of local depression have different
mechanisms but common effect, it is reasonable to
suggest that piracetam has a nonspecific action on
neuronal function resulting in protection and
maintenance of the cortical activity of the brain.
The effects of piracetam have been studied in
rabbits given an overdose of barbiturates (Moyersoons & Giurgea 1974). When administered orally
or intravenously before a lethal dose of secobarbital (quinalbarbitone), piracetam afforded a high
degree of protection against death compared to the
control animals. As well as protection against lethality, piracetam also protected against the EEG
correlates of barbiturate intoxication.
1.2 Facilitation of Memory and Learning
The beneficial effect of piracetam on learning
and memory has been demonstrated in several animal models (table I), using a number of tests relating to acquisition and retention. These tests have
included learning of a water maze, a learning test
using the 'Y'-maze in an avoidance procedure, and
learning of a 'drinking' test in which rats are trained
to drink only when a light is on. Pharmacological
studies of piracetam in conditions more specifically related to memory storage or consolidation
include an avoidance operant conditioning task and
a passive avoidance conditioning task. In the former, animals are trained to avoid electric shock
and learning is measured by the number of correct
responses, while in the latter, animals are confined
to one compartment of a 2-compartment cage
where they receive an unavoidable electric shock.
Memory retention is tested 24 hours later and the
results are expressed either as mean latency to enter
the shock compartment, or as the percentage of time
spent there in the time allowed for exploration.
Experiments have been conducted both in normal
animals and in animals in which amnesia has been
induced by exposing the animals to conditions of
hypoxia or electroconvulsive shock (ECS).
Rats trained on a bar-press response for water
reward and retested for retention 7 days later had
significantly shorter response latencies when given
piracetam than saline-treated animals (Sara et al.
1979). Similar results have been reported by Giurgea et al. (1971) and Wolthuis (1971) in rats. Goldfish treated with piracetam had higher mean levels
of correct active dark avoidance than non-drugtreated controls (Bryant et al. 1973). It is interesting that in most of these studies a facilitative effect
was seen only after several days of training, which
may imply a facilitation of memory retrieval and
not initial learning. In this regard, piracetam injected prior to trials has been reported to accelerate
retrieval of information acquired at' previous trials
in rats (Sara et al. 1975; Wolthuis .& Nickolson
1975).
In a T-maze learning test with food and water
reinforcement, learning was significantly facilitated
in piracetam-treated rats (Koupilova et al. 1980).
Similar results were obtained on acquisition of the
conditioned avoidance reaction but only after repeated high dosages were administered.
Prolongation of step-down latencies for a passive avoidance task in young rats has been dem-
Piracetam: An Overview
21
Table 1. Some tests which have indicated piracetam facilitates learning and memory in experimental animals
onstrated with piracetam (Yamada et al. 1985), and
acute administration of the drug facilitated acquisition of a 2-way shuttle avoidance in mice (Kuribara & Tadokoro 1988).
Piracetam activity may differ according to the
age of animals, and this has led to a number of
studies comparing its effects in both young and aged
mice and rats. Piracetam significantly improved
learning in young mice, but was remarkably more
effective in improving the performance of old mice
in an avoidance learning acquisition test (Valzelli
et al. 1980); these results agree with those obtained
in previous tests with aged rats (Kruse & Konler
1978). Similarly, Hassmanova et al. (1980) found
that piracetam improved learning and memory in
5-week-old rats, but that the effect was much more
pronounced in 8-week-old animals.
The anti-amnesic effects of piracetam have been
demonstrated in a few studies. Piracetam antagonises the amnesias induced by scopolamine (hyoscine), diazepam and ECS in mice during passive
avoidance testing (Lenegre et al. 1988). These effects appear to be unrelated to the specific nature
of the amnesia-inducing agents, since piracetam
does not interact with the major behavioural effects of these treatments. Similar anti-amnesic effects to scopolamine pretreatment have been demonstrated in rats (Piercey et al. 1987).
Although there is much evidence showing that
piracetam is effective in memory and learning in
animals, a few studies have failed to show such
effects. In acquisition and retention testing of active and passive avoidance in older and younger
rats, piracetam failed to facilitate performance
(Means et al. 1980). This failure was not attributable to the dose or injection procedure employed,
since these were the same as those used in other
studies demonstrating facilitation. Piracetam also
neither affected delayed alternation or two-way
avoidance tests in rats (Ennaceur & Delacour 1987),
nor modified memory retention in mice (Valzelli et
al. 1986).
1.3 Facilitation of Interhemispheric
Connectivity
'Monocular' learning can be demonstrated in rats
by subjecting them to avoidance learning using a
visual signal while one eye is covered. Information
arrives primarily in the hemisphere opposite the
uncovered eye. While one hemisphere is learning
this engram or primary trace the other hemisphere
forms a secondary trace via information received
through the corpus callosum. This secondary engram is weaker than the primary engram, and depends on the functional integrity of the corpus callosum. The influence of piracetam on this
interhemispheric connectivity in animals is summarised in table II.
Electrical stimulation of the median suprasylvian gyrus in curarised cats results in an evoked
potential in the contralateral area of the cerebral
cortex (Giurgea & Moyersoons 1972). Piracetam
increases the amplitude of this potential without
changing the shape of the waveform, indicating that
the quantity of information transferred from one
22
Drugs & Aging I (1) 1991
Table II. Some studies with piracetam indicating the facilitation of interhemispheric (IH) transfer'
hemisphere to the other is increased. Learning mediated by transcomissural information flow in rats
was more rapid in animals injected with 100 mg/
kg piracetam 30 minutes before training (Buresova
& Bures 1973, 1976). Relearning with one hemisphere eliminated demonstrated that the strength
of the secondary trace in the ipsilateral hemisphere
was considerably stronger after piracetam treatment.
Piracetam also augments the propagation of discharges from symmetrical epileptogenic foci in rats
(Maresova & Mares 1984), which is in agreement
with results obtained in cats (Giurgea & Moyersoons 1970) and rabbits (Voronina et a!. 1986), but
contrary to the suppression of responses in rabbits
reported by Moyersoons et al. (1969).
This improvement in efficiency of interhemispheric connectivity is one of the differential properties of nootropic drugs, and no other group of
drugs has been shown to possess this selective effect.
1.4 Electrophysiological Studies
The influence of piracetam on cortical bioelectrical activity has been studied by Krug et al. (1977).
Investigations focused on the influence of piracetam on the post-tetanic facilitation of cortical
evoked potentials elicited by peripheric tetanic
stimulation in rabbits. Piracetam significantly increased the amplitude of the first surface positive
wave of the cortical evoked potential, suggesting
that it facilitates, in a nonspecific manner, responses to externally applied electrical stimuli
through central structures. Specifically, piracetam
increased intracortically and transcallosally elicited
potentials. Differing species and measurements
taken at different time intervals after application
may explain variations in results obtained by other
workers (Myslivecek & Hassmannova 1975).
In experimentally induced traumatic brain oedema in cats, piracetam 100 mg/kg restored bioelectrical activity to a normal pattern 20 minutes
after injection (Moyanova et al. 1985). It is thought
that this was not an anti-oedema effect but rather
the result of the action of piracetam as a nonspecific activator of brain excitability, optimising the
functional state of the brain in normal and pathological states. Krug et al. (1977) not only reported
a lowering of the stimuli intensity necessary to
evoke potentials of a constant amplitude after piracetam administration, but also a considerable increase in duration and quantity of the post-tetanic
intensification under conditions of constant stimuli intensity of the evoked potentials tested.
The influence of piracetam on evoked potentials in the somatosensory auditory and visual cortical projection areas due to stimulation of the contralateral projection area in rats was studied by
Myslivecek and Hassmannova (1974): no enhancement of the transcallosal response as described by
Giurgea and Moyersoons (1972) was observed. This
may have been due to the different animal species
Piracetam: An Overview
used. Administered intravenously in a dose of 100
mg/kg, piracetam did not produce any changes in
the primary responses of the flash evoked potential
in cats (Nikolova et al. 1980). However, it did increase the amplitude of the late components of the
flash evoked responses with latency of 150 to 200
msec. The changes were most pronounced in the
responses evoked in the visual cortex, and piracetam had a particular effect on the transcallosal
evoked potential.
Piracetam increased the responsiveness of pyramidal neurons to stimulation of the stratum radiatum in rat hippocampal slices (Olpe & Lynch
1982). Also, it was noted that the actions of piracetam on the in vitro slice closely resembled those
of opiate compounds, notably morphine and enkephalin, but the significance of this observation
is as yet unclear. Administration of intravenous
piracetam provoked a moderate increase in brain
excitability of cats (Dimov et al. 1984), and also
increased the power density in the
and
frequency of the spontaneous EEG, these changes
again being related to an increase in the brain excitability level. This is in agreement with results
obtained by Bente et al. (1978) and Saletu and
Grunberger (1985).
Finally, Olpe et al. (1986) studied the effects of
piracetam on the hippocampus, the locus coeruleus
and the medial septum - all brain structures which
are thought to play a role in cognitive functions.
These structures also show age-related declines in
cellular functions, and are affected by senile dementia of the Alzheimer's type. Piracetam activated neuronal activity in the locus coeruleus of
rats, but had no effect on hippocampal neurons in
vivo or in vitro, and no significant effect on the
medial septum neuronal firing rate in rats.
1.5 Effects on the Microcirculation
Piracetam improves the microcirculation under
certain circumstances: this effect has been observed at both central and peripheral levels. In a
study of cerebral blood flow in cats, piracetam exerted a beneficial action on brain tissue whose
function was impaired by deficient blood supply
23
(Sato & Heiss 1985). In surgically created ischaemic abdominal cutaneous flaps of rats, piracetam markedly improved skin viability and this effect appeared to be via an increase in capillary blood
flow. Similarly, the drug improved renal, medullary and cortical blood flows in ischaemically injured kidneys in rats (Gianello et al. 1988). Intravenous administration of piracetam 6 to l0g in 18
patients with acute cerebral ischaemia resulted in
an overall increase in blood flow in grey matter,
but no corresponding increase in cerebral blood
flow in white matter (Herrschaft 1978). However,
piracetam had no influence on cerebral blood flow
at dosages of 4.8g or 9.6g daily in 8 patients displaying symptoms of moderate dementia (Gustafson-et al. 1978).
Improvement in microcirculation appears to
occur via reduction of platelet aggregation (Bick et
al. 1981), enhancement of red blood cell deformability (Henry et al. 1981), reduction of adherence
of damaged erythrocytes to endothelial cells (Nalbandian et al. 1983) and an antispasmodic effect
(Reuse-Blom & Polderman 1980; Wahl & Kuschinsky 1980).
1.6 Effects in Healthy Volunteers
The effects of piracetam in healthy volunteers
have been studied in a few limited trials, some of
which are summarised in table III. In a placebocontrolled trial, 16 students receiving piracetam 4.8g
for 14 days were assessed in a verbal learning test
(Dimond 1975). There was no significant difference between the drug group and controls after 1
week, but after 2 weeks there was significant improvement in the active treatment group, both in
direct recall of learned information and after a delay in which subjects were prevented from rehearsal by counting backwards. Piracetam also increased verbal capacity in a dichotic listening task
(fig. 2) compared with controls, but had no effect
in other learning tests (Dimond 1975). It thus appeared that piracetam improved verbal learning in
normal volunteers.
Acute administration of piracetam in single oral
doses to 18 healthy volunteers (Sannita et. al. 1985)
24
Drugs & Aging I (I)
1991
Table III. Some studies summarising the results of oral piracetam administration in healthy volunteers
resulted in systematic EEG effects, namely a decrease in the low-frequency components and an increase in the power of the 8.5 to 12.0 Hz and of
the fast-frequency components. These EEG modifications were similar to those occurring in elderly
patients during long term treatment (Bente et al.
1978) and appeared to be qualitatively opposite to
those regarded as being peculiar to brain aging. No
neuropsychological or behavioural changes were
noted during drug administration.
In a double-blind placebo-controlled trial, the
effect of piracetam on mental performance was
measured in healthy aging individuals (Mindus et
al. 1976). The subjects were rated using conventional and computerised perceptual motor tasks including the Digit Symbol Test, the Bourdon-
Fig. 2. Effect of piracetam in a dichotic listening test in 12
healthy volunteers given piracetam 4.8g daily for 4 days followed by 7.2g on the fifth day in a placebo-controlled trial
(after Dimond 1975).
Wiersma Test, the Spoke Test, Critical Flicker Fusion Test and Krakau Visual Acuity Test. Overall,
mental functioning was better with piracetam than
with placebo in most of the tests used. Ratings with
paper and pencil tasks were consistent with the
computerised ones. The performance in the type
of tasks used has been shown to reflect the level of
cortical functioning caused by piracetam. It is interesting to note that there was no improvement
in self ratings, which may be considered a major
drawback; however, the reliability of self ratings is
typically low.
A recent study examined the reaction capacity
of 101 elderly motorists regarding their driving
ability (Schmidt et al. 1990). Piracetam 4.8g or placebo was given daily for 6 weeks in randomised
double -blind fashion. Orientation and perception
under real traffic conditions was significantly better
with piracetam compared with placebo.
The antihypoxic effect of piracetam in experimental animals is well documented (Giurgea &
Salama 1977) [see section 1.1]. The effects of piracetam on mental concentration were thus investigated in double-blind crossover fashion in 12
healthy volunteers under hypoxic conditions (Demay & Bande 1980). Subjects were rated using a
visual attention test, which was not influenced by
intelligence but measured the ability to concentrate. The speed with which the test was carried
out was not influenced by piracetam but the number of errors was significantly reduced after piracetam administration (fig. 3).
Piracetam: An Overview
25
1.7 Mechanism of Action
The mechanism by which piracetam influences
memory and cognitive disorders is uncertain. Much
of the recent work investigating the mechanism of
action of piracetam has centred on its cholinergic
effects. Piracetam diminishes hippocampal acetylcholine levels in rats (Wurtman et al. 1981) without significantly modifying choline levels, indicating that it may act by accelerating the release of
acetylcholine and other neurotransmitters. Alterations in density and function of several neurotransmitter receptors occur in animal and human brain
during the normal aging process. Chronic treatment of aged mice with piracetam restores deficits
of muscarinic cholinergic receptor density and
function (Muller et al. 1990; Pilch & Muller 1988),
indicating that it may act as a cell communication
modulator. It has also been shown to facilitate
neurotransmission in the cat (Hall & von Voigtlander 1987) and although the exact mechanism
for this is uncertain, it is thought to result from
increased synthesis and/or release of acetylcholine
in motor nerve terminals. However, if due to an
increased synthesis, then the most likely mechanism would be enhancement of high affinity uptake
of choline, which has been observed in hippocampal synaptosomes in the rat (Pedata et al. 1984).
Piracetam and choline have synergistic facilitatory
effects on central cholinergic transmission (Bartus
et al. 1981), supporting the theory that high affinity
choline uptake and acetylcholine synthesis is the
primary mechanism of action
It has been suggested that piracetam influences
the permeability of mitochondrial membranes
(Pede et al. 1971), but this does not clarify its typical central action (Moyersoons & Giurgea 1974).
The drug stimulates the main energy pathway of
glucose degradation in rat brain cortex slices, supporting the theory that piracetam may have a protective effect against oxygen deficiency (Domanska-Janik & Zaleska 1977). Stimulation of adenylate
kinase catalysing the conversion of ADP to ATP
has been observed (Wolthuis & Nickolson 1975),
and piracetam also enhances 32P incorporation into
Fig. 3. The protective effect of piracetam on decreased performance with hypoxia in 12 healthy volunteers given piracetam 4.8g daily for 4 days followed by 7.2g on the fifth
day in a placebo-controlled trial (after Demay & Bande 1980).
brain phospholipids (Rochus & Reuse 1974; von
Woelk 1979).
Since piracetam has been shown to be effective
in the treatment of Parkinsonism and the psychotic
state in schizophrenics (Kabes et al. 1979), it is
thought that some of its behavioural effects may
be connected with an action on dopaminergic
transmission. Piracetam increases the concentration of dopamine metabolites in rat striatal tissue,
without significantly changing dopamine levels,
suggesting that it increases the turnover of the
neurotransmitter, thus influencing central neurotransmitter activity (Rago et al. 1981).
Although structurally related to GABA, piracetam has no effect on uptake, content or activity of
GABA in different areas of the brain. However,
Bering and Muller (1985) investigated the effects
of piracetam on several neurotransmitter receptor
systems in rat and calf brain, and discovered that
piracetam has some affinity for L-glutamate receptors and, to a lesser extent, for GABA receptors.
The increased potency at L-glutamate receptors may
be related to the long but unproven history of Lglutamate as a drug able to enhance memory and
learning. Piracetam also increases the firing rate of
noradrenergic neurons in the locus coeruleus of rats
(Olpe & Steinmann 1982): the firing rate of this
26
Drugs & Aging I (I) 1991
nucleus has been shown to be directly related to
the level of vigilance, so this action may well be
linked to the beneficial effects of the drug.
A number of peptide hormones which may
function in the CNS have been identified, and many
are activated via an increase in cellular cyclic AMP
levels. Piracetam increases cyclic AMP levels in the
frontal brain of guinea-pigs (Weth 1983), and so
this may represent another mechanism by which it
exerts its effects. The memory enhancing effects
may also depend on the presence of the adrenals
in mice (Mondadori & Petschke 1987), since piracetam has no such effects on adrenalectomised
animals. In animals pretreated with aminoglutethimide, an inhibitor of several cytochrome P45Qmediated hydroxylation steps in steroid biosynthesis in the adrenal cortex, effects of piracetam on
the retention performance of the mice were hindered, indicating that the effects of piracetam may
depend on the involvement of the products of the
adrenal cortex. These were the first pharmacological experiments in which all tested piracetam-like
drugs behaved in a similar way. Thus it is possible
that steroids may mediate the action of nootropes
on memory, or vice versa.
Completed studies give the impression that piracetam most probably acts through cholinergic
mechanisms. This theory is all the more plausible
when the growing body of evidence supporting the
significance of the cholinergic system in learning
and memory (Bartus et al. 1982; Pedata et at. 1984),
and the selective degeneration of cholinergic function in patients with Alzheimer's disease (Moos &
Hershenson 1989) is examined.
2. Pharmacokinetic Properties
The pharmacokinetic properties of piracetam
have been evaluated in a few limited animal and
human studies. Human plasma and serum concentrations of piracetam have been measured by both
gas chromatography (Gobert & Baltes 1977; Schuiz
& Wittier 1980) and high performance liquid chromatography (Platt et al. 1985). Autoradiographic
and scintillation counting techniques have been
employed in distribution studies using several ani-
Table IV, Comparison of half-life and areas under the plasma
concentration-time curve (AUC) after administration of intravenous and various oral forms of piracetam 800mg. Mean values
of 6 volunteers (after Gobert & Baltes 1977)
mal species (von Ostrowski & Keil 1978; von Ostrowski et al. 1975).
Peak plasma concentrations of piracetam are
achieved 30 to 40 minutes after oral administration (Gobert & Baltes 1977). After reaching peak
concentration, piracetam levels decline exponentially, with an elimination half-life ranging from 5.2
to 5.7 hours in healthy volunteers. In elderly
patients aged between 69 and 87 years with multiple diseases, including heart failure, arteriosclerosis, diabetes mellitus and artery disease, plasma
half-life was increased by a factor of 2 to 8 (Platt
et al. 1985). The areas under the plasma concentration-time curves (AUCs) are equivalent for both
intravenous and various oral preparations (table
IV), indicating 100% oral bioavailability.
Distribution studies with oral [14C]piracetam in
dogs and rats indicate that the drug is rapidly distributed in most essential organs. Whilst brain uptake is somewhat delayed, piracetam persists longer
in the CNS than in most of the other organs and
is preferentially concentrated in the grey matter of
the cerebrum and cerebellum, caudate nucleus,
hippocampus, lateral geniculate body and chorioid
plexus (von Ostrowski et al. 1975). Distribution
patterns appear to be independent of species for
dog, rat and monkey (von Ostrowski et al. 1975;
von Ostrowski & Keil 1978).
Piracetam readily crosses the blood-brain and
placental barriers in humans (Comely et al. 1977;
Nickolson & Wolthuis 1976). The plasma half-life
in rats is about 1.7 hours, compared with 1.9 hours
in the brain, demonstrating a greater affinity of piracetam for brain tissue in this animal model. Sim-
Piracetam: An Overview
ilarly, the CNS half-life in humans is about 7.7
hours, compared with about 5 hours in plasma
(Gobert 1972).
Piracetam is completely absorbed after oral
administration: no metabolites have yet been detected in the blood, liver or brain and the drug is
excreted unchanged in the urine: urinary excretion
accounts for between 85 and 100% (mean 98%) of
the given dose (Gobert 1972). Elimination is practically complete after 30 hours.
In young, middle-aged and elderly patients with
varying degrees of renal impairment, a close correlation between piracetam elimination and renal
function was observed (unpublished data on file,
UCB). Thus, the daily dosage in such patients
should be reduced according to the diminished creatinine clearance (see section 5).
3. Therapeutic Properties in Patients with
Senile Cognitive Disorders
One of the problems of assessing the literature
on learning and memory deficits in the elderly is
the lack of homogeneity in therapeutic trials. The
assessment of piracetam therapy for dementias and
Alzheimer's disease suffers from the lack of standardised objective measurements of efficacy. Objective evaluation is further complicated by the
subjective nature and diversity of the symptoms of
these mental disorders and also by the profusion
of diagnostic criteria used to define cognitive disorders in the elderly. Despite this, piracetam in oral
doses ranging from 2.4g to 10g daily has been studied in a number of therapeutic trials involving aged
patients suffering from cognitive disorders.
The various rating scales, psychometric and
computerised tests employed to assess the effectiveness of piracetam therapy include the d-2 test,
the Pauli Test, Critical Flicker Fusion Test, Brief
Psychiatric Rating Scale, Nurse's Improvement
Scale and others designed to measure factors such
as intelligence, attention, short term memory and
recall memory.
27
3.1 Comparative Studies
Some of the double-blind studies comparing
piracetam with placebo in elderly patients with
cognitive disorders are listed in table V. The effects
of piracetam on the symptoms of psycho-organic
senility, which included failure of memory, reduced alertness, mood changes, asthenia and psychomotor disturbances were investigated in 196
patients of mean age 67 years (Stegink 1972). Piracetam improved alertness, asthenia and psychomotor agitation significantly during the 8 weeks of
treatment. The general mental condition of the
patients showed significant improvement as assessed by weekly follow-up examinations consisting of neurological and brief psychological testing.
Piracetam was also shown to be better than placebo using subjective assessment and clinical rating methods in short term trials (6 weeks) when
2.4 or 2.6g was given daily to geriatric patients with
senile cognitive disorders (Hronek et al. 1979;
Macchione et al. 1976; Parrisius 1977). In one of
the larger trials conducted to date, piracetam 4.8g
given daily to 130 elderly patients with impaired
brain function produced more marked results than
placebo on the different measurement levels, and
also on observer ratings by physician, clinical psychologist and nursing staff (Herrmann & Kem
1987). Bjurwill assessed the effects of piracetam 2.4g
given daily to 40 patients with psycho-organic disorders using a geriatric rating scale of 12 selected
items which included measurement of irritability,
absent-mindedness and short term memory. Significant improvement was observed in 7 of 12 items
in favour of piracetam (unpublished data on file,
UCB).
In 18 normally aging individuals, piracetam 4.8g
daily for 4 weeks resulted in greater improvement
than placebo on a number of computerised and paper-and-pencil tests designed to detect drug-induced changes in perceptuo-motor functioning
(Mindus et al. 1976). Similarly, in 63 patients with
primary deterioration of intellectual function, piracetam 4.8g for 4 weeks followed by piracetam 2.4g
for 4 weeks was more effective clinically and statistically than placebo (Marin Perez 1981). In con-
28
Drugs & Aging 1 (1) 1991
Table V. Some double-blind studies comparing piracetam with placebo in elderly patients with varying degrees of memory impairment
Piracetam: An Overview
trast, Abuzzahab et al. (1978) observed no significant differences in psychological testing in 56
patients treated with piracetam 2.4 to 4.8g for 3
days to 8 weeks. This may have been due to this
group of patients having a significant amount of
organic brain deficits, and memory changes may
have been irreversible in this population because
of the level of deterioration. However, Chouinard
et al. (1983) studied the effects of piracetam 2.4 or
4.8g daily for 12 weeks in 60 elderly psychiatric
patients with mild diffuse cerebral impairment.
Piracetam at both dosage levels was significantly
better than placebo as assessed by the Nurse's
Clinical Global Improvement rating scale. Alertness, socialisation, and orientation were the most
characteristic improvements observed. On the
Sandoz Clinical Assessment Geriatric scale (SCAG)
and the Crichton Geriatric Rating Scale, piracetam
was superior to placebo. The higher dose had a
more rapid onset of action than the lower dose but
its therapeutic effect tended to diminish at 12
weeks. Patients also showed significant improvement in IQ and memory scores at a daily dose of
2.4g, and a greater response was seen in those
patients with lower initial scores.
No significant results were found favouring piracetam in 21 senile dementia patients in either psychometric or clinical measuring scales in a doubleblind placebo-controlled trial conducted by Gedye
et al. (1978), results which were in agreement with
29
those obtained by Gustafson et al. (1978), although
in this latter study trends towards an improved
performance were seen in Critical Flicker Fusion
and Reaction Time tests. Disappointing results were
likewise reported by Lloyd-Evans et al. (1979),
where only 1 of a series of 19 psychometric tests
showed consistent superiority of piracetam over
placebo at a daily dosage of 2.4g for 6 weeks in a
group of 78 patients with minimal to moderate
chronic brain failure. However, in 20 patients diagnosed as suffering from primary degenerative dementia, piracetam 7.2 g/day for 4 weeks resulted
in significant differences compared with placebo in
verbal associative memory and visual attention and
speed (Reisberg et al. 1982).
In a placebo-controlled double-blind study involving 60 patients with post-concussional syndrome, piracetam 4.8g daily for 8 weeks significantly reduced the severity of symptoms, especially
vertigo and headache which gradually improved
throughout the 8-week observation period (Hak~
karainen & Hakamies 1978), although no beneficial effect on memory was detected. Similar improvement was seen in 5 elderly patients with
presbyvertigo given piracetam 800mg daily for 4
weeks (Fernandes & Samuel 1985).
The use of electroconvulsive therapy (ECT) in
the treatment of severe depression can lead to
memory disturbances which may last for several
weeks. In a controlled trial involving 30 patients
Drugs & Aging I (1)
1991
30
divided into 2 groups, memory was tested before
and after ECT using the Wechsler Memory Test
(Ezzat et al. 1985), The memory scores after ECT
were significantly greater in the piracetam-treated
group than in the untreated group.
3.2 Piracetam in Combination with
Acetylcholine Precursors
Memory impairment in senile dementia of the
Alzheimer's type (SDAT) is highly correlated with
brain cholinergic dysfunction (Moos & Hershenson 1989). The effects of enhanced cholinergic
function have been examined using choline or lecithin treatment alone, but this approach has produced inconsistent results (Bartus et al. 1982; Ferris et al. 1979; Pomara et al. 1981). Experiments
in aged rats have shown that choline plus piracetam is superior to treatment with either agent alone
in reversing age-related impairment of memory retention in a passive avoidance test (Bartus et al.
1981). This has prompted the testing of piracetam
and acetylcholine precursors in patients with senile
dementia.
Choline 9g plus piracetam 4.8g given daily for
7 days in 10 patients diagnosed as having SDAT
with mild to moderate memory impairment yielded
small but nonsignificant improvements in most
cognitive measures for the entire group as assessed
by objective tests of cognitive function, and behavioural rating scales (Friedman et al. 1981). Three
patients were psychiatrically evaluated and deemed
to be clinically improved. Scores on Buschke Selective Reminding Test showed a mean improvement of 70% in verbal memory retrieval. It was
also noted that responders had higher baseline levels of red cell choline than nonresponders and levels were also higher after treatment with piracetam
and choline. This agreed with a small trial involving 5 patients given increasing doses of lecithin and
piracetam in single-blind fashion (Serby et al. 1983).
Assessment was carried out using Inventory of
Psychic and Somatic Complaints in the Elderly
(IPSC-E) ratings, and various cognitive assessments were performed at baseline and at the end
of each treatment period. Combination treatment
resulted in clinical improvement in 3 of 5 patients
measured by the final IPSC-E score. Similarly, cognitive improvement was manifested in 2 patients
in short term memory function, and again 3 responders and 1 nonresponder had high erythrocyte
choline levels and erythrocyte: plasma choline ratios both before and after treatment. The red blood
cell choline levels and the ratio to plasma concentrations may be predictive of outcome of treatment, but further trials are necessary to validate
this observation.
In a double-blind study involving 9 patients with
primary degenerative dementia given piracetam
plus lecithin, piracetam plus placebo or double placebo in random order for successive 2-week periods, no superiority of piracetam plus lecithin
compared with piracetam alone was observed (Pomara et al. 1984), Methodological differences and
different methods of assessment between studies
may have resulted in the differences. Longer periods than those employed in the studies conducted thus far may be necessary for the drug to
exert its effect. Longer term treatment with lecithin
plus piracetam (5 months) has yielded beneficial
effects on selective memory deficits in some
patients with SDAT (Smith et al. 1984). Memory
scores improved much more than aphasia or general mental status scores, consistent with the suggestion that piracetam plus lecithin enhanced brain
cholinergic function. Negative results in some
patients may have resulted from differences in the
optimum dosage or to the stage of the disease.
However, in a trial involving 18 patients with Alzheimer's disease receiving piracetam according to
3 separate protocols in a wide range of doses, piracetam administered alone or in combination with
lecithin did not significantly affect cognition, or
dramatically restore memory function in any
patient (Growdon et al. 1986).
4. Adverse Effects
Piracetam appears to be extremely well tolerated in clinical trials, with a very low incidence of
adverse effects having been reported in dosages of
up to 2.4g to 4.8g daily for up to 8 weeks (Abuz-
Piracetam: An Overview
zahab et al. 1978; Oosterveld 1980; Reisberg et al.
1982; Stegink 1972). A standard dose of piracetam
lOg daily, given for 10 to 21 days either orally or
intravenously, produced no adverse effects in a
group of 100 patients undergoing neurosurgery
(Richardson & Bereen 1977). The drug also did not
interact with antibiotics, anticonvulsants, analgesics, muscle relaxants, corticosteroids, antifibrinolytic drugs, antidepressants, hormone replacements
or antihypertensive drugs being taken concurrently
by some of the patients. Side effects which have
been reported include mild dizziness, insomnia and
nausea, but none of these have necessitated discontinuation of therapy (Chouinard et al. 1983; von
Dorn 1978). In only one trial has piracetam treatment been withdrawn - due to a feeling of tremor
when 2.4g was administered daily for the treatment
of head injuries (Aantaa & Meurman 1975).
Although a relatively high incidence of adverse
effects was reported in one trial involving 60
patients receiving piracetam 4.8g daily for postconcussional syndrome (Hakkarainen & Hakamies
1978) including agitation, anxiety and insomnia,
these may well have been attributable to the symptoms of cerebral concussion itself.
5. Dosage and Administration
Piracetam has been administered either orally
or intravenously in daily dosages ranging from 20
to 150 mg/kg. The manufacturer recommends that
the drug be administered in 2, 3 or 4 divided daily
doses, in severe cases, large doses of up to 12g daily
may have to be administered as an intravenous infusion.
A recommended oral dosage schedule for the
long term treatment of senility is 2.4 to 4.8g daily.
In patients with impaired renal function, piracetam dosage regimens should be adjusted according
to creatinine clearance (table VI).
6. Place of Piracetam in Therapy
As the developed countries of the world face the
problems of a rapidly aging population, senile
cognitive decline and other disorders affecting
31
Table VI. Adjustment of piracetam dosage regimen in pat.ents
with renal impairment according to creatinine clearance (manufacturer's recommendations)
memory and intellectual functioning are becoming
increasingly widespread. Thus, pharmacological research to find drugs which enhance human cognitive function is becoming even more important.
The dementias of the elderly often involve short
term working memory loss and decreases in alertness, attention span and motivation. Untreatable
cognitive disorders, including Alzheimer's disease
and age-associated memory impairment, present
the greatest challenges to research.
Alzheimer's disease now ranks as one of the major killer diseases in modern society and is the
fourth leading cause of death in the United States
(Moos & Hershenson 1989). This ranking will grow
in the coming years as the geriatric segment of the
population increases. The pathogenesis of Alzheimer's disease is presently unknown. A number
of possible factors are thought to be involved, including the presence of abnormal proteins, blood
flow disorders and neurotransmitter deficits. Recently, it has been suggested that chromosomal abnormalities may also be involved since it has been
observed that individuals with Down's syndrome
who survive to the age of 40 years develop Alzheimer type brain lesions and clinical dementia.
Additionally, Alzheimer's disease and Down's syndrome share a unique cerebrovascular amyloid fibril protein. At present, there is no drug available
which will prevent or limit the progress of Alzheimer's disease, only therapies which may in some
cases improve some of the associated symptoms.
The first cognition activators were discovered
during the testing of agents in behavioural studies.
Early therapeutic strategies involved the use of vasodilators or anticoagulants to improve cerebral
blood flow. A mixture of ergot alkaloids (Hyder-
32
Drugs & Aging I (!) 1991
gine®) has been used in senile cognitive decline
with mixed results. Beneficial effects observed after
the administration of this drug are now thought to
be due to its nootropic rather than its vasodilator
action (Armstrong 1986). Newer agents represent
a shift to better defined mechanisms of action; for
example, because of the cholinergic deficits observed in Alzheimer's disease, cholinesterase inhibitors and cholinergic precursors have been tried
in therapy, although these have met with little success,
Piracetam may well be the forerunner of a new
group of clinically useful compounds for treating
cognitive disorders, being the first of the true nootropic drugs designed to improve mental function.
It crosses the blood-brain barrier and is selectively
concentrated in the brain cortex where it influences
a number of localised cortical functions. Although
it has definite effects on GNS activity, it differs from
known classes of drugs with CNS effects. It has no
analgesic, sedative or tranquillising properties and
lacks the typical behavioural effects seen with amphetamine in animals. It does not appear to have
antihistaminic, anticholinergic or antiserotoninergic properties.
Caution is necessary when drawing any conclusions from the clinical trials conducted to date in
patients with senile cognitive disorders. The differences in results may well be due to the complexity of the neuropathological and neurochemical abnormalities found in such patients.
The clinical usefulness of piracetam is still the
subject of much debate. Whilst piracetam and related nootropes have been shown to facilitate
learning and memory in animal models, clinical
trials in elderly patients with senile cognitive disorders continue to give mixed results. However
some of the more encouraging results have been
obtained from larger scale trials with more homogeneous patient groups (Herrmann & Kern 1987;
Israel 1990; Passeri 1990; Stegink 1972).
References
Aaniaa E, Meurman OH. The effect of piracetam (nootropil, UCB6215) upon the late symptoms of patients with head injuries.
Journal of International Medical Research 3: 352-355, 1975
Abuzzahab Sr FS, Merwin GE, Zimmermann RL, Sherman MC.
A double-blind investigation of piracetam (nootropil) versus
placebo in the memory of geriatric inpatients. Psychopharmacology Bulletin 14: 23-26, 1978
Armstrong A. Recent trends in research on Alzheimer's disease.
Scrip. 1986
Bartus RT, Dean 3rd RL, Beer B, Lippa A. The cholinergic hypothesis of geriatric memory dysfunction. Science 217: 408-417,
1982
Bartus RT, Dean RL, Sherman KA, Friedman E, Beer B. Profound effects of combining choline and piracetam on memory
enhancement and cholinergic function in aged rats. Neurobiology of Aging 2 (2): 105-111, ;981
Bente D, Glatthaar G, Ulrich G, Lewinsky M. Piracetam und
Vigilanz. Elektroenzephalographische und klinische Ergebmsse
einer Langzeitmedikation bei gerontopsychiatrischen Patienten. Arzneimittel-Forschung 28: 1529-1530, 1978
Be ga P, Beckett PR, Roberts DJ, Llenas J, Massingham R. Syn^rgistic interactions between piracetam and dihydroergocrisJne in some animal models of cerebral hypoxia and ischaemia.
Arzneimittel-Forschung 36 (2): 1314, 1986
Bering B, Muller WE. Interaction of piracetam with several
neurotransmitter receptors in the central nervous system. Relative specificity for 3H-glutamate sites. Arzneimittel-Forschung 35 (2): 1350-1352, 1985
Bick RL, Farced J, Skondia V. Piracetam: a new platelet suppressing drug. Abstract. Thrombosis and Haemostasis 46: 67,
1981
Bryant RC, Petty F, Byrne WL. Effects of piracetam (SKF 38462)
on acQuisition, retention and activity in the goldfish. Pharmacologia 29 (2): 121-130, 1973
Buresova O, BureS J. Mechanisms of interhemispheric transfer of
visual information in rats. Acta Neurobioiogiae Experimentalis 33: 673-688, 1973
BureSova O, Bures J. Piracetam-induced facilitation of interhemispheric transfer of visual information In rats. Psychopharmacologia 46: 93-102, 1976
Cavazzuti L, Bertoidin T, Volpe D, Crepaldi G. influence of
treatment with piracetam on psychocognitive decline in elderly
hospitalized patients. In Symposium on Piracetam: 5 years'
progress in pharmacology and clinics, pp. 67-74, Technicas
Graficas Forma, Madrid, 1990
Chouinard G, Annable L, Ross-Chouinard A, Olivier M, Fontaine F. Piracetam in elderly pyschiatric patients with mild
diffuse cerebral impairment. Psychopharmacology 81: 100-106,
1983
Comely M, Henkel E, Kunzel W, Zimmermann P. Pharmacokinetic of piracetam during labour influence to acid-base-status
in material and fetal blood. Zeitschrift fur Geburtshilfe und
Perinatoiogie 18 1 :199-205," 1977
Demay F, Bande J. The effect of piracetam on volunteers in a
low-pressure tank. Journal of International Medical Research
8: 90-94, 1980
Dimond SJ, Use of a nootropic substance to increase the capacity
for verbal learning and memory in normal man. 3rd Congress
of the Internationa! College of Psychosomatic Medicine, 1975
Dimov S, Moyanova S, Nikolov R, Nikolova M. Piracetam and
brain excitability: an electrophysiological study in cats. Methods and Findings in Experimental and Clinical Pharmacology
6 (2): 83-89, 1984
Dimov S, Nikolov R, Nikolov M, Moyanova S. Effect of piracetam in some models of general and local depression of the
cortical bioelectrical activity in cats. Archives Internationales
de Pharmacodynamie et de Therapie 262: 13-23, 1983
Domariska-Janik K, Zaleska M. The action of piracetam on !4Cglucose metabolism in normal and posthypoxic rat cerebral
cortex slices. Polish Journal of Pharmacology and Pharmacy
29: 111-116, 1977
Ennaceur A, Delacour J. Effect of combined or separate admin-
Piracetam: An Overview
istration of piracetam and choline on learning and memory in
the rat. Psychopharmacoiogy 92: 58-67, 1987
Ezzat DH, Ibraheem MM. Makhawy B. The effect of piracetam
on ECT-induced memory disturbances. British Journal of Psychiatry 147: 720-721, 1985
Fcrnandes CMC, Samuel J. The use of piracetam in vertigo. South
African Medical Journal 11: 806-808, 1985
Ferris SH, Sathananthan G, Reisberg B, Gershan S. Long term
treatment of memory impaired elderly patients. Science 205:
1039-1040, 1979
Friedman E, Sherman KA, Ferris KA, Reisberg B, Bartus R, et
al. Clinical response to choline plus piracetam in senile dementia: relation to red-cell choline levels. New England Journal of Medicine 304: 1490-1491, 1981
Gcdye JL Ibrahimi GS, McDonald C. Double blind controlled
trial of piracetam (2-pyrrolidone acetamide) on two groups of
psychogeriatric patients. IRCS Medical Science: Clinical Medicine; Clinical Pharmacology and Therapeutics; Psychology and
Psychiatry; Social and Occupational Medicine 2: 202, 1978
Giancllo P, Janssen T, Chatzopoulos C Kartheuser A, Lambotte
L, et al. Beneficial effect of piracetam on renal blood flow in
ischemically injured kidneys in the rat. Transplantation Proceedings 20: 914-916, 1988
Giurgea C, Lefevre D, Lescrenier C, David-Remacle M. Pharmacological protection against hypoxia-induced amnesia in rats.
Psychopharmacologia (Berl) 20: 160-168, 1971
Giurgea C, Mourarieff-Lesuisse F, Leemans R. Correlations electro-pharmacologiques all cavs de Tanoxie exyprive chez le lapin
en respiration libre ou artificielle. Revue Neurologique 122: 484486, 1970
Giurgea C, Moyersoons F. Differential pharmacological reactivity
of three types of cortical evoked potentials. Archives Internationals de Pharmacodynamie et de Therapie 183: 401-404,
1970
Giurgea C, Moyersoons F. On the pharmacology of cortical evoked
potentials. Archives Internationales de Pharmacodynamie et
de Therapie 1 9 9 ( 1 ) : 67-68, 1972
Giurgea C, Moyersoons F. Contribution to the experimental
pharmacotherapy of acute drug intoxications. Journal of
Pharmacology 5 (Suppl. 2): 37, 1974
Giurgea C, Salama M. Nootropic drugs. Progress in Neuro-Psychopharmacology and Biological Psychiatry 1: 235-247, 1977
Gobert JG. Genese d'un medicament: le piracetam rnetabolisation ct recherche biochimique. Journal de Pharmacie dc Belgique 27: 281-304, 1972
Gobert JG, Baltes EL. Availability and plasma clearance of piracetam in man. Farmaco 2: 83-91, 1977
Growdon JH, Corkin S, Huff FJ, Rosen TJ. Piracetam combined
with lecithin in the treatment of Alzheimer's disease. Neurobiology of Aging 7: 269-276, 1986
Gustafson L, Risberg J, Johanson M, Fransson M, Maximilian
VA. Effects of piracetam on regional cerebral blood flow and
mental functions in patients with organic dementia. Psychopharmacology 56: 115-117, 1978
Hakkarainen H, Hakamies L. Piracetam in the treatment of postconcussional syndrome: a double-blind study. European Neurology 17: 50-55, 1978
Hall ED, von Voigtlander PF. Facilitatory effects of piracetam on
excitability of motor nerve terminals and neuromuscular
transmission. Neuropharmacology 26 (11): 1573-1579, 1987
Hassmannova J, Myslivecek J, Romoliniova A. Learning and
memory in the ontogeny of rats given piracetam. Activitas
Nervosa Superior 22: 95-96, 1980
Henry RL, Nalbandian RM, Dzandu JK. Effect of membranebound protein phosphorylation of intact normal and diabetic
human erythrocytes: enhanced membrane deformability. Diabetes 30 (Suppl. 1): 83a, 1981
Herrmann WM, Kern U. Nootropic drugs - effects and thera-
33
peutic efficacy: a phase II study with piracetam as a model.
Nervenarzt 58: 358-364, 1987
Herrschaft H. The effect of piracetam on global and regional cerebral blood flow in acute cerebral ischemia of man. Medtzinische Klinik 73: 195-202, 1978
Hronek J. Drahokoupil L, Fait V, Hudeova T, Laciga Z, et al.
Clinical experience with piracetam therapy in gerontology.
Comm. 21st Annual Psychopharmacoiogy Meeting, Tchecoslovaquie, Jesenir, pp. 121-129, 1979
Israel L. Memory training programs (MTPs) combined with drug
therapy in primary care, including patients with age-associated
memory impairment. In Symposium on Piracetam: 5 years'
progress in pharmacology and clinics, pp. 17-22, Technicas
Graficas Forma, Madrid, 1990
Kabes J, Erban L, Hanzlider L, Skondia V. Biological correlates
of piracetam clinical effects in psychotic patients. Journal of
International Medical Research 7: 277-284, 1979
Koupilova M, Fusek J, Hrdina V, Herink J. Piracetam effect on
learning and memory in rats. Activitas Nervosa Superior 22:
193-194, 1980
Krug M, Ott T, Schulzeck K, Matthies H. Effects of orotic acid
and pirazetam on cortical bioelectrical activity in rabbits. Psychopharmacoiogy 53: 73-78, 1977
Kruse H, Konler H. Memory enhancing effects-of piracetam in
aged rats. Abstract. Federation Proceedings 37: 888, 1978
Kuribara H, Tadokoro S. Facilitating effect of oxiracetam and
piracetam on acquisition of discrete two-way shuttle avoidance
in normal mice. Japanese Journal of Pharmacology 48: 494498, 1988
Lenegre A, Chermat R, Avril I, Steru L, Porsolt RD. Specificity
of piracetam's anti-amnesic activity in three models of amnesia in the mouse. Pharmacology, Biochemistry and Behavior
29: 625-629, 1988
Lloyd-Evans S, Brockiehurst JC, Palmer MK. Piracetam in chronic
brain failure. Current Medical Research and Opinion 6: 3 51 357, 1979
Macchione C, Moiaschi M, Fabris F, Feruglio FS. Results with
piracetam in the management of senile psycho-organic syndromes. Acta Therapeutica 2: 261-269, 1976
Marcs" P, MarcSova D. Effect of piracetam on excitability cycle
of cortical interhemispheric responses in the rat. Activitas Nervosa Superior (Praha) 27 (4): 285-286. 1985
Maresova D, Mares P. Effect of piracetam on cortical epileptogcnic foci in the rat. Activitas Nervosa Superior 26: 67-68,
1984
Marin Perez GM. Evaluation of the clinical effects of piracetam
in the deterioration of the intellectual functions of a geriatric
population: a double-blind study. 2nd International Symposium on Nootropic Drugs, Mexico, May 21-22, 1981
Means LW, Franklin RD, Cliett CE. Failure of piracetam to facilitate acquisition or retention in younger or older rats. Experimental Aging Research 6: 175-180, 1980
Mindus P, Cronholm B, Levander SE, Schalling D. Piracetaminduced improvement of mental performance: a controlled
study on normally aging individuals. Acta Psychiatrica Scandinavica 54: 150-160, 1976
Mondadori C, Petschke F. Do piracetam-like compounds act centrally via peripheral mechanisms? Brain Research 435: 310314, 1987
Moos WH, Hershenson FM. Potential therapeutic strategies for
senile cognitive disorders. Drug News and Perspectives 2: 397409, 1989
Moyanova S, Nikolov R. Dimov S. Effect of piracetam on the
electrocardiogram after traumatic brain oedema in cats. Methods and Findings in Experimental and Clinical Pharmacology
7 (12): 623-626, 1985
Moyersoons F, Everard A, Dauloy J, Giurgea C. A particular
pharmacological effect on the propagation of experimental
34
strychnine and penicillin epilepsy. Archives Internationales de
Pharmacodynamie et de Therapie 179 (2): 388-400, 1969
Moyersoons F, Giurgea CE. Protective effect of piracetam in experimental barbiturate intoxication: EEC and behavio.ural
studies. Archives Internationales de Pharmacodynamie et de
Therapie 210: 38-48, 1974
Muller WE, Pilch H, Stoll L, Schubert T. Piracetam as a possible
cell communication modulator - focus on central M-cholinoceptors. Pharmazeutische Zeitung 3: 1-8, 1990
Myslivecek J, Hassmannova J. An electrophysiological analysis
of action of piracetam in rats. Activitas Nervosa Superior 16:
242-244, 1974
Myslivecek J, Hassmannova J. Effect of piracetam on learning
and brain potentials in rats with early sensory deprivation. Risks
of Psychotropic Drugs 19: 171-175, 1975
Nalbandian RM, Henry RL, Burek CL, Diglio CA, Goldman AI,
et al. Diminished adherence of sickle erythrocytes to cultured
vascular endothelium by piracetam. American Journal of
Hematology 15: 147-151, 1983
Nickolson VJ, Wolthuis OL. Differential effects of the acquisition
enhancing drug pyrrolidone acetamide (piracetam) on the release of proline from visual and parietal rat cerebral cortex in
vitro. Brain Research 113: 616-619, 1976
Nikolova M, Nikolov R, Milanova D. Anti-hypoxic effect of piracetam and its interaction with prostacyclin. Methods and
Findings in Experimental and Clinical Pharmacology 6 (7): 367371, 1984
Nikolova M, Nikolov R, Tsikalova R, Popivanov D. Piracetam
effect on the visual evoked potentials in cats. Drugs Under
Experimental and Clinical Research 6 (7): 33-37, 1980
Olpe H-R, Lynch GS. The action of piracetam on the electrical
activity of the hippocampal slice preparation: a field potential
analysis. European Journal of Pharmacology 80: 415-419, 1982
Olpe H-R, Pozza MF, Jones RSG, Haas HL. Comparative electrophysiological investigations on oxiracetam and piracetam.
Clinical Neuropharmacology 9 (Suppl. 3): 48-55, 1986
Olpe H-R, Steinmann MW. The cfleet of vincaniine, hydergine
and piracetam on the firing rate of locus coeruleus neurons.
Journal of Neural Transmission 55: 101-109, 1982
Oosterveld WJ. The efficacy of piracetam in vertigo. Arzneim-itteiForschung 30 (2): 1947-1948, 1980
Parrisius HW. Doppelblindstudie mit Piracetam in der Geriatric.
Geriatric 7(1): 32-37, 1977
Passeri M. A multicentre study of piracetam in patients with lateonset senile dementia. In Symposium on Piracetam: 5 years'
progress in pharmacology and clinics, pp. 75-80, Technicas
Graficas Formas, Madrid, 1990
Pede JP, Schimpfessel L, Grokaert R. The action of piracetam
on the oxidative phosphorylation. Archives Internationales de
Physiologic et de Biochimie 79: 1036-1037, 1971
Piercey MF, Vogelsang GD, Franklin SR, Tang AH. Reversal of
scopolamine-induced amnesia and alterations in energy metabolism by the nootropic piracetam: implications regarding
identification of brain structures involved in consolidation of
memory traces. Brain Research 424: 1-9, 1987
Pilch H, Muller WE. Piracetam elevates muscarinic cholinergic
receptor density in the frontal cortex of aged but not of young
mice. Psychopharmacology 94: 74-78, 1988
Platt D, Muhlberg W, Rieck W. The effect of age on clinical pharmacokinctics of piracetam. Arzneimittel-Forschung 35 (1): 533535, 1985
Pomara N, Block R, Moore N, Rhiew HB, Berchou R, et al. Combined piracetam and cholinergic precursor treatment for primary degenerative dementia. IRCS Medical Science 12: 388389, 1984
Pomara N, Reisberg B, Ferris SH, Gershan S. Drug treatment in
cognitive decline. In Maletta GJ, Pirozzolo FJ (Eds) Advances
in neurogerontology, Praeger, New York, 1981 Rago LK,
Allikmets LH. Zarkovsky AM. Effects of piracetam on
Drugs & Aging I (I) 1991
the central dopaminergic transmission. Naunyn-Schmiedeberg's Archives of Pharmacology 318: 36-37, 1981
Reisberg B, Ferris SH, Schneck MK, Corwin J, Mir P, el al. Piracetam in the treatment of cognitive impairment in the elderly.
Drug Development Research 2: 475-480, 1982
Reuse-Blom S, Polderman J. Influence of piracetam upon the pial
micro-circulation. In Loose & Loose (Eds) 6th International
Angiography and Angiology Seminar, Baden-Baden, March 1517, 1979. Verlag-Gerhard Witzstrock, Koln, 1980
Richardson AE, Bereen FJ. Effect of piracetam on level of consciousness after neurosurgery. Lancet 2: 1110, 1977
Rochus L, Reuse JJ. Chlorpromazine and phospholipid metabolism in the rat hypothalamus. Effect of pretreatment with piracetam. Archives Internationales de Physiologic et de Biochimie 82: 1010-1011, 1974
Saletu B, Grunberger J. Memory dysfunction and vigilance: neurophysiological and pharmacological aspects. Annals of the New
York Academy of Sciences 444: 406-427, 1985
Sannita WG, Balestra V, Rosadini G, Salama M, Timitilli C.
Quantitative EEG and neuropsychological effects of piracetam
and of the association piracetam-lecithin in healthy volunteers.
Neuropsychobiology 14: 203-209, 1985
Sara SJ, David-Remacle M, Lefevre D. Passive avoidance behaviour in rats after electroconvulsive shock: facilitative effect
of response retardation. Journal of Comparative and Physiological Psychology 89: 489-407,'1975
Sara SJ, David-Remacle M, Weyers M, Giurgea C. Piracetam facilitates retrieval but does not impair extinction of bar-pressing
in rats. Psychopharmacology 61: 71-75, 1979
Sara SJ, Lefevre D. Hypoxia-induced amnesia in one-trial learning and pharmacological protection by piracetam. Psychopharmacologia 25: 32-40, 1972
Sato M, Heiss W-D. Effect of piracetam on cerebral blood flow
and somatosensory evoked potential during normotension and
hypotensive ischemia in cats. Arzneimittel-Forschung 35: 790792, 1985
Schmidt U, Brendemiihl D, Engels K, Sehenk N, Lud< mann E.
Piracetam and the driving behaviour of elderly motorists in
standardized test runs under road traffic conditions. Symposium on Piracetam: 5 years' progress in pharmacology and clinics,
pp. 47-60, Technicas Graficas Formas, Madrid, 1990
Schulz H-U, Wittier Th. Age-related changes in pharmacokinetics
of 2-oxo-pyrrolidine-l-acetamide (piracetam) in man. Abstract
211. Naunyn-Schmiedeberg's Archives of Pharmacology 313
(Suppl.): R53, 1980
Serby M, Co/win J, Rotrosen J, Ferris SH, Reisberg B, et al. Lecithin and piracetam in Alzheimer's disease. Psychopharmacology Bulletin 19: 126-129, 1983
Smith RC, Vroulis G, Johnson R, Morgan R. Comparison of
therapeutic response to long-term treatment with lecithin versus piracetam plus lecithin in patients with Alzheimer's disease. Psychopharmacology Bulletin 20 (3): 542-545, 1984
Stegink AJ. The clinical use of piracetarr\, a new nootropic drug.
The treatment of symptoms of senile involution. ArzneimittelForschung 22: 975-977, 1972
Valzelli L, Baiguerra G, Giraud O. Difference in learning and
retention by albino Swiss mice. Part III. Effect of some brain
stimulants. Methods and Findings in Experimental and Clinical
Pharmacology 8 (6): 337-341, 1986
Valzelli L, Bernasconi S, Sab A. Piracetam activity may differ
according to the age of the recipient mouse. International
Phanmacdpsychiatry 15: 150-156, 1980
von Dorn M. Piracetam bei vorzeitiger biologischer Alterung:
doppelblind-prufung nach medikamentoser Vorselektion.
Fortschritte der Medizin 96: 1525-1530, 1978
von Kretschmar JH, Kretschmar L. On the dose-effect relationship in the therapy with piracetam. Arzneimittel-Forschung 26:
1158-1159, 1976
von Ostrowski J, Keil M. Autoradiographischc Untcrsuchungcn
Piracetam: An Overview
zur Verteilung von l4C-Piracetam im AfTengehirn. Arzneimittel-Forschung 28 (1): 29-35, 1978
von Ostrowski J, Keil M, Schraven E. Autoradiographische Untersachungen zur Verteilung von Piracetam-l4C bci Ratte und
Hund. Arzneimittel-Forschung 25: 589-596, 1975
von Woelk H. Zum Einfluss von Piracetam auf die neuronale
und synaptosomale Phospholipase-Ai-Aktivitat. ArzneimittelForschung 29 (1): 615-618, 1979
Voronina TA, Krapivin SV, Nerobkova LN. Specificity of action
of pyracetam, pyritinol, and cleregil on the transcallosal evoked
potential. Bulletin of Experimental Biology and Medicine 101:
326-329. 1986
Wahl M. Kuschinsky W. Report on the study of the direct vasoactive action of piracetam upon the cerebral vascular system
of the cat. In Loose & Loose (Eds) 6th International Angiography and Angiology Seminar, Baden-Baden, March 15-17,
1979. Verlag Gerhard Witzstrock, Koln, 1980
Weth G. The influence of piracetam on the cyclic adenosine
monophosphate (cAMP) concentration in the brain and colon
of guinea pigs. Arzneimittel-Forschung 33 (1): 812-814, 1983
35
Wolthuis OL Experiments with UCB 6215, a drug which enhances acquisition in rats: its effects compared with those of
metamphelamine. European Journal of Pharmacology 16: 283297, 1971
Wolthuis OL, Nickolson VJ. Piracetam and acquisition behaviour in rats: electrophysiological and biochemical effects. 3rd
Congress International College of Psychosomatic Medicine,
Rome: 135-149, 1975
Wurtman RJ, Magic SG, Reinsteia DK. Piracetam diminishes
hippocampal ACh levels in rats. Life Sciences 28: 1091-1093,
1981
Yamada K, Inoue T, Tanaka M, Furukawa T. Prolongation of
latencies for passive avoidance responses in rats treated with
aniracetam or piracetam. Pharmacology, Biochemistry and Behavior 22: 645-648, 1985
Correspondence: Margaret Vernon, Adis International Limited,
Private Bag, 41 Centorian Drive, Mairangi Bay, Auckland 10,
New Zealand.