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Piracetam Information

Piracetam - James South Article - reviewing piracetam, aniracetam, pramiracetam, and oxiracetam by James South M.A.

Over 30 years have passed since the "Nootropic Revolution" quietly began with the development of Piracetam in the late medical efficacy with a virtual absence of toxicity and side effects; something rarely seen with more standard medical drugs.

More importantly, they offered promise not only in the realm of fighting disease, but also in the virtually unexplored realm of drugs that could not only postpone or even reverse "normal" brain aging, but could even make "normal" brains work better!

The Piracetam-nootropics have been exhaustively researched; since the first scientific studies on Piracetam in the late 1960's over 1000 scientific papers on Piracetam, Oxiracetam, Pramiracetam, and Aniracetam have been published,with about two thirds of them on Piracetam.

The action of the Piracetam-nootropics has been studied in a broad range of animals; goldfish, mice, rats, guinea pigs, rabbits, cats, dogs, marmosets, monkeys and humans.

The toxicity of Piracetam and its "cousins" is amazingly low- almost non-existent. In acute toxicity studies, intravenous doses of Piracetam given to rats (8g/ Kg bodyweight) and oral doses given to mice, ra ts, and dogs (10g/ Kg or more) produced no toxicity.

This would be equivalent to 560-700 grams (1.23 to 1.54 pounds) for a 154 pound human. Rats given 100-1000mg/ Kg orally for 6 months and dogs given 10,000mg/ Kg orally for one year showed no toxic effect, a teratogenic (birth defect causing) effects were found, either (Tacconi and Wurtman 1986).

The Piracetam-nootropics are among the toxicologically safest drugs ever developed.

The four main commercially available "racetam" nootropics all share a pyrrolidine nucleus, while Piracetam, Oxiracetam, and Pramiracetam, also share an acetyl group. The racetams (especially Piracetam and Oxiracetam) are closely related in structure to the amino acid Pyroglutamic Acid. Pyroglutamic Acid has been shown in some studies to have weak nootropic activity (Gouliaev and Senning 1994). Pyroglutamic Acid is naturally present in many human foods, as well as the mammalian brain.

The concept and definition of a "nootropic drug" was first proposed in 1972 by C.E. Giurgea, the principal Piracetam researcher and research coordinator for UCB, the Belgian company that launched Piracetam. "The main features... defining a nootropic drug are: (A) the enhancement, at least under some conditions, of learning acquisitions as well as the resistance of learned behaviors to agents that tend to impair them; (B) the facillitation of interhemispheric flow of information; (C) the partial enhanc ement of the general resistance of the brain and particularly its resistance to physical and chemical injuries; (D) the increase in the efficacy of the tonic cortico -subcortical control mechanisms; and (E) [absence of the usual negative pharmacologic effects of psychotropic drugs]." Giurgea,and Salama 1977). Giurgea derived the term "nootropic" from the i words "noos" (=mind) and "tropein" (=to turn toward).

Schaffler and Klausnitzer (1988) have given an excellent brief overview of some of the chief effects of the Piracetam-nootropics. "From animal biochemistry it is known that [Piracetam-nootropics] enhance brain metabolism by stimulation of oxidative catabolism, increcrease of ATP-turnover and cAMP levels, enhancement of phospholipid -metabolism and protein biosynthesis. [PIR-nootropics have] an impact on t he hippocampal release of acetylcholine and on the dopaminergic turnover, too. Pharmacologically there exist protective effects with regard to several noxes [harmful agents] and an impact on the associative cortical sphere and on hippocampal structures, which are related with learning and memory, especially when the respective functions are impaired. The performatory enhancements

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are related with an increase d arousability of hippocampal pyramid cells, facilitated transmission of the thalamic

reased arousability of hippocampal pyramid cells, facilitated transmission of the thalamic afferences, increased release eased release of hippocampal acetylcholine and enhanced synaptic transmission.

nced synaptic transmission. ose under the conditions of decreased brain metabolism, as well as improvements in local perfusion. Due to this le [Piracetam -

nootropics] can be expected to be of value in the treatment of disease which are related to impairments in the above e above mentioned features, such as several types of senile dementia , (e.g. Primary Degenerative Dementia= zheimer’s type: Multi Infarct [stroke] Demen

stroke] Dementia), ischaemic [poor brain blood flow] insults, hypoxia , anoxia and toxicologically or dietary based encies." (Footnotes in the original text omitted here). he Piracetam -nootropics to partly or completely prevent or reverse the toxic action of a broad array of chemicals

prevent or reverse the toxic action of a broad array of chemicals and conditions has been repeatedly demonstrated. niracetam reverses the memory impairment in rats induced by Clonidine

lonidine, Piracetam, Oxiracetam, Pramiracetam, and Aniracetam all antagonise the normally lethal neuromuscularde induced by Hemicholinium-3 (HC3) in mice. Piracetam, Oxiracetam, and Aniracetam have all attenuated or copalamine (anticholinergic agent)- induced

t)- induced amnesia in rats and mice under a broad range of experimental conditions. sed the typical "spaced out" electroencephalogram (EEG) of healthy humans given Valium , restoring a normal ilance EEG while maintaining Valium 's anti-anxiety effects. Piracetam and Aniracetam have ameliorated the

ated the amnesia produced by the protein synthesis inhibitor Cycloheximide.

tam, Pramiracetam and Aniracetam all attenuate or reverse the amnesia in mice and rats induced by shock treatment (ECS) in both passive and active learning conditions. ting curare-like agent which induces asphyxia, at a dose sufficient to kill 90-100% of the placebo treated controls, two groups of Piracetam treated mice had a 90 and 100% survival rate. put under diverse hypoxic experimental conditions, Pira cetam, Oxiracetam, and Aniracetam have acted to attenuate

Piracetam, Oxiracetam, and Aniracetam have acted to attenuate or reverse the hypoxia-induced amnesia and culties. as well as to speed up recovery time from hypoxia and reduce the time needed to renormalize the EEG iaev and Senning Giurgea and Salama 1977). ainst barbiturate poisoning was reported by Moyersoons and Giurgea in 1974. Rabbits connected to EEG machines either Piracetam or saline injections before intravenous (I.V.) administration of the fast acting barbiturates-(SEC). aline. EEG records showed only minimal abnormalities in the Piracetam rabbits, while the saline rabbits showed ilence, rapidly followed by death. When given only one-half hour before SEC, 7/11 Piracetam rabbits survived versus /1 1 control rabbits.

rol rabbits. -treatment, but still far more normal appearing than the saline control rabbits' EEG's. Piracetam was also given orally iven orally one hour before SEC. 8/9 Piracetam rabbits survived while only 3/9 controls survived. The EEG records of groups were similar to those of the rabbits given Piracetam and saline I.V. one hour before SEC. treated Piracetam against a more slow acting barbiturate Allobarbital (ALB), giving the Piracetam I.V. two minutes e ALB infusion 11/13 Piracetam rabbits survived, while only 2/13 saline control rabbits survived EEG records of the Piracetam rabbits again showed electrical silences to be almost absent, and if present, to be shorter and appear la ter

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are related with an increased arousability of hippocampal pyramid cells, facilitated transmission of the thalamic afferences, increased release of hippocampal acetylcholine and enhanced synaptic transmission.

The clinical biochemistry indicates enhancing functions on the utilization of oxygen and glucose under the conditions of decreased brain metabolism, as well as improvements in local perfusion. Due to this profile [Piracetam -nootropics] can be expected to be of value in the treatment of disease which are related to impairments in the above mentioned features, such as several types of senile dementia , (e.g. Primary Degenerative Dementia= Alzheimer’s type: Multi Infarct [stroke] Dementia), ischaemic [poor brain blood flow] insults, hypoxia, anoxia and toxicologically or dietary based deficiencies." (Footnotes in the original text omitted here).

From the beginning of Piracetam research, the ability of the Piracetam -nootropics to partly or completely prevent or reverse the toxic action of a broad array of chemicals and conditions has been repeatedly demonstrated. Aniracetam reverses the memory impairment in rats induced by Clonidine, Piracetam, Oxiracetam, Pramiracetam, and Aniracetam all antagonise the normally lethal neuromuscular blockade induced by Hemicholinium-3 (HC3) in mice. Piracetam, Oxiracetam, and Aniracetam have all attenuated or reversed the Scopalamine (anticholinergicagent) - induced amnesia in rats and mice under a broad range of experimental conditions.

Oxiracetam has reversed the typical "spaced out" electroencephalogram (EEG) of healthy humans given Valium , restoring a normal vigilance EEG while maintaining Valium's anti-anxiety effects. Piracetam and Aniracetam have ameliorated the amnesia produced by the protein synthesis inhibitor Cycloheximide.

Piracetam, Oxiracetam, Pramiracetam and Aniracetam all attenuate or reverse the amnesia in mice and rats induced by electroconvulsive shock treatment (ECS) in both passive and active learning conditions.

When mice were given Oxydipen+onium, a short acting curare-like agent which induces asphyxia, at a dose sufficient to kill 90-100% of the placebo treated controls, the two groups of Piracetam treated mice had a 90 and 100% survival rate.

When humans, rats, mice and rabbits have been put under diverse hypoxic experimental conditions, Piracetam, Oxiracetam, and Aniracetam have acted to attenuate or reverse the hypoxia -induced amnesia and learning difficulties. as well as to speed up recovery time from hypoxia and reduce the time needed to renormalize the EEG (Gouliaev and Senning Giurgea and Salama 1977).

A classic series of experiments on the protective power of Piracetam against barbiturate poisoning was reported by Moyersoons and Giurgea in 1974. Rabbits connected to EEG machines were given either Piracetam or saline injections before intravenous (I.V.) administration of the fast acting barbiturates-Secobarbital (SEC ).

When Piracetam was given I.V. one hour before SEC, 10/10 rabbits survived versus 3/10 survivors given saline. EEG records showed only minimal abnormalities in the Piracetam rabbits, while the saline rabbits showed massive EEG silence, rapidly followed by death. When given only one-half hour before SEC, 7/11 Piracetam rabbits survived versus 3/1 1 control rabbits.

EEG records of the Piracetam rabbits showed somewhat more abnormalities than those given one hour Piracetam pre-treatment, but still far more normal appearing than the saline control rabbits' EEG's. Piracetam was also given orally one hour before SEC . 8/9 Piracetam rabbits survived while only 3/9 controls survived. The EEG records of both groups were similar to those of the rabbits given Piracetam and saline I.V. one hour before SEC.

The experiments then treated Piracetam against a more slow acting barbiturate Allobarbital (ALB), giving the Piracetam I.V. two minutes after the ALB infusion 11/13 Piracetam rabbits survived, while only 2/13 saline control rabbits survived EEG records of the Piracetam rabbits again showed electrical silences to be almost absent, and if present, to be shorter and appear later than in the control animals.

In the ALB experiment, one of the two surviving control rabbits actually presented a more normal EEG after ALB than did one of the survivors eleven Piracetam survivors..

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Yet an EEG recorded the next morning (about 18 hours later) showed that the control was still asleep, and it was not aroused by a loud noise. The Piracetam rabbit, however, was well awake, behaved normally, moved around, and its EEG was normal.

Thus, whether given I.V. or orally, and before or after general lethal (to controls) barbiturate infusion, Piracetam served to protect both life and brain structure and function, as evidenced by EEG records and post recovery behavior.

The rabbit experiments just described are hardly unusual. The Piracetam -nootropics routinely show an ability to stabilise or normalise the EEG's of humans and animals under a broad range of experimental and medical conditions.

The EEG records the electro-chemical activity of large groups of cortical neurons, and thus provides a "macro" picture of brain activity. Aging, dementia, hypoxia and benzodiazepines all promote a similar shift in EEG frequency patterns.

Low frequency delta waves (0-4 cycles per second) and theta waves (4-8 cps) are increased, while alpha waves (8-12 cps) and beta waves (beta-1; 12 -20 cps, beta 2; 20-32 cps) diminish. The average frequency of the delta and alpha waves also drops, as compared to healthy normal subjects. Nootropics - clinical studies

Giaguinto and colleagues (1986) gave 12 healthy humans 5mg Valium orally at 10PM the night before their experiment. The next morning they were given either I.V. Oxiracetam or saline in a double blind crossover experiment. Oxiracetam strongly decreased the excessive delta activity while simultaneously strongly increasing alpha activity, and also induced a modest increase in beta activity. Thus Oxiracetam restored the EEG to a pattern indicating increased vigilance and alertness, yet without destroying Valium 's anti-anxiety effect.

Itil and co -workers (1986) treated four groups of 15 patients suffering mild to moderate dementia with either Oxiracetam or placebo for three months. The double blind study used Oxiracetam in doses of 800, 1600 and 2400mg daily. Quantitative EEG data indicated that in patients with dementia, Oxiracetam had a mode of action similar to other vigilance enhancing compounds. The majority of patients who had abnormal slow EEG patterns before treatment showed a "normalization" of their brain waves- i.e. a decrease in slow (delta and theta) and an increase in alpha waves. Saletu and colleagues ( 1985) conducted a four week double blind trial of Oxiracetam (2400 mg per day) or placebo in 40 patients (mean age; 80 years) suffering from the "organic brain syndrome of late life." Their results showed a clear trend towards a decrease in delta and theta wave activity, an increase in alpha and beta wave activity, as well as an increase in the dominant frequency and the centroid of alpha activity after Oxiracetam treatment.

Their report noted: "The attenuation of the slow activity and the elevation of the alpha and/or slow wave beta activity after [Oxiracetam - other studies have shown similar results with Piracetam and Aniracetam] reflect CNS changes that are just oppositional to those seen in normally and pathologically aging subjects... The increase in delta and theta activities and decrease in alpha activity in normal and pathological aging are due to deficits in the vigilance regulatory systems which can be counteracted by nootropic drugs." Nootropics - and the healthy

Piracetam -nootropics have also shown the ability to improve learning and memory in healthy individuals not suffering from disease or severe age-related degeneration. In 1976 Dimond and Brouwers reported the results of some of a series of seven double blind trials, involving 16 second and third year college students "in excellent health and good physical and mental condition."

Subjects received either 4.8 grams a day Piracetam or placebo for 14 days. In three different measures of verbal learning and memory, the results showed a highly significant difference in favor of the Piracetam students over the controls, with confidence levels of P=.01, P=.02 and P=.01. The authors stated "the fact is that Piracetam improves verbal learning and in this it would appear to be a substance which is.. capable of extending the intellectual functions of man.. our subjects were not senile, suffering from generalized brain disorder, confusional states, or any other

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pathology of the brain... It is therefore possible to extend the power which [individuals gifted with high intelligence and good memory] possess to still higher levels despite the fact that the range of their achievement is a high."

Giurgea and Salama report the confirmation of Dimond/ Brouwer's work by Wedl and Suchenwirth in 1977. Wedl found significant improvement in mental performance in a group of 17 healthy young volunteers given 3.2 grams per day Piracetam for five days.

Mindus and colleagues (1976) reported the results of a double blind crossover trial with 18 healthy middle aged people (median age 56), with no evidence of somatic or mental disease, based on medical records and administration of several intelligence tests (group mean IQ; 120 plus or minus 11).

Most of the subjects were in intellectually demanding jobs, but had reported a slight reduction for some years in their capacity to retain or recall information.

After four weeks of 4.8 grams per day Piracetam, Piracetam subjects were switched to placebo for four weeks, while the original placebo group then received Piracetam for four weeks.

Results of a series of paper and pencil tests, as well as computerised tests to measure perceptual motor reactions, showed a clear benefit of Piracetam over placebo.

The three different paper and pencil tests showed superior effects on performance compared to placebo, with confidence levels of P<.001, P<.001 and P<.05. In four of the six computerised tests Piracetam showed a significant effect over placebo, with confidence levels of P<.05 for three and P<.029 for the fourth.

A fifth test showed a clear trend in favor of Piracetam, with P<.10. Wilsher and co -workers (1979) related their results with 4.8 grams per day Piracetam in a double blind, crossover trial to study the benefits of Piracetam for dyslexic students.

Interestingly, the 14 healthy student controls, matched for IQ with the dyslexic subjects, demonstrated a significantly better result on a test measuring ability to memorise nonsense syllables while using Piracetam as compared to placebo.

Their improvement from baseline was a 19.5% decrease in the number of trials needed to learn the nonsense syllables while using Piracetam, versus a 10.9% decrease from baseline while using placebo. P<.05. Piracetam-nootropics may increase learning and memory in healthy individuals, where they are not merely attenuating or reversing pathology, through their distinctive power to promote what has been termed "hemispheric super-connection."

The cerebral cortex in humans and animals is divided into two hemispheres- the left and right cortex. In most humans the left hemisphere (which controls the right side of the body) is the language center, as well as the dominant hemisphere. The left cortex will tend to be logical, analytical, linguistic and sequential in its information processing, while the right cortex will usually be intuitive, holistic, picture oriented and simultaneous in its information processing. Research has shown most people favor one hemisphere over the other, with the dominant cortex being more electrically active and the nondominant cortex relatively more electrically silent (when the person is being tested or asked to solve problems, or respond to information). The two cortical hemispheres are linked by a bundle of nerve "cables"; the corpus callosum and the anterior commisure. In theory these two structures should unite the function of the two hemispheres; in practice they act more like a wall separating them. This "functionally -split" neurology produces a parallel set of dichotomies in consciousness; logic vs. intuition; reason vs. emotion; analysis vs. synthesis; parts vs. whole; words vs. pictures; science vs. art and religion, etc. As noted earlier, the word "nootropic" is derived from the Greek word "nous" (the more standard philosophical spelling). Yet in the philosophy of Plato and Aristotle, "nous" did not simply mean "mind." In ancient Greek philosophy, "nous" referred to the faculty of "higher mind" or "reason," as opposed to the more concrete, sensory oriented mind which humans share even with the lower animals. And "reason" did not merely mean logic or analysis.

The Greek philosophers saw the role of philosophy to be a method of developing and perfecting nous/ reason. They understood nous/ reason to be the integrative mind, where logic works complementarily with intuition, and reason

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and emotion are in harmony. With a developed nous, one could clearly see and understand "the forest and the trees" simultaneously. From a modern neurological perspective it is obvious that the cerebral basis for a well-functioning nous would be the effective, complementary, simultaneous integrated function of cortical hemispheres, with neither hemisphere being automatically dominant or silent.

This in turn would require the corpus callosum and anterior commisure to optimise information flow between the two hemispheres. Research has shown the Piracetam-nootropics to facilitate such intercebral information transfer-indeed, it's part of the definition of a "nootropic drug."

Giurgea and Moyersoons reported in 1970 that Piracetam increased by 100% the transcallosal evoked responses elicited in cats by stimulation of one hemisphere and recorded from a symmetrical region of the hemisphere.

Buresova and Bures (1976) in a complex series of experiments involving monocular (one-eye) learning in rats, demonstrated that "...Piracetam enhances transcommisural encoding mechanisms... and some forms interhemispheric transfer..."

Dimond (1976, 1979) used a technique called "dichotic listening" to verify the ability of Piracetam to promote interhemispheric transfer in humans. In a dichotic listening test, different words are transmitted simultaneously into each ear by headphone. In most people the speech center is the left cortex, because the nerves from the ears cross over to the opposite side of the brain, most people will recall more of the words presented right ear than the left ear. Words received by the right ear directly reach the left cortex speech center, while words presented to the left ear must reach the left cortex speech center indirectly, by crossing the corpus callosum. Dimond's experiments with young healthy volunteers showed that Piracetam significantly improved left ear word recall, indicating Piracetam increased interhemispheric information transfer.

Okuyama and Aihara (1988) tested the effect of Aniracetam on the transcallosal response of anaesthetised rats. The transcallosal response was recorded from the surface of the frontal cortex following stimulation of the corresponding site on the opposite cortical hemisphere. Aniracetam at two different I.V. doses (10 mg and 30mg per Kg) significantly increased the amplitude of the negative wave compared to its level prior to drug, P<.01 and P<.001. The researchers stated that "the present results indicate that Aniracetam.. increased the amplitude of the negative wave, thereby facilitating interhemispheric transfer... Thus, it is considered that the functional increase in interhemispheric neurotransmission by nootropic drugs may be related to the improvement of the cognitive function."

In spite of the many and diverse neurological and psychological benefits they have shown in human, animal and cell studies, the Piracetam-nootropics are generally considered NOT to be major agonists or inhibitors of the synaptic action of most neurotransmitters. Thus, major nootropic researchers Pepeu and Spignoli (1990) state; "the pyrrolidinone derivatives [Piracetam-nootropics] show little or no affinity for CNS receptors for dopamine, glutamate, serotonin, GABA or benzodiazepine... So far, little effect of nootropic drugs has been demonstrated on brain monoamine and amino acid neurotransmitters' metabolism and release."

They also note however that "... a number of investigations on the electrophysiological actions of nootropic drugs have been carried out... Taken together, these findings indicate that the nootropic drugs of the [Piracetam-type] enhance neuronal excitability within specific neuronal pathways."

Gouliaev and Senning similarly state "... we think that the racetams exert their effect on some species [of molecule] present in the membrane of all excitable cells, i.e. the ion carriers or ion channels and that they somehow accomplish an increase in the excitatory response... It would therefore seem that the racetams act as potentiators of an already present activity (also causing the increase in glucose utilization observed), rather than possessing any activity of their own, in keeping with their very low toxicity and lack of serious side effects. The result of their action is therefore an increase in general ne sensitivity towards stimulation."

Thus the Piracetam-nootropics would NOT be prone to the (often serious effects of drugs which directly amplify or inhibit neurotransmitter c e.g. MAO inhibitors, Prozac-style "selective serotonin reuptake inhibitors, tricyclic antidepressants, amphetamines, benzodiazepines, etc.

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The notable absence of biochemical, physiological, neurotogical ( chological side effects, even with high dose and/ or long terr nootropic use, is routinely attested to in the vast literature on them. Thus in their 1977 review Giurgea and Salama point out: "Piracetam active in previously described situations, is devoid of usual 're pharmacologic activities even in high doses... In normal subjects.. no side effects or 'doping' effects were ever observed. Nor did Piracetam induce any sedation, tranquillisation. locomotor stimulation or psychodysleptic symptomatology.."

Itil and co-workers.reported in 1983 that "This investigation has confirmed that [Pramiracetam] is a safe and well tolerated compound that can be given in dosages up to 1500 mg without significant side effects. In fact side effects were reported more frequently following both placebo and... phenelzine sulfate [an 'active control' drug] than following any of the four doses evaluated."

After a major 12 week study with 272 Alzheimer and stroke dementia patients, Maina and colleagues (1989) reported; "Thirty five mininor side effects were recorded in 30 patients on [Oxiracetam] and 33 unwanted efl 26 patients on placebo, but none of these was withdrawn from the study... As far as tolerability is concerned, clinical assessments and laboratory evaluations did not reveal any difference between treatment and placebo]."

Moglia and co-workers (1986) concluded from a study of 43 organic syndrome patients that "side effects during [Oxiracetam] treatment headache (3 cases), constipation (1 case), sleep disturbances (1 Side effects during placebo treatment were headache (2 case constipation (1 case). The side effects spontaneously disappears required neither medication nor treatment interruption. No significant [adverse] change in neurological and laboratory ex( lions, ECG and EEG could be detected at the end of treatment, both in the [Oxiracetam] and in the placebo groups." When side effects are occasionally reported in the clinical literature on Piracetam-nootropics. they are usually of a type to suggest slight overstimulation, mainly headaches, agitation, insomnia and irritability. Yet other studies find these same symptoms to be improved by Piracetam-nootropics when these symptoms are pre -existing in the patients. Thus Itil (1986) notes, "...[ Piracetam] showed more improvement than [Oxiracetam] in factors of paranoid delusion and agitation." Maina (1989) noted that "[Oxiracetam] does not act only by increasing arousal and alertness. If this were the case, there would probably be a worsening of the IPSC-E anxiety and tension [scores]. However, in our study there was actually a decrease in anxiety and tension." Branconnier (1983), reporting on his group's study of Pramiracetam in 32 Alzheimer patients noted that after four weeks' treatment, there was a significant decrease in anxiety -tension (P=.004) and hostility (P=.03), and a clean trend over placebo (P=.08) for Pramiracetam to improve existing sleep disturbances.

One potentially limiting factor in obtaining clinical benefit from Piracetam-nootropics has been bought to light through the research of Mondadori (1992) on steroid interactions with nootropics. Mondadori has shown that either deficient or excessive levels of adrenal steroids can block the memory benefits of Piracetam-nootropics in animals. High doses of either corti-costerone or aldosterone abolish the memory enhancing benefits of Piracetam-nootropics, while giving corticosterone or aldosterone to rats with no adrenals restores the positive memory effects of nootropics. Mandadori also notes that cortisol levels are frequently elevated in Alzheimer patients, which might explain the inconsistent results obtained with nootropics in different Alzheimer clinical studies. Nootropics - Synergy.

Since Piracetam-nootropics act (in part) through subtly amplifying neuronal electrical excitability, they will tend to increase the activity of other drugs that modify neural activity taken simultaneously. This in turn may increase both the positive action of the other drug, as well as possibly lead to the occasional nootropic over-stimulation effects. Thus even caffeine may be sufficiently stimulating to bring on the "nootropic over stimulation effect," especially in those very sensitive to caffeine. A key normal regulator of neuronal sensitivity is the essential mineral, Magnesium (Mg). Dietary surveys in the Western world routinely show most people to be at least marginally Mg deficient, with many getting half or less of the recommended dietary Mg intake (Wester 1987).

Thus, the occasional over stimulation seen with Piracetam-nootropics may simply evidence an undetected synaptic Mg deficiency, and Mg supplementation may provide a natural remedy to minimize such over stimulation Piracetam-nootropics have been combined in many clinical and experimental situations with other drugs, almost always with a positive, synergistic effect. Many clinical experiments have demonstrated Piracetam and Oxiracetam to synergise with anti-epileptic medications, especially carbamazepine (Tegretol). A simultaneous enhancement of the

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anti-epileptic drug's anti-seizure activity, combined with improvement or elimination of the memory, alertness and comprehension cognitive deficits induced 1: anti-epileptic drug, have been found in multiple studies (Chaudhry Piracetam combined with Pentoxifylline (a caffeine analogue cerebral flow enhancer) increased both "psycho-intellectual performance measures of cerebral blood flow), significantly more than place either drug alone (Parnetti 1985).

Human and animal studies have shown increased benefit from combining Piracetam with Choline. the raw material for neuronal production of be neurotransmitter Acetylcholine, as well as Phosphatidylcholine, a fluidising component of cell membranes (Ferris 1982). When Piracetam was combined with Hydergine in experiments with mice • both brain survival time and learning/ memory deficits induced poxia, it was noted that "The effect of the combination was greater than the sum of the effects of the individual agents and indicates that synergism had occurred" (Berga 1986). A 1994 report looked at the synergy between Piracetam and intensive speech therapy given to post -stroke aphasic patients; "In general, changes under [Piracetam] were 160% of the changes observed in patients receiving placebo, while getting the same intensive speech therapy" (Di 1994).

Those wishing to get the maximum benefit from Piracetam-nootropics may to include in their regimen nutrientsknown to enhance brain structure function in various ways.

The B-complex vitamins (including NADH), Lipoic Acid, CoQ10 (Idebenone-ed.), Magnesium and Manganese are all essential to brain ATP energy production through the glyolytic and citric acid cycles and the electron transport side chain.

DMAE (Cyprodenate or Lucidril) is an excellent Choline precursor passes the blood brain barrier better than Cholineor Lecithin. Acetyl-L-carnitine (ALC) enhances the activity of the enzyme (Choline Acetyl Transferase (CAT) that combines Acetyl groups with Choline to produce Acetylcholine.

ALC also renews the structure and energy generating power of aging neuronal mitochondria. Phosphatidylserine is a natural neuronal membrane component and stabilizer. Anti-oxidanants, such as vitamins C and E, as well as Pycnogenol or grape seed extract, may protect polyunsaturate fat-rich neuronal and mitochondrial membranes from the damage caused by the inevitable release of large numbers of free radicals, generated through brain mito -chondrial energy production. Nootropics - their differences

Individual differences of action between Piracetam, Oxiracetam, Pramiracetam, and Aniracetam are often subtle, and in many studies they show similar modes of action. One intriguing benefit I have seen reported only for Pramiracetam, is its ability to increase goal directed and purposive behavior (Branconnier 1983). After trying Pramiracetam in my regimen several years ago. I did notice an increase in my tendency to quickly take care of routine household, auto and personal maintenance chores I habitually tended to ignore, avoid or postpone.

I have taken Piracetam for eight years, Pramiracetam and Aniracetam for the past two years and Oxiracetam for about 9 months. During the past year, my lifelong severe writer's block has gradually disappeared, and my writing output of the past year has exceeded that of the previous decade. Some studies on dementia comparing Piracetam and Oxiracetam (the two most nearly identical racetams). have suggested that Oxiracetam may be more effective in restoring the cognitive deficits of dementia (decreased memory, concentration and alertness), while Piracetam may be more effective at normalising the emotional problems of dementia (agitation, tension-anxiety, hostility, insomnia, uncooperativeness).

Quantitatively, Piracetam is the least potent racetam, with clinical doses typically being 2400 mg to 4800 mg per day, occasionally even 6000 mg to I0,000 mg per day.

Oxiracetam is usually given 500 mg to 2400 mg per day. Aniracetam doses are typically 750 mg to 1500mg per day, while Pramiracetam has shown benefit even at 150 mg to 500 mg per day, although 600 mg to 1500 mg per day is more typical.

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Piracetam and Oxiracetam are highly water soluble (96-98%), while Aniracetam and Pramiracetam are more fat soluble. Their lipophilicity may allow for less frequent dosing (once or twice daily) with Aniracetam and Pramiracetam, compared to 3 to 4 doses a day with Piracetam and Oxiracetam.

Aniracetam is favored by the Japanese , who have contributed much research on it. It is widely used there as an agent to rapidly promote clarity of thought. Nootropics - uses and conclusion

During the past 30 years, the Piracetam -nootropics have been used to treat an amazingly broad range of human ailments and conditions, either or with other drugs, with moderate to major benefit. Piracetam-nootropics have been used to treat various forms of dementia and "organic brain syndrome." They have been used successfully to treat dyslexia, epilepsy and age-associated memory impairment. Piracetam-nootropics have successfully treated post-concussional syndrome, vertigo, alcohol withdrawal, cerebrovascular insufficiency and hypoxia . They have shown benefit in normalising blood flow parameter creased platelet aggregation, increased red blood cell (RBC) deformability, decreased adherence of damaged and sickle cell RBC's dothelium (blood cell lining) and increased Prostacyclin (PG12) production and activity.

Yet the most exciting potential benefits of the racetams have yet seriously explored in clinical studies.

The racetams are cerebral homeostatic normalizers, neuroprotectants, cerebral metabolic enhancers and brain integrative agents. They enhance brain energy, especially under deficit condition: hypoxia, chemical toxicity or impaired cerebral microcirculation. They preserve, protect and enhance synaptic membrane and receptor structure and plasticity.

They enhance brain integration- horizontally, by increased coupling of the cerebral hemispheres; and vertically by enhancing cerebral connection with and tonic control of the limbic system, through nootropics effects on the hippocampus - a major link between cerebrum and system.

This vertical integration increase may help to integrate reason (cerebrum and emotion (limbic system- sometimes called the "horse brain"). The increased tonic cortico -subcortical control and regulation me prevent our limbic passions and desires from "running away with us" as in crimes of passion.

In middle aged and older individuals who do not yet suffer any specific neural malady or major mental impairment, nootropics may not only slow down or postpone entropic brain aging, but they may even reverse mild neural/ mental decline. Thus a person at 50 might be smarter, have better memory, quicker reflexes and greater vigilance and alertness than when they were 40. The racetams may literally be safe and effective pharmacologic tools to enhance, protect and optimize truly normal, fully human neuropsychological structures and function, well into old age.

1. P. Berga et al (1986) "Synergistic interactions between Piracetam and [Hydergine] in some aninnal models of cerebral hypoxia and ischaemia" Arzneim Forsch/ Drug Res 36, 1314-20.

2. R.J. Branconnier et al (1983) "The therapeutic efficacy of Pramiracetam in Alzheimer’s disease- preliminary observations" Psychopharmacol Bull 19,726 -30.

3. 0. Buresova, J. Bures "Piracetam induced facilitation of interhemispheric transfer of visual information in rats" Psychopharmacologia (Berlinr) 46,93-102.

4. H.R. Chaudhry et al (1992) "Clinical use of Piracetam in epileptic patients" Curr Ther Res 52, 355 -60.

5. W. Deberdt (1994) "Interaction between psychological and pharmacological treatment in cognitive impairment" Life Sci 55, 2057 -66.

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6. S.J.Dimond (1976) "Drugs to improve learning in man" in the neuropsychology of learning disorders, R. Knight, D. Bakker, eds., 367-79. Univ. Park Baltimore.

7. S.J. Dimond, E. Brouwers (1976) "Increase in the power of human memory in normal man through the use of drugs" Psychopharmacol 49, 307-09.

8. S.J. Dimond et al (1979) "Some effects of Piracetam.. on chronic schizophrenia" Psychopharmacol 64,341 -48.

9. S.H. Ferris et al (1982) "Combination Choline/ Piracetam treatment of senile dementia " Psychopharm Bull 18, 94-98.

10. S. Giaquinto (1986) "EEG changes induced by Oxiracetam on Diazepam-Medicated volunteers" Clin. Neuropharmacol 9, S79-S84.

11. C. Giurgea, F. Moyersoons (1970) "Differential pharmacological reactivity of three types of cortical evoked potentials" Arch Int. Pharmacodyn Ther. 188,401-04.

12. C. Giurgea, M. Salama (1977) "Nootropic drugs" Prog. Neuro-Pharmac. 1.235-47.

13. A. Goutiaev, A. Senning (1994) "Piracetam and other structurally related nootropics" Brian Res. Rev. 19, 180-222.

14. T. Itil et al (1983) "Pramiracetam, a new nootropic, a controlled quantitative pharmaco -EEG study" Psychopharm. Bull. 19, 708-16.

15. T. Itil et al (1986) "CNS pharmacology and clinical therapeutic effects of Oxiracetam" Clin. Neuropharmacol. 9, S70-S72.

16. G. Maina et al (1989) "Oxiracetam in the treatment of p degenerative and multi infarct dementia" Neuropsychobiol. 21. 141

17. P. Mindu et al (1976) "Piracetam induced improvement of n performance" Acta Psychiat. Scanda.

18. A. Moglia et al (1986) "Activity of Oxiracetam in patients with organic brain syndrome" Clin. Neuropharmac 9, S73-S78.

19. C. Mondadori et al (1992) "Elevated corticosteroid levels block the memory improving effects of nootropics" Psychopharmac. 108, 1 1-'

20. F. Moyersoons, C. Giurgea (1974) "Protective effect of Piracetam in experimental barbiturate intoxication: EEG and behavioural studies Arch. Int. Pharmacodyn Ther 210. 38-48.

21. S. Okuyama, H. Aihara (1988) "Action of nootropic drugs on transcollosal responses of rats" Neuropharmac. 27. 67-72.

22. L. Parnetti et al (1985) "Haemorheological pattern in initial mental deterioration; Results of a long term study using Piracetam and Pe fylline" Arch Gerontol. Geriatr4, 141 -55.

23. G. Pepeu. G. Spignoli (1990) "Neurochemical actions of nootropic drugs" in Advances in Neurology V51; Alzheimer’s disease. R. Wu ed. 247-52, Raven Press.

24. B. Saletu et al (1985) "..Oxiracetam in the organic brain syndrome of late life" Neuropsychobiol 13, 44-52.

25. K. Schaffler, W. Klausnitzer (1988) "..Antihypoxidotic effects of Piracetam using psychophsiological measures in

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healthy volunteers" Ar Forsch. Drug Res. 38, 288-91.

26. M. Tacconi, R. Wurtman (1986) "Piracetam, physiological disposition and mechanisms of action" in Advances in Neurology V43; Myocio Fahn, ed. 675-685, Raven Press.

27. P. Wester (1987) "Magnesium" Am. J. Clin. Nutr. 45, 1305-12.

28. C. Wilsher et al (1987) "Piracetam and dyslexia: Effects on reading tests" J. Clin. Psychopharmac. 7, 230-37.

Smart Drugs & Nutrients: Piracetam (Nootropyl)

Piracetam is reported to be an intelligence booster and CNS (central nervous system) stimulant with no known toxicity or addictive properties. Piracetam is inexpensive (under $0.85 per day) and available by mail (see appendix A.) The subjective effect described by some people is that piracetam, "wakes up your brain." You'll find more personal accounts of the effects of this remarkable drug in the case histories and testimonials appendix. It's effects and safety are so impressive that piracetam prompted the creation of a new pharmaceutical category called nootropics.

The term nootropic comes from a Greek word meaning "acting on the mind". Since the invention of piracetam by UCB Laboratories in Belgium, other pharmaceutical companies have been scrambling to develop their own nootropics. Some of them being researched now include; vinpocetine, aniracetam, pramiracetam, and oxiracetam. As yet, there is no nootropic compound that id FDA approved for sale in the US, but there is plenty of motivation on the part of pharmaceutical companies to get that approval. Financial analysts expect that the US market for these cognitive enhancers will soon be in excess of $1-billion per year (Pelton, 1989).

Piracetam is very similar in molecular structure to the amino acid pyroglutamate (see Pyroglutamate). Piracetam and pyroglutamate have the same "base" chemical structure, the 2-oxo-pyrrolidine, but they differ by the side chain. Pyroglutamate is 2-oxo-pyrrolidine carboxylic acid, and piracetam is 2-oxo-pyrrolidine acetamide.

Piracetam enhances cognition under conditions of hypoxia (too little oxygen), and also enhances memory and some kinds of learning in normal humans. Outside of the US, piracetam is used to treat alcoholism, stroke, vertigo, senile dementia , sickle cell anemia , dyslexia, and numerous other health problems (Pelton, 1989).

The effect of piracetam can be increased if taken with DMAE, centrophenoxine, choline, or Hydergine. When choline and piracetam are taken together there is a synergistic effect that causes a greater improvement in memory than the sum of each when taken alone (Bartus, 1981).

We know of one person who claims she feels slightly agitated and depressed if she takes piracetam for more than a week without a choline supplement. This feeling is alleviated for her with a single dose of choline. It may be that the piracetam causes acetylcholine to be used up more quickly and that the choline helps to replace this important neurotransmitter.

Once fascinating study suggests that piracetam might increase the number of cholinergic receptors in the brain. Older mice were given piracetam for two weeks and then the density of muscarinic cholinergic receptors in their frontal cortexes was measured. The researchers found that these older mice had 30-40% higher density of these receptors than before. (Pilch, 1988). Piracetam, unlike many other drugs, appears to have a regenerative effect on the nervous system.

One theory of Alzheimer's disease is that the decline of intellectual functions is partly caused by a decreased activity of the cholinergic system in the brain caused by cell death and cell degeneration. The researchers in the above study

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speculated that their findings could explain how piracetam works and could also explain the finding of Bartus, et. al. regarding a profound effect of combining choline with piracetam on memory enhancement of old rats.

As mentioned previously the late drug researcher Arthur Cherkin related to us that he believed the combination of Hydergine and Piracetam potentiate each other by 5 times. This highlights the importance of adjusting the dosage when multiple substances are taken because, some of these substances will cause paradoxical effects when excessive amounts are taken.

Although piracetam is a derivative of GABA (gamma amino butyric acid, a neurotransmitter), there is no evidence that piracetam works through the GABAergic system. Some research even suggests GABA may even inhibit memory and learning (Zhang, 1989).

Precautions: Piracetam may increase the effects of certain drugs, such as amphetamines, psychotropics, and Hydergine, as stated. Adverse effects are rare but include insomnia, psychomotor agitation, nausea, gastrointestinal distress, and headaches. Piracetam has virtually no known toxicity or contraindications.

Dosage: Piracetam is supplied in 400mg or 800mg capsules or tablets. The usual dose is 2400 to 4800 mg per day in three divided doses. Some literature recommends that the first two days a high "attack" dose should be taken. We have noticed that often when people first take piracetam they do not notice any effect at all until they take a high dose (approximately 4000 to 8000mg). Thereafter, they may notice that a lower dosage is sufficient. Piracetam takes effect within 30 to 60 minutes.

Sources: Piracetam is not sold in the US. It can be purchased over the counter in Mexico or by mail form the sources listed in appendix A.

Other names include: Avigilen, Cerebroforte, Cerebrospan, Cetam, Dinagen, Encefalux, Encetrop, Euvifor, gabacet, Genogris, Memo-Puren, Nootron, Nootrop, Nootropil, Nootropyl, Normabrain, Norzetam, Pirroxil, Psycotron, Stimucortex, and UCB-6215.

Piracetam Abstracts 1133 Piracteam Abstracts in Medline

200ish Aniracetam Abstracts in Medline

142 Oxiracetam Abstracts in Medline

75 Nefiracetam Abstracts in Medline

34 Pramiracetam Abstracts in Medline

Short Term Memory

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Effects of piracetam on the performance of rats in a delayed match-to-position task.

Christoffersen GR, von Linstow Roloff E, Nielsen KS

August Krogh Institute, University of Copenhagen, Denmark.

1. The influence of acute and chronic treatment with piracetam on spatial working memory of rats was examined. A new version of an operant chamber "delayed match-to-position task" was used, in which the animals had to visit one randomly baited box out of three boxes ("choice boxes") in a front panel. Hereafter a delay period began, in which the subjects had to visit an alcove in the back panel ("reference box"). At the end of the delay the animals should return to the front panel and choose the same choice box that was baited before the delay, thereby obtaining a reward. 2. Rats were trained to a stable level of performance, measured as per cent correct responses during sessions of 20 trials. Additionally, the time spent between leaving the choice box and entering the reference box was recorded. Results were obtained from a single group of rats tested repeatedly under different experimental conditions. 3. Injections of scopolamine (0.6 mg/kg) significantly reduced the percentage of correct choices and increased the time spent to reach the reference box. The impairment of correct choices was reversed after chronic treatment with piracetam (250 mg/kg). However, the same treatment did not reverse the effect of scopolamine on the time performance. 4. Scopolamine also induced an increase of repetitive errors (a measure of perseverance), and the chronic treatment with piracetam caused full reversal of this increase. These results represent the first observation of a piracetam induced reversal of scopolamine impairments in a working memory test. 5. In normal animals not treated with scopolamine, acute injection of piracetam had no effect compared to saline injected controls, but chronic treatment with the nootropic significantly enhanced working memory performance. The drug did not affect the time used to reach the reference box.

PMID: 9533177, UI: 98194372

Aniracetam improves radial maze performance in rats.

Martin JR, Cumin R, Aschwanden W, Moreau JL, Jenck F, Haefely WE

Pharma Division, Preclinical Research, F. Hoffman-La Roche Ltd, Basel, Switzerland.

The memory enhancing effect of the pyrrolidinone derivative aniracetam was investigated in rats trained in a delayed-response task in an 8-arm radial maze. Oral administration of aniracetam (100, 200, 400, or 800 mg kg-1) 16 h and again 1 h prior to a first trial of exposure to a given configuration of 4 baited arms resulted in a significant improvement in performance during a second trial in the maze given 3 h later in which there was access to all 8 arms but only the other 4 arms were baited. The pattern of baited arms was varied daily. The performance enhancement was greatest for the highest doses. These results extend the demonstration of the cognition enhancing effects of aniracetam to a spatial memory task in rats.

PMID: 1611039, UI: 92305255

Long Term Memory

Increase in the power of human memory in normal man through the use of drugs

Dimond SJ, Brouwers EM

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Nootropyl (Piracetam) a drug reported to facilitate learning in animals was tested for its effect on man by administering it to normal volunteers. The subjects were given 3x4 capsules at 400 mg per day, in a double blind study. Each subject learned series of words presented as stimuli upon a memory drum. No effects were observed after 7 days but after 14 days verbal learning had significantly increased.

Publication Types:

l Clinical trial l Controlled clinical trial l Randomized controlled trial

PMID: 826948, UI: 77079535

Piracetam-induced improvement of mental performance. A controlled study on normally aging individuals.

Mindus P, Cronholm B, Levander SE, Schalling D

A double-blind, intra-individual cross-over comparison of the mental performance of 18 aging, non-deteriorated individuals during two 4-week periods of piracetam (1-acetamide -2-pyrrolidone) and placebo administration was performed using conventional and computerized perceptual-motor tasks. In a majority of these tasks the subjects did significantly better when on piracetam than on placebo, a finding consistent with ratings completed by two independent observers. The findings indicate new avenues for the treatment of individuals with reduced mental performance possibly related to disturbed alertness--a neglected group of psychiatric conditions.

"

Mindus and colleagues (1976) reported the results of a double blind crossover trial with 18 healthy middle aged people (median age 56), with no evidence of somatic or mental disease, based on medical records and administration of several intelligence tests (group mean IQ; 120 plus or minus 11).

Most of the subjects were in intellectually demanding jobs, but had reported a slight reduction for some years in their capacity to retain or recall information.

After four weeks of 4.8 grams per day Piracetam, Piracetam subjects were switched to placebo for four weeks, while the original placebo group then received Piracetam for four weeks.

Results of a series of paper and pencil tests, as well as computerised tests to measure perceptual motor reactions, showed a clear benefit of Piracetam over placebo.

The three different paper and pencil tests showed superior effects on performance compared to placebo, with confidence levels of P<.001, P<.001 and P<.05. In four of the six computerised tests Piracetam showed a significant effect over placebo, with confidence levels of P<.05 for three and P<.029 for the fourth.

"

Publication Types:

l Clinical trial l Controlled clinical trial

PMID: 785952, UI: 76274634

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Piracetam as an aid to learning in dyslexia. Preliminary report.

Wilsher C, Atkins G, Manfield P

Sixteen male dyslexic children were seen again when adults and matched with 14 student volunteers for a 21-day trial of piracetam. It was found, using a double-blind cross-over technique, that dyslexics significantly increased their verbal learning by 15.0% and students by 8.6% (over and above their placebo increase).

"A fifth test showed a clear trend in favor of Piracetam, with P<.10. Wilsher and co -workers (1979) related their results with 4.8 grams per day Piracetam in a double blind, crossover trial to study the benefits of Piracetam for dyslexic students.

Interestingly, the 14 healthy student controls, matched for IQ with the dyslexic subjects, demonstrated a significantly better result on a test measuring ability to memorise nonsense syllables while using Piracetam as compared to placebo.

Their improvement from baseline was a 19.5% decrease in the number of trials needed to learn the nonsense syllables while using Piracetam, versus a 10.9% decrease from baseline while using placebo. P<.05. Piracetam-nootropics may increase learning and memory in healthy individuals, where they are not merely attenuating or reversing pathology, through their distinctive power to promote what has been termed "hemispheric super-connection.""

Publication Types:


PMID: 116285, UI: 80057408

[Effects of the GABA-derivative piracetam: a double-blind study in healthy probands].

Wedl W, et al. [See Related Articles] Nervenarzt. 1977 Jan;48(1):58-60. German. No abstract available. PMID: 846621; UI: 77147228.

"Giurgea and Salama report the confirmation of Dimond/ Brouwer's work by Wedl and Suchenwirth in 1977. Wedl found significant improvement in mental performance in a group of 17 healthy young volunteers given 3.2 grams per day Piracetam for five days.""

Piracetam inhibits Pavlovian extinction and reversal learning in a spatial task for rats.

Christoffersen GR, Kemp A, Orlygsdottir G

Neuroscience Centre for Cognition and Memory, August Krogh Institute, University of Copenhagen, Denmark.

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[email protected]

Young male rats, trained in a spatial three-choice test, showed improved task acquisition after chronic treatment with piracetam (250 mg kg(-1)). After reaching a learning criterion, one group of animals was observed during Pavlovian extinction of the task skill and another group was assigned to reversal learning. The rate of extinction was slowed down in piracetam treated specimens compared to control animals. During reversal training, a new choice had to be learned while the previously acquired choice was no longer reinforced. Acquisition of the new skill was significantly impeded by piracetam in contrast to acquisition of the first skill, which was facilitated. Also during reversal learning, the piracetam treated group persevered longer than the control group in repeating the first acquired choice at the expense of learning the new choice. It is therefore suggested, that the impediment of reversal learning was caused by inhibition of extinction. In an open-field test, the time spent exploring in motion was increased by piracetam while the velocity of locomotion was unaffected by the drug. In a novelty test, piracetam increased the rate of loss of interactions with the novel object.

PMID: 9707295, UI: 98370792

Piracetam facilitates long-term memory for a passive avoidance task in chicks through a mechanism that requires a brain corticosteroid action.

Loscertales M, Rose SP, Daisley JN, Sandi C

Brain and Behaviour Research Group, The Open University, Milton Keynes, UK.

We investigated the effects of piracetam, a nootropic, on learning and memory formation for a passive avoidance task in day-old chicks. To test for the possible cognitive-enhancing properties of piracetam, a weak learning version of this task --whereby chicks maintain a memory to avoid pecking at a bead coated in a diluted aversant for up to 10 h--was used. Post-training (5, 30 or 60 min), but not pretraining, injections of piracetam (10 or 50 mg/kg, i.p.) increased recall for the task when the chicks were tested 24 h later. Because previous studies showed that long-term memory for the passive avoidance task is dependent upon a brain corticosteroid action, and because the efficacy of piracetam-like compounds is also modulated by corticosteroids, we tested whether the facilitating effect of piracetam was dependent upon a corticosteroid action through specific brain receptors (mineralocorticoid receptor and glucocorticoid receptor). First, increased plasma levels of corticosterone were found 5 min after piracetam injection. In addition, intracerebral administration of antagonists for each receptor type (RU28318, for mineralocorticoid receptors, and RU38486 for glucocorticoid receptors; i.c.) given before the nootropic inhibited the facilitative effect of piracetam on memory consolidation. These results give further support to a modulatory action of piracetam on the mechanisms involved in long-term memory formation through a neural action that, in this learning model, requires the activation of the two types of intracellular corticosteroid receptors.

PMID: 9749752, UI: 98420181

Effect of chronic piracetam on age-related changes of cross-maze exploration in mice.

Salimov R, Salimova N, Shvets L, Shvets N

Institute of Pharmacology, Russian Academy of Medical Sciences, Moscow, Russian Federation.

Normal aging is known to deteriorate memory, spatial orientation, and perceptual recognition. Experiment 1 examined behavioral manifestations of aging by using a cross-maze exploration test in 2-, 6-, and 10-month-old hybrid mice (CBA x C57BL). A decrease in explorative patrolling and an increase in arm reentries, a latency to start and a total time of exploration were found in 10-month-old mice. In Experiment 2, administration of the cognition

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enhancer piracetam (2-oxo-1-pirrolidone acetamide) (400 mg/kg, IP, once a day for 10 days) enhanced arm patrolling and decreased reentries in 10-month-old mice to the level displayed by the 2-month-old animals. The results suggest that the cross -maze test may be useful for a preliminary screening of antisenescent drugs.

PMID: 8545486, UI: 96104182

Learning & Flexibility

[Differences in the effects of piracetam and fenazepam in emotional stress caused by the spatial reversal of a habit].

[Article in Russian]

Inozemtsev AN, Voronina TA, Pragina LL, Krutikova IA, Tushmalova NA

Emotional stress was caused in rats by changing the location of the gate in the shuttle chamber through which training had been accomplished in the previous experiments. The procedure led to disorder of the avoidance response (AR) and increase of intertrial responses (ITR). Phenazepam (0.1 mg/kg) prevented increase in the number of ITS. Piracetam (300 mg/kg) reduced the sharp growth of ISR but, in contrast to phenazepam, it provided a higher level of AR reproduction. The ISR were greater in piracetam than in phenazepam administration. The obtained results show that the suggested model allows the difference in the effects of piracetam and phenazepam to be disclosed.

PMID: 9181869, UI: 97262764

Acute reorganization of the forepaw representation in the rat SI cortex after focal cortical injury: neuroprotective effects of piracetam treatment.

Coq JO, Xerri C

Laboratoire de Neurobiologie des Restaurations Fonctionnelles, Universite de Provence/CNRS, UMR 6562, Neurosciences Integratives et Adaptatives, 52 Faculte des Sciences St Jerome, Marseille, France.

Immediate postlesion reorganization of the somatosensory cortical representation was examined in adult rats. Response properties of small clusters of neurons were recorded in the area of the primary somatosensory cortex (SI) devoted to the contralateral forepaw representation. Electrophysiological maps were elaborated on the basis of the sensory 'submodality' (cutaneous or noncutaneous) and the location of the peripheral receptive fields (RFs) of layer IV neurons. Recordings were made prior to, and from 1 to 12 h after, induction of a focal neurovascular lesion to the SI cortex that initially destroyed a part (8.5%) of the cutaneous representation. Moreover, the influence of an anti-ischaemic substance (piracetam) on lesion -induced changes was analysed. The main observations were: (i) a gradual outward expansion of the area of the functional lesion, which was smaller in the piracetam-treated (PT) rats than in the control, placebo-treated (PL) rats; (ii) a substantial remodelling of the spared representational zones, both in cortical sectors adjoining the site of injury and those remote from the site; (iii) a significant postlesion increase in the size of cutaneous RFs in the PT rats, but not in the PL rats; (iv) a better preservation of RF submodality and topographic organization in the PT maps than in the PL maps; and (v) a decrease in neuronal responsiveness to cutaneous stimulation which was less pronounced in the PT than in the PL rats. Our results can be ascribed to a rapid change in the balance of excitatory and inhibitory connections which leads to unmasking of subthreshold inputs converging onto cortical neurons. Our findings also indicate that acute piracetam treatment exerts a protective function on the physiological response properties of cortical neurons after focal injury.

PMID: 10457159, UI: 99388258

[Pharmacological correction of central nervous system function in exposure to Coriolis acceleration].

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Karkishchenko NN, Dimitriadi NA, Molchanovskii VV

Healthy volunteers with a low vestibular tolerance were exposed to Coriolis acceleration. Potassium orotate, pyracetame and riboxine were used as prophylactic measures against disorders in the function of the vestibular apparatus and higher compartments of the higher nervous system. The central nervous function was assessed with respect to the spectral power of electroencephalograms, short-term memory and mental performance. Potassium orotate given at a dose of 40 mg/kg body weight/day during 12-14 days as well as pyracetame given at a dose of 30 mg/kg body weight/day during 3 or 7 days increased significantly statokinetic tolerance and produced a protective effect on the central nervous function against Coriolis acceleration.

PMID: 3784525, UI: 87062395

Choice Behavior

Effects of piracetam on indices of cognitive function in a delayed alternation task in young and aged rats.

Roux S, Hubert I, Lenegre A, Milinkevitch D, Porsolt RD

I.T.E.M.-LABO, Le Kremlin-Bicetre, France.

The effects of piracetam (64, 128, and 256 mg/kg PO) on the performance of a delayed alternation in a Skinner Box were investigated. Test sessions consisted of 36 trials during which animals were first presented with a single lever (left or right) followed 5, 10, or 20 s later by two levers. A press on the lever opposite to that presented previously (nonmatching to sample) was rewarded. The number of correct responses and the reaction times to the one- and two-lever presentations were recorded. All animals received all treatments in a balanced order. Aged animals showed clear deficits on all three parameters. Piracetam was without effect on the performance of young animals but dose -dependently decreased the choice reaction times (two levers) in aged animals without affecting the other two parameters. These results suggest that piracetam does not affect short-term memory but may facilitate choice behavior in aged animals.

PMID: 7862724, UI: 95166867

Dyslexia

Depression

Hypertension

[Effects of piracetam on occupationally significant functions of patients with arterial hypertension working under conditions of psychoemotional stress].


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Dasaeva LA

The study covered influence of Piracetam on occupationally important functions of memory and attention in hypertensive patients exposed to psychoemotional stress at work. The medicine appeared to improve psychic state, mental performance and the occupationally important function of memory, causing no effects on the attention. Besides hypotensive effect the medicine resulted in better clinical and physiologic parameters and increased physical performance.

PMID: 8646455, UI: 96229731

[The treatment with antihypertensive and nootropic preparations of hypertension patients working under neuroemotional stress].


Dasaeva LA, Vertel' AE

The authors' aim was to develop schemes of hypertension stage I-II treatment in subjects exposed to nervous and emotional stress at their jobs. These patients benefited from ambulatory monotherapy with obsidan or piracetam (improvement in psychic status, mental and muscular performance, in memory and attention). Reserpin worsened the patients' activity, mental performance and cognitive functions. Combination of piracetam plus reserpin promoted positive changes in psychic status, mental performance and amnestic function in stage IB-II hypertension. This combination is thought effective for inpatient treatment of hypertensive subjects exposed to psychoemotional stress.

Publication Types:

l Clinical trial l Randomized controlled trial

PMID: 9054044, UI: 97176314

[Pharmacological correction of behavioral and memory disorders in rats with vasorenal arterial hypertension given propranolol].


Petrov VI, Grigorev IA, Gorbunov SG

It was established that propranolol in a daily dose of 2 mg/kg causes disturbance of behavior of rats with arterial hypertension in the open field, deteriorates retention of memory traces in passive avoidance paradigm, and leads to the development of depression in the test for zoosocial interrelation. Administration of nootropic piracetam (200 kg/mg/24 h). as well as the original compounds ACP-94 (20 mg/kg/24 h) and PIR-87--6-0 (50-mg/kg/24 h) facilitates the correction of negative changes in the behavior and memory of hypertensive rats.

PMID: 9324403, UI: 97381198

Breath Holding Spells

Clinical efficacy of piracetam in treatment of breath-holding spells.

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Donma MM

Ministry of Health, Bakirkoy State Hospital, Clinics of Paediatrics, Istanbul, Turkey.

To evaluate the efficacy of piracetam therapy, 76 children with breath-holding spells admitted to the Outpatient Clinic of Dicle University Medical Faculty Paediatrics Department and Bakirkoy State Hospital, Paediatrics Department between 1988 and 1990 and 1991 and 1996, respectively, were included in this placebo-controlled trial. Diagnosis of breath-holding spells was made for all cases by medical history, pediatric physical examination, electroencephalogram, and laboratory findings. Placebo or piracetam as suspension was administered to patients on a randomized basis; piracetam was administered to children in suspension 40 mg/kg/day in 2 divided doses for a period of 2 months. Of the 76 children enrolled, 39 received piracetam and 37 received placebo. Overall, control of breath-holding spells was observed in 92.3% of the patients in the group taking piracetam as compared with 29.7% in the group taking placebo (P < .05). No differences between the 2 groups in adverse events or side effects were observed. Complete blood count, biochemical profile, and urine analysis taken before and after treatment revealed no change from beginning to end and no difference between the 2 groups. It is suggested that piracetam is a safe and effective drug, with an incidence of side effects no different from that of placebo, for the treatment of breath-holding spells.

Publication Types:


PMID: 9492090, UI: 98151054

Misc Neuroprotection

Comparative Analysis of Neuroprotective Activity of New Chemical Agent Vp and Piracetam.

Burov YV, Uzdenskii AB, Robakidze TN

Research Center for Safety of Bioactive Compounds, Staraya Kupavna, Moscow Region.

[Record supplied by publisher]

The effect of new agent Vp (9-butylamine-3,3-dimethyl-3,4-dihydroacridine-1(2H) hydrochloride) on lifetime of isolated mechanoreceptive crayfish neurons was evaluated by the duration of its impulse activity. Vp significantly and dose-dependently prolonged the lifetime of both spontaneously degrading neurons and neurons degrading under conditions of inhibition of various stages of the energy metabolism: glycolysis and oxidative phosphorylation. The effect of Vp in a concentration of 10(-7) M surpassed that of amiridine. Piracetam also prolonged the lifetime of spontaneously degrading neurons, but only in very high concentration (10(-2) M). It is concluded that Vp possesses a neuroprotective activity.

PMID: 10977921

Other Formats:

J Ethnopharmacol 2000 Sep 1;72(1 -2):119-128

[The effect of nootropic agents on brain mitochondrial function in the dynamics of

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craniocerebral trauma from the age aspect].


Novikov VE, Kovaleva LA

Smolensk Medical Academy, Russia.

A craniocerebral trauma was modelled in experiments on one-month-old rats. Oxidative phosphorylation in the brain mitochondria was studied by polarography 1, 4, 7 days and 4 weeks after the trauma. In the posttraumatic period the animals received piracetam (1 g/kg), picamilon (500 mg/kg), pyriditol (100 mg/kg), pantogam (160 mg/kg), ACTH (5-10) (0.1 mg/kg), nooglutyl (25 mg/kg), and GVS (0.5 mg/kg). It was found that piracetam, picamilon, and nooglutyl have a protective effect on the function of the brain mitochondria during the course of a craniocerebral trauma. Nooglutyl surpasses all the other drugs in its influence on the effectiveness of oxidative phosphorylation of mitochondria in immature rats in the posttraumatic period.

PMID: 9621180, UI: 98284200

Trauma

[Piracetam in severe cranio-cerebral injuries].

[Article in Polish]

Goscinski I, Sliwonik S, Sondej T, Kwiatkowski S, Moskala M, Cichonski J, Wegrzyn D, Uhl H

Kliniki Neurotraumatologii Instytutu Neurologii Collegium Medicum UJ.

A group of 100 patients treated immediately following a cranio -cerebral injury was analyzed. The patients, administered piracetam either in an intravenous infusion (GCS 3-8) or orally (GCS above 9), were divided into groups depending on the dose and clinical status. Piracetam participates in the activity of the majority of neurotransmitters, increases glucose and oxygen consumption in the ischaemic nervous tissue and increases blood flow through cerebral terminal vessels. In cranio-cerebral injuries, piracetam is employed to achieve cytoprotection and improve cerebral blood flow. In patients with neurological deterioration following the administration of 6-10 mg/day, no good results were obtained. A dose of 24-30 mg/day had a significant positive effect on therapeutic results providing certain conditions were met, such as ensuring proper partial oxygen pressure (oxygen therapy) and proper blood glucose levels. The use of piracetam is justified immediately after an injury; after the discharge oral piracetam therapy is recommended.

Publication Types:

l Clinical trial

PMID: 10463232, UI: 99392528

Alcohol

Effects of red ginseng saponins and nootropic drugs on impaired acquisition of ethanol-treated rats in passive avoidance performance.

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Lee SC, Moon YS, You KH

College of Pharmacy, Chungnam National University, Taejon, South Korea. [email protected]

Effects of single and repeated administration of red ginseng total saponins (ROTS) and nootropic drugs were examined on impairment of acquisition induced by single oral administration of 3 g/kg ethanol (EtOH) in a step through test. The inhibitory effect of EtOH on acquisition was significantly reduced following single or repeated RGTS administration. The nootropic drugs, piracetam and N -methyl-D-glucamine, given orally significantly reduced impairment of acquisition induced by EtOH. On the other hand, the inhibitory effect of repeated RGTS on the EtOH-induced amnesia was blocked by the pretreatment of alpha-methyl-p-tyrosine (alpha-MT), an inhibitor of catecholamine synthesis, in a dose-dependent manner but not p-chlorophenylalanine (PCPA), an inhibitor of serotonin synthesis, whereas the inhibitory effect of repeated N -methyl-D-glucamine on the EtOH-induced amnesia was blocked neither by alpha-MT nor PCPA. These results suggest that repeated RGTS and N-methyl-D-glucamine ameliorate the impairing effect of EtOH on acquisition, and the effect of RGTS on EtOH-induced amnesia is dependent on the catecholaminergic but not serotonergic neuronal activity, while RGTS and N-methyl-D-glucamine seem to have a different mechanism on EtOH-induced amnesia.

PMID: 10661877, UI: 20125519

GM1 and piracetam do not revert the alcohol-induced depletion of cholinergic fibers in the hippocampal formation of the rat.

Brandao F, Ribeiro-da-Silva A, Cadete-Leite A

Department of Anatomy, Porto Medical School, Alameda do Prof. Hernani Monteiro, Portugal.

Chronic alcohol consumption causes a depletion of the cholinergic fiber network in the rat hippocampal formation, which is not ameliorated by alcohol withdrawal. Following withdrawal from alcohol, there is a further loss of intrinsic hippocampal cholinergic neurons. In this study, we investigated whether treatment with putative neuroprotective agents during the entire withdrawal period would have beneficial effects upon the hippocampal cholinergic innervation. Adult male rats were alcohol-fed for 6 months and subsequently withdrawn from alcohol for 6 months. Some animals were treated with either ganglioside GM1 (35 mg/kg body weight s.c.), vehicle (saline s.c.), or piracetam (800 mg/kg body weight p.o.) for the entire withdrawal period. Choline acetyltransferase (ChAT) immunoreactive (IR) fibers and neurons were analyzed quantitatively in all four animal groups. There were no significant differences in the density of the ChAT-IR hippocampal fiber network when the pure withdrawal and withdrawal + vehicle groups were compared to the withdrawal + GM1 or withdrawal + piracetam groups. In contrast, the number of ChAT-IR interneurons in the hippocampal formation was higher in the withdrawal + GM1 or withdrawal + piracetam groups than in the pure withdrawal and withdrawal + vehicle groups. These results indicate that, in the doses used, neither neuroprotective agent had an effect upon the extrinsic cholinergic innervation, but they had a beneficial effect upon the hippocampal intrinsic cholinergic system.

PMID: 10487390, UI: 99415331

Piracetam impedes hippocampal neuronal loss during withdrawal after chronic alcohol intake.

Brandao F, Paula -Barbosa MM, Cadete -Leite A

Department of Anatomy, Porto Medical School, Portugal.

In previous studies we have demonstrated that prolonged ethanol consumption induced hippocampal neuronal loss.

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In addition, we have shown that withdrawal after chronic alcohol intake augmented such degenerative activity leading to increased neuronal death in all subregions of the hippocampal formation but in the CA3 field. In an attempt to reverse this situation, we tested, during the withdrawal period, the effects of piracetam (2-oxo-1-pyrrolidine acetamide), a cyclic derivative of gamma -aminobutyric acid, as there is previous evidence that it might act as a neuronoprotective agent. The total number of dentate granule, hilar, and CA3 and CA1 pyramidal cells of the hippocampal formation were estimated using unbiased stereological methods. We found out that in animals treated with piracetam the numbers of dentate granule, hilar, and CA1 pyramidal cells were significantly higher than in pure withdrawn animals, and did not differ from those of alcohol-treated rats that did not undergo withdrawal. These data suggest that piracetam treatment impedes, during withdrawal, the pursuing of neuronal degeneration.

PMID: 7639963, UI: 95367208

[The efficacy of Piracetam on the mental functional capacity of chronic alcoholics].

[Article in German]

Binder S, Doddabela P

Piracetam, 1-pyrrolidone acetamid, was tested in 40 chronic alcoholics with a more or less marked psycho-organic syndrome by means of psychological tests. It was a double-blind-cross-over study. Statistical analysis of the results showed that Piracetam improves the energo-functional capacity of the cortex i.e. the basal functions of the cortical cells such as activating capacity, vital dynamic, flexibility, intellectual reactivity and stress tolerance. Apart from the overall improvement we also observed an improvement of specific cerebral performances which is however unimportant in comparison with the greneralized effect.

Publication Types:


PMID: 775275, UI: 76195721

Vertigo

The effectiveness of piracetam in vertigo.

Oosterveld WJ

Department of Otorhinolaryngology, University of Amsterdam, The Netherlands.

Vertigo is a sensation of altered orientation in space and may be defined as an illusion of movement. It is a subjective symptom and therefore difficult to assess. Examination and diagnosis remain difficult. Although treatment should be directed at the underlying cause or disorder, the origin of vertigo is frequently unknown or untreatable. Pharmacotherapy is required for symptomatic treatment. Piracetam has been shown to be effective in vertigo of both central and peripheral origin. It is thought to act on vestibular and oculomotor nuclei in the brain stem and thus on the central control of balance enhancing mechanisms of compensation and habituation. This review of double-blind trials shows that piracetam alleviates vertigo after head injury, vertigo of central origin as, for example, in vertebrobasilar insufficiency and in peripheral vestibular disorders, especially in middle-aged and elderly subjects. Piracetam decreases the frequency but probably not the severity of exacerbations in patients with chronic or

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recurrent vertigo. The usual dosage of piracetam in vertigo is 2.4-4.8 g daily. Tolerability of piracetam is good and adverse effects have been mild and infrequent.

Publication Types:

l Review l Review literature

PMID: 10338110, UI: 99268432

[The effect of pharmacological treatment in the compensation of vertigo].

[Article in Spanish]

Pons Rocher F

Servicio de O.R.L. Hospital Dr. Peset-S.V.S. Valencia.

From the age of sixty, vertigo is mainly due to vertebro-basilar insufficiency. It has been described that the association of Dihydroergocristine-Piracetam (D-P) is a useful treatment for vertebro -basilar insufficiency. That is why we have designed a comparative study between D-P an a Placebo, so that to prove if this association can be usefull in the treatment of vertigo occasioned by cerebrovascular insufficiency. Fifty patients complaining of vertigo were included in the study after an untreated term. 19 received a daily capsule of Placebo, and the other 31, treated with D-P, were divided in two groups: 16 patients received a dose of 3 mg Dihydroergocristine + 1.6 g Piracetam every 12 hours per os; and 15 other were treated with 1.5 mg Dihydroergocristine + 0.8 g Piracetam every 8 hours during 90 days. The patients were evaluated at the beginning of the study and 90 days later, with anamnesis and vestibular tests. In the last consultation the patients autoevaluated themselves the effect and the tolerance to the drugs received. In the Placebo group it was observed an improvement or disappearance of vertiginous symptoms in the 68.5% of the cases, while with D-P was 93.7% at the dose of 3 mg Dihydroergocristine + 1.6 g Piracetam each 12 hours and 100% with the dose 1.5 mg Dihydroergocristine + 0.8 g Piracetam each 8 hours. None of the treated patients with D-P worsened their symptoms. We observe a considerable decrease in the number of patients with vegetative symptoms in the group treated with D -P related to the Placebo group, though the symptoms persisted more time in the group treated with D-P that in the Placebo group. The group treated with D-P get a higher percentage of improvements and disappearance of auditive and cervical symptoms that the groups treated with Placebo. In the vestibulo -spinal and cerebellous tests it was observed a better improvement with D -P at the dose of 1.5 mg of Dihydroergocristine + 0.8 g Piracetam each hours compared with the other two groups. It can be concluded that the association D-P is an effective treatment for vertigo, getting also a higher normalization of the vestibular tests than Placebo.

Publication Types:

l Clinical trial

PMID: 10394686, UI: 99322990

Stroke

Piracetam improves activated blood flow and facilitates rehabilitation of poststroke aphasic patients.

Kessler J, Thiel A, Karbe H, Heiss WD

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Max-Planck -Institute for Neurological Research, Cologne, Germany. [email protected]

BACKGROUND AND PURPOSE: In a prospective, double-blind, placebo-controlled study, it was investigated whether piracetam improves language recovery in poststroke aphasia assessed by neuropsychological tests and activation PET measurement of cerebral blood flow. METHODS: Twenty-four stroke patients with aphasia were randomly allocated to 2 groups: 12 patients received 2400 mg piracetam twice daily, 12 placebo. Before and at the end of the 6-week treatment period in which both groups received intensive speech therapy, the patients were examined neuropsychologically and studied with H(2)(15)O PET at rest and during activation with a word -repetition task. Blood flow was analyzed in 14 language-activated brain regions defined on reconstructed surface views from MRI coregistered to the PET images. RESULTS: Before treatment, both groups were comparable with respect to performance in language tasks and to type and severity of aphasia. In the piracetam group, increase of activation effect was significantly higher (P:<0.05) in the left transverse temporal gyrus, left triangular part of inferior frontal gyrus, and left posterior superior temporal gyrus after the treatment period compared with the initial measures. The placebo group showed an increase of activation effect only in the left vocalization area. In the test battery, the piracetam group improved in 6 language functions, the placebo group only in 3 subtests. CONCLUSIONS: Piracetam as an adjuvant to speech therapy improves recovery of various language functions, and this effect is accompanied by a significant increase of task -related flow activation in eloquent areas of the left hemisphere.

Publication Types:


PMID: 10978039, UI: 20433490

Other Formats:

Bull Exp Biol Med 2000 Apr 1;129(4):430 -433

Anti-Hypoxia

Metabolic features of the adaptive effect of delta-sleep inducing peptide and piracetam under hyperoxic conditions.

Lysenko AV, Alperovich DV, Uskova NI, Mendzheritsky AM

Neurocybernetics Institute, Rostov State University, Rostov-on-Don, 344090, Russia. [email protected].

Adaptive effects of delta-sleep inducing peptide (DSIP, 12 microgram/100 g body weight, single intraperitoneal injection) and piracetam (3 mg/100 g body weight, daily intraperitoneal injection for 3 days) are manifested via differential changes in neurotransmitter amino acids (GABA, glutamate, aspartate), modulation of transport ATPase activity, and decreased accumulation of lipid peroxidation products (conjugated dienes, malonic dialdehyde, Schiff bases) in various fractions of neuronal membranes (myelin, synaptic and mitochondrial membranes) in the sensomotor cortex of rat brain. Under hyperbaric oxygenation (0.3 MPa for 2 h), the combination of DSIP and piracetam enhanced the protective effect of each compound.

PMID: 10395980, UI: 99327177

Anti-Amnesia

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Effects of piracetam on the performance of rats in a delayed match-to-position task.

Christoffersen GR, von Linstow Roloff E, Nielsen KS

August Krogh Institute, University of Copenhagen, Denmark.

1. The influence of acute and chronic treatment with piracetam on spatial working memory of rats was examined. A new version of an operant chamber "delayed match-to-position task" was used, in which the animals had to visit one randomly baited box out of three boxes ("choice boxes") in a front panel. Hereafter a delay period began, in which the subjects had to visit an alcove in the back panel ("reference box"). At the end of the delay the animals should return to the front panel and choose the same choice box that was baited before the delay, thereby obtaining a reward. 2. Rats were trained to a stable level of performance, measured as per cent correct responses during sessions of 20 trials. Additionally, the time spent between leaving the choice box and entering the reference box was recorded. Results were obtained from a single group of rats tested repeatedly under different experimental conditions. 3. Injections of scopolamine (0.6 mg/kg) significantly reduced the percentage of correct choices and increased the time spent to reach the reference box. The impairment of correct choices was reversed after chronic treatment with piracetam (250 mg/kg). However, the same treatment did not reverse the effect of scopolamine on the time performance. 4. Scopolamine also induced an increase of repetitive errors (a measure of perseverance), and the chronic treatment with piracetam caused full reversal of this increase. These results represent the first observation of a piracetam induced reversal of scopolamine impairments in a working memory test. 5. In normal animals not treated with scopolamine, acute injection of piracetam had no effect compared to saline injected controls, but chronic treatment with the nootropic significantly enhanced working memory performance. The drug did not affect the time used to reach the reference box.

PMID: 9533177, UI: 98194372

Anti-Oxidant

Brain Metabolism & Blood Flow

Piracetam improves activated blood flow and facilitates rehabilitation of poststroke aphasic patients.

Kessler J, Thiel A, Karbe H, Heiss WD

Max-Planck -Institute for Neurological Research, Cologne, Germany. [email protected]

BACKGROUND AND PURPOSE: In a prospective, double-blind, placebo-controlled study, it was investigated whether piracetam improves language recovery in poststroke aphasia assessed by neuropsychological tests and activation PET measurement of cerebral blood flow. METHODS: Twenty-four stroke patients with aphasia were randomly allocated to 2 groups: 12 patients received 2400 mg piracetam twice daily, 12 placebo. Before and at the end of the 6-week treatment period in which both groups received intensive speech therapy, the patients were examined neuropsychologically and studied with H(2)(15)O PET at rest and during activation with a word -repetition task. Blood flow was analyzed in 14 language-activated brain regions defined on reconstructed surface views from MRI coregistered to the PET images. RESULTS: Before treatment, both groups were comparable with respect to performance in language tasks and to type and severity of aphasia. In the piracetam group, increase of activation effect was significantly higher (P:<0.05) in the left transverse temporal gyrus, left triangular part of inferior frontal gyrus, and left posterior superior temporal gyrus after the treatment period compared with the initial measures. The placebo group showed an increase of activation effect only in the left vocalization area. In the test battery, the piracetam group improved in 6 language functions, the placebo group only in 3 subtests. CONCLUSIONS: Piracetam as an adjuvant to speech therapy improves recovery of various language functions, and

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this effect is accompanied by a significant increase of task -related flow activation in eloquent areas of the left hemisphere.

Publication Types:


PMID: 10978039, UI: 20433490

Other Formats:

Bull Exp Biol Med 2000 Apr 1;129(4):430 -433

Misc Mechanisms of Action

Piracetam improves cognitive performance by restoring neurochemical deficits of the aged rat brain.

Scheuer K, Rostock A, Bartsch R, Muller WE

Department of Psychopharmacology, Central Institute of Mental Health Mannheim, Germany.

In order to test the hypothesis that piracetam improves cognitive functions by restoring biochemical deficits of the aging brain, we investigated the effects of piracetam treatment (300 mg/kg daily for 6 weeks) on the active avoidance performance of young and aged rats. After testing, the rats were killed and membrane fluidity and NMDA as well muscarinic cholinergic receptor densities were determined in the frontal cortex, the hippocampus, the striatum, as well as the cerebellum. Piracetam treatment improved active avoidance learning in the aged rats only and elevated membrane fluidity in all brain regions except the cerebellum in the aged animals. Moreover, we observed a positive effect of piracetam treatment on NMDA receptor density in the hippocampus and on muscarinic cholinergic receptor densities in the frontal cortex and the striatum and to a lesser extent in the hippocampus. Again, these effects were only observed in aged animals. Discrimination analysis indicated that piracetam effects on membrane fluidity in the frontal cortex, the hippocampus, and the striatum and its effects on NMDA densities in the hippocampus might be involved in its positive effects on cognitive performance.

PMID: 10338103, UI: 99268425

MAO effects

Biull Eksp Biol Med 1992 Feb;113(2):149 -50

[Effects of amiridin and tacrine, drugs effective in Alzheimer's disease, on the activity of monoamine oxidase A and B].


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Burov IuV, Baimanov TD, Tat'ianenko LV, Sokolova NM, Tereshchenkova IM

In vitro comparative studies of effects of amiridin (9-amino-2, 3, 5, 6, 7, 8-hexahydro-1H-cyclopentane (b) choline monohydrate hydrochloride) and tacrine physostigmine and piracetam on monoamine oxidase A (MAO-A) and B (MAO-B) activity in the rat brain were carried out. Piracetam (1 x 10(-4)-1 x 10(-3) M) dose -dependently increased MAO-A and MAO-B activity. At all concentrations used (1 x 10(-7)-5 x 10(-4) M) physostigmine had no effect on MAO-A and MAO-B activity. Amiridin was found to inhibit MAO-B activity at 5 x 10(-4) M concentration only. Tacrine inhibited MAO-A activity at 5 x 10(-4) M concentration. The therapeutical effects of amiridin and tacrine in treatment of Alzheimer disease were not related to their action on MAO-A and -B activity.

PMID: 1611059, UI: 92305284

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Chung Kuo Yao Li Hsueh Pao 1992 Jan;13(1):48-50

[Effects of piracetam on Na(+)-K(+)-ATPase and monoamine oxidase in rat brain and its antioxidation effect].

[Article in Chinese]

Qian ZN, Gu ZL, Jin LQ, Xie ML, Chen BQ

Department of Pharmacology, Suzhou Medical College, China.

Piracetam, ig 600 mg.kg-1.d-1 for 30 d, caused a 20% decrease in the activity of Na(+)-K(+)-ATPase and monoamine oxidase (MAO) in vivo. In vitro, it presented an inhibitory effect on MAO, but had no direct effect on Na(+)-K(+)-ATPase at a concentration of 100 mmol.L -1. Piracetam had a potential action in scavenging free radicals. This action may be related to its clinical effects on amnesia and Alzheimer's disease.

PMID: 1318632, UI: 92295874


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Farmakol Toksikol 1988 May-Jun;51(3):16-8

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[Effect of centrophenoxine, piracetam and aniracetam on the monoamine oxidase activity in different brain structures of rats].


Stancheva SL, Alova LG

In vitro studies of effects of some nootropic drugs (centrophenoxine, piracetam and aniracetam) on monoamine oxidase (MAO) activity in the rat striatum and hypothalamus, using tyramine, serotonin and beta-phenylethylamine as substrates, were carried out. At all concentrations used (5.10(-5)-1.10(-3) M) centrophenoxine inhibited total MAO, MAO A and MAO B in both brain structures. Piracetam activated striatal and hypothalamic total MAO, hypothalamic MAO A and MAO B but exerted a pronounced inhibitory effect on MAO A and MAO B activity in the striatum. Aniracetam inhibited total MAO and MAO A in both brain structures but activated striatal and hypothalamic MAO B. The different effects of centrophenoxine, piracetam and aniracetam on MAO activity in the brain structures support the view for the independent mode of action of nootropic drugs in spite of their similar molecular and metabolic activity.

PMID: 3137089, UI: 88312947

Safety

The clinical safety of high-dose piracetam--its use in the treatment of acute stroke.

De Reuck J, Van Vleymen B

Department of Neurology, University Hospital, Ghent, Belgium.

Recent post-marketing surveillance reports have confirmed the benign safety profile and lack of organ toxicity shown by piracetam during its 25 years of clinical usage. Tolerance has proved equally good with the more recent use of larger doses (up to 24 g/day) for the long -term control of cortical myoclonus and when given intravenously to patients with acute stroke. This paper provides a brief review of these findings and records the safety of piracetam as found in the Piracetam in Acute Stroke Study (PASS), a randomized multicenter placebo-controlled study in 927 patients with acute ischemic stroke. Patients receive one intravenous bolus injection of placebo or 12 g piracetam, piracetam 12 g daily for 4 weeks and maintenance treatment for 8 weeks. The major results have been reported (De Deyn et al., Stroke 28 [1997] 2347-2352). Safety was assessed taking into account adverse events including abnormal laboratory test results and mortality. Death within 12 weeks occurred more frequently in the piracetam group but the difference from placebo was not significant. Of many potential risk, prognostic and treatment-related factors examined by logistic regression, 6 contributed significantly to death of which the most important were initial severity of stroke and age. Neither treatment nor any treatment-related factor contributed significantly to death. Adverse events were similar in frequency, type and severity in piracetam and placebo groups. Events of cerebral, non-cerebral and uncertain origin likewise occurred with similar frequency. Few patients discontinued because of adverse events. There was no difference between treatments in the frequency of events associated with bleeding, including hemorrhagic transformation of infarction. An important finding was that, of 31 patients with primary hemorrhagic stroke enrolled, 3 piracetam-treated patients died compared with 6 on placebo. The results suggest that piracetam in high dosage may be given to patients with acute stroke without significant adverse effects.

Publication Types:

l Clinical trial

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l Randomized controlled trial

PMID: 10338106, UI: 99268428

EEG Effects

Misc Data taken from http://www.smart-drugs.com

Giurgea and Moyersoons reported in 1970 that Piracetam increased by 100% the transcallosal evoked responses elicited in cats by stimulation of one hemisphere and recorded from a symmetrical region of the hemisphere.

Dimond (1976, 1979) used a technique called "dichotic listening" to verify the ability of Piracetam to promote interhemispheric transfer in humans. In a dichotic listening test, different words are transmitted simultaneously into each ear by headphone. In most people the speech center is the left cortex, because the nerves from the ears cross over to the opposite side of the brain, most people will recall more of the words presented right ear than the left ear. Words received by the right ear directly reach the left cortex speech center, while words presented to the left ear must reach the left cortex speech center indirectly, by crossing the corpus callosum. Dimond's experiments with young healthy volunteers showed that Piracetam significantly improved left ear word recall, indicating Piracetam increased interhemispheric information transfer.

Okuyama and Aihara (1988) tested the effect of Aniracetam on the transcallosal response of anaesthetised rats. The transcallosal response was recorded from the surface of the frontal cortex following stimulation of the corresponding site on the opposite cortical hemisphere. Aniracetam at two different I.V. doses (10 mg and 30mg per Kg) significantly increased the amplitude of the negative wave compared to its level prior to drug, P<.01 and P<.001. The researchers stated that "the present results indicate that Aniracetam.. increased the amplitude of the negative wave, thereby facilitating interhemispheric transfer... Thus, it is considered that the functional increase in interhemispheric neurotransmission by nootropic drugs may be related to the improvement of the cognitive function."

Piracetam-induced facilitation of interhemispheric transfer of visual information in rats.

Buresova O, Bures J

The effect of Piracetam (UCB 6215, 2-pyrrolidoneacetamide) on learning mediated by transcommissural information flow was studied in hooded rats. Acquisition of monocular pattern discrimination was faster in drug-treated rats (100 mg/kg, 30 min before training) than in untreated controls. Subsequent relearning with one hemisphere functionally eliminated by cortical spreading depression showed that the strength of the primary engram formed under Piracetam in the hemisphere contralateral to the trained eye remained unaffected but that the secondary trace (in the ipsilateral hemisphere) was considerably improved and almost equalled the primary one (savings increased from 20-30% to 50-60%). Learning with uncrossed optic fibers was unaffected by the drug. Interhemispheric transfer of lateralized visual engrams acquired during functional hemidecortication was facilitated by Piracetam administration preceding the five transfer trials performed with the untrained eye open (imperative transfer). Piracetam was ineffective when the trained eye was open during transfer trials (facultative transfer). After a visual engram had been lateralized by 5 days of monocular overtraining, Piracetam facilitated formation of the secondary engram induced by 3 interocular transfer trials. It is concluded that Piracetam enhances transcommissural encoding mechanisms activated in the initial stage of monocular learning and in some forms of interhemispheric transfer, but does not affect the transcommissural readout. This effect is interpreted as a special case of the Piracetam-induced facilitation of the phylogenetically old mechanisms of redundant information storage which improve liminal or subnormal learning.

PMID: 1257371, UI: 76152798

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Characterization of the transcallosal response in aged rats and its susceptibility to nootropic drugs.

Morio Y, Takushiji T, Morimoto Y, Fukuda T, Setoguchi M

Research Laboratories, Yoshitomi Pharmaceutical Industries, Fukuoka, Japan.

The transcallosal response in aged rats was recorded and its susceptibility to certain nootropic drugs was compared with adult animals, under urethane-anesthesia. The transcallosal response in 24-month old rats was significantly reduced in the amplitude of both positive and negative waves, as compared with 5 -month old animals. In adult rats, intravenous administration of 100 mg/kg of calcium hopantenate augmented the amplitude of both the positive and the negative waves. Intraperitoneal administration of 300 mg/kg of calcium hopantenate or 10-100 mg/kg of aniracetam increased the amplitude of the negative wave by 20-30% above the control level but had no effect on the positive one. In aged rats, these drugs, given intraperitoneally, also increased the negative wave without affecting the positive one and the degree of augmentation was more prominent; both drugs increased the amplitude of the negative wave by about 190% of the control. These results suggest that the susceptibility to the nootropic drugs became even more striking in older animals, the function in the brain of which are reduced by the natural ageing process.

PMID: 1436389, UI: 93063703

Single-dose piracetam effects on global complexity measures of human spontaneous multichannel EEG.

Kondakor I, Michel CM, Wackermann J, Koenig T, Tanaka H, Peuvot J, Lehmann D

The KEY Institute for Brain-Mind Research, University Hospital of Psychiatry, Zurich, Switzerland.

Global complexity of 47-channel resting electroencephalogram (EEG) of healthy young volunteers was studied after intake of a single dose of a nootropic drug (piracetam, Nootropil UCB Pharma) in 12 healthy volunteers. Four treatment levels were used: 2.4, 4.8, 9.6 g piracetam and placebo. Brain electric activity was assessed through Global Dimensional Complexity and Global Omega-Complexity as quantitative measures of the complexity of the trajectory of multichannel EEG in state space. After oral ingestion (1-1.5 h), both measures showed significant decreases from placebo to 2.4 g piracetam. In addition, Global Dimensional Complexity showed a significant return to placebo values at 9.6 g piracetam. The results indicate that a single dose of piracetam dose-dependently affects the spontaneous EEG in normal volunteers, showing effects at the lowest treatment level. The decreased EEG complexity is interpreted as increased cooperativity of brain functional processes.

PMID: 10555876, UI: 20022802

Cognition-enhancing drugs increase stimulated hippocampal theta rhythm amplitude in the urethane-anesthetized rat.

Kinney GG, Patino P, Mermet-Bouvier Y, Starrett JE Jr, Gribkoff VK

Bristol-Myers Squibb Pharmaceutical Research Institute, Neuroscience Drug Discovery, Department of Electrophysiology, Wallingford, Connecticut, USA. [email protected]

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Synchronous hippocampal electroencephalographic activity occurring in a frequency range of 3 to12 Hz (i.e., hippocampal theta rhythm) has been associated with mnemonic processes in vivo. However, this link is tenuous and theta rhythm may be secondary to processes that underlie mnemonic function. If theta rhythm is associated with mnemonic or cognitive function, cognition-enhancing drugs should enhance theta rhythm regardless of their primary biological target. In the current study, we evaluated several drugs that were shown to have cognition-enhancing properties in preclinical behavioral models and that vary with respect to their primary biological target: 1) the nootropic piracetam (250 and 500 mg/kg); 2) the small-conductance calcium-activated potassium-channel blocker apamin (0.1 and 0.4 mg/kg); and 3) the acetylcholinesterase inhibitor donepezil (0.1-10.0 mg/kg). All of the cognition-enhancing drugs produced dose -dependent increases in hippocampal theta rhythm amplitude elicited by stimulation of the brainstem reticular formation at doses that did not affect peak theta frequency in the urethane-anesthetized rat. These increases were reversed by the muscarinic receptor antagonist scopolamine, suggesting a common final cholinergic action of these compounds. The use -dependent N-methyl-D-aspartate antagonist dizocilipine maleate and scopolamine reduced theta amplitude (both) and frequency (dizocilipine maleate only). These data demonstrate that hippocampal theta rhythm is sensitive to cognition-modulating compounds, suggesting that theta rhythm may be closely associated with cognitive function.

PMID: 10490892, UI: 99421890

Factors regulating the magnitude of long-term potentiation induced by theta pattern stimulation.

Arai A, Lynch G

Center for the Neurobiology of Learning and Memory, University of California, Irvine 92717.

Electrical stimulation patterned after the hippocampal theta rhythm produces a robust and stable long -term potentiation (LTP) effect. Pharmacological manipulations were used in the present studies in an effort to relate characteristics of the responses occurring during theta stimulation to the magnitude of potentiation which follows it. Comparisons were made using five or ten bursts of stimulation which respectively induce sub-maximal or near maximal degrees of LTP. DPCPX, a drug that increases release by blocking adenosine A1 receptors, was used to enhance the depolarization produced by individual theta bursts. This resulted in a marked increase in the amount of stable LTP induced by five theta bursts but did not affect that resulting from ten bursts. This finding suggested that depolarization occurring during a burst response influences per burst potentiation but not the ceiling on maximum LTP. Aniracetam, a nootropic drug that enhances responses via an action on glutamate (AMPA) receptors, was used to test this conclusion. Like DPCPX, aniracetam increased the size of the burst response and enhanced the degree of LTP caused by five but not ten theta bursts. Forskolin, an activator of adenylate cyclase, was used to test the effects of blocking the hyperpolarization normally present between theta bursts on the induction of LTP. The drug augmented the degree of LTP resulting from five theta bursts and, in contrast to DPCPX and aniracetam, nearly doubled that obtained with ten bursts. Thus the drug affected both per burst potentiation and the ceiling on LTP. These results are discussed in terms of an hypothesis in which the magnitude of NMDA receptor mediated currents affects the degree of potentiation produced by individual theta bursts while the duration of the currents is related to the limit on the maximum LTP induced by a series of bursts. The possible implications of the findings for learning are also considered.

PMID: 1486479, UI: 93137006

Action of nootropic drugs on transcallosal responses in rats.

Okuyama S, Aihara H

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Research Center, Taisho Pharmaceutical Co. Ltd, Saitama, Japan.

The effects of nootropic drugs and related compounds on transcallosal responses were examined in urethane-anesthetized rats. The transcallosal response was recorded from the surface of the anterior neocortex following electrical stimulation of the contralateral corpus callosum. The transcallosal response consisted of a biphasic positive-negative waveform. Hopantenate increased the amplitude of the positive- and negative-waves, without affecting the latency. Aniracetam, idebenone, bifemelane hydrochloride, TRH and meclofenoxate increased the amplitude of the negative-wave, without affecting the latencies. Vinpocetine and eburunamonine had no effect on the transcallosal response. Muscimol, amino-oxyacetic acid, diazepam and pentobarbital increased the amplitude of the positive-wave and decreased the amplitude of the negative-wave, without affecting the latencies. Bicuculline and picrotoxin increased the amplitude of the negative-wave, without affecting the latencies. Physostigmine decreased the amplitude of the negative-wave, without affecting the latency. Atropine was without effect. The pharmacological nature of the transcallosal response is discussed, based on findings with 16 different pharmacological agents.

PMID: 3352867, UI: 88175422

Depression

[Comparative study of the indices of the antidepressive activity of potassium orotate and piracetam].


Karkishchenko NN, Khaitin MI

It has been established in mouse experiments that potassium orotate (100 mg/kg) and piracetam (500 mg/kg) given in chronic oral doses have an antidepressant activity according to the "behavioral despair" test. It has been demonstrated that antidepressant activity of potassium orotate (20 and 50 mg/kg) and piracetam (50 and 100 mg/kg) is associated with a psychostimulant effect.

PMID: 3996568, UI: 85204319

Anxiety

Evidence that piracetam has an anxiolytic action.

File SE, Hyde JR

In the social interaction test of anxiety Piracetam (100 mg/kg) had an anxiolytic profile very similar to that seen after 5 days of administration of chlordiazepoxide (5 mg/kg). Piracetam (50-300 mg/kg) produced no signs of sedation and it was therefore suggested that it might be a non-sedative anxiolytic drug. Piracetam (100 mg/kg) produced significantly higher cortical concentrations of 5-hydroxytryptamine and lower concentrations of 5-hydroxyindoleacetic acid, indicating a reduced 5 -HT turnover. There were no drug-induced changes in noradrenaline or dopamine in any brain region, either with or without pretreatment with alpha-methylparatyrosine. The cortical concentrations of 7 amino acids were measured and were unchanged by treatment with Piracetam.

PMID: 95599, UI: 82168483

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Long Term Potentiation

Factors regulating the magnitude of long-term potentiation induced by theta pattern stimulation.

Arai A, Lynch G

Center for the Neurobiology of Learning and Memory, University of California, Irvine 92717.

Electrical stimulation patterned after the hippocampal theta rhythm produces a robust and stable long -term potentiation (LTP) effect. Pharmacological manipulations were used in the present studies in an effort to relate characteristics of the responses occurring during theta stimulation to the magnitude of potentiation which follows it. Comparisons were made using five or ten bursts of stimulation which respectively induce sub-maximal or near maximal degrees of LTP. DPCPX, a drug that increases release by blocking adenosine A1 receptors, was used to enhance the depolarization produced by individual theta bursts. This resulted in a marked increase in the amount of stable LTP induced by five theta bursts but did not affect that resulting from ten bursts. This finding suggested that depolarization occurring during a burst response influences per burst potentiation but not the ceiling on maximum LTP. Aniracetam, a nootropic drug that enhances responses via an action on glutamate (AMPA) receptors, was used to test this conclusion. Like DPCPX, aniracetam increased the size of the burst response and enhanced the degree of LTP caused by five but not ten theta bursts. Forskolin, an activator of adenylate cyclase, was used to test the effects of blocking the hyperpolarization normally present between theta bursts on the induction of LTP. The drug augmented the degree of LTP resulting from five theta bursts and, in contrast to DPCPX and aniracetam, nearly doubled that obtained with ten bursts. Thus the drug affected both per burst potentiation and the ceiling on LTP. These results are discussed in terms of an hypothesis in which the magnitude of NMDA receptor mediated currents affects the degree of potentiation produced by individual theta bursts while the duration of the currents is related to the limit on the maximum LTP induced by a series of bursts. The possible implications of the findings for learning are also considered.

PMID: 1486479, UI: 93137006

A 'long-term-potentiation-like' facilitation of hippocampal synaptic transmission induced by the nootropic nefiracetam.

Nishizaki T, Matsuoka T, Nomura T, Matsuyama S, Watabe S, Shiotani T, Yoshii M

Department of Physiology, Kobe University School of Medicine, 7-5-1 Kusunoki -cho, Chuo-ku, Kobe 650-0017, Japan. [email protected]

Nefiracetam, a nootropic agent, enhanced the slope of field excitatory postsynaptic potentials in the CA1 region of rat hippocampal slices to about 170% of basal levels, being evident still at 4-h washing-out of the drug. A similar sustained enhancement (>/=16 h after i.m. injection with nefiracetam) was observed in the population spikes recorded from the granular cell layer of the intact mouse hippocampus. Saturation of the enhancement in the synaptic strength occluded potentiation obtained with long-term potentiation (LTP) induced by high-frequency (tetanic) stimulation, and vice versa. Interestingly, the facilitatory action of nefiracetam was blocked by either the nicotinic acetylcholine (ACh) receptor antagonists, alpha-bungarotoxin and mecamylamine, or the selective protein kinase C (PKC) inhibitor, GF109203X, but in contrast, it was not affected by D-2-amino-5-phosphonovaleric acid (APV), a selective N-methyl-D-aspartate (NMDA) receptor antagonist. The results of the present study suggest that

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nefiracetam, whereas the action is independent of NMDA receptors, induces an 'LTP-like' facilitation of hippocampal synaptic transmission as a consequence of modulation of nicotinic ACh receptors and PKC. This may represent a likely mechanism underlying the cognition-enhancing actions of nefiracetam. Copyright 1999 Elsevier Science B.V.

PMID: 10224305, UI: 99242390

Addictive Potential

[Drug dependence test on a cerebral insufficiency improver, aniracetam].

[Article in Japanese]

Kuwahara A, Kubota A, Hakkei M, Nakamura K

Aniracetam, 1-p-anisoyl -2-pyrrolidinone, is known to be a nootropic or cognitive activator. Aniracetam protects against memory and learning deficits without causing effects on motor function and the autonomic nervous system. A drug dependence study on aniracetam utilizing the intragastric route of administration was performed in male cynomolgus monkeys. The behavioral observation test after acute administration revealed that aniracetam at the dose of 25-400 mg/kg did not change the gross behavior. In the self-administration initiation test, animals were exposed to two or three unit doses of aniracetam and references for a total available period of 7 weeks. Aniracetam at the dose of 25, 50 and 75 mg/kg/injection did not initiate self-administration in the respective group of 4, 4 and 2 animals. In the study with d -methamphetamine hydrochloride at the dose of 0.1 mg/kg/injection, 1 out of 4 animals started to consistently self-administer the drug. Self-administration of cocaine hydrochloride at the dose of 10 mg/kg/injection was confirmed in 3 out of 5 animals, and these 3 animals died from overdosing later. In the physical dependence direct induction test, animals received aniracetam (50 mg/kg) and sodium pentobarbital (25 mg/kg: the dose inducing intermediate CNS depression) intragastrically twice a day for 31 consecutive days. Abrupt withdrawal of aniracetam did not elicit abstinent signs (including changes in appetite and body weight) in all 6 animals, whereas withdrawal of pentobarbital produced typical abstinent behavioral signs and decreases in appetite and body weight. In conclusion, aniracetam was confirmed to develop neither physical dependence nor psychic dependence in cynomolgus monkeys.

PMID: 3570103, UI: 87192329

Dyslexia

Evaluation of the efficacy of piracetam in treating information processing, reading and writing disorders in dyslexic children.

Tallal P, Chase C, Russell G, Schmitt RL

Piracetam, a new class of drug (nootropil) thought to enhance specific cognitive skills, was given in a 3300 mg daily dose to half of a group of fifty-five dyslexic boys aged 8-13 years, in a 12 -week, double-blind, placebo-controlled study. The other half of the subjects received placebo. All subjects met the following criteria: normal intelligence, normal educational opportunities, no severe emotional problems, no neurological handicaps, good physical health, not taking other psychotropic medication, and scoring at least one and one half years below their mental age equivalent on the Gilmore Oral Reading Test. Non-verbal (auditory and visual) and verbal perceptual, and memory skills were examined, and reading, spelling, language and writing abilities were measured using standardized

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instruments. Compared to the placebo control group, individuals treated with Piracetam did not show statistically significant improvements above their baseline scores on measures of perception, memory, language, reading accuracy or comprehension, or writing accuracy. However, reading speed and numbers of words written in a timed period were significantly enhanced in subjects treated with Piracetam as compared to placebo. Effective reading and writing ability, taking both rate and accuracy into consideration, were also significantly improved in the Piracetam as compared to the placebo treatment group. The medication was well-tolerated and medical examinations showed no significant adverse reactions. These results encourage further study of Piracetam to determine more precisely the mechanism of action by which specific cognitive skills are affected.

Publication Types:


PMID: 3522509, UI: 86250260

The effect of piracetam on short- and long-term verbal retrieval in dyslexic boys.

Helfgott E, Rudel RG, Kairam R

Studies of 60 dyslexic boys age 8-14, carefully selected for exclusion of intellectual, sensory, psychiatric and neurological impairment and educational deprivation, were conducted to determine the efficacy of Piracetam, over a 12-week period, in improving reading and other related skills. There were no changes at the end of 12 weeks to distinguish the groups in accuracy or comprehension of prose-reading. Short-term memory gains, however, were recorded for the treated group on two different tests, digit span, and a test (Neimark) of immediate and delayed recall. The mean digit span scaled score for the entire group was one S.D. below their mean IQ. Considering only the performance of children whose digit span scaled scores were one S.D. or below the mean (7 or less), the treated group made a significant gain at the end of 12 weeks. On the Neimark test the treated group was significantly superior to the untreated group on first trial learning and they also lost significantly fewer object names after a delay. Improved retrieval from long-term storage could be demonstrated for the treated group on the rapid automatized naming test. Although there was no significant difference between the group at screening, the treated group was significantly faster on letter naming at the end of the drug trial. The treated group also improved their single word reading on the WRAT.

Publication Types:


PMID: 3522510, UI: 86250261

The effects of piracetam in children with dyslexia.

Di Ianni M, Wilsher CR, Blank MS, Conners CK, Chase CH, Funkenstein HH, Helfgott E, Holmes JM, Lougee L, Maletta GJ, et al

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Following previous research which suggests that piracetam improves performance on tasks associated with the left hemisphere, a 12-week, double-blind, placebo-controlled study of developmental dyslexics was conducted. Six study sites treated 257 dyslexic boys between the ages of 8 and 13 years who were significantly below their potential in reading performance. Children were of at least normal intelligence, had normal findings on audiologic, ophthalmologic, neurologic, and physical examination, and were neither educationally deprived nor emotionally disturbed. Piracetam was found to be well tolerated in this study population. Children treated with piracetam showed improvements in reading speed. No other effects on reading were observed. In addition, improvement in auditory sequential short-term memory was observed in those piracetam-treated patients who showed relatively poor memory at baseline. It is suggested that longer term treatment with piracetam may result in additional improvements.

Publication Types:


PMID: 3900148, UI: 86009005

Interactions with Other Drugs

[Influence of piracetam on the effects of narcotic analgesics and opioid peptides].


Krylova IN, Drozd IuV, Naumova VI, Iasnetsov VV, Shashkov VS

Piracetam possesses some properties not related to the nootropic activity. The purpose of the work was to study piracetam influence on effects of narcotic analgesics and opioid peptides at intracerebroventricular administration. In experiments on cats it was found that piracetam in a dose-dependent way prevented the emetic effect of morphine and leu-enkephalin. In experiments on rats (tail-flick test) piracetam was shown to be able of blocking the analgesic effect of fentanyl. Experiments on the study of the anticataleptogenic effect of piracetam also showed antagonism between piracetam and agonists of opioid receptors. Thus, it was shown on a number of models that piracetam exhibits antagonistic properties with respect of opioid peptides and narcotic analgesics.

PMID: 2897934, UI: 88242786

Attenuation of the development of morphine dependence/tolerance by nefiracetam: involvement of adenosine 3':5'-cyclic monophosphate system.

Itoh A, Shiotani T, Nakayama S, Mamiya T, Hasegawa T, Noda Y, Nabeshima T

Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, 466-8560, Nagoya, Japan.

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[Medline record in process]

Biochemical changes such as intracellular cAMP and Ca(2+) underlying morphine dependence and tolerance have been suggested. Therefore, we investigated the effects of nefiracetam (N-(2, 6-dimethyl-phenyl) -2(2-oxo-1-pyrrolidinyl) acetamide), which increases intracellular cAMP and Ca(2+) levels, on the development of morphine dependence and tolerance. Mice administered morphine (6 or 20 mg kg( -1)) twice daily for 5 days, showed withdrawal symptoms (jumping, diarrhea and body weight loss) after naloxone challenge (5 mg kg( -1)), indicating morphine dependence. Furthermore, tolerance to the analgesic effect of morphine was observed in these mice. Co-administration of nefiracetam (5 or 10 mg kg(-1)) with morphine during the pretreatment period, significantly reduced the signs of withdrawal symptoms, moreover, the tolerance was significantly attenuated. Elevation of cAMP levels in the cortex was observed in morphine-dependent mice, but not in mice co -administered nefiracetam. Acute administration of nefiracetam shows no effect on the withdrawal symptoms and the analgesic effect in morphine-naive mice. Theophylline (3 or 10 mg kg(-1)) tended to attenuate and enprofylline (10 or 30 mg kg(-1)) significantly attenuated the development of morphine dependence and tolerance. These findings suggest that co -administration of nefiracetam or compounds, which increase the cAMP level, may be a useful strategy for attenuating the development of morphine dependence and tolerance in the clinic.

PMID: 10996409, UI: 20452770

Evidence that piracetam has an anxiolytic action.

File SE, Hyde JR

In the social interaction test of anxiety Piracetam (100 mg/kg) had an anxiolytic profile very similar to that seen after 5 days of administration of chlordiazepoxide (5 mg/kg). Piracetam (50-300 mg/kg) produced no signs of sedation and it was therefore suggested that it might be a non-sedative anxiolytic drug. Piracetam (100 mg/kg) produced significantly higher cortical concentrations of 5-hydroxytryptamine and lower concentrations of 5-hydroxyindoleacetic acid, indicating a reduced 5 -HT turnover. There were no drug-induced changes in noradrenaline or dopamine in any brain region, either with or without pretreatment with alpha-methylparatyrosine. The cortical concentrations of 7 amino acids were measured and were unchanged by treatment with Piracetam.

PMID: 95599, UI: 82168483

[The influence of piracetam on the effects of narcotic analgesics].


Chichenkov ON, Krylova IN, Borozdin MIu, Pokatilov DV

In experiments on white male mice there was studied the influence of piracetam (250-300 mg/kg) on the analgesic effect of ligands of different types of opioid receptors (morphine, 7.5 mg/kg, DADLE, 7.5 mg/kg, pentazocine, 15 mg/kg) and also on the action of morphine concerning the cardiovascular system and respiration. Piracetam was shown to possess the antagonistic properties with respect to some effects of morphine, however they are not of the universal character and do not depend on the interaction with a certain type of opioid receptors.

PMID: 1973390, UI: 90316243

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Elevated corticosteroid levels block the memory-improving effects of nootropics and cholinomimetics.

Mondadori C, Ducret T, Hausler A

Ciba-Geigy Ltd., Pharmaceutical Research Department, Basle, Switzerland.

Oral pretreatment of mice with aldosterone or corticosterone blocked the memory-enhancing effects of piracetam, pramiracetam, aniracetam and oxiracetam in a dose -related manner, without, however, impairing the animals' learning performance. The improvement of memory induced by physostigmine, arecoline, and tacrine (THA) was similarly inhibited. The fact that elevated steroid levels suppress the memory-enhancing effects of entirely different substances could indicate that these substances have a common site of action. In the light of new observations showing increased cortisol concentrations in Alzheimer patients, this steroid dependency of the effects of memory enhancers might explain why only a limited number of these patients respond to therapy with nootropics or cholinomimetics.

PMID: 1410129, UI: 93029072

Effects of citicholine and of the combination citicholine + piracetam on the memory (experiments on mice).

Mosharrof AH, Petkov VD

Institute of Physiology, Bulgarian Academy of Sciences.

The memory effects of citicholine (CCh) and piracetam (Pc) were tested in experiments on mice using the training method with passive avoidance and negative reinforcement (step-through). In single doses of 25, 50, 100 and 500 mg/kg, CCh applied one hour prior to training enhanced to the same degree and statistically significantly the retention of the memory traces in tests both 24 h and 7 days after the training session; Pc in a dose of 500 mg/kg improved the retention in memory tests 24 h after training, but had no significant effect during the tests 7 days after the training. Combined application of CCh and Pc in doses which are ineffective with respect to the memory process (CCh--10 mg/kg and Pc--200 mg/kg) caused a significant enhancement of the retention during the tests both 24 h and 7 days after the training. Scopolamine (2 mg/kg i.p.), applied 30 min prior to the training, manifested a marked amnestic effect during the tests 24 h after the training, but this effect was totally prevented if either CCh in a dose of 50 mg/kg or Pc in a dose of 500 mg/kg were applied before scopolamine. Citicholine in a dose of 100 mg/kg, as well as the combination of 50 mg/kg CCh and 500 mg/kg PC, not only completely prevented the scopolamine-induced amnesia, but they also significantly increased the retention of the memory traces in the scopolamine-treated mice compared with the retention observed in the control animals.

PMID: 2392950, UI: 90364913

Effect of combined or separate administration of piracetam and choline on learning and memory in the rat.

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Ennaceur A, Delacour J

Different groups of rats received combined or separate administration of different doses of piracetam (P1:100, P2:200, and P4:400 mg/kg) and choline (C1:100 and C2:200 mg/kg). Compared to control treatment, C1 significantly improved performance in a delayed alternation (DA) task, while P1, P2, P4 or P1C1 had no effect. Moreover, rats receiving P2C1 and P4C1 were significantly inferior in acquiring DA to rats receiving the vehicle or separate administration of P1, P2 or C1. The different treatments with combined or separate administration of P and C had no effect on spontaneous locomotor activity and two-way avoidance conditioning. In a recognition-task only groups C1 and P4 were able to discriminate between familiar and new objects. The combined or separate administration of P1 and C1 on NA, DA, DOPAC, 5-HT, 5-HIAA levels, CAT activity and choline uptake were measured in frontal cortex and hippocampus: the only significant effect was a 5-HT increase in the hippocampus of rats treated with C1.

PMID: 3110830, UI: 87261637

Habituation of exploratory activity in mice: effects of combinations of piracetam and choline on memory processes.

Platel A, Jalfre M, Pawelec C, Roux S, Porsolt RD

The effects of various piracetam + choline combinations on an experimental model of memory were investigated. Mice were given two sessions in a simple photo-cell activity cage and the decrease in activity at the second session (habituation) served as an index of retention. Retention was facilitated by post-session administration of 2000 mg/kg piracetam IP and 50 mg/kg piracetam + 50 mg/kg choline IP. Similar injections of choline alone (10 to 200 mg/kg IP), piracetam alone (10 to 1000 mg/kg IP) or other combinations of piracetam and choline were without effect. These results, consistent with those reported elsewhere, suggest that piracetam can interact with choline to facilitate memory processes in mice.

PMID: 6483933, UI: 85015088

Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats.

Bartus RT, Dean RL 3d, Sherman KA, Friedman E, Beer B

In an attempt to gain some insight into possible approaches to reducing age-related memory disturbances, aged Fischer 344 rats were administered either vehicle, choline, piracetam or a combination of choline or piracetam. Animals in each group were tested behaviorally for retention of a one trial passive avoidance task, and biochemically to determine changes in choline and acetylcholine levels in hippocampus, cortex and striatum. Previous research has shown that rats of this strain suffer severe age -related deficits on this passive avoidance task and that memory disturbances are at least partially responsible. Those subjects given only choline (100 mg/kg) did not differ on the behavioral task from control animals administered vehicle. Rats given piracetam (100 mg/kg) performed slightly better than control rats (p less than 0.05), but rats given the piracetam/choline combination (100 mg/kg of each) exhibited retention scores several times better than those given piracetam alone. In a second study, it was shown that

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twice the dose of piracetam (200 mg/kg) or choline (200 mg/kg) alone, still did not enhance retention nearly as well as when piracetam and choline (100 mg/kg of each) were administered together. Further, repeated administration (1 week) of the piracetam/choline combination was superior to acute injections. Regional determinations of choline and acetylcholine revealed interesting differences between treatments and brain area. Although choline administration raised choline content about 50% in striatum and cortex, changes in acetylcholine levels were much more subtle (only 6-10%). No significant changes following choline administration were observed in the hippocampus. However, piracetam alone markedly increased choline content in hippocampus (88%) and tended to decrease acetylcholine levels (19%). No measurable changes in striatum or cortex were observed following piracetam administration. The combination of choline and piracetam did not potentiate the effects seen with either drug alone, and in certain cases the effects were much less pronounced under the drug combination. These data are discussed as they relate to possible effects of choline and piracetam on cholinergic transmission and other neuronal function, and how these effects may reduce specific memory disturbances in aged subjects. The results of these studies demonstrate that the effects of combining choline and piracetam are quite different than those obtained with either drug alone and support the notion that in order to achieve substantial efficacy in aged subjects it may be necessary to reduce multiple, interactive neurochemical dysfunctions in the brain, or affect activity in more than one parameter of a deficient metabolic pathway.

PMID: 7301036, UI: 82058347

Metabolic features of the adaptive effect of delta-sleep inducing peptide and piracetam under hyperoxic conditions.

Lysenko AV, Alperovich DV, Uskova NI, Mendzheritsky AM

Neurocybernetics Institute, Rostov State University, Rostov-on-Don, 344090, Russia. [email protected].

Adaptive effects of delta-sleep inducing peptide (DSIP, 12 microgram/100 g body weight, single intraperitoneal injection) and piracetam (3 mg/100 g body weight, daily intraperitoneal injection for 3 days) are manifested via differential changes in neurotransmitter amino acids (GABA, glutamate, aspartate), modulation of transport ATPase activity, and decreased accumulation of lipid peroxidation products (conjugated dienes, malonic dialdehyde, Schiff bases) in various fractions of neuronal membranes (myelin, synaptic and mitochondrial membranes) in the sensomotor cortex of rat brain. Under hyperbaric oxygenation (0.3 MPa for 2 h), the combination of DSIP and piracetam enhanced the protective effect of each compound.

PMID: 10395980, UI: 99327177

Modulation of the effects on learning and memory of nootropic drugs and central stimulants when applied together.

Petkov VD, Konstantinova E, Petkov VV, Lazarova M, Petkova B

Institute of Physiology, Bulgarian Academy of Sciences, Sofia.

In experiments on rats using passive avoidance with punishment reinforcement (step-through) and two-way active avoidance with punishment reinforcement (shuttle-box), we examined the effects on acquisition and retention of different combinations of the nootropic drugs meclofenoxate (Mf), citicholine (CCh), piracetam (Pc), the structural analogues of aniracetam p-P and p -F, standardized extract from ginseng roots (PG) and the psychostimulants

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caffeine (Caf) and amphetamine (Amph). Favorable effects (more pronounced improvement of learning and/or memory as compared to that caused by the drugs when given alone) were in some cases obtained by the combination Mf+Caf, Pc+Caf, CCh+Caf, p-F+Caf, Mf+CCh, as well as by the combination Mf+PG applied to rats with electroconvulsive shock-induced amnesia. However, in some cases the combined administration of two drugs with favorable effects on memory did not led to summation or potentiation but rather to disappearance of these effects. This was observed under certain experimental conditions with some combinations of Caf and CCh, Mf, Pc and p-P and with some combinations of Amph and Mf. Based on our earlier results and data in the literature, we present some considerations about the role of the neurotransmitter mechanisms of action of the drugs tested as neurochemical correlates of their effects on memory. It is suggested that the unfavorable results obtained in some cases with combinations of nootropics and psychostimulants are due to the possible disturbance of selective acquisition by the psychostimulant drug.

PMID: 1688150, UI: 93034322

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Stroke 2000 Sep;31(9):2112-6

Effect of Indian Hypericum perforatum Linn on animal models of cognitive dysfunction.

Kumar V, Singh PN, Muruganandam AV, Bhattacharya SK

Pharmacology Laboratory, Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, 221005, Varanasi, India


The effect of a standardised 50% ethanolic extract of Indian Hypericum perforatum (IHp) was investigated for its putative nootropic activity on various experimental paradigms of learning and memory, viz. transfer latency (TL) on elevated plus-maze, passive avoidance (PA), active avoidance (AA), scopolamine and sodium nitrite induced amnesia (SIA & NIA) in albino rats. Pilot studies indicated that single dose administration of IHp had little or no acute behavioural effects, hence the extract of IHp was administered orally at two dose levels (100 and 200 mg/kg, p.o.), once in daily for three consecutive days, while piracetam (500/kg, i.p.), a clinically used nootropic agent, was administered acutely to rats as the standard drug. Control rats were treated with equal volume of vehicle (0.3% carboxymethyl cellulose (CMC)). IHp and piracetam when given alone shortened the TL on day 1, 2, 9 and also antagonised the amnesic effects of scopolamine and sodium nitrite on the TL significantly. IHp had no significant per se effect on the retention of the PA in rats. Only the higher dose (200 mg/kg, p.o.) produced a significant reversal of scopolamine induced PA retention deficit but no significant reversal was observed with sodium nitrite. Piracetam showed significant per se facilitatory effect on PA retention and also reversed the scopolamine and sodium nitrite induced impaired PA retention. In the AA test, IHp in both the doses, and piracetam, facilitated the acquisition and retention of AA in rats and the IHp effects were found to be dose dependent. Both the doses of IHp and piracetam significantly attenuated the scopolamine and sodium nitrite induced impaired retention of AA. These

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results indicate a possible nootropic action of IHp, which was qualitatively comparable with that induced by piracetam.

PMID: 10967462

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Chem Pharm Bull (Tokyo) 2000 Aug;48(8):1121-4

Synthesis of 1-azabicyclo[3.3.0]octane derivatives and their effects as piracetam-like nootropics.

Oka M, Matsumoto Y, Hirooka K, Suzuki T

Central Research Laboratory, Sanwa Kagaku Kenkyusho, Co., Ltd., Inabe-gun, Mie, Japan. [email protected] -net.com


A useful pharmaceutical intermediate, 5-nitromethyl-1-azabicyclo[3.3.0]octane (1), was prepared in one step from 1,7-dichloro-4-heptanone (4) under mild conditions. Catalytic hydrogenation of 1 over Raney Ni in the presence of sodium hydroxide afforded 5-aminomethyl-1-azabicyclo[3.3.0]octane (2) in high yield. Piracetam analogues 20-23, which were pyrrolidine derivatives involving a 1-azabicyclo[3.3.0]octane ring, were synthesized. Pharmacological tests showed that N -[(1-azabicyclo[3.3.0]octan-5-yl)methyl] -2-oxo-1-pyrrolidineacetamide (20) improves cerebral function.

PMID: 10959574, UI: 20414132

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Epileptic Disord 2000 Jun;2(2):99-105

Piracetam and levetiracetam: close structural similarities but different pharmacological and clinical profiles.

Genton P, Van Vleymen B

Centre Saint-Paul, Marseille, France. [email protected]


Piracetam (PIR) and levetiracetam (LEV), an S-enantiomer, are pyrrolidone derivatives that share similar chemical structures but have distinct pharmacological profiles and consequently different clinical uses. Although the mode of action of neither drug has been fully elucidated, they do not interact with inhibitory or excitatory neurotransmission or alter membrane excitability. A brain -specific stereoselective binding site has been identified for

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which LEV and other S-enantiomers, but not PIR, have high affinity. In preclinical studies, PIR significantly improves learning and memory; in contrast, LEV has less effect but is much more active in preventing seizures. Both drugs have a high therapeutic index and are well tolerated. PIR, a nootropic drug, is used in the therapy of age-related cognitive disturbances and poststroke aphasia. Clinical experience has also shown that at high doses it is effective against cortical myoclonus. LEV is an antiepileptic drug. Clinical trials have confirmed its efficacy in partial seizures and preliminary findings suggest that it is also effective in generalized seizures and myoclonus.

PMID: 10954241, UI: 20408344

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Fitoterapia 2000 Aug;71 Suppl 1:S124-S130

Pro-cognitive activity induced in the rat by low doses of R-(+)-hyoscyamine.

Ghelardini C, Galeotti N, Bartolini A

Department of Pharmacology, Viale G. Pieraccini 6, 1-50139, Florence, Italy


In the passive-avoidance test R-(+)-hyoscyamine (10-100 mug kg( -1) i.p.) prevented amnesia induced by antimuscarinic treatment with AF-64A and benzhexol. The antiamnesic effect of R-(+)-hyoscyamine was comparable to that exerted by the cholinesterase inhibitor physostigmine (0.2 mg kg(-1) i.p) and the M(1) selective agonist AF-102B (10 mg kg(-1) i.p.). In the social learning test, R-(+)-hyoscyamine (10-100 mug kg( -1) i.p.) in adults rats, reduced the duration of active exploration of the familiar partner in the second session of the test similar to the nootropic drug piracetam (30 mg kg(-1) i.p.). These results demonstrated the ability of R-(+)-hyoscyamine to modulate memory functions and suggest that R-(+)-hyoscyamine could be useful in the treatment of cognitive deficits.

PMID: 10930723

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J Neural Transm 1999;106(7-8):757-61

Piracetam reverses hippocampal membrane alterations in Alzheimer's disease.

Eckert GP, Cairns NJ, Muller WE

Department of Pharmacology, Biocenter, University of Frankfurt, Federal Republic of Germany.

The in vitro effects of piracetam treatment on the fluidity of membranes from the hippocampus of Alzheimer's Disease patients (AD) and non-demented controls were studied. Hippocampal membranes of AD patients showed a significant lower hydrocarbon core fluidity compared with membranes from elderly non-demented controls.

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Preincubation with piracetam enhanced the hydrocarbon core fluidity of hippocampal membranes from AD-patients as well as elderly controls in a concentration depending fashion, although the effect was more pronounced for the AD membranes. In the presence of piracetam, the difference of the membrane fluidity between AD and control membranes was not longer apparent.

PMID: 10907734, UI: 20362980

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Zh Nevrol Psikhiatr Im S S Korsakova 2000;100(6):33-7

["Fast" and "slow" components of psychotropic activity of the drugs with nootropic effects].


Neznamov GG, Siuniakov SA, Davydova IA, Teleshova ES

A clinical-pharmacological study was carried out to evaluate correlation of "fast" (nonspecific) and "slow" (specific) components of the action of the drugs with nootropic properties (piracetam, mexidol, tanacan) and to estimate their contribution to achieving therapeutic efficacy. The study was performed during 28 days using standard quantitative assay techniques in 79 patients with "Organic emotional-liable (asthenic) disorders" (F06.6, ICD -10). It was found that "fast" component of the psychotropic action of the drugs tested was presented by stimulating and anxiolytic effects, while a "slow" one--by specific nootropic activity. All these effects were fully independent with no correlation found, and this could, probably, be attributed to different mechanisms of their realization. It is shown that nootropic activity of piracetam was most significant in its therapeutic effect; and anxiolytic effect was most important for mexidol action. Meanwhile, stimulating and anxiolytic activities as well as positive influence on long -term memory were main components of tanacan effect. The results obtained show an important role of both specific and nonspecific ("fast") effects in realization of therapeutic action of the drugs with nootropic effects in patients with cognitive-mnestic and neurosis-like disorders.

PMID: 10900686, UI: 20357907

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Brain Res 2000 Jul 7;870(1 -2):157-62

Nefiracetam facilitates hippocampal neurotransmission by a mechanism independent of the piracetam and aniracetam action.

Nomura T, Nishizaki T

Department of Physiology, Kobe University School of Medicine, 7-5-1 Kusunoki -cho, Chuo-ku, 650-0017, Kobe, Japan.

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Nefiracetam, a nootropic (cognition -enhancing) agent, facilitated neurotransmission in the dentate gyrus of rat hippocampal slices in a dose-dependent manner at concentrations ranged from 1 nM to 1 microM, being evident at 60-min washing-out of the drug. The facilitatory action was blocked by the nicotinic acetylcholine (ACh) receptor antagonists, alpha-bungarotoxin and mecamylamine. A similar facilitation was induced by the other nootropic agents, piracetam and aniracetam, but the facilitation was not inhibited by nicotinic ACh receptor antagonists and it did not occlude the potentiation induced by nefiracetam. In the Xenopus oocyte expression systems, nefiracetam potentiated currents through a variety of neuronal nicotinic ACh receptors (alpha 3beta 2, alpha 3beta 4, alpha 4 beta 2, alpha 4 beta 4, and alpha 7) to a different extent. In contrast, neither piracetam nor aniracetam had any potentiating action on alpha 7 receptor currents. While aniracetam delayed the decay time of currents through the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, GluR1, -2, -3, expressed in oocytes, nefiracetam or piracetam had no effect on the currents. Nefiracetam, thus, appears to facilitate hippocampal neurotransmission by functionally targeting nicotinic ACh receptors, independently of the action of piracetam and aniracetam.

PMID: 10869513, UI: 20329784

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Orv Hetil 2000 May 28;141(22):1189-93

[Cognitive enhancement effect of piracetam in patients with mild cognitive impairment and dementia].

[Article in Hungarian]

Tariska P, Paksy A

Memoria Klinika, Orszagos Pszichiatriai es Neurologiai Intezet, Budapest.

Effectiveness and tolerability of two piracetam-containing drugs were compared in the frame of an open, multicentre, Phase -IV, prospective study with group and self control carried out in 9 Hungarian centres in 1998. Patients with cognitive decline from Alzheimer's disease and/or cerebrovascular origin have received the drug, in the first 4 weeks in 4800, later 2400 mg daily doses. One hundred four patients finished the study. No relevant difference with statistically significant degree was registered between the two groups. Based on this fact in this study data of the 104 patients were examined together. Authors examined two problems. The first: on which cognitive function is more effective the drug. Five factors of the modified Mini-Mental State Examination were separated and compared. Nearly all of them significantly increased especially the factors of memory, and concentration-psychomotor speed. The second examined field: are there certain subgroups with prognostic value about the effectiveness of piracetam treatment. Neither the duration of the illness, nor etiologic diagnosis, severity of cognitive decline, or former treatment with piracetam did influence significantly the efficacy. In case of depressive symptoms such connection was established: the more pronounced the severity of these symptoms the higher improvement can be expected in cognitive functions. This was also stressed by the logistic regression analysis. Authors described an original evaluation method of the trail-making test, which could widen the application of this popular test in psychopharmacologic studies. Final conclusions: the cognitive enhancer effect of piracetam appeared in a few weeks. This treatment could be effective even in Alzheimer's disease, in case of more pronounced cognitive decline, longer duration of the illness, and in case of former piracetam treatment as well. The degree of cognitive improvement was most pronounced in patients with comorbid depressive symptoms.

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l Clinical trial l Clinical trial, phase iv l Multicenter study

PMID: 10853348, UI: 20311807


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Seizure 2000 Mar;9(2):80-7

A multicentre, double-blind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2000 mg daily and 4000 mg daily, without titration in patients with refractory epilepsy.

Betts T, Waegemans T, Crawford P

Birmingham University Seizure Clinic, UK.

The aim of this study was to determine the tolerability and efficacy of two oral regimens of levetiracetam, 1000 mg and 2000 mg twice daily, as add-on treatment without titration in patients with refractory epilepsy. After a 1- to 4-week baseline, 119 patients were randomized to receive levetiracetam 2000 mg daily, 4000 mg daily, or placebo for a 24-week double-blind period, then levetiracetam 4000 mg daily in a 24-week open-label phase. Somnolence was the most common reason for discontinuation, and along with asthenia, occurred more frequently with levetiracetam than placebo. Responder rates were higher with levetiracetam 2000 mg and 4000 mg daily (48.1% [P < 0.05] and 28.6% [NS], respectively) than placebo (16.1%). In the open-label phase, the overall responder rate was 43.0%. Switching from placebo to levetiracetam increased the overall responder rate from 16.7% to 44.0%. No such increase was observed with patients initiated on levetiracetam 2000 mg daily. Levetiracetam initiated at doses of 2000 mg or 4000 mg daily without titration is well-tolerated and effective as add-on therapy in patients with partial and/or generalized seizures. The higher dose may be related to an increased incidence of somnolence and is not necessarily more effective than the lower dose.

Publication Types:

l Clinical trial l Multicenter study l Randomized controlled trial

PMID: 10845730, UI: 20302353


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Alzheimer Dis Assoc Disord 2000;14 Suppl 1:S95-102

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Cellular mechanism of action of cognitive enhancers: effects of nefiracetam on neuronal Ca2+ channels.

Yoshii M, Watabe S, Murashima YL, Nukada T, Shiotani T

Department of Neurophysiology, Tokyo Institute of Psychiatry, Japan.

Cellular mechanisms underlying the cognition-enhancing actions of piracetam-like nootropics were studied by recording Ca2+ channel currents from neuroblastoma x glioma hybrid (NG108-15) cells and Xenopus oocytes expressing Ca2+ channels. In NG108-15 cells, nefiracetam (1 microM) produced a twofold increase in L-type Ca2+ channel currents. A similar, but slightly less potent effect was observed with aniracetam, whereas piracetam and oxiracetam exerted no such effects. Cyclic AMP analogs mimicked the nefiracetam action. N-type Ca2+ channel currents inhibited by leucine (Leu)-enkephalin by means of inhibitory G proteins (Go/Gi) were recovered promptly by nefiracetam, whereas those inhibited by prostaglandin E1 via stimulatory G proteins were not affected by nefiracetam. Cells treated with pertussis toxin (500 ng/mL, > 20 hours) were insensitive to nefiracetam. In Xenopus oocytes functionally expressing N -type (alpha1B) Ca2+ channels and delta-opioid receptors, nefiracetam was also effective in facilitating the recovery from Leu-enkephalin-induced inhibition. These results suggest that nefiracetam, and possibly aniracetam, may activate N- and L-type Ca2+ channels in a differential way depending on how they recover from Go/Gi-mediated inhibition.

PMID: 10850736, UI: 20306909


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Alzheimer Dis Assoc Disord 2000;14 Suppl 1:S82-94

Presynaptic nicotinic acetylcholine receptors as a functional target of nefiracetam in inducing a long-lasting facilitation of hippocampal neurotransmission.

Nishizaki T, Matsuoka T, Nomura T, Kondoh T, Watabe S, Shiotani T, Yoshii M

Department of Physiology, Kobe University School of Medicine, Japan.

Nefiracetam (1 -10 microM), a nootropic (or cognition -enhancing) agent, persistently potentiated currents through Torpedo acetylcholine (ACh) receptors expressed in Xenopus oocytes as a result of interacting with a protein kinase C pathway and the ensuing protein kinase C phosphorylation of the receptors. A similar effect was found in neuronal nicotinic ACh receptors (alpha4beta2 and alpha7). In contrast, the other nootropic agents such as piracetam and aniracetam had no potentiating action on the receptors. A sustained enhancement in the activity of nicotinic ACh receptors induced by nefiracetam caused a marked increase in the glutamate release, leading to a long-term potentiation-like facilitation of hippocampal synaptic transmissions. One of the consistent neuropathologic features of the Alzheimer brain is a loss of nicotinic ACh receptors. This fact, together with the results of our study, raises the possibility that the loss of nicotinic ACh receptors may be a key factor in the decline of cognitive function observed in Alzheimer disease and that agents targeting neuronal nicotinic ACh receptors like nefiracetam could, therefore, be of great therapeutic importance.

PMID: 10850735, UI: 20306908

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J Neurol 2000 Apr;247(4):263-6

Piracetam in acute stroke: a systematic review.

Ricci S, Celani MG, Cantisani TA, Righetti E

Servizio Malattie Cerebrovascolari, Perugia, Italy, [email protected]

We studied whether the administration of piracetam in acute, presumed ischemic stroke affects case fatality and functional outcome. The Cochrane Stroke Group strategy was used to evaluate all randomized controlled trials of patients with presumed ischemic stroke examined within 48 h; death and (when available) functional outcome were used as end points. Three studies were included; the most recent one contributed more than 97% of the data. There were 501 patients treated with piracetam and 501 controls. Piracetam was associated with a nonsignificant 31% increase in the odds of death (95% CI -5% to 81%). This result was due almost completely to the effect of the larger trial, which, however, reported that the difference in case fatality rate between piracetam and control disappeared after correcting for the imbalance in stroke severity between the two groups. Data on functional outcome were available only for the largest study, and no difference was reported. Data obtained from the manufacturer suggested a nonsignificant trend ( -10%) towards reduction in dependency with piracetam (CI -33% to 20%); the proportions of patients dead or dependent in the two groups were the same. Relevant adverse effects were not reported. The evidence from this review does not support routine administration of piracetam in patients with acute ischemic stroke; however, since a possible beneficial effect cannot completely be ruled out, further controlled trials are warranted.

Publication Types:

l Meta -analysis

PMID: 10836617, UI: 20294606


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Eksp Klin Farmakol 2000 Mar-Apr;63(2):9 -11

[The nootropic and anxiolytic properties of different doses of piracetam].


Voronina TA, Molodavkin GM, Borlikova GG, Ostrovskaia RU, Tushmalova NA, Naznamov GG

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Laboratory of Psychopharmacology, Russian Academy of Medical Sciences, Moscow, Russia.

The effect of piracetam at various doses on the behavioral and electrophysiological characteristics was studied, including the development of passive and active avoidance conditional reflexes in rats, their behavior in conflict situations, and the transcallosal evoked response (TER) in rabbit brain. In the dose range from 50 to 300 mg/kg, piracetam improved the avoidance performance of both types and produced a dose -dependent increase in the TER amplitude, but did not affect the behavior of rats in conflict situations. As the drug dose was increased to 400-1000 mg/kg, the positive learning influence disappeared (sometimes the effect was even negative) and the TER increase changed to decrease. In contrast, the conflict situation tests revealed pronounced anxiolytic activity of piracetam at elevated doses. Thus, the nootropic and anxiolytic effects of piracetam (and, probably, of the other tranquilizers as well) do not coexist and are significantly shifted relative to one another on the dose scale, being probably realized via different mechanisms.

PMID: 10834086, UI: 20293996


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J Med Chem 2000 May 18;43(10):1969-74

Design, synthesis, and preliminary pharmacological evaluation of 1, 4-diazabicyclo[4.3.0]nonan-9-ones as a new class of highly potent nootropic agents.

Manetti D, Ghelardini C, Bartolini A, Bellucci C, Dei S, Galeotti N, Gualtieri F, Romanelli MN, Scapecchi S, Teodori E

Dipartimento di Scienze Farmaceutiche, Universita di Firenze, Via G. Capponi 9, I-50121 Firenze, Italy.

Several 4-substituted 1,4-diazabicyclo[4.3.0]nonan-9-ones have been synthesized and tested in vivo on mouse passive avoidance test, to evaluate their nootropic activity. The results show that they represent a new class of nootropic drugs with a pharmacological profile very similar to that of piracetam, showing much higher potency with respect to the reference. Among the compounds studied, 7 (DM 232) shows outstanding potency, being active at the dose of 0. 001 mg kg(-1) sc.

PMID: 10821709, UI: 20281729


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Pol J Pharmacol 1999 Nov -Dec;51(6):485-95

Influence of piracetam and oxiracetam on the content of high-energy phosphates and morphometry of astrocytes in vitro.

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Gabryel B, Trzeciak HI, Pudelko A, Cieslik P

Department of Pharmacology, Silesian Medical University, Katowice, Poland.

The nootropic drugs, including piracetam (PIR) and oxiracetam (OXI) are used in the adjunctive treatment of dementia. They are thought to directly influence energetic processes in the brain and, therefore, they are supposed to improve memory and cognition. The content of adenosine triphosphate (ATP) and phosphocreatine (PCr) and 3H-valine incorporation into proteins were measured, and the morphometry was performed after PIR and OXI treatment of astrocytes cultured in vitro with or without dibutyryl 3',5'-cyclic adenosine monophosphate (dBcAMP). Nootropics were added into the culture medium for 2 weeks at a final concentration of 10(-7) M. It was shown that OXI increased ATP content in astrocytes cultured with or without dBcAMP. The increase in 3H-valine incorporation into astrocytes after PIR and OXI together with dBcAMP treatment was found. These results indicate that the presented research model allows to study energetic processes in cultured astrocytes. However, nootropic drugs changed morphometric parameters (cell area, perimeter and form factor) of cultured astrocytes as well. It can be concluded that PIR and OXI as nootropics have an opposing effect on the content of high-energy phosphates and shape of astrocytes in vitro.

PMID: 10817526, UI: 20275227


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Cochrane Database Syst Rev 2000;(2):CD001011

Piracetam for dementia or cognitive impairment.

Flicker L, Grimley Evans J

Department of Medicine-RPH, University of Western Australia, Royal Perth Hospital Box X2213 GPO, Perth, Western Australia, Australia, 6847. [email protected]

OBJECTIVES: To determine the clinical efficacy of piracetam for the features of dementia or cognitive impairment, classified according to the major subtypes of dementia: vascular, Alzheimer's disease or mixed vascular and Alzheimer's disease or unclassified dementia or cognitive impairment not fulfilling the criteria for dementia. SEARCH STRATEGY: The Cochrane Dementia and Cognitive Impairment Group Register of Clinical Trials was searched using the terms "piracetam", "nootropic" and "2-oxo-l-pyrrolidine acetamide". Electronic bibliographic databases including Medline, Embase, PychLit, Current Contents, Sociofile were searched back to 1966 with the terms piracetam, nootropics, 2-oxo-1-pyrrolidine and trials. In addition the pharmaceutical company responsible for marketing most of the piracetam worldwide, UCB Pharma, provided a comprehensive list of abstracts, which included many unpublished studies. As many of these unpublished, placebo control studies will be reviewed as possible. SELECTION CRITERIA: All unconfounded trials specified as randomised in which treatment with piracetam was administered for more than a day and compared with placebo in patients with dementia of the Alzheimer's type, vascular dementia or mixed vascular and Alzheimer's disease or uncalssified dementia or cognitive impairment not fulfilling the criteria for dementia. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers. Each study was independently verified as fulfilling the inclusion criteria. Studies were rated for methodological quality by assessment of blinding and loss before analysis as described by Jadad et al. (1996). Studies were pooled if appropriate and possible, and the pooled odds ratios (95%CI) or the average differences (95%CI) were estimated. Where possible, intention-to-treat data were used. Sensitivity analyses were performed to determine if successive elimination of those studies performing most poorly on these quality criteria changed the effect estimate. MAIN RESULTS: Unfortunately, many of these studies were crossover in design and data were unavailable from the

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first period. In many other studies data were not able to be extracted from the first period. From the data that were pooled there was only one outcome where significant amounts of evidence were available, Global Impression of Change. There was evidence of heterogeneity in the results from the individual studies, Chi squared test = 20.8 (df=5). Using a fixed effects model the odds ratio for improvement in the Piracetem group compared with the Placebo group was 3.55, [95% CI][2.45, 5.16]. If a random effects model was used the odds ratio was 3.47 [1.29, 9.30]. If one single-blind study was excluded, the fixed effects model yielded an odds ratio of 3.36 [2.29, 4.99] and if a random effects model was applied then the odds ratio was 2.89 [1.01, 8.24]. The evidence of effects on cognition and other measures, was inconclusive. REVIEWER'S CONCLUSIONS: At this stage the evidence available from the published literature does not support the use of Piracetem in the treatment of people with dementia or cognitive impairment because effects were found only on global impression of change but not on any of the more specific measures. There is a need for further evaluation of piracetam by : 1) Obtaining the data from these studies for an individual patient database review, 2) Performing a randomised trial of Piracetam in patients with diagnoses made by currently accepted diagnostic criteria. Piracetam should be trialled for a period of at least 6 months and preferably longer. Specific cognitive instruments which are sensitive to change, Clinician Global Impression of Change, levels of dependency and caregiver quality of life scales should also be incorporated in such a study.

Publication Types:

l Review l Review, academic

PMID: 10796585, UI: 20257675


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Piracetam for acute ischaemic stroke.

Ricci S, Celani MG, Cantisani AT, Righetti E

Stroke Service, USL 2, Via Guerra 17, 06127 Perugia, Italy. [email protected]

BACKGROUND: Piracetam has neuroprotective and antithrombotic effects which may help to reduce death and disability in people with acute stroke. OBJECTIVES: The objective of this review was to assess the effects of piracetam in acute presumed ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Review Group trials register, Medline (from 1965), Embase (from 1980), BIDIS ISI (from 1981). We also contacted manufacturers and handsearched 15 journals. SELECTION CRITERIA: Randomised trials comparing piracetam with control, with at least mortality reported and entry to the trial within approximately 48 hours of stroke onset. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data and assessed trial quality and this was checked by the other two reviewers. Study authors were contacted for missing information. MAIN RESULTS: Three trials involving 1002 people were included, with one trial contributing 97% of the data. Participants' ages ranged from 40 to 85, and both sexes were equally represented. Piracetam was associated with a statistically non significant increase in death (31% increase, 95% confidence interval 81% increase to 5% reduction). This trend was no longer apparent in the large trial after correction for imbalance in stroke severity. Limited data showed no difference between the treatment and control groups for functional outcome, dependency or proportion of patients dead or dependent. Adverse effects were not reported. REVIEWER'S CONCLUSIONS: There is some suggestion of an unfavourable effect of piracetam on early death, but this may have been caused by baseline differences in stroke severity in the trials. Piracetam does not appear to reduce dependency for stroke patients.

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PMID: 10796359, UI: 20257457


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Piracetam for fetal distress in labour.

Hofmeyr GJ, Kulier R

Department of Obstetrics and Gynaecology, Coronation Hospital and University of the Witwatersrand, 7 York Road, Parktown 2193, Johannesburg, South Africa. [email protected]

BACKGROUND: Piracetam is thought to promote the metabolism of brain cells when they are hypoxic. It has been used to prevent adverse effects of fetal distress. OBJECTIVES: The objective of this review was to assess the effects of piracetam for suspected fetal distress in labour on method of delivery and perinatal morbidity. SEARCH STRATEGY: The Cochrane Pregnancy and Childbirth Group trials register and the Cochrane Controlled Trials Register were searched. Date of last search: February 1999. SELECTION CRITERIA: Randomised trials of piracetam compared with placebo or no treatment for suspected fetal distress in labour. DATA COLLECTION AND ANALYSIS: Both reviewers assessed eligibility and trial quality. MAIN RESULTS: One study of 96 women was included. Piracetam compared with placebo was associated with a trend to reduced need for caesarean section (relative risk 0.57, 95% confidence interval 0.32 to 1.03). There were no statistically significant differences in relative risk between the piracetam and placebo group for neonatal morbidity (measured by neonatal respiratory distress) or Apgar score. REVIEWER'S CONCLUSIONS: There is not enough evidence to evaluate the use of piracetam for fetal distress in labour.

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PMID: 10796235, UI: 20257325


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Rev Neurol 1999 Feb;28 Suppl 2:S81-93

[Neurocognitive and pharmacological approach to specific learning disorders].

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Etchepareborda MC

Laboratorio para el estudio de las Funciones Cerebrales Superiores, Buenos Aires, Argentina. [email protected]

INTRODUCTION: Specific learning disorders are distinguished from general development disorders since, in general, only a certain number of processing mechanisms are involved whilst the remainder are unaffected. DEVELOPMENT: The classification proposed by the DSM -IV takes a step towards clinical understanding and use of a common nomenclature. However, neuropsychological assessment is essential to understanding clinical subtypes. The neuro-cognitive approach, when taking into account the processing systems affected or involved, should include the strategies and principles of a cognitive-behavioural approach, accompanied by computerized cognitive training. Pharmacological treatment uses drugs with different modes of action depending on the specific neuropsychological characteristics of each type of disorder of nerve development. We discuss the clinical use of various drugs in view of investigations, present and past: methylphenidate for the dys-attentional subtype of ADHD; piracetam in developmental dyslexia of dysideatic type; citocolina in the infantile dysphasias of sensory input predominance, thiapride in dysfluencial and combined subtype of ADHD; pipamperona in behaviour disorders and the hyperactive-impulsive subtype of ADHD, with or without associated and selegilina in the dysattention subtype of ADHD and the dysgraphias of the subtype with predominance of calligraphy and spatial disorders.

Publication Types:

l Review l Review, tutorial

PMID: 10778495, UI: 20240963


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Eur J Med Chem 2000 Jan;35(1):77-82

4-Aminopyridine derivatives with antiamnesic activity.

Andreani A, Leoni A, Locatelli A, Morigi R, Rambaldi M, Pietra C, Villetti G

Dipartimento di Scienze Farmaceutiche, Universita' di Bologna, Via Belmeloro 6, 40126, Bologna, Italy. [email protected]

Acetylcholine (Ach) enhancement, useful in the treatment of Alzheimer's disease (AD), may be obtained by means of ion channel modulators such as 4-aminopyridine (4-AP). 4 -AP is also the central ring of tacrine, the first drug approved for the treatment of AD. The synthesis and pharmacological activity of three 4-AP derivatives, prepared with the aim of improving their antiamnesic activity, is here described. In two of these compounds 4-AP is connected to 4-aminobutyric acid (GABA), whereas in the third it is connected to 2-indolinone, i.e., the skeleton of linopirdine, another Ach enhancing agent. The new compounds showed potent antiamnesic activity in comparison with piracetam.

PMID: 10733605, UI: 20198521

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Eur J Pharmacol 2000 Mar 17;391(3):251-4

Piracetam and levetiracetam, two pyrrolidone derivatives, exert antidystonic activity in a hamster model of paroxysmal dystonia.

Loscher W, Richter A

Department of Pharmacology, School of Veterinary Medicine, Bunteweg 17, D -30559, Hannover, Germany. [email protected]

The effects of the nootropic drug piracetam and its analogue, the antiepileptic drug levetiracetam (ucb L059) on severity of dystonic attacks were studied in a mutant hamster model of idiopathic generalized dystonia. Both drugs significantly decreased the severity of dystonia. In contrast to seizure models, in which levetiracetam is much more potent as an anticonvulsant than piracetam, the antidystonic potency of levetiracetam was only moderately higher than that of piracetam. The antidystonic activity of piracetam and levetiracetam was not associated with any behavioral side effects. The data indicate that piracetam and levetiracetam are interesting novel treatments for idiopathic dystonia.

PMID: 10729365, UI: 20195598


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Brain Res 2000 Mar 24;859(2):255-61

Anticonvulsant actions of nefiracetam on epileptic EL mice and their relation to peripheral-type benzodiazepine receptors.

Shiotani T, Nakamoto Y, Watabe S, Yoshii M, Nabeshima T

Department of Neuropsychopharmacology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Japan. [email protected]

Anticonvulsant actions of the nootropic drug nefiracetam were studied using EL mice, an animal model of epilepsy, in which peripheral-type benzodiazepine receptors (PBRs) might be involved in their epileptogenesis. Nefiracetam, when administered orally t o EL mice, inhibited convulsions induced by the PBR agonist, Ro 5 -4864, with an ED(50) of 17.2 mg/kg, whereas it did not inhibit the drug -induced convulsions in control DDY mice. When administered intravenously (i.v.) to DDY mice, nefiracetam and other piracetam-like nootropics inhibited the Ro 5-4864-induced convulsions in the sequence of nefiracetam>aniracetam>>oxiracetam, piracetam. Spontaneous EL mouse seizures were also inhibited by these nootropics with a similar rank order of potencies. Binding studies for PBRs, performed on crude membranes of brain tissues of these mice, revealed that [3H]Ro 5-4864 and [3H]PK 11195 bindings were both inhibited by micromolar concentrations of nootropic agents in the sequence of nefiracetam> aniracetam>>oxiracetam, piracetam. The results suggest that nefiracetam may exert an anticonvulsant

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action through interacting with a low-affinity type of PBR in the brain, and could be developed as a promising therapeutic drug for neurological disorders including epilepsies.

PMID: 10719072, UI: 20185374


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J Ethnopharmacol 2000 Jan;69(1):1-8


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Neurologia 1999 Dec;14 Suppl 6:77 -83

[New treatments in cerebrovascular diseases].


Davalos A

Unidad de Ictus Agudos, Hospital Universitari Doctor Josep Trueta, Girona. [email protected]

Acute stroke is a neurologic emergency which should be preferentially treated in a Stroke Unit. The applications of general therapeutic measures in these units decreases the mortality or dependence in 29% of the cases. Thrombolytic treatment with rt-PA in the first 3 hours of cerebral ischemia reduces the risk of mortality or dependence at 3 months by 51%. This treatment should be used in centers with an adequate organization and experience in the management of stroke. Careful patient selection allows a favorable conscious risk/benefit when rt-PA is used in clinical practice. In the last decade numerous neuroprotector drugs have been developed which, despite decreasing the volume of the infarction in animal models, have not currently achieved a reduction in the mortality and morbidity of cerebral infarction in clinical trials. Ebselen, citicoline, piracetam and clomethiazol have shown beneficial effects in preliminary studies or in some subgroups of patients, but their use based on evidence is not recommendable. Anticoagulants and antiplatelet drugs have not been shown to be effective in the acute phase of cerebral infarction. The neuroprotector effect of unfractionated heparin and glycoprotein IIb IIIa antagonists is still under study. Clopidogrel and the association of aspirin and dipiridamol are new alternatives to aspirin in the secondary prevention of cerebral infarction. Both options provide a lower risk of recurrence, and clopidogrel also shows better tolerance. The preventive effect of low intensity anticoagulation and statins is being analyzed in clinical studies.

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PMID: 10659607, UI: 20124832

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J Int Med Res 1999 Jul -Aug;27(4):201-5

Beneficial effect of piracetam monotherapy on post-ischaemic palatal myoclonus.

Karacostas D, Doskas T, Artemis N, Vadicolias K, Milonas I

B' Department of Neurology, Aristotelian University School of Medicine, AHEPA Hospital, Thessaloniki, Greece.

A 70-year-old hypertensive woman suffered a subarachnoid haemorrhage followed by delayed vasospasm in the basal cerebral arteries. This resulted in multiple ischaemic lesions in the right middle cerebral artery region and contralateral post-ischaemic palatal myoclonus. In this setting, piracetam administered in high doses (24 -36 g/day), abolished the myoclonus observed in this patient. Although there is evidence from case reports and clinical trials of the therapeutic efficacy of piracetam in patients with skeletal myoclonus of various causes, to our knowledge this is the first report indicating the beneficial effect of piracetam monotherapy on post-ischaemic palatal myoclonus.

PMID: 10599034, UI: 20067091


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Am J Chin Med 1999;27(3-4):289-98

Effects of acupuncture at pai-hui on the deficit of memory storage in rats.

Chang YH, Hiseh MT, Wu CR

Department of Acupuncture, China Medical College Hospital, Taichung, Taiwan.

In this study, we investigated the effects of Pai-Hui by acupuncture on cycloheximide (CXM)-induced impairment of the passive avoidance response in rats. Acupuncture at Pai-Hui (Go-20) treated 15 min before or immediately after training trial for 15 min significantly attenuated CXM-induced impairment of passive avoidance response in rats, but did not have the same effect 30 and 60 min before or 30 min after the training trial or before the retention trial. Acupuncture at Pai-Hui 15 min before the training trial for 15, 30 and 60 min significantly attenuated CXM-induced impairment of passive avoidance response in rats, and its efficacy paralleled the acupuncture duration. Furthermore, acupuncture at Pai-Hui did not attenuate scopolamine (SCOP)-induced impairment of passive avoidance response, but was slightly inhibited by SCOP at 0.3 mg/kg. Second, acupuncture at Pai-Hui attenuated p -chloroamphetamine (PCA)-induced impairment of passive avoidance response and was significantly antagonized by PCA at 1 mg/kg. These results suggest that acupuncture at Pai-Hui mainly affects the memory storage process and has preventive and immediate therapeutic effects on CXM-induced impairment of passive avoidance response. Its

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efficacy paralleled the acupuncture duration. The preventive effect of acupuncture at Pai-Hui on CXM-induced impairment is significantly reduced by serotonergic 5-HT releaser, and slightly by cholinergic manipulations.

PMID: 10592837, UI: 20060422


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J Clin Pharm Ther 1999 Oct;24(5):369-74

Piracetam in the treatment of schizophrenia: implications for the glutamate hypothesis of schizophrenia.

Noorbala AA, Akhondzadeh S, Davari-Ashtiani R, Amini -Nooshabadi H

Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran.

OBJECTIVE: There is a growing interest in investigating the role of glutamate receptors in the pathophysiology of schizophrenia. Indeed, the hyperdopaminergic theory of schizophrenia can explain only the positive symptoms of schizophrenia, whereas the glutamate hypothesis may provide a more comprehensive view of the illness. We undertook a trial to investigate whether the combination of haloperidol with piracetam, a nootropic agent which modulates the glutamate receptor positively was more effective than haloperidol alone. METHODS: Thirty patients who met the DSM IV criteria for schizophrenia completed the study. Patients were allocated in a random fashion, 14 to haloperidol 30 mg/day plus piracetam 3200 mg/day and 16 to haloperidol 30 mg/day plus placebo. RESULTS: Although both protocols significantly decreased the score of the positive symptoms, the negative symptoms, the general psychopathological symptoms and the total score of PANSS scale over the trial period, the combination of haloperidol and piracetam showed a significant superiority over haloperidol alone in the treatment of schizophrenic patients. CONCLUSION: Piracetam, a member of the nootropic class of drugs and a positive modulator of glutamate receptor, may be of therapeutic benefit in treating schizophrenic patients in combination with typical neuroleptics. However, a larger study to confirm our results is warranted

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PMID: 10583700, UI: 20051341


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Int J Psychophysiol 1999 Oct;34(1):81-7

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Naunyn Schmiedebergs Arch Pharmacol 1999 Oct;360(4):413-20

Effects of piracetam on pentylenetetrazol-kindling development, hippocampal potentiation phenomena and kindling-induced learning deficit.

Ruthrich H, Grecksch G, Krug M

Otto -von-Guericke University Magdeburg, Faculty of Medicine, Institute of Pharmacology and Toxicology, Germany.

Kindling is a generally accepted model for studying epilepsy development in the context of overexpression of processes of neuronal plasticity. In previous studies we have shown that establishment of kindling by repeated application of subconvulsive doses of pentylenetetrazol (PTZ) also led to marked changes in hippocampal excitability and an impairment in learning behaviour. With the intention of further investigating the relationship between kindling development, kindling-induced changes in excitability and learning deficits, rats were chemically kindled under pretreatment with the nootropic drug piracetam. Furthermore, we tested acute piracetam effects on developed kindling seizures, the learning deficit and potentiation effects. At the investigated dose piracetam did not influence the kindling development. The kindling-induced potentiation of hippocampal field potentials was significantly diminished in piracetam-pretreated rats. Piracetam acutely injected completely antagonized this potentiation effect. Piracetam brought about a significant improvement in impaired learning performance in rats pretreated during kindling induction and acutely injected before the learning experiment, respectively. Possible correlations between the suppressing of the kindling related potentiation in hippocampal structures by piracetam and its beneficial effect on learning impairment are discussed as antagonizing overexpression of potentiation in the course of kindling.

PMID: 10551278, UI: 20017440


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J Pharmacol Exp Ther 1999 Oct;291(1):99-106


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Alcohol 1999 Aug;19(1):65 -74

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Neurol Neurochir Pol 1998 Sep-Oct;32(5):1189-97


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Eur J Neurosci 1999 Aug;11(8):2597-608


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Biochemistry (Mosc) 1999 Jun;64(6):652-7


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An Otorrinolaringol Ibero Am 1999;26(3):271-91


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Pediatrics 1999 May;103(5 Pt 1):1078-9

Concern about Piracetam treatment for children with Down syndrome.

Holmes LB

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l Letter

PMID: 10357649, UI: 99277328


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Pharmacopsychiatry 1999 Mar;32 Suppl 1:54-60


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Piracetam in the treatment of cortical myoclonus.

Genton P, Guerrini R, Remy C

Centre Saint Paul, Marseille and Department of Neurophysiology, Hopital Pasteur, Nice, France.

This paper reviews existing publications on the use of piracetam for the treatment of cortical myoclonus of various etiologies and includes the personal experience of the authors in progressive myoclonus epilepsy. Two double-blind comparisons with placebo provided results which allow recommendations for the dosage and usage of piracetam in cortical myoclonus. Wide individual variation (7-24g daily) exists in dosage requirements but responses are dose-related so that dosage should be increased until an optimum effect is obtained. Tolerability after long-term use of piracetam in high dosage has been very good and without toxicity or serious adverse effects. Side effects have been occasional, mild and transient. The authors present their experience of 12 patients with progressive myoclonus epilepsy in whom the administration of up to 45 g piracetam daily, when added to existing anti-epileptic treatment, caused marked and sometimes spectacular improvement and was without significant adverse effects. Improvement was maintained for up to 7 years. The use of piracetam for disabling cortical myoclonus of any etiology, either as an addition to existing antimyoclonic drugs or as monotherapy, may bring about profound improvement in disability and quality of life. Piracetam should be considered a first-line drug for the treatment of cortical myoclonus.

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PMID: 10338109, UI: 99268431


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Piracetam in the treatment of acute stroke.

Orgogozo JM

Department of Neurology, Pellegrin Hospital, University of Bordeaux II, France.

The neuroprotective properties of the nootropic agent piracetam together with reported hemorrheologic and antithrombotic effects provided the rationale for the evaluation of piracetam in acute stroke. Pilot studies showed an increase in compromised regional cerebral blood flow and improvement in motor function, aphasia and level of consciousness. Subsequently the Piracetam in Acute Stroke Study (PASS) was performed and the chief results have recently been reported (Stroke 28 (1997) 2347-2352). This was a multicenter double-blind trial in 927 patients to determine whether, compared with placebo, piracetam improved outcome when given within 12 hours of the onset of acute ischemic stroke, confirmed by computed tomography within 24 hours of admission (but not necessarily prior to treatment). Patients received an initial iv bolus of placebo or 12g piracetam, 12g piracetam daily for 4 weeks and maintenance treatment for a further 8 weeks. Neurologic status at 4 weeks was the primary end point; secondary outcome measures were functional outcome and aphasia at 12 weeks. Results in aphasic patients have not previously been reported. Analysis was planned both in all patients (n = 927) and an early treatment subgroup (n = 460) treated within 6 hours of stroke onset. This period was subsequently redefined as 7 hours. Intention-to-treat analyses in the total population showed a significant (P = 0.04) increase compared with placebo in the number of patients recovered from aphasia but no significant neurologic or functional improvement. Post hoc analysis in the early treatment subgroup showed improved neurologic outcome (P = 0.07), better function (P = 0.02) and a greater recovery rate from aphasia (P = 0.02). Additional analysis in this early treatment subgroup confined to 360 patients with moderate and severe stroke showed significant improvement in all 3 outcomes. There was no significant difference in mortality between treatment groups after 12 weeks. There were fewer deaths in piracetam-treated patients in those patients in the intention-to-treat population admitted with primary hemorrhagic stroke.

PMID: 10338105, UI: 99268427


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Piracetam: novelty in a unique mode of action.

Muller WE, Eckert GP, Eckert A

Department of Pharmacology, Biocenter University of Frankfurt, Germany.

Extensive research of the recent years has demonstrated that piracetam is effective in the treatment of cognitive decline in aging and dementia. It is usually much more active in situations of impaired brain function. Accordingly, its mechanism of action has been associated with neurochemical deficits of the aged brain relevant to cognitive dysfunctions. Since many of these neurochemical deficits depend on changes of membrane properties, including fluidity, it is of special importance that piracetam not only modifies membrane properties by interacting with the polar head moieties of the phospholipid bilayer, but also that this effect is more pronounced in membranes of aged as opposed to young animal and human brains, and that this mechanism also has specific relevance for brain membranes of Alzheimer's disease patients. Altering membrane properties might also be involved in vascular effects of piracetam such as improved erythrocyte deformability and normalization of hyperactive platelet aggregation. This novel mechanism of piracetam thus combines a rather non-specific physico-chemical mode of action with the pharmacological and clinical experience with this unique drug - effects are always much more pronounced when function is impaired.

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PMID: 10338102, UI: 99268424


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Ann Pharmacother 1999 Jan;33(1):61-72

Medication-induced headache: overview and systematic review of therapeutic approaches.

Zed PJ, Loewen PS, Robinson G

Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.

OBJECTIVE: To review medication-induced headache (MIH) through a systematic evaluation of the literature regarding the pharmacologic management of this condition. METHODOLOGY: To identify and evaluate all pharmacologic interventions for MIH, we conducted a qualitative systematic review of the English-language literature from 1966 to June 1998 using MEDLINE. The following search terms were used: chronic daily headache,

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transformed migraine, analgesic withdrawal headache, analgesic rebound headache, drug-associated headache, medication-induced headache, detoxification, and dihydroergotamine. In addition, a review of the references from relevant literature was also conducted to collect reports not identified in the MEDLINE search. RESULTS: Numerous therapies for acute management of MIH have been evaluated, although no rigorously conducted clinical trials were identified. Therapies evaluated include abrupt withdrawal of analgesics, initiation of dihydroergotamine, nonsteroidal antiinflammatory agents, methylergonovine, dihydroergotamine, sumatriptan, amitriptyline, dexamethasone, piracetam, prothipendyl, and valproate. Epidemiology, diagnosis, clinical features, pathophysiology, and long -term prognosis of therapy are discussed and therapeutic guidelines are offered. CONCLUSIONS: MIH is an underrecognized and difficult condition affecting headache-prone patients. The published literature concerning treatment of patients with MIH is scant and of poor quality, making it difficult for clinicians to decide on appropriate therapy. Recognition and treatment of MIH may lead to a long -term improvement in headache relief for many patients. It appears that complete withdrawal of the medications being overused is required for favorable long-term results.

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PMID: 9972386, UI: 99138333


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Semin Neurol 1998;18(4):485-92

Neuroprotective therapy.

Hickenbottom SL, Grotta J

Department of Neurology, University of Texas at Houston Medical School, 77030, USA.

The concept of neuroprotection relies on the principle that delayed neuronal injury occurs after ischemia. The phenomenon of the "ischemic cascade" has been described, and each step along this cascade provides a target for therapeutic intervention. In animal models of global and focal cerebral ischemia, numerous preclinical studies have demonstrated various agents to be neuroprotective at different steps along this cascade. A wide variety of drugs has also been studied in humans. Ten classes of neuroprotective agents have reached phase III efficacy trials but have shown mixed results. They include calcium channel antagonists, NMDA receptor antagonists, lubeluzole, CDP-choline, the free radical scavenger tirilizad, anti-intercellular adhesion molecule -1 (ICAM-1) antibody, GM-1 ganglioside, clomethiazole, the sodium channel antagonist fosphenytoin, and piracetam. In the future, clinicians may have an armamentarium of treatments for acute ischemic stroke at their disposal, with a combination of agents directed at different sites in the ischemic cascade being the ultimate goal.

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PMID: 9932619, UI: 99129399

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Drug Metab Dispos 1999 Feb;27(2):250-4

In vitro evaluation of potential drug interactions with levetiracetam, a new antiepileptic agent.

Nicolas JM, Collart P, Gerin B, Mather G, Trager W, Levy R, Roba J

Department of Product Safety and Metabolism, UCB S.A. Pharma Sector, Braine-l'Alleud, Belgium.

Levetiracetam and its carboxylic metabolite (AcL) were tested for their potential inhibitory effect on 11 different drug metabolizing enzyme activities using human liver microsomes. The following specific assays were investigated: testosterone 6beta-hydroxylation [cytochrome P -450 3A4 (CYP3A4)], coumarin hydroxylation (CYP2A6), (R)-warfarin hydroxylation (CYP1A2), (S)-mephenytoin hydroxylation (CYP2C19), p-nitrophenol hydroxylation (CYP2E1) tolbutamide hydroxylation (CYP2C9), dextromethorphan O-demethylation (CYP2D6), epoxide hydrolase and UDP-glucuronyltransferase (UGT) toward paracetamol (UGT1*6), ethinyloestradiol (UGT1*1), p-nitrophenol (UGT(pl 6.2)), and valproic acid. None of these activities were affected by levetiracetam or AcL added at concentrations up to 1 mM. Additionally, primary cultures of rat hepatocytes were used to assess a potential inducing effect of levetiracetam on CYPs. Phenobarbital (2 mM), beta-naphtoflavone (40 microM), dexamethasone (1 microM), and phenytoin (up to 300 microM) were tested as positive controls. When added to cells for 48 h, all the positive controls increased 7-ethoxycoumarin O-deethylase activity demonstrating the inducibility of CYPs in the present culture conditions. By contrast, levetiracetam did not affect the activity up to 1 mM. The highest levetiracetam concentrations examined in the above in vitro studies are well in excess of those measured in the plasma of patients receiving therapeutic doses. It is thus concluded that levetiracetam is unlikely to produce pharmacokinetic interactions through inhibition of CYPs, UGTs, and epoxide hydrolase. Furthermore, based on the in vitro assays with rat hepatocytes, it could be speculated that levetiracetam does not act as a CYP inducer.

PMID: 9929511, UI: 99130038


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Izv Akad Nauk Ser Biol 1998 Nov-Dec;(6):758-61

[Heparin-piracetam complex and its effect on blood and blood circulation].


Kondashevskaia MV, Liapina LA

Moscow State University, Faculty of Biology, Moscow, Russia.

High-molecular-weight heparin-piracetam complex (1:1 w/w ratio) was obtained in vitro. The complex, its

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components, or physiological solution were introduced intraperitoneally in rats (0.3 ml, 0.1%). Piracetam had no effect on homeostasis. The heparin-piracetam complex had a more pronounced anticoagulant and fibrinolytic activities than the individual components. In addition, this complex accelerated blood flow in the brain. In conditions of acute hypoxia (a 12,000 -m altitude chamber), heparin protected animals from hypoxia more effectively than other substances.

PMID: 9891432, UI: 99108581


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Biochem Pharmacol 1999 Jan 15;57(2):163-70

Effect of piracetam on polyphosphoinositide metabolism, cytosolic calcium release, and oxidative burst in human polymorphonuclear cells: interaction with fMLP-induced stimulation.

Tissot M, Sarfati G, Roch-Arveiller M, Giroud JP

Departement de Pharmacologie, UPRES_A CNRS 8068, Hopital Cochin, Paris, France. [email protected]

We investigated the action of piracetam on human polymorphonuclear leukocyte (PMN) responsiveness in vitro. We first studied phosphoinositide metabolism and calcium release with and without fMLP (formyl-methionyl-leucyl-phenylalanine) stimulation. Piracetam at concentrations from 10(-4) to 10(-2) M induced a slight increase in inositol 1,4,5-trisphosphate (IP3) release and phosphatidylinositol 4,5-bisphosphate (PIP2) breakdown. At concentrations above 10( -3) M, piracetam sensitized PMNs to subsequent stimulation by fMLP used at subliminal concentrations (10(-9) and 10(-8) M), inducing a significant increase in IP3 release and PIP2 breakdown similar to that obtained with cells stimulated by the highest effective concentrations of fMLP (10(-7) and 10(-6) M). In the same way, piracetam greatly enhanced calcium release induced by weak concentrations of fMLP. However, piracetam had no effect on oxidative metabolism. We then studied the binding of (3H)fMLP to the PMN membrane in the presence of various concentrations of piracetam. We were not able to demonstrate an obvious action of piracetam either on receptor recruitment or on receptor affinity to fMLP. The difference between the actions of piracetam on phosphoinositide metabolism and calcium release on the one hand and oxidative burst on the other could be explained by an uncoupling of the triggering and activating effects of piracetam on PMNs. The enhancement by piracetam of intracellular cyclic AMP levels rapidly induced termination of the PMN response and accounted for the lack of effect on superoxide production. Thus, piracetam was able to modulate human PMN reactivity and in particular to exert a "priming effect" (rather due to structural modifications of the membrane), which might be of importance in infectious episodes given the absence of deleterious actions such as oxygen free radical production leading to tissue injury.

PMID: 9890564, UI: 99105570


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Clin Nucl Med 1999 Jan;24(1):29-34

SPECT monitoring of improved cerebral blood flow during long-term treatment of elderly patients with nootropic drugs.

Dormehl IC, Jordaan B, Oliver DW, Croft S

Atomic Energy Corporation, Institute for Life Sciences, University of Pretoria, Republic of South Africa. [email protected]

PURPOSE: In normal aging persons, oxygen and glucose consumption progressively decreases with reduced cerebral blood flow (CBF), which could be responsible for age-related changes in cognitive functions. A data processing model with the use of Tc-99m SPECT of the human brain has been developed and found to be sensitive for monitoring the effects of drugs that increase CBF. In this study, the effect of two vasodilator drugs (the combination of pentifylline and nicotinic acid versus piracetam) was compared with the effect of placebo on CBF. MATERIALS AND METHODS: Thirty elderly volunteers had three different procedures using the Peelproc method to spatially standardize and compare CBF patterns by SPECT before and after drug intervention. The 30 patients were divided into five groups of six persons each who were randomly assigned in a 1:1 ratio to the treatment sequences consisting of three phases: the combination of pentifylline and nicotinic acid (C), piracetam (N), and placebo (P), or C-N-P; P-N-C; P-C-N; N -C-P; C-P-N; or N -P-C. Phases 1 to 3 each consisted of a baseline recording of parameters (day 0), treatment for 60 days (days 1 to 60), and recording of parameters after treatment (day 61). RESULTS: In elderly human volunteers (ages, 52 to 70 years), after 2 months of oral treatment with a combination of pentifylline and nicotinic acid (800 mg pentifylline, 200 mg nicotinic acid daily), SPECT results for the Peel-proc program indicated a statistically significant improvement in CBF of the total brain, with a more pronounced improvement in the cerebellum and frontal regions, where a definite shift from abnormal to normal blood flow was detected. Spontaneous communication from most of the volunteers suggested that they experienced an improvement in memory and general well-being from the combination treatment. After 2 months of oral treatment with piracetam (2.4 g daily) in elderly human volunteers, SPECT results indicated a regional improvement in CBF, particularly in the cerebellum. However, no beneficial effects with this drug were spontaneously reported. CONCLUSION: The in vivo method to quantitatively monitor the progress of long-term drug therapy on CBF described here could be useful to assess and even direct changes in therapy.

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PMID: 9890490, UI: 99105496


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Behav Pharmacol 1997 Aug;8(4):293-308

Effects of psychoactive drugs on temporal discrimination in rats.

Bizot JC

Service de Pharmacologie, Centre d'Etudes du Bouchet, Vert -le-Petit, France.

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Male Wistar rats were trained, in two-lever operant chambers, to press one lever (L5) after the presentation of a conditioned stimulus (a light) for 5 s (CS5) or the other lever (L20) after a conditioned stimulus for 20 s (CS20). Various drugs were administered before experimental sessions, during which CS5, CS20 and a stimulus of the intermediate duration of 12 s (CS12) were randomly presented. Rats pretreated with vehicle made approximately 50% of presses on L5 after the presentation of CS12. Atropine, diazepam, desipramine, clomipramine and moderate doses of haloperidol or of scopolamine increased the percentage of responses made on L5 after the presentation of CS20 and/or CS12. These effects could be due to a reduction of the speed of an internal clock. High doses of either haloperidol or scopolamine decreased the percentage of correct responses, an effect that was interpreted as a disruption of temporal discrimination. Nicotine and d -amphetamine decreased the percentage of responses made on L5 after the presentation of CS5 and/or CS12, an effect that could reflect an acceleration in the speed of the internal clock. Physostigmine, buspirone, mianserin and piracetam did not consistently alter performance, suggesting that these drugs do not affect timing processes.

PMID: 9832989, UI: 99050183


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Psychopharmacol Bull 1998;34(3):391 -7

The pharmacological effects of ginkgo biloba, a plant extract, on the brain of dementia patients in comparison with tacrine.

Itil TM, Eralp E, Ahmed I, Kunitz A, Itil KZ

New York Institute for Medical Research, Tarrytown 10591, USA.

In 1994, a standardized dry extract of Ginkgo biloba leaves (SeGb), has been approved by German health authorities for the treatment of primary degenerative dementia and vascular dementia. More than 24 different brands of Ginkgo biloba extract are sold in the United States. Tacrine, also known as tetrahydroaminoacrine (THA), and donepezil are currently the only drugs approved in the United States for the treatment of Alzheimer's disease. Previous studies demonstrated that SeGb and tacrine induce significant pharmacological effects on the brains of young, healthy human males, as determined by bioelectrical activity measurements obtained using the quantitative pharmaco-electroencephalogram (QPEEG) method. The type of central nervous system (CNS) effects we have seen on computer-analyzed EEGs (CEEGs) after administration of tacrine or EGb suggests both are "cognitive activators" which are, as a class of products, characterized by a (prepost) relative increase of 7.5 to 13 Hz ("alpha") and decrease of 1.3 to 7.5 Hz ("delta" and "theta") activity. To determine whether EGb or tacrine had noticeable pharmacological effects on elderly subjects diagnosed with possible or probable Alzheimer's, the present open, uncontrolled trial was conducted. Data from 18 subjects (11 males, 7 females) at an average age of 67.4 years with light to moderate dementia (Mini Mental mean score = 23.7, ranges: 15-29 [Geriatric Depression Scale mean scores = 3.7; range: 3.2-5.4]) were analyzed for this presentation. Each subject was randomly administered a single oral "Test -Dose" of either 40 mg of tacrine or 240 mg of EGb2 in two separate sessions within 3- to 7-day intervals. Before drug administration and at 1- and 3-hour intervals after drug administration, CEEGs were recorded for a minimum of 10 minutes. The CEEGs were analyzed using Period Analysis programs we developed for QPEEG. The results indicated that both EGb and, to a lesser degree, tacrine induced pharmacological effects, as established by QPEEG measurements, in the CNS similar to those previously established in healthy, young subjects. The type of CNS effects produced by EGb (as established by HZI's CEEG psychotropic drug database) in elderly dementia patients were similar to those induced by tacrine responders as well as those seen after the administration of other "cognitive activators" (pramiracetam, vinpocetine, BMY-21502, suloctidil, and lisuride) and anti-dementia drugs approved in the United States or Europe (tacrine, donepezil, nimodipine, piracetam, and oxiracetam) from our database. The

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results also showed that 240 mg of EGb has typical cognitive activator CEEG profiles (responders) in more subjects (8 of 18) than 40 mg tacrine (3 of 18 subjects). Because of the small sample size, we could not test the hypothesis that subjects who showed cognitive activator-type pharmacological response to the first Test-Dose of EGb or tacrine also exhibit more therapeutic effects (compared to nonresponders) when drugs are administered chronically.

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PMID: 9803773, UI: 99020614


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Eur J Neurosci 1998 Jul;10(7):2238-43


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Ross Fiziol Zh Im I M Sechenova 1998 Mar;84(3):218-25

[Effects of diazepam and piracetam on the rat behavior responses after combined exposure to the low doses of ionizing radiation and heat].


Murzenok PP, Chura NA

Institute of Physiology of the Belaruss. Acad. Sci., Minsk.

Effects of low doses of ionizing radiation and heat on behavioural responses of white rats and effects of diazepam and pyracetam long after separate and combined exposure to the two factors were studied. These changes were not present in a month after cessation of the exposure. Certain features of the modulating effect of pyracetam on behavioural responses, were revealed.

PMID: 9742595, UI: 98415020


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Neuropharmacology 1998 Jun;37(6):815-25


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Arzneimittelforschung 1998 Jul;48(7):720-6

Dose-effect relationship of idebenone in an experimental cerebral deficit model. Pilot study in healthy young volunteers with piracetam as reference drug.

Schaffler K, Hadler D, Stark M

Institute for Pharmacodynamic Research, Munich, Germany.

Within a general cerebral deficit model--inspiratory hypoxia-the dose --effect relationship of idebenone (CAS 58186-27-9), an antioxidant, was studied with regard to selected electrophysiological and psychometric parameters. Seventeen healthy male volunteers (mean age = 32 years, mean BW = 75 kg) received three different oral medications: placebo, idebenone and piracetam (CAS 7491-74-9) as reference. The test drug idebenone was administered in five different dosages, ranging --in 60 mg steps --from 60 to 300 mg t.id. Piracetam was given at a dose level of 800 mg t.i.d. A strict dose -regimen was used in idebenone for safety reasons. Each dosage/medication--except idebenone 300 mg t.i.d.--was given for one week without washouts in between. On each 7th treatment day, pharmacodynamic assessments comprising electroretinography (ERG), auditory evoked potentials (AEP) and visual analogue scales (VAS) were run. Immediately after the phases with the lower dosages, the study was continued with the highest dosage of idebenone (300 mg t.i.d.) for a period of four weeks with pharmacodynamic assessments on the 7th, 14th and 28th day. In this pilot study, the target variable, the amplitude of the ERG b-wave indicated a definite antihypoxidotic effect after the highest dosage of idebenone. With 300 mg idebenone t.i.d., ERG b-wave amplitudes increased linearily with increasing duration of treatment. The 'central' AEP P2-amplitude demonstrated a different dose -effect relationship. AEP P2 -amplitudes increased with increasing dosages of idebenone. The prolongation of treatment with 300 mg t.i.d. resulted in no further improvement of this parameter (ceiling effect). Subjective ratings (VAS) by the volunteers confirmed the results seen in electrophysiological variables. The findings, however, remain to be confirmed within an adequate double-blind, crossover study design.

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l Clinical trial

PMID: 9706371, UI: 98371660


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Eksp Klin Farmakol 1998 Mar-Apr;61(2):65-8

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Neurol Neurochir Pol 1997 Nov -Dec;31(6):1101-9

[Piracetam treatment in ischemic stroke].

[Article in Polish]

Tomczykiewicz K, Domzal T

Kliniki Neurologicznej Centralnego Szpitala Klinicznego Wojskowej Akademii Medycznej, Warszawie.

The increase of interest in piracetam in the treatment of stroke has been noticed lately. The reason of that is the unique double-action of this drug which depends on: 1. its effect on vascular system, and 2. improving of the metabolic process in a nerve cell. The purpose of our work was the evaluation of the therapeutic action of piracetam in comparison with other drugs, which are applied in treating stroke. 171 patients were examined, and piracetam was given to 40 of them. The effects of the treatment were evaluated after 14 days of using piracetam in dose of 12.0 g i.v. The authors estimate, that this drug is efficient in ischaemic stroke. However, its definite superiority over other drugs has not been firmly stated.

PMID: 9591298, UI: 98253523


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Prog Neuropsychopharmacol Biol Psychiatry 1998 Jan;22(1):211-28


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Pediatr Neurol 1998 Jan;18(1):41-5


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Eksp Klin Farmakol 1997 Sep-Oct;60(5):15-8

[Dipeptide nootropic agent GVS-111 prevents accumulation of the lipid peroxidation products during immobilization].


Lysenko AV, Uskova NI, Ostrovskaia RU, Gudasheva TA, Voronina TA

Institute of Neurokibernetics, Rostov State Uneversity, Rostov-na-Donu, Russia.

Immobilization of rats in a narrow plastic chamber for 24 h caused a sharp increase in the level of diene conjugates and the content of schiff bases in the synaptosomes of the brain cortex as well as accumulation of extraerythrocytic hemoglobin in blood serum. The dipeptide nootropic agent GVS-111 (ethyl ether of phenylacetylprolylglycine), when administered 15 and particularly 60 min before immobilization reduced the accumulation of these products of lipid peroxidation in the brain and blood. GVS-111 demonstrated these signs of its antioxidant effect after a single i.p. injection in doses of 0.12 and 0.5 mg/kg. Pyracetam produced a similar effect on the listed parameters in injection in a dose of 300 mg/kg for three successive days. The protective effect of the new pyracetam dipeptide analog GVS-111 in relation to activation of free-radical processes induced by immobilization is additional proof of the antistress action of this dipeptide.

PMID: 9483398, UI: 98144392


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Behav Brain Res 1997 Dec;89(1-2):229 -36

Prevention of amitriptyline-induced avoidance impairment by tacrine in mice.

Pavone F, Battaglia M, Sansone M

Istituto di Psicobiologia e Psicofarmacologia, CNR, Roma, Italy. [email protected]

The effects of two cognition enhancers on avoidance impairment induced by the tricyclic antidepressant amitriptyline were assessed during shuttle-box avoidance acquisition and in previously trained mice of the DBA/2 strain. The nootropic agent piracetam (50, 100 or 200 mg/kg, i.p.) had slight or no effect in mice receiving amitriptyline (5 or 10 mg/kg, i.p.). Conversely, the acetylcholinesterase inhibitor tacrine (0.5, 1, 2 or 3 mg/kg, i.p.) prevented the avoidance impairment induced by 5 mg/kg amitriptyline on shuttle-box avoidance acquisition as well as on a previously learned avoidance response. The avoidance disrupting action produced by 10 mg/kg of the antidepressant drug was not affected by the anticholinesterase drug. The preventing action of tacrine seems specifically related to the avoidance impairment induced by amitriptyline, since the acetylcholinesterase inhibitor did not reduce, but enhanced the avoidance impairing action of the neuroleptic chlorpromazine. Taken together, the results indicate that amitriptyline-induced avoidance impairment, and the related preventing action of tacrine, may be ascribed to drug effects on the performance of the avoidance response, rather than to interferences with learning processes.

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PMID: 9475630, UI: 98133777


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Eksp Klin Farmakol 1997 Nov -Dec;60(6):62-70

[Pharmacokinetics of the nootropic drugs].


Boiko SS, Vitskova GIu, Zherdev VP

Laboratory of Pharmacokinetics and Neurochemical Pharmacology, Russian Academy of Medical Sciences 8, Moscow, Russia.

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PMID: 9460604, UI: 98121936


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Thromb Haemost 1998 Jan;79(1):222-7

Inhibitory effect of piracetam on platelet-rich thrombus formation in an animal model.

Stockmans F, Deberdt W, Nystrom A, Nystrom E, Stassen JM, Vermylen J, Deckmyn H

Center for Molecular and Vascular Biology, IRC, K.U. Leuven, Leuven-Kortrijk, Belgium.

Intravenous administration of piracetam to hamsters reduced the formation of a platelet-rich venous thrombus induced by a standardised crush injury, in a dose-dependent fashion with an IC50 of 68 +/- 8 mg/kg. 200 mg/kg piracetam also significantly reduced in vivo thrombus formation in rats. However, in vitro aggregation of rat platelets was only inhibited with piracetam-concentrations at least 10-fold higher than plasma concentrations (6.2 +/- 1.1 mM) obtained in the treated animals. No effects were seen on clotting tests. In vitro human platelet aggregation, induced by a variety of agonists, was inhibited by piracetam, with IC50's of 25-60 mM. The broad inhibition spectrum could be explained by the capacity of piracetam to prevent fibrinogen binding to activated human platelets. Ex vivo aggregations and bleeding times were only minimally affected after administration of 400 mg/kg piracetam i.v. to healthy male volunteers, resulting in peak plasma levels of 5.8 +/- 0.3 mM. A possible antiplatelet effect of piracetam could be due to the documented beneficial effect on red blood cell deformability

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leading to a putative reduction of ADP release by damaged erythrocytes. However similarly high concentrations were needed to prevent stirring-induced "spontaneous" platelet aggregation in human whole blood. It is concluded that the observed antithrombotic action of piracetam cannot satisfactorily be explained by an isolated direct effect on platelets. An additional influence of piracetam on the rheology of the circulating blood and/or on the vessel wall itself must therefore be taken into consideration.

PMID: 9459351, UI: 98119439


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Pharmacol Res 1997 Nov;36(5):373 -80

Economic evaluation of Nootropil in the treatment of acute stroke in France.

Murphy N, Kazek MP, Van Vleymen B, Melac M, Souetre E

Benefit International SNC, Gennevilliers, France.

The primary objective of this study was to investigate the economic impact of treatment of acute ischaemic stroke with piracetam vs placebo according to the societal perspective in France. Socio-demographic, clinical and resource utilisation data for piracetam and placebo patients during the acute phase following stroke was obtained from the Piracetam Acute Stroke Study (PASS) clinical trial database. The economic analysis was based on the population defined as being treated within 6 h 59 min following stroke and presenting an initial Orgogozo score of less than 55. Resource utilisation data concerning the rehabilitation phase, outpatient follow-up and institutionalisation was obtained from decision tree analysis. There was a higher percentage of autonomous patients in the piracetam group (27.8%) compared to placebo (22.9%). The mean duration of hospitalisation (autonomous 21.8 days; non-autonomous 30.3 days) and the cost of an autonomous patient was lower than a non-autonomous patient. The total cost per stroke patient receiving piracetam was estimated at 103 KF during the 6-month period, compared to 106 KF per placebo patient. The major cost driver was hospitalisation during the acute phase, representing approximately 50% of the total cost per patient. In patients with moderate to severe stroke treated within 6.59 h, piracetam was cost-effective compared to placebo over the 6-month study period.

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PMID: 9441728, UI: 98110719


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Zh Nevrol Psikhiatr Im S S Korsakova 1997;97(10):29 -34

[Nootropil in the treatment of disorders of the higher mental functions in patients with an ischemic stroke].


Burd GS, Gekht AB, Bogolepova AN, Buklina SB

47 patients with acute ischemic stroke were treated with nootropil (pyracetam, UCB, Belgium) from the first day of the disease (12 g, intravenously, by drops during 2 weeks, then 4.8 g, per os) on the background of basic therapy. There was revealed increase of spontaneous activity, expressive and impulsive speech, audio- and speaking memory (especially delayed memory), tactile, acoustic and visual gnosis, space praxis. There was observed more pronounced positive dynamics of functions of damaged hemisphere in patients with localisation of ischemic focus in left hemisphere. Meanwhile restoration was slower when ischemic focus was localized in right hemisphere. Restoration of high mental functions occurred to be faster during nootropil treatment as compared with basic therapy only. The conclusion was made that nootropil can be prescribed for the patients with hemispheric ischemic stroke and especially for the patients with alterations of cerebral circulation in system of internal carotid artery including such disturbances on the background of insufficiency of circulation in vertebrobasilar system.

PMID: 9424344, UI: 98031350


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Zh Nevrol Psikhiatr Im S S Korsakova 1997;97(10):24 -8

[The metabolic therapy of ischemic stroke: the use of nootropil].


Gusev EI, Burd GS, Gekht AB, Skvortsova VI, Selikhova MV, Pavlov NA, Bolotov DA, Beliakov VV, Vanichkin AV, Konstantinova MV

54 patients were treated by notropil (pyracetam). The results of therapy were evaluated statistically according to a number of clinical scales and neurophysiologic indices (EEG and evoked potentials with mapping of bioelectric activity). The results were compared with the data about 56 patients of the control group which were treated by traditional method without application of notropil. Notropil was applied by two ways: small doses (4-12 g daily) during 5 days or high doses (10-12 g daily) during 30 days from the moment when the patient admitted to the hospital. Intravenous injections of the drug were used in all cases as well as its internal administration. It was showed either efficiency of the drug, especially in high doses, in early beginning of the treatment and its duration for at least 30 days or good tolerance of the drug. Authors supposed that application of pyracetam is not adequate in strokes with severe disorders of consciousness and cerebral edema.

PMID: 9424343, UI: 98031349

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Stroke 1997 Dec;28(12):2347-52

Treatment of acute ischemic stroke with piracetam. Members of the Piracetam in Acute Stroke Study (PASS) Group.

De Deyn PP, Reuck JD, Deberdt W, Vlietinck R, Orgogozo JM

Department of Neurology, Middelheim Hospital, Antwerp, Belgium.

BACKGROUND AND PURPOSE: Piracetam, a nootropic agent with neuroprotective properties, has been reported in pilot studies to increase compromised regional cerebral blood flow in patients with acute stroke and, given soon after onset, to improve clinical outcome. We performed a multicenter, randomized, double-blind trial to test whether piracetam conferred benefit when given within 12 hours of the onset of acute ischemic stroke to a large group of patients. METHODS: Patients received placebo or 12 g piracetam as an initial intravenous bolus, 12 g daily for 4 weeks and 4.8 g daily for 8 weeks. The primary end point was neurologic outcome after 4 weeks as assessed by the Orgogozo scale. Functional status at 12 weeks as measured by the Barthel Index was the major secondary outcome. CT scan was performed within 24 hours of the onset of stroke but not necessarily before treatment. Analyses based on the intention to treat were performed in all randomized patients (n = 927) and in an "early treatment" population specified in the protocol as treatment within 6 hours of the onset of stroke but subsequently redefined as less than 7 hours after onset (n = 452). RESULTS: In the total population, outcome was similar with both treatments (the mean Orgogozo scale after 4 weeks: piracetam 57.7, placebo 57.6; the mean Barthel Index after 12 weeks: piracetam 55.8, placebo 53.1). Mortality at 12 weeks was 23.9% (111/464) in the piracetam group and 19.2% (89/463) in the placebo group (relative risk 1.24, 95% confidence interval, 0.97 to 1.59; P = .15). Deaths were fewer in the piracetam group in those patients in the intention -to-treat population admitted with primary hemorrhagic stroke. Post hoc analyses in the early treatment subgroup showed differences favoring piracetam relative to placebo in mean Orgogozo scale scores after 4 weeks (piracetam 60.4, placebo 54.9; P = .07) and Barthel Index scores at 12 weeks (piracetam 58.6, placebo 49.4; P = .02). Additional analyses within this subgroup, confined to 360 patients with moderate and severe stroke (initial Orgogozo scale score < 55), showed significant improvement on piracetam in both outcomes (P < .02). CONCLUSIONS: Piracetam did not influence outcome when given within 12 hours of the onset of acute ischemic stroke. Post hoc analyses suggest that piracetam may confer benefit when given within 7 hours of onset, particularly in patients with stroke of moderate and severe degree. A randomized, placebo-controlled, multicenter study, the Piracetam Acute Stroke Study II (PASS II) will soon begin.

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PMID: 9412612, UI: 98074088


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Eksp Klin Farmakol 1997 May -Jun;60(3):6-8

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J Ethnopharmacol 1997 Mar;56(1):45-54

Gastrodin and p-hydroxybenzyl alcohol facilitate memory consolidation and retrieval, but not acquisition, on the passive avoidance task in rats.

Hsieh MT, Wu CR, Chen CF

Institute of Chinese Pharmaceutical Sciences, China Medical College, Taichung, Taiwan, ROC.

Gastrodin (GAS) and p-hydroxybenzyl alcohol (HBA) which is an aglycone of gastrodin, are active ingredients of Gastrodia elata Blume. In this study, we attempted to investigate the effects of acute administration of GAS and HBA on learning and memory processes such as acquisition, consolidation and retrieval, on the passive avoidance task in rats; piracetam was used as a positive control. Scopolamine, impairing learning acquisition, shortened the step-through latency in the retention test in rats. GAS and HBA did not prolong the step-through latency induced by scopolamine in the passive avoidance task, but piracetam could prolong the step-through latency induced by scopolamine. Cycloheximide, impairing memory consolidation, shortened the step-through latency in the retention test in rats. GAS at 50 mg/kg, HBA at 5 mg/kg and piracetam at 100 mg/kg could prolong the step-through latency induced by cycloheximide in the passive avoidance task. Apomorphine, impairing memory retrieval, shortened the step-through latency in the retention test in rats. GAS at 5 mg/kg, HBA at 1 mg/kg and piracetam at 300 mg/kg could prolong the step-through latency induced by apomorphine in the passive avoidance task. From the above results, we concluded that the facilitating effects of HBA on learning and memory are better than those of GAS. In conclusion, GAS and HBA can improve cycloheximide- and apomorphine-induced amnesia, but not scopolamine-induced acquisition impairment in rats. Thus, GAS and HBA can facilitate memory consolidation and retrieval, but not acquisition. The facilitating effects of GAS and HBA are different from those of piracetam.

PMID: 9147253, UI: 97292742


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Arch Phys Med Rehabil 1997 Mar;78(3):245-50

Piracetam as an adjuvant to language therapy for aphasia: a randomized double-blind placebo-controlled pilot study.

Huber W, Willmes K, Poeck K, Van Vleymen B, Deberdt W

Department of Neurology, School of Logopedics, Rheinisch-Westfalische Technische Hochschule (RWTH), Braine-l'Alleud, Belgium.

OBJECTIVE: To determine whether piracetam 4.8 g/day together with intensive language therapy improved

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language function more than language therapy alone. DESIGN: Double-blind, placebo-controlled parallel group study. SETTING: Referral speech and language clinic of a university department of neurology. PATIENTS: Sixty-six inpatients with aphasia present between 4 weeks and 36 months. INTERVENTIONS: Intensive language therapy for 6 weeks in all patients. Thirty-two patients received piracetam 4.8 g daily and 34 patients received placebo. MAIN OUTCOME MEASURE: The Aachen Aphasia Test (AAT), a standardized procedure for evaluating the severity of aphasia, was performed at baseline and after 6 weeks' treatment. RESULTS: In 50 patients evaluated for efficacy, a trend toward improvement in the active group was observed in all subtests of the AAT. This trend was statistically significant for absolute differences in recovery of "written language" and "profile level." CONCLUSION: Piracetam appears to have a positive adjuvant effect on the recovery of aphasia in patients receiving intensive language therapy.

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PMID: 9084344, UI: 97238007


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Biochem Pharmacol 1997 Jan 24;53(2):135-40

Effects of piracetam on membrane fluidity in the aged mouse, rat, and human brain.

Muller WE, Koch S, Scheuer K, Rostock A, Bartsch R

Department of Psychopharmacology, Central Institute of Mental Health, Mannheim, Germany.

In vitro preincubation of brain membranes of aged mice with piracetam (0.1-1.0 mmol/L) enhanced membrane fluidity, as indicated by decreased anisotropy of the membrane-bound fluorescence probe 1,6-diphenyl-1,3,5-hexatriene (DPH). Piracetam had similar in vitro effects on brain membranes of aged rats and humans, but it did not alter brain membrane fluidity in young mice. Chronic treatment of young and aged rats with piracetam (300 mg/kg once daily) significantly increased membrane fluidity in some brain regions of the aged animals, but had no measurable effect on membrane fluidity in the young rats. The same treatment significantly improved active avoidance learning in the aged rats only. It is suggested that some of the pharmacological properties of piracetam can be explained by its effects on membrane fluidity.

PMID: 9037245, UI: 97188973


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Eksp Klin Farmakol 1996 Nov-Dec;59(6):3-5

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Neurosci Behav Physiol 1996 Nov-Dec;26(6):507 -15

Piracetam-induced changes in the functional activity of neurons as a possible mechanism for the effects of nootropic agents.

Verbnyi YaI, Derzhiruk LP, Mogilevskii AYa

Physical-Technical Low Temperature Institute, National Academy of Sciences of Ukraine, Khar'kov.

Studies were carried out on the effects of piracetam (4-20 mM) on the electrical activity of identified neurons in the isolated central nervous system of the pond snail in conditions of single-electrode intracellular stimulation and recording. Piracetam-induced changes were seen in 60-70% of the neurons studied. Different parameters showed different sensitivities to piracetam: the most frequent changes were in the action potential generation threshold, the slope and shape of the steady-state voltage -current characteristics of neuron membranes, and the appearance of piracetam-induced transmembrane ion currents. Nifedipine and cadmium ions, both of which are calcium channel blockers, generally reversed or weakened the effects of piracetam on the changes seen in test cells. This indicates that the effects of piracetam result from its action on calcium channels; selective changes in calcium channels may determine which piracetam-induced effects appear at the cellular level. It is hypothesized that the piracetam-sensitive cellular plasticity mechanisms may make a significant contribution to its nootropic action at the behavioral level.

PMID: 9121626, UI: 97173873


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Burns 1996 Sep;22(6):468-73

Hyperbaric oxygen therapy and piracetam decrease the early extension of deep partial-thickness burns.

Germonpre P, Reper P, Vanderkelen A

Center for Hyperbaric Oxygen Therapy, Military Hospital Queen Astrid, Brussels, Belgium.

During the first 24 h, a progression of the burn wound in histological depth or extension is often noted. This can only partially be prevented by the routinely used protocols of fluid resuscitation and burn wound dressing. In a rat model of 5% TBSA burn, hyperbaric oxygen therapy (HBOT) and piracetam were evaluated for their ability to further prevent this early deepening of the burn wound. After infliction of the burn wound, the animals were treated with an accepted basic burn wound treatment consisting of mafenide 10% solution humid dressings. They were then randomized into three groups: a control group (n = 10), receiving no other treatment, a HBOT group (n = 17), receiving 60 min of HBOT (203 kPa) twice daily, and a piracetam group (n = 19), receiving piracetam (200 mg/kg IM) twice daily. On the third day of treatment, the entire burn wound was exised and examined histologically. It was found that both HBOT and piracetam had statistically significant effects on the preservation of epidermal basal

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membrane (P < 0.001 and P < 0.01, respectively). HBOT, but not piracetam, further had significant effects on the destruction of skin appendages (P < or = 0.05 and P > 0.05, respectively) and on the degree of subepidermal inflammation, as measured by leucocyte infiltration (P < 0.001 and P > 0.05, respectively). Furthermore, the HBOT group showed significantly less leucocyte infiltration than the piracetam group (P < 0.01). It was concluded that, although the clinical importance of the small effects on skin appendage and basal membrane preservation may be questionable, the effect on subepidermal leucocyte infiltration is striking and warrants further investigation of the anti-inflammatory effects of HBOT and possibly piracetam.

PMID: 8884008, UI: 97038414


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Arzneimittelforschung 1996 Sep;46(9):844-7

Cerebral blood flow effects of piracetam, pentifylline, and nicotinic acid in the baboon model compared with the known effect of acetazolamide.

Jordaan B, Oliver DW, Dormehl IC, Hugo N

Department of Pharmacology, Potchefstroom University for Christian Higher Education, Republic of South Africa.

In normal aging humans there is a progressive decrease of oxygen and glucose consumption with a reduction of cerebral blood flow (CBF), which could be responsible for age-related changes in cognitive functions. A baboon model under anaesthesia using single photon emission computed tomography (SPECT) of the brain and the radiopharmaceutical hexamethylpropylene amine oxime (99mTc-HMPAO) has been developed and found to be sensitive to the effects of drugs that are known to increase CBF. In the present study, the effect of two haemorrheologically active drugs, viz a combination of pentifylline (CAS 1028-33-7) and nicotinic acid (CAS 59-67-6) vs. piracetam (CAS 7491 -74-9) were compared with the known effect of acetazolamide (CAS 59-66-5) on CBF in the baboon model using the 99mTc-HMPAO split dose method. Acetazolamide (p < 0.05) and the combination of pentifylline and nicotinic acid (p < 0.01) increased the CBF when compared with the control baseline. The CBF was not significantly increased upon treatment with piracetam, pentifylline alone and nicotinic acid alone, when compared with the control values for total brain ratios (p > 0.05). However, an increased regional effect was observed for piracetam. These results indicate that the above haemorrheologically active drugs exhibit specific but different effects on cerebral blood flow with possible clinical implications.

PMID: 8876930, UI: 97031002


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Pharmacopsychiatry 1996 Jul;29(4):150-5

Prescribing practice with cognition enhancers in outpatient care: are there differences regarding type of dementia?--Results of a

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representative survey in lower Saxony, Germany.

Stoppe G, Sandholzer H, Staedt J, Winter S, Kiefer J, Ruther E

Department of Psychiatry, University of Goettingen, Germany.

Previous studies of cognition enhancers have mainly focused on insufficiently defined groups of cognition disorders, e.g., "cerebral insufficiency". With regard to the various biological changes in senile dementia of Alzheimer's type (SDAT) and in vascular dementia (VD), which together make up the great majority of senile dementias, many authors have encouraged different studies of these types of dementias, especially since both can be diagnosed clinically with satisfying certainty. Since primary care physicians treat the majority of elderly and demented patients, they have their own experience with cognition enhancers. We were therefore interested to know, how far these physicians differ in their treatment of SDAT and VD. We performed a representative survey (response rate 83.2%; 145 family physicians and 14 neuropsychiatrists) in the Goettingen area. A written case vignette described a 70-year-old widow with moderate dementia and vascular risk factors which are easily treated with drugs. Two versions were randomly assigned, in which (version A) either a "typical" VD history or a typical SDAT history (version B) were described. After perusal, the physician was asked whether and which drugs he would choose to treat the cognitive disorders in this patient. Most frequently, piracetam (A/B: 25.6%/30.9%), ginkgo biloba (24.4%/28.4%), and nimodipine (14.1%/25.9%) were considered. Aspirin was cited by 29.5%(A) and 17.3%(B) of the physicians respectively. As far as the type of dementia was concerned, significant differences were found only for co -dergocrine, which was preferred in SDAT. The following inter-group trends were observed: family physicians considered ginkgo biloba more often than nimodipine or co-dergocrine. The results show the apparent importance of cost-and safety aspects, while the type of dementia has hardly any impact. The latter impression corresponds to the results of drug trials demonstrating no different efficacy. In our opinion, aspirin was not sufficiently taken into consideration.

PMID: 8858714, UI: 97011722


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Alcohol 1996 May-Jun;13(3):239-49

Piracetam promotes mossy fiber synaptic reorganization in rats withdrawn from alcohol.

Brandao F, Cadete -Leite A, Andrade JP, Madeira MD, Paula-Barbosa MM

Department of Anatomy, Porto Medical School, Portugal.

Prolonged alcohol intake affects the morphology of the hippocampal formation of the rat and the resulting alterations do not reverse after withdrawal. Actually, an increase of the degenerative activity might occur in this condition. This unexpected observation prompted us to test the efficacy of neuronoprotective drugs during withdrawal. Because in a previous study we found that piracetam, a cyclic derivative of GABA, once added during withdrawal impedes hippocampal cell loss, we decided to evaluate the effect of this compound at the synaptic level. Using unbiased stereological techniques, we estimated the total number of contacts between mossy fibers and CA3 pyramids, as well as the volume and the surface area of the respective pre - and postsynaptic compartments. We found that in piracetam-treated withdrawn rats the number of synapses was higher than that observed in nonpiracetam-treated and alcohol-fed animals. The mechanisms leading to the synaptic reorganization took place at the mossy fiber level. The postsynaptic compartment does not seem to participate in the reorganization. It is

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suggested that the role of piracetam in this process might depend on the protective effect that this compound has upon glutamatergic receptors.

PMID: 8734838, UI: 96316987


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Pharmacol Biochem Behav 1996 Apr;53(4):943-50

Piracetam and aniracetam antagonism of centrally active drug-induced antinociception.

Galeotti N, Ghelardini C, Bartolini A

Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.

The effects of the nootropic drugs piracetam and aniracetam on antinociception induced by baclofen, bicuculline, and picrotoxin and on baclofen-induced muscle relaxation were studied in mice. Antinociception was investigated using both the hot plate (thermal stimulus) and abdominal constriction (chemical stimulus) tests. Both behaviour inhibition and muscle relaxation were observed by using the rota-rod test. Piracetam (30 mg/kg, IP) and aniracetam (10 mg/kg, PO) reduced baclofen, bicuculline, and picrotoxin antinociception without modifying analgesia induced by non-GABAergic drugs such as morphine, physostigmine, clomipramine, and diphenhydramine. In this concentration range, piracetam, and aniracetam were also able to reduce the inhibition of rota -rod performance. At higher doses piracetam (100 mg/kg, IP) and aniracetam (100 mg/kg, PO) were able to completely prevent baclofen antinociception. However, when prevention of GABAergic antinociception was complete, piracetam and aniracetam were able to block non-GABAergic antinociception also. comparing the effects of piracetam and aniracetam with those exerted by the GABAB antagonist CGP 35348, a reduction of non-GABAergic analgesia was also observed using higher doses of CGP 35348 (2.5 micrograms per mouse ICV). The present results indicate that piracetam and aniracetam, by preventing both of the investigated effects of baclofen, have some selectivity against GABAB-mediated inhibition. The well-known activity of piracetam and aniracetam on learning and memory might, therefore, depend, at least in part, on the removal of inhibitory GABAB mechanisms that impair attention and cognitive functions.

PMID: 8801601, UI: 96250515


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Eksp Klin Farmakol 1996 Mar-Apr;59(2):6-8

[The effect of a low dose of piracetam on the activity of the dopaminergic system in the rat striatum].


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Budygin EA, Gainetdinov RR, Titov DA, Kovalev GI

The low-dose effect (100 mg/kg, intraperitoneally) of the nootropic drug pyracetam on some DA-ergic neurochemical parameters of the rat striatum, as well as on the locomotion activity of rats were studied using the "open-field" test. It was shown that pyracetam (l mM) in vitro increases the K(+)-stimulated (28 mM) DA release from the perfused isolated striatum to 148 +/- 14 pmole/mg tissue compared to the control animals: 101 +/- 10 pmole /mg (p < 0.05, Student's t -test). Pyracetam in a dose of 100 mg/kg increased the DA level and decreased the 5-HT level in the striatum homogenates: DA - to 121% and 5-HT-to 81% (p < 0.05), respectively. The content of DOPAC, HVA and 5-HIAA in the tissue remained the same. In addition to the mentioned effects pyracetam promoted the locomotion activity of rats in the "open field" -putative behavioral marker of the striatum DA-ergic function. Thus pyracetam is capable of modifying the DA-ergic activity of the rat striatum, thus stimulating the neuromediator release.

PMID: 8974570, UI: 96437322


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Brain Res 1996 Jan 22;707(1):13-21

Cholinergic improvement of a naturally-occurring memory deficit in the young rat.

Smith RD, Kistler MK, Cohen-Williams M, Coffin VL

Schering-Plough Research Institute, Kenilworth, NJ 07033-0539, USA.

In a single-trial, passive-avoidance response (PAR) paradigm, young rats at post-natal day (PND) 16 were found to exhibit a performance deficit that diminished progressively with age. When administered prior to training, single peripheral injections of cholinomimetic drugs, either a muscarinic agonist (arecoline, pilocarpine or oxotremorine), an acetylcholinesterase inhibitor (tacrine or E2020), or nicotine, increased the response latencies for young rats to that of adult levels in a dose -dependent manner (overall dose range = 0.003 microgram/kg-10 mg/kg). Neither the cholinergic antagonists scopolamine, atropine or mecamylamine, nor a series of non-cholinergic drugs, diazepam, haloperidol, phenobarbital, pargyline, D -amphetamine, imipramine, piracetam or N-methyl-D-aspartate (NMDA) increased PAR latencies. When 0.1 mg/kg scopolamine was given to young rats prior to arecoline, the dose -effect curve for enhanced latency times was shifted to the right. Higher doses of scopolamine completely blocked the effects of arecoline. Scopolamine (0.001-1.0 mg/kg) administered subsequent to, rather than before PAR training, blocked the usual arecoline-induced enhancement of response latencies. Alternatively, consolidation could be facilitated with different doses of tacrine (0.0003-10 mg/kg). These results demonstrate that young rats fail to remember the PAR but that retention for this task can be specifically enhanced with cholinomimetic drugs.

PMID: 8866709, UI: 97020330


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Wien Med Wochenschr 1996;146(21-22):546-8

[Therapy approaches in cerebral cognitive deficits--neuropsychiatric aspects].

[Article in German]

Reisecker F

Neurologisch-psychiatrischen Abteilung, Krankenhauses, Barmherzigen Bruder-Graz-Eggenberg.

According to the latest research the therapy of dementia includes following strategies: Above all there is a necessity for thoroughly diagnostic tests to exclude diseases which secondary induce reduced brain function. The early onset of non pharmacological treatments e.g. "brain-jogging" is essential. Pharmacological therapy with nootropics (e.g. Codergocrin, Nicergolin, Ginkgo biloba, Piracetam, Pyritinol, Naftidrofuryl) is recommended as early as possible, because they have no relevant side effects. Calcium antagonists may also be administered because of their neuroprotective properties. One pharmacological approach to enhance cholinergic functions involves inhibiting ACH-degradation by inhibiting acetylcholinesterase. Although this relatively new therapy has benefits, in some patients it has not been effective and has a potential to cause serious adverse (hepatic) events; only mild to medium severe dementias of Alzheimer's disease should be treated with this therapeutic principle. In the case of personality disorders there are psychotherapy and the administration of psychoactive drugs necessary.

PMID: 9092214, UI: 97170372


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Ter Arkh 1996;68(12):60-3


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Drugs Aging 1996 Jan;8(1):47-55

Drug treatment of Alzheimer's disease. Effects on caregiver burden and patient quality of life.

Hollister L, Gruber N

Department of Psychiatry and Behavioural Sciences, University of Texas Houston Health Science Center, USA.

Alzheimer's disease is a devastating illness that will become more common as the population ages. Although clinical diagnosis of the illness is not certain without histological examination of the brain, and misdiagnosis may occur,

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broad working criteria to help diagnose the likely presence of Alzheimer's disease are available. Thoughtful clinical evaluation improves diagnostic accuracy, and appropriately diagnosed patients are critical for involvement in research into new antidementia agents. Essential to the discovery of new drugs is careful measurement of illness response. A variety of scales--some aimed at patients, others at their caregivers, and yet others for clinicians--assess Alzheimer's disease severity, progression, symptom response, and quality of life. Of note, patient response is not the only measurement of treatment benefit today. Growing interest is also being placed on tracking the possible amelioration of caregiver 'burden'. This burden refers to the psychological, physical, and material costs of providing care for an Alzheimer's patient over long periods of time. A number of scales and questionnaires have been developed and are occasionally used. Many drugs have been tried in Alzheimer's disease, but very few have produced any benefit, and this is often modest. Ergoloid mesylates, initially thought to be effective, are now considered of little value. The cholinomimetic drugs, especially the acetylcholinesterase inhibitor tacrine, have provided a very modest benefit, slowing the progression of the illness for a number of months. No cognitive improvement has been noted with the various nootropic agents such as piracetam. Early studies with levacecarnine (acetyl-L-carnitine), a substance that facilitates the use of fatty acids, memantidine, the dimethyl derivative of amantidine, and the calcium channel blocker nimodipine, have shown some promise, but require larger, more rigorous studies. As mentioned above, documenting effects in individual patients is crucial; examining for potential benefit to caregivers is a growing part of research design. Current treatment efforts will become more sophisticated as a deeper understanding of the neurobiology of Alzheimer's disease develops. For the immediate future, the goal is not cure but slowing of the disease process. Achieving this limited goal would have a substantial impact on the financial and human costs of the illness.

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PMID: 8785468, UI: 96263637


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Yao Hsueh Hsueh Pao 1996;31(2):91-4

[Antagonism of piracetam on the amnestic effect of diazepam in mice].

[Article in Chinese]

Pan JC, Zhang SS

Department of Pharmacology, Wenzhou Medical College.

In step-down test, diazepam (1 mg.kg-1 po, 1 h before training) was shown to significantly impair memory acquisition in mice. But piracetam (200 mg.kg-1 ip, 1 h before training) was found to improve the diazepam -induced impairments of learning. By photocell cage method, piracetam showed no significant inhibitory effect on the diazepam-induced spontaneous motor activity in mice. In Y-maze test, Glutamic acid (0.1 microgram, icv, 3 min before training) significantly improved learning in normal mice and the amnesic effect of GABA and diazepam were completely antagonized by Glutamic acid and piracetam (200 mg.kg-1 ip, 1 h before training). These results suggest that increasing GABA-ergic neuronal transmission is unfavorable to learning and memory, but increasing Glu-ergic transmission is contrary to the former. It seemed that the presence of Glu/GABA system in the brain could regulate learning and memory.

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PMID: 8762467, UI: 96286734


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Dtsch Med Wochenschr 1995 Nov 24;120(47):1614-9

[Factors influencing the prescribing of nootropic drugs. Results of a representative inquiry in Lower Saxony].

[Article in German]

Stoppe G, Sandholzer H, Staedt J, Kiefer J, Winter S, Kochen MM, Ruther E

Psychiatrische Klinik und Poliklinik, Universitat Gottingen.

AIM OF INVESTIGATION: To discover (1) to what extent patients' wishes and the extent of any abnormality of brain performance influence the frequency with which "nootropic" drugs (those thought to affect brain activity, e.g. piracetam, pyritinol, or improve cerebral circulation, e.g. xanthine derivatives, Ginkgo biloba, secale alkaloids, calcium antagonists) are prescribed; (2) the medical practitioner's expectations of the effectiveness of such medications. METHOD: In a personal interview, 145 family doctors and 14 neurologists in private practice in the Gottingen area of Germany (participation rate: 83.2% of those asked to participate) were questioned about fictitious cases (case 1: mild memory problem with or without expressed wish for medication; case 2: moderate dementia, of Alzheimer or multi-infarct type). The previously arranged interviews, which took place in the doctors' practice rooms, consisted of standardized open questions to the written case reports. RESULTS: Regardless of the wish of the patient and the extent and type of the abnormal brain function about 70% of all participating doctors would prescribe those drugs, even though about 56% had doubts about their effectiveness. About 28% expected a positive effect on brain performance. A nearly equal proportion of doctors would continue an existing drug regimen as would prescribe one. CONCLUSION: The prescription of the named group of drugs is influenced less by medical criteria than by factors which concern doctor-patient relationship.

PMID: 7493562, UI: 96096506


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Z Gerontol Geriatr 1995 Nov-Dec;28(6):457-62

[Possibilities and limits of therapy of cognition disorders in the elderly].

[Article in German]

Hoyer S

Arbeitsgruppe Hirnstoffwechsel, Universitat Im Neuenheimer Feld, Heidelberg.

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Pharmacological treatment of patients suffering from sporadic late-onset dementia of Alzheimer type (DAT) is controversely discussed, omitting the fact that this age-related most frequently occurring DAT form is based on a heterogenous pathogenesis, but forms a rather uniform clinical phenotype. Furthermore, sporadic late-onset DAT is influenced in two different ways, 1) by the aging process, and 2) by the disease process itself. In this context, changes in brain glucose/energy metabolism, maintenance of calcium homeostasis, and membrane stability are discussed. It is concluded that some nootropic drugs such as dihydroergotoxine, Ginkgo biloba, nicergoline, nimodipine, piracetam, and pyritinol-HCI, registered in FRG, exert a positive effect on the clinical phenotype in approximately 30% of treated cases being in an incipient state of the disease. This effect has not been proven for advanced states. There is clear evidence that Ginkgo biloba acts on membrane lability, nimodipine on the maintenance of calcium homeostasis, and both piracetam and pyritinol-HCI on glucose/energy metabolism. These diverse effects on different underlying pathogenetic abnormalities can be assumed to be the reason why only subgroups of patients respond to the treatment with nootropic drugs.

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PMID: 8581765, UI: 96151376


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Pharmacol Biochem Behav 1995 Nov;52(3):637 -40


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Bull Cancer 1995 Nov;82(11):929-38

[In vitro effects of piracetam on the radiosensitivity of hypoxic cells].

[Article in French]

Lagarde P, Gheuens EE, De Pooter CM, De Bruijn EA, van der Heyden S, Chomy F, Van Oosterom AT, Scalliet PG

Laboratoire de cancerologie experimentale, universite d'Anvers (UIA), Wilrijk, France.

This paper describes the adaptation of the MTT assay to hypoxic conditions in order to test the in vitro effect of piracetam on hypoxic cells and particularly on the radiosensitivity of hypoxic cells since this drug has shown clinical effect on acute and chronic hypoxia. The V79 cell line was selected by reference to preliminary hypoxic experiments using clonogenic assay and euoxic experiments using clonogenic and MTT assays. Cell growth and survival in our hypoxic conditions were assessed using MTT assay with an enclosure and special 48-well plates both made of glass. Growth curves on glass versus reference polystyrene plates were comparable and confirm the validity of using special glass plates. Growth curves on glass plates after 1-hour exposure to nitrogen versus air were comparable, so there is

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no bias effect due to gas composition. Survival curves using MTT versus reference clonogenic assay were comparable after radiation exposure in eu- and hypoxic conditions, and confirm the validity of our original technique for creating hypoxia. The Oxygen Enhancement Ratio was of about 3 for 1-hour hypoxic exposure. Piracetam gave no cytotoxic effect up to 10 mM of piracetam. Growth curves after continuous drug exposure and 1-hour euoxic versus hypoxic exposure gave no cytotoxic effect up to 10 mM of piracetam. Survival curves after continuous drug exposure to 10 mM of piracetam gave no significant effect on the radiosensitivity of hypoxic V79 cells using MTT or clonogenic assay. However, this does not preclude a potential in vivo effect of piracetam on the radiosensitivity owing to its action on microcirculation and its rheologic properties. The adaptation of the MTT assay to hypoxic irradiation conditions yields the easy screening of radiosensitizing drugs: shorter incubation, semi-automatic method and simultaneous analysis with different serial concentrations thanks to the special 48-well glass plates.

PMID: 8535019, UI: 96140493


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Pharmacol Res 1995 Sep;32(3):115-22

Nootropic drugs have different effects on kindling-induced learning deficits in rats.

Becker A, Grecksch G

Otto von Guericke University, Magdeburg, Germany.

Kindling represents an accepted model of human epileptogenesis. Furthermore, it has been demonstrated that kindled rats show a diminished learning performance in an active avoidance task. In our study we administered different nootropic drugs to kindled rats to test their effects on learning a two-way active avoidance task in the shuttle-box. Kindling was induced by repeated intraperitoneal injections of 45 mg kg-1 pentylenetetrazol (PTZ) once every 48 h. The substances vinpocetine (0.1 and 1.0 mg kg-1), methylglucamin orotate (225 and 450 mg kg-1), piracetam (100 mg kg-1), and meclofenoxate (100 mg kg-1) were administered during kindling development and after kindling completion prior to each session in the learning experiment. The nootropic drugs had little if any effect on severity of seizures. Concerning their effect on learning the substances each acted in a specific manner. Methylglucamin orotate enhanced the learning deficit induced by kindling. Meclofenoxate injected prior to the kindling stimulation was ineffective, whereas administration prior to the learning test improved the learning performance effectively. A complementary action was shown in experiments with vinpocetine. Only piracetam prevented the occurrence of kindling -induced learning deficits regardless the administration schedule.

PMID: 8745340, UI: 96361756


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Eur J Pharmacol 1995 Aug 15;281(3):R11-3

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Effects of putative cognition enhancers on the NMDA receptor by [3H]MK801 binding.

Hamelin SM, Lehmann JC

Department of Neurosurgery, Medical College of Pennsylvania and Hahnemann University, Philadelphia 19102-1192, USA.

Piracetam, aniracetam, and D-cycloserine were tested for their ability to reduce inhibition of [3H]MK801 (dizocilpine) binding by 100 microM kynurenate. Piracetam (100 microM-1 mM) failed to reduce inhibition by kynurenate but stimulated [3H]MK801 binding in the absence of kynurenate. In contrast, D-cycloserine (30 microM-1 mM) and aniracetam markedly reduced this inhibition by kynurenate. Thus, cognition enhancers might function via at least some subtypes of NMDA receptors.

PMID: 8521903, UI: 96047118


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J Neurochem 1995 Aug;65(2):912-8

[3H]aniracetam binds to specific recognition sites in brain membranes.

Fallarino F, Genazzani AA, Silla S, L'Episcopo MR, Camici O, Corazzi L, Nicoletti F, Fioretti MC

Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Italy.

[3H]Aniracetam bound to specific and saturable recognition sites in membranes prepared from discrete regions of rat brain. In crude membrane preparation from rat cerebral cortex, specific binding was Na+ independent, was still largely detectable at low temperature (4 degrees C), and underwent rapid dissociation. Scatchard analysis of [3H]aniracetam binding revealed a single population of sites with an apparent KD value of approximately 70 nM and a maximal density of 3.5 pmol/mg of protein. Specifically bound [3H]aniracetam was not displaced by various metabolites of aniracetam, nor by other pyrrolidinone-containing nootropic drugs such as piracetam or oxiracetam. Subcellular distribution studies showed that a high percentage of specific [3H]aniracetam binding was present in purified synaptosomes or mitochondria, whereas specific binding was low in the myelin fraction. The possibility that at least some [3H]aniracetam binding sites are associated with glutamate receptors is supported by the evidence that specific binding was abolished when membranes were preincubated at 37 degrees C under fast shaking (a procedure that substantially reduced the amount of glutamate trapped in the membranes) and could be restored after addition of either glutamate or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) but not kainate. The action of AMPA was antagonized by DNQX, which also reduced specific [3H]aniracetam binding in unwashed membranes. High levels of [3H]aniracetam binding were detected in hippocampal, cortical, or cerebellar membranes, which contain a high density of excitatory amino acid receptors.

PMID: 7616253, UI: 95341331


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Biull Eksp Biol Med 1995 Jul;120(7):60 -1

[Effect of low doses of piracetam on conditional reflex memory in rats].


Tushmalova NA, Pragina LL, Inozemtsev AN, Gumargalieva KZ, Solov'ev AG, Burlakova EB

PMID: 8527785, UI: 96141022


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Fortschr Med 1995 Jun 30;113(18):288-90

[Piracetam infusions in acute tinnitus and sudden deafness].

[Article in German]

Gutmann R, Mees K

Klinik und Poliklinik fur Hals-, Nasen- und Ohrenkranke, Ludwig-Maximilians-Universitat Munchen.

In a prospective randomised clinical study on 39 patients with tinnitus and sudden hearing loss the therapeutic efficacy of piracetam/HAES 6% was compared with that of naftidrofuryl/HAES 6%. The two groups of patients were comparable in terms of demographic and audiological baseline data. The parameters evaluated were hearing improvement and the reduction in intensity of tinnitus. Improvement in hearing was 15 dB (piracetam) versus 18.5 dB (naftidrofuryl). The improvement in tinnitus amounted 27 dB (piracetam) and 19.9 dB (naftidrofuryl). Both differences were not significant. Tolerability was very good in both groups. Piracetam, which improves rheology and has a positive effect on metabolism, would appear of particular interest for the treatment of acute tinnitus.

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PMID: 7657193, UI: 95386026


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Eksp Klin Farmakol 1995 May-Jun;58(3):15-6

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[A comparative analysis of the effect of nootropic preparations with different chemical structures on the failure of the escape reaction in rats].


Inozemtsev AN, Pragina PL, Firova FA, Trofimov SS, Gudasheva TA, Tushmalova NA, Ostrovskaia RU, Voronina TA

The nootropic agents pyroglutamyl-D-alanine amide (TGS-20), mechlofenoxate, and mexidole versus piracetam were tested for their effects on the reversible impairments of cognitive brain functions, on the demolition of active avoidance responses in rats. TGS-20 (1 mg/kg/day) and mexidole (10 mg/kg/day) injected intraperitoneally 30 minutes prior to the experiment showed a normalizing effect in smaller doses than did piracetam (300 mg/kg/day). Mechlofenoxate (50 mg/kg/day) displayed a lower protective effect.

PMID: 7663285, UI: 95392329


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Alcohol 1995 May-Jun;12(3):279-88


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Neurosci Lett 1995 Mar 31;188(3):163-6

Nootropic compound L-pyroglutamyl-D-alanine-amide restores hippocampal long-term potentiation impaired by exposure to ethanol in rats.

Chepkova AN, Doreulee NV, Trofimov SS, Gudasheva TA, Ostrovskaya RU, Skrebitsky VG

Brain Research Institute, Russian Academy of Medical Sciences, Moscow.

The characteristics of long -term potentiation (LTP) in the hippocampus of rats prenatally exposed to ethanol and treated postnatally with nootropic compounds L-pyroglutamyl-D-alanine-amide (L -pGlu-D-AlaNH2, PGA) or piracetam were studied using in vitro slice preparations. LTP was induced in the CA1 region by the orthodromic stimulation of the stratum radiatum with one train of 100 pulses (100 Hz, 1 s). The probability of LTP development in the hippocampus of young rats was significantly reduced by prenatal exposure to alcohol. This plasticity deficit was completely reversed by daily injections of PGA, 1 mg/kg for 12 days (8-19 days of postnatal development) but not of piracetam, 100 mg/kg. PGA (0.5 microM) also prevented the inhibition of LTP development in hippocampal slices perfused with ethanol, 20 or 50 mM. The data indicate that PGA effectively restores synaptic plasticity after

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both prenatal and acute exposure to ethanol and suggest that impaired LTP may be a useful model for studying the mechanisms of action of nootropic compounds.

PMID: 7609900, UI: 95334218


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Behav Brain Res 1995 Jan 23;66(1-2):143-50

Therapeutic approaches for memory impairments.

Hock FJ

HOECHST AG, General Pharmacology Research, Pharmacological Screening, Frankfurt/M., Germany.

Pharmacological treatment strategies for the treatment in dementia disorders were described. A selection of the 15 different classes described by Frostl and Maitre was made. In the paper there were included and described in detail the following classes: piracetam-type compounds, co-dergocrine-type compounds, vasodilators and haemorheological agents, cholinesterase inhibitors, ACTH and vasopressin analogs and angiotensin II and angiotensin converting enzyme inhibitors. Some compounds e.g. propentofylline, vincamine, THA and RA-octil were described in more detail.

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PMID: 7755885, UI: 95275430


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Med Tr Prom Ekol 1995;(10):26-8


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Pharmacol Biochem Behav 1994 Nov;49(3):683-8

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Acta Physiol Pharmacol Bulg 1990;16(1):25-31


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Acta Physiol Pharmacol Bulg 1988;14(1):3-13

Comparative studies on the effects of the nootropic drugs adafenoxate, meclofenoxate and piracetam, and of citicholine on scopolamine-impaired memory, exploratory behavior and physical capabilities (experiments on rats and mice).

Petkov VD, Mosharrof AH, Petkov VV

Institute of Physiology, Bulgarian Academy of Sciences, Sofia.

The effects of adafenoxate (Adf), meclofenoxate (Mf), piracetam (Pc), and citicholine (CCh) on scopolamine (Scop)--impaired memory and exploratory behavior (experiments on rats) and on physical capabilities (experiments on mice) were studied. In the experiments with scopolamine (2 mg/kg i.p.) we used the step-through passive avoidance method to determine the memory changes. In the case of single treatment with the drugs tested scopolamine was injected immediately after training and Adf, Mf, and CCh at doses of 20 and 100 mg/kg and Pc at a dose of 100 mg/kg were administered immediately after scopolamine. In the case of multiple administration the drugs were applied at the same doses for 7 days before training. Scopolamine was injected immediately after training. Retention tests were given 3 and 24 hours later. All the four drugs tested prevented to a large extent or completely the scopolamine-induced retrograde amnesia. However, significant quantitative differences in the antiamnestic effects of the drugs tested were observed. The effects of the four drugs on exploratory behavior were tested in the Opto Varimex apparatus. After 7-day treatment with the drugs at the doses utilized, the behavior of experimental animals was observed for 10 min, checking out the changes in the frequency of rearing, ambulation, and rotation. Only Adf at a dose of 50 mg/kg significantly decreased rearing and ambulation frequencies; this effect was considered to be an expression of accelerated habituation. The physical capabilities of mice were studied, using the method of treadmill (revolving drum activity cage) training. Before the experiment the mice received orally Adf, Mf, and Pc at a dose of 100 mg/kg or were injected intraperitoneally with CCh at doses of 50 and 100 mg/kg once daily for 7 days. The number of revolutions of the drum cages was counted for 4 hours. Only Pc significantly increased the physical capabilities of mice and much delayed the occurrence of fatigue.

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PMID: 3136617, UI: 88306803


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Psychopharmacology (Berl) 1987;92(1):58-67


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Clin Neuropharmacol 1986;9 Suppl 3:S39-47

Effect of oxiracetam and piracetam on central cholinergic mechanisms and active-avoidance acquisition.

Spignoli G, Pedata F, Giovannelli L, Banfi S, Moroni F, Pepeu G

Oxiracetam at 100 and 300 mg/kg i.p. dose levels increased acetylcholine (ACh) utilization in the rat cerebral cortex and hippocampus. ACh utilization was assessed by measuring, with a gas chromatographic method, the decrease in ACh level after inhibiting its synthesis by 15 micrograms intracerebroventricularly (i.c.v.) injection of hemicholinium (HC-3). ACh steady state levels were not affected. Piracetam (300 mg/kg i.p.) also increased ACh utilization in the hippocampus. Repeated daily administration of oxiracetam 100 mg/kg i.p. caused a 31% increase in high-affinity choline uptake (HACU) in the hippocampus. A single administration of 300 mg/kg i.p. of oxiracetam and piracetam also increased HACU rate in the hippocampus. However, the effect of piracetam was over within 3 h, while 3 h after its administration oxiracetam still caused a 40% increase in HACU rate. Oxiracetam (100 mg/kg i.p.) significantly antagonized the impairment in the acquisition of an active-avoidance conditioned response (pole climbing) associated with the inhibition of ACh synthesis by HC-3. These results indicate that oxiracetam enhances the activity of the septohippocampal cholinergic pathways, and to a lesser extent, of the cortical cholinergic network.

PMID: 3594455, UI: 87244094


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Life Sci 1984 Sep 10;35(11):1183-9

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Effect of piracetam plus choline treatment on hippocampal rhythmic slow activity (RSA) and behavior in rabbits.

Fontani G, Grazzi F, Meucci M

The effects of chronic treatment with piracetam (100 mg/Kg) plus choline (100 mg/Kg) on rabbits' hippocampal electrical activity and behavior have been studied. Animals were exposed to a neutral environment, in the absence of any external stimulus, and then to an object and a stuffed sparrow-hawk. Results show a drug related reduction in the amount of the hippocampal rhythmic slow activity (RSA) and an increase in RSA high frequency values in the presence of the object and of the stuffed animal, but not in the neutral environment. This would suggest that piracetam plus choline treatment has an effect on RSA in situations in which selective attention is required.

PMID: 6472050, UI: 84294622


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Pharmacol Biochem Behav 1984 Aug;21(2):209-12


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Biull Eksp Biol Med 1983 Jan;95(1):52 -4

[Experimental substantiation of the possible optimization of integrative brain activity by the psychotropic drugs].


Selivanova AT, Markova AE, Mutovkina LG, Potapenko EG

The authors studied the influence of psychotropic drugs on nervous process integration corresponding to an external stereotype of the conditioned reflexes. The latter ones were worked out in dogs by the method of motor situational conditioned reflexes. The drugs that block M -choline- and adrenoreceptors (amizyl, amedin, pyrroxan) decreased

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the integration level. At the same time they optimized conditioned reflex activity and raised the integration coefficient of drugs having different action mechanisms: N -cholinolytic (pediphen), adrenostimulant (sydnocarb), and anticholinesterase (armine). Nootropyl (piracetam) produced the most powerful action. A suggestion is made about chemical heterogeneity of integrative mechanisms of higher nervous activity and about possibilities of optimizing disturbed integration induced by the influences on various neurotransmitter brain systems.

PMID: 6830960, UI: 83154088


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Neurobiol Aging 1981 Summer;2(2):105-1

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piracetam inpiracetam informationformation

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