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Piracetam and vigilance. A study of EEG changes and clinical effects in gerontopsychiatric patients
Abstract
The electroencephalographic and clinical effects of piracetam were studied in a group of 11 hospitalized gerontopsychiatric patients treated with a daily dosage of 4.8 g for 8--13 months. The EEG was evaluated by power spectral analysis, followed by a principal component analysis of frequency parameters. The statistical analysis of the resulting factor scores shows that piracetam induces significant EEG changes: decrease of slow frequencies, augmentation and acceleration of alpha-activity and increase of beta-activity. These EEG changes, indicating an increase in vigilance, correspond clinically to an improvement of communicative behavior and cognitive functioning.
... Piracetam has been reported to possess a beneficial eVect in patients with mild dementia and with impaired cognitive function. 26 27 It may also increase vigilance 28 and improve dyslexia. 29 30 These eVects may partly explain our findings. ...
To compare the efficacy, tolerability, and safety of three daily dosage regimens of oral piracetam in patients with progressive myoclonus epilepsy.
Twenty patients (12 men, eight women), aged 17-43 years, with classical Unverricht-Lundborg disease were enrolled in a multicentre, randomised, double blind trial of crossover design in which the effects of daily doses of 9.6 g, 16.8 g, and 24 g piracetam, given in two divided doses, were compared with placebo. The crossover design was such that patients received placebo and two of the three dosage regimens of piracetam, each for two weeks, for a total treatment period of six weeks and thus without wash out between each treatment phase. The primary outcome measure was a sum score representing the adjusted total of the ratings of six components of a myoclonus rating scale in which stimulus sensitivity, motor impairment, functional disability, handwriting, and global assessments by investigators and patients were scored. Sequential clinical assessments were made by the same neurologist in the same environment at the same time of day.
Treatment with 24 g/day piracetam produced significant and clinically relevant improvement in the primary outcome measure of mean sum score (p=0.005) and in the means of its subtests of motor impairment (p=0.02), functional disability (p=0.003), and in global assessments by both investigator (p=0.002) and patient (p=0.01). Significant improvement in functional disability was also found with daily doses of 9.6 g and 16.8 g. The dose-effect relation was linear and significant. More patients showed clinically relevant improvement with the highest dosage and, in individual patients, increasing the dose improved response. Piracetam was well tolerated and adverse effects were few, mild, and transient.
This study provides further evidence that piracetam is an effective and safe medication in patients with Unverricht-Lundborg disease. In addition, it shows that a dose of 24 g is highly beneficial, more effective than lower doses and that a dose-effect relation exists. There is considerable variation in optimal individual dosage.
Mit seinem Vigilanzkonzept hat der englische Neurologe Head (1923) eine Beziehung hergestellt zwischen der funktionalen Verfassung eines neuralen Systems einerseits und der Differenziertheit und dem Anpassungsgrad seiner Reaktionen andererseits (Head 1923,1926). Vigilanz im Sinne Head ist demnach eine neurodynamische Größe, die den Organisationsgrad des aktuellen Verhaltens und sein adaptives Niveau bestimmt.
Cerebral aging is associated with psychological and intellectual modifications elated to haemodynamic, metabolic disturbances which are often reflected by electroencephalographic alteration (frequency variations, alpha dominant frequency changes).
Different tests, based on visual and automatic E.E.G. analysis, have been used to determine the CNS effect of vincamine, ifenprodil and dihydroergotoxine which are used for the treatment of cerebral insufficiency.
1.1. Encephalotropic, psychotropic and pharmacodynamic properties of orally and intravenously administered Instenon forte® (60 mg hexobendine + 60 mg ethophylline + 100 mg ethamivan) and intravenously injected Instenon® ampuls (10 mg hexobendine + 100 mg ethophylline + 50 mg ethamivan), were studied in a double-blind placebo-controlled trial in ten normal volunteers.2.2. Power spectral analysis of the EEG showed a decrease of delta waves and and increase of alpha and beta waves as compared with placebo.3.3. Psychometric tests demonstrated, especially after high doses, an increase in psychomotor activity, critical flicker-frequency; improvement in quantitative and deterioration in qualitative aspects of attention; improvement of mood and affectivity.4.4. These findings indicate that Instenon forte® induces an increase in vigilance.5.5. The potency and duration of action of the various oral and intravenous preparations are discussed.
Transcallosal response was investigated using 30 random-bred rabbits (not rendered motionless by muscle relaxants, but tethered by the paw in a special box), which had had implanted in the precentral region of the cortex of one cerebral hemisphere a bipolar Nichrome stimulating electrode (0.5 mm long, 120 #m in diameter) 5-6 days before the experiment began. A monopolar recording electrode (1 mm diameter) was placed at a symmetrical point in the opposite hemisphere, and an inert electrode in the nasal bone of the skull. Stimulation (20-40 V, 7-12 mA square-wave pulse, 0.2-1.0 msec), recording (500 msec after stimulus), averaging (from 20 procedures), processing and component analysis of induced potential (IP) were carried out using a BASIS analyzer (O. T. E. Biomedica, Italy). Firstly, the induced response threshold was determined, then the activity of the substances was investigated using a stimulus equal to one-and-a-half times the threshold value. An assessment was made of the latent periods, the amplitude and the shape of the primary positive (P1), primary negative (N 1) and secondary positive (P2) IP components and the way in which they changed when I and other preparations were administered. Fourier EEG spectral analysis was performed using 50 random-bred laboratory male rats kept under free-movement conditions, which had had Nichrome electrodes (70-90/~m diameter) implanted under pentobarbital sodium narcosis (50 mg/kg intramuscularly) in the sensorimotor cortex and dorsal hippocampus of both cerebral hemispheres 5-6 days before the experiments [3, 8]. Electrograms of these structures were recorded over a five-minute period before (background) and after (0.5, 1.0, 1.5, 2.0, 2.5, and 3.0 h) intraperitoneal injection of the substances. Recording, processing, and analysis of the rat EEG were carded out using a specialized neurophysiological complex (O. T. E. Biomedica, Italy), while experimental data was registered and processed by means of the L-M specialized electrophysiological complex (W. A. B. Technology); analysis details have been described in previous works [1-3, 7-9].
Piracetam is the first of the so-called 'nootropic' drugs, a unique class of drugs which affect mental function. In animal models and in healthy volunteers, the drug improves the efficiency of the higher telencephalic functions of the brain involved in cognitive processes such as learning and memory. The pharmacology of piracetam is unusual because it protects against various physical and chemical insults applied to the brain. It facilitates learning and memory in healthy animals and in animals whose brain function has been compromised, and it enhances interhemispheric transfer of information via callosal transmission. At the same time, even in relatively high dosages it is devoid of any sedative, analeptic or autonomic activities. How piracetam exerts its effects on memory disorders is still under investigation, although among other proposed mechanisms of action it is thought to facilitate central nervous system efficiency of cholinergic neurotransmission. Results from trials involving elderly patients with senile cognitive disorders have been equivocal, as have the results obtained when piracetam has been combined with acetylcholine precursors. Piracetam seems to be almost completely devoid of adverse effects, and is extremely well tolerated. In conclusion, opinion is divided as to the benefits of piracetam in the treatment of senile cognitive decline. Although double-blind studies in the elderly have produced mixed results, some such trials (particularly those involving larger numbers of patients) have reported favourable findings, thus offering some reason for cautious optimism in a notoriously difficult area of therapeutics. However, further investigations of piracetam alone and in combination therapy are required before any absolute conclusions can be drawn.
The electroencephalographic (EEG) and neuropsychological effects of single, oral doses or piracetam (800-6,400 mg) and of its association with lecithin (4,800 mg and 25 g, respectively) were investigated in two groups of healthy volunteers in placebo-controlled studies. The EEG was quantified by power spectral analysis; both parametric and nonparametric procedures were applied to process the EEG and neuropsychological data statistically. The drug plasma concentration was assessed (gas chromatography) in concomitance with the EEG and neuropsychological measurements. Piracetam was found to elicit systematic EEG effects, namely a decrease in the low-frequency components and an increase in the power of the 8.5- to 12.0-Hz and of the fast-frequency components. The EEG modifications were restricted to the anterior scalp areas; its detection by means of parametric statistics was conditioned by the relevant individual variability and was inferred resting upon a number of criteria (indication at nonparametric tests, topography, consistency across subjects, replicability, etc). The correlation between EEG changes and drug plasma concentration was ambiguous, and the compound was not found to be effective on any of the neuropsychological variables considered. The study exemplifies some of the methodological problems in quantitative pharmaco-EEG and emphasizes the relevance of topography and replication.
The basal EEG profile of the aged Fisher-344 rat was consistently different from that of the young rat, showing dominant high voltage slow-wave components. These slow waves were present in both the frontal cerebral cortex and dorsal hippocampus. Absent or greatly attenuated in the aged rat's hippocampal EEG was rhythmic theta activity, which was always dominant in the young awake rat's hippocampus. These EEG differences were clearly apparent only under basal test conditions, i.e., following habituation to the test situation. Pramiracetam sulfate acted strongly to normalize the aged rat's EEG, while the action of piracetam was weak and appeared to undergo tolerance development.
While their importance in the market-place is steadily increasing in developed (mainly continental Europe) and even in developing countries, compounds included in the broad category of ‘cerebroactive’ drugs hardly rate a mention in reference pharmacology and therapeutics textbooks. It is an undeniable fact, however, that the principal users or targets of this drug class, mainly elderly people, represent an increasingly worrying problem, with their often puzzling cohort of ill-definable and even less predictable neurological and mental symptoms.
The combination of the above factors cannot but produce a rather confused situation, in which the pressure to treat and the adherence to scientifically rigorous assessment are likely to prevail alternately, on a purely casual basis.
This review aims to provide sound methodological guidelines for assessment of ‘cerebroactive’ drugs in a not always easily accessible literature. It covers firstly the general problems of stroke, dementia and ‘common symptoms’ of the elderly, and then looks in detail at those compounds which have to date attracted most attention (ergot derivatives, cinnarizine, flunarizine, vincamine, eburnamonine, naftidrofuryl, oxpentifylline, piracetam and citicoline), as well as those which are currently considered investigational (choline and lecithin). The pharmacology and available clinical studies of each drug are examined.
No therapeutic indication can be derived from the available evidence, as the few positive results do not go beyond random improvement of symptoms. More fundamentally, the lines of research which need to be pursued most intensively relate to better preliminary definition of diagnostic and prognostic criteria and, with the establishment of adequate testing tools for the assessment of behaviour and neuropsychological performance, those basal conditions which are modified ‘naturally’ or by drugs.
In a 12-week double-blind study, piracetam at two dose levels (2.4 and 4.8 g/day) was compared to placebo in the treatment of 60 elderly psychiatric patients with mild diffuse cerebral impairment, but no signs of focal brain lesion. The psychiatric illness, schizophrenia or affective disorder, of patients selected was in remission at the time of the study. Monthly evaluations by the nurse revealed that piracetam improved overall functioning, particularly alertness, socialization, and cooperation, relative to the control group. Patients treated with 2.4 g/day piracetam also showed significant improvement in scores for the full IQ and the memory quotient on the Wechsler Adult Intelligence and Memory Scales; greater response was seen in those with lower initial scores. Piracetam at 4.8 g/day had a more rapid onset of action on behavioral variables than 2.4 g/day, but its therapeutic effect tended to diminish at 12 weeks, possibly as the result of overstimulation. Piracetam did not appear to interfere with concomitant psychotropic maintenance medication or affect the psychiatric illness itself.
1.1. In several double-blind placebo-controlled studies the encephalotropic and pharmacodynamic properties of antihypoxidotics and nootropics such as dihydroergotoxine, nicergoline, Instenon forte (a hexobendine-combination), cinnarizine, isoxsuprine, pirazetam and etirazetam- a new pirazetam analogue — were investigated by means of quantitative EEG analysis in normal young and geriatric subjects.2.2. Power pectral density analysis of the EEG demonstrated after the ergot alkaloids HydergineR and nicergoline as well as after Instenon forte statistically significant changes as compared with placebo. The latter were characterized by an increase in alpha and slow beta activity as well as by a decrease in delta and theta activity, which indicates an increase in vigilance.3.3. Pirazetam and the new pirazetam analogue etirazetam — produced a significant increase in beta activity as well, while alpha activity was augmented or attenuated according to the given dosage. After chronic administration of UCB 6474 and especially after high doses, an increase in theta activity was observed. Psychometric tests showed also activating qualities in low doses and slight sedative properties in high doses.4.4. Cinnarizine and isoxsuprine produced in the R-EEG different alterations typified by an increase of slow and decrease of fast waves.5.5. Time-efficacy and dose-efficacy relationships in various EEG parameters give valuable information about the pharmacodynamics of such substances in man already at an early stage of drug development.
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.
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).
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.
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.
Extracts of Ginkgo biloba (EGb) are among the most prescribed drugs in France and Germany. EGb is claimed to be effective in peripheral arterial disorders and in "cerebral insufficiency." The mechanism of action is not yet well understood. Three of the ingredients of the extract have been isolated and found to be pharmacologically active, but which one alone or in combination is responsible for clinical effects is unknown. The recommended daily dose (3 x 40 mg extract) is based more on empirical data than on clinical dose-findings studies. However, despite these, according to double-blind, placebo-controlled clinical trials, EGb has therapeutic effects, at least, on the diagnostic entity of "cerebral insufficiency," which is used in Europe as synonymous with early dementia. To determine whether EGb has significant pharmacological effects on the human brain, a pharmacodynamic study was conducted using the Quantitative Pharmacoelectroencephalogram (QPEEG(R)) method. It was established that the pharmacological effects (based on a predetermined 7.5--13.0-Hz alpha frequency band in a computer-analyzed electroencephalogram = CEEG(R)) of EGb on the central nervous system (CNS) are significantly different than placebo, and the high and low doses could be discriminated from each other. The 120-mg, but particularly the 240-mg, single doses showed the most consistent CNS effects with an earlier onset (1 h) and longer duration (7 h). Furthermore, it was established that the electrophysiological effects of EGb in CNS are similar to those of well-known cognitive activators such as "nootropics" as well as tacrine, the only marketed "antidementia" drug currently available in the United States.
In the present study, we investigated the effects of a single and a repeated (5 days) administration of naftidrofuryl, a serotonin 5-HT2 receptor inhibitor having neuroprotective properties, on functional brain physiology in male healthy elderly subjects, using quantitative electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Twelve subjects aged 60 +/- 3.8 years completed the quantitative EEG study, where the effects of 400 and 600 mg were assessed, and 12 other subjects (aged 56 +/- 4.7 years) completed the fMRI study, where the effect of 400 mg was assessed on the brain activation induced by the continuous performance test (CPT). Naftidrofuryl induced a transient reduction in alpha activity followed by a specific synchronisation of the 9.5- to 11-Hz EEG activity most pronounced after repeated administration. Such regimen also increased the CPT-induced brain activation visualized by way of fMRI. The results of the present study can be interpreted at the functional level that naftidrofuryl induced an improved level of vigilance or an increased capacity of alertness in healthy elderly subjects.
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