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Pharmaco-EEG, psychometric and plasma level studies with two novel alpha-adrenergic stimulants CRL 40476 and 40028 (Adrafinil) in elderly
Abstract
Studied the encephalotropic and psychotropic properties of adrafinil (CRL 40028) and its main metabolite CRL 40476 in 10 elderly Ss (aged 56–76 yrs) by quantitative EEG and psychometric analyses. They received randomized and, at weekly intervals, single oral doses of 200 mg, 400 mg, and 600 mg CRL 40476, 900 mg CRL 40028, and placebo. Results show that the 2 metabolites of adrafinil showed a slower absorption and elimination than adrafinil itself. Computer-assisted spectral analysis of the EEG demonstrated after both drugs a significant central nervous system (CNS) effect as compared with placebo, characterized by an increase of alpha activity, decrease of delta and theta, and fast beta activity. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
... Modafinil, 2-[(diphenylmethyl) sulfinyl] acetamide, is a new central wake-promoting non-amphetamine with a lower risk of CNS, cardiovascular or gastrointestinal adverse events, abuse and dependence (Billiard 1998). As early as in 1986, the first human pharmaco- EEG studies in normal elderly subjects demonstrated a vigilance-promoting effect of modafinil (CRL 40476), characterized by an increase in alpha and slow beta activity and a decrease in delta, theta and very fast beta activity as compared with placebo, which was indeed proven also at the behavioral level by means of psychometry (Saletu B et al. 1986) and confirmed by later clinical trials in patients with an alcoholic organic brain syndrome (Saletu B et al. 1990b, 1993). The efficacy, safety and tolerance of modafinil in narcolepsy patients have been demonstrated in controlled (Besset et al. 1993; Billiard et al. 1994; Boivin et al. 1993; Broughton et al. 1997; Mitler et al. 2000; Moldofsky et al. 2000; US Modafinil in Narcolepsy Multicenter Study Group 1998, 2000) and uncontrolled trials (Bastuji and Jouvet 1988; Laffont et al. 1994). ...
... Modafinil, 2-[(diphenylmethyl) sulfinyl] acetamide, is a new central wake-promoting non-amphetamine with a lower risk of CNS, cardiovascular or gastrointestinal adverse events, abuse and dependence (Billiard 1998 ). As early as in 1986, the first human pharmaco- EEG studies in normal elderly subjects demonstrated a vigilance-promoting effect of modafinil (CRL 40476), characterized by an increase in alpha and slow beta activity and a decrease in delta, theta and very fast beta activity as compared with placebo, which was indeed proven also at the behavioral level by means of psychometry (Saletu B et al. 1986) and confirmed by later clinical trials in patients with an alcoholic organic brain syndrome (Saletu B et al. 1990bSaletu B et al. , 1993). The efficacy, safety and tolerance of modafinil in narcolepsy patients have been demonstrated in controlled (Besset et al. 1993; Billiard et al. 1994; Boivin et al. 1993; Broughton et al. 1997; Mitler et al. 2000; Moldofsky et al. 2000; US Modafinil in Narcolepsy Multicenter Study Group 1998 Group , 2000) and uncontrolled trials (Bastuji and Jouvet 1988; Laffont et al. 1994). ...
... EEG mapping made it possible to visualize significant vigilance improvements under modafinil 400 mg/d (p ≤ 0.01), as total power, alpha-2 and beta power increased and the centroid became accelerated. These vigilance improvements are in line with the first human pharmaco-EEG data obtained in normal elderly subjects (Saletu B et al. 1986), as well as with findings in patients with vigilance decrements. As compared with placebo, modafinil augmented the spontaneous restitution of the alcoholic organic brain syndrome in doses of 200 mg per day given over six weeks (Saletu B et al. 1990 b), which, however, became even more evident after a higher dose of 400 mg (Saletu B et al. 1993). ...
The aim of the present study was to investigate the role of EEG mapping as an objective and quantitative measure of vigilance in untreated and modafinil-treated narcoleptics, and compare it with the conventional neurophysiological method of the Multiple Sleep Latency Test (MSLT) and the subjective Epworth Sleepiness Scale (ESS). In 16 drug-free narcoleptics and 16 normal controls a baseline 3-min vigilance-controlled EEG (V-EEG) and a 4-min resting EEG (R-EEG) were recorded during midmorning hours. Thereafter, in a double-blind, placebo-controlled crossover design, patients were treated with a 3-week fixed titration of modafinil (200, 300, 400 mg) and placebo. EEG-mapping, MSLT and ESS measures were obtained before and at the end of the third week of therapy. Statistical overall analysis by means of the omnibus significance test demonstrated significant EEG differences between untreated patients and controls in the resting condition only (R-EEG). Subsequent univariate analysis revealed an increase in absolute and relative theta power, a decrease in alpha-2 and beta power as well as a slowing of the dominant frequency and the centroids of the alpha, beta and total power spectrum and thus objectified a vigilance decrement in narcolepsy. Modafinil 400 mg/d significantly improved vigilance as compared with placebo (p < or = 0.01), inducing changes opposite to the aforementioned baseline differences (key-lock principle). The MSLT and the ESS also improved under modafinil as compared with placebo, but changes were less consistent. Spearman rank correlations revealed the highest correlations between EEG mapping and the ESS, followed by those between EEG mapping and the MSLT, while the lowest correlation was found between the MSLT and the ESS. In conclusion, EEG mapping is a valuable instrument for measuring vigilance decrements in narcolepsy and their improvement under psychostimulant treatment.
... In the alcohol-induced organic brain syndrome, modafinil has been shown to improve vigilance and activate the electroencephalogram at doses of 200 mg/day (Saletu et al. 1990). In elderly patients, doses of 200 to 400 mg/day improve concentration, complex reactions, mood, affect, and cognitive functions (Saletu et al. 1986). At the dose of 200 mg/day, the electroencephalographic rhythm is inceased and the slow and activities are decreased in both the absolute and relative power (Saletu et al. 1986). ...
... In elderly patients, doses of 200 to 400 mg/day improve concentration, complex reactions, mood, affect, and cognitive functions (Saletu et al. 1986). At the dose of 200 mg/day, the electroencephalographic rhythm is inceased and the slow and activities are decreased in both the absolute and relative power (Saletu et al. 1986). In young healthy adults (Goldenberg 1986), there is no change in behaviour, no change in psychomotor performance, but a transitory decrease in slow-wave sleep (SWS) after morning administration. ...
Polysomnograms were obtained from 37 volunteers, before (baseline) and after (two consecutive recovery nights) a 64-h sleep deprivation, with (d-amphetamine or modafinil) or without (placebo) alerting substances. The drugs were administered at 23.00 hours during the first sleep deprivation night (after 17.5 h of wakefulness), to determine whether decrements in cognitive performance would be prevented; at 05.30 hours during the second night of sleep deprivation (after 47.5 h of wakefulness), to see whether performance would be restored; and at 15.30 hours during the third day of continuous work, to study effects on recovery sleep. The second recovery night served to verify whether drug-induced sleep disturbances on the first recovery night would carry over to a second night of sleep. Recovery sleep for the placebo group was as expected: the debt in slow-wave sleep (SWS) and REM sleep was paid back during the first recovery night, the rebound in SWS occurring mainly during the first half of the night, and that of REM sleep being distributed evenly across REM sleep episodes. Recovery sleep for the amphetamine group was also consistent with previously published work: increased sleep latency and intrasleep wakefulness, decreased total sleep time and sleep efficiency, alterations in stage shifts, Stage 1, Stage 2 and SWS, and decreased REM sleep with a longer REM sleep latency. For this group, REM sleep rebound was observed only during the second recovery night. Results for the modafinil group exhibited decreased time in bed and sleep period time, suggesting a reduced requirement for recovery sleep than for the other two groups. This group showed fewer disturbances during the first recovery night than the amphetamine group. In particular, there was no REM sleep deficit, with longer REM sleep episodes and a shorter REM latency, and the REM sleep rebound was limited to the first REM sleep episode. The difference with the amphetamine group was also marked by less NREM sleep and Stage 2 and more SWS episodes. No REM sleep rebound occurred during the second recovery night, which barely differed from placebo. Hence, modafinil allowed for sleep to occur, displayed sleep patterns close to that of the placebo group, and decreased the need for a long recovery sleep usually taken to compensate for the lost sleep due to total sleep deprivation.
... A 200 mg par jour, le modafinil accroît la vigilance et active l'électroencéphalogramme de patients atteints de syndrome cérébral organique induit par l'alcool (Saletu et al., 1990). Chez des vieillards, des doses de 200 à 400 mg par jour de modafinil améliorent la concentration, les réactions complexes, l'humeur, le moral et les fonctions cognitives (Saletu et al., 1986). L'électroencéphalogramme est alors activé avec augmentation de l'activité et diminution des activités et . ...
... Digit symbol substitution was not differentially affected by placebo versus modafinil, but this was probably because the subjects were not sleep deprived. The EEG findings are consistent with those of Saletu et al. (1986) who found that Modafinil (200,400, and 600 mg) administered to elderly subjects produced reductions in delta and theta activity concurrent with increases in alpha and fast beta. ...
... The wake-promoting effect of modafinil has been successfully employed in excessive daytime sleepiness, especially narcolepsy (Bastuji and Jouvet 1988;Besset et al. 1993;Billiard et al. 1994;Laffont et al. 1994;Broughton et al. 1997). In patients with organic brain syndrome, in the elderly and in air force personnel, modafinil was reported to decrease electroencephalographic (EEG) slow-wave activity, indicating an enhancement of alertness (Saletu et al. 1986(Saletu et al. , 1993bCaldwell et al. 2000). In healthy sleep-deprived subjects, modafinil improves psychomotor and cognitive performance as well as subjective alertness (Lagarde et al. 1995;Pigeau et al. 1995; Baranski and Pigeau 1997;Wesensten et al. 2002). ...
... Modafinil has been used primarily in either clinical studies to treat sleeping disorders (Bastuji and Jouvet 1988;Besset et al. 1992;Billard et al. 1987;Laffont et al. 1987;Laffont et al. 1992) or in animal studies to investigate its pharmacological properties (Duteil et al. 1979;Hermant et al. 1991;Lagarde 1990;Milhaud and Klein 1985). Of the studies performed on healthy human adults, none has investigated the relative effectiveness of modafinil under sleep loss conditions involving more than 1 night or under continuous workload conditions (Bensimon et al. 1989;Lagarde and Batejat 1994;Saletu et al. 1986). The results of Bensimon et al. (1989), where healthy subjects displayed positive effects of modafinil after a single night of sleep loss with low workload, are encouraging but cannot be extended to include more extreme workload conditions. ...
Modafinil is an alerting substance that is considered safer than amphetamine with fewer side effects. Although modafinil has been used successfully to treat narcolepsy, relatively little is known about its ability to ameliorate fatigue and declines in mental performance due to sleep deprivation (SD) in a normal population. Forty-one military subjects received either 300 mg of modafinil, 20 mg of d-amphetamine, or placebo on 3 separate occasions during 64 hours of continuous cognitive work and sleep loss. Three drug treatments were given: at 23.30 hours and 05.30 hours during the first and second SD nights, respectively, and once at 15.30 hours during the third day of continuous work. Subjective estimates of mood, fatigue and sleepiness, as well as objective measures of reaction time, logical reasoning and short-term memory clearly showed better performance with both modafinil and amphetamine relative to placebo. Both modafinil and amphetamine maintained or increased body temperature compared to the natural circadian cycle observed in the placebo group. Also, from subject debriefs at the end of the study, modafinil elicited fewer side-effects than amphetamine, although more than the placebo group. Modafinil appears to be a good alternative to amphetamine for counteracting the debilitating mood and cognitive effects of sleep loss during sustained operations.
This up-to-date, superbly illustrated book is a practical guide to the effective use of neuroimaging in the patient with sleep disorders. There are detailed reviews of new neuroimaging techniques – including CT, MRI, advanced MR techniques, SPECT and PET – as well as image analysis methods, their roles and pitfalls. Neuroimaging of normal sleep and wake states is covered plus the role of neuroimaging in conjunction with tests of memory and how sleep influences memory consolidation. Each chapter carefully presents and analyzes the key findings in patients with sleep disorders indicating the clinical and imaging features of the various sleep disorders from clinical presentation to neuroimaging, aiding in establishing an accurate diagnosis. Written by neuroimaging experts from around the world, Neuroimaging of Sleep and Sleep Disorders is an invaluable resource for both researchers and clinicians including sleep specialists, neurologists, radiologists, psychiatrists, psychologists.
The aim of this study is to evaluate the effectiveness of adrafinil (Olmifon®), through a random trial versus placebo, on the memory complaint in patients seen in consultation by general practitioners, and aged over 50 years. The criterion of inclusion was the existence of a memory complaint measured with the help of the McNair auto-questionnaire, that of the abridged version of 26 items. The criteria of exclusion included the existence of neurological and psychological antecedents, serious cranial trauma, neurological complications resulting from alcoholism, and chronic disease. The patients were randomly divided into two parallel groups and received, over three months, either adrafinil with a dose of 900mg per day (two tablets in the morning and one at lunchtime), or the placebo The initial clinical assessment included the Folstein's MMS, in order to eliminate early cognitive deterioration, and an auto-questionnaire on depression, abridged from Pichot et Boyer, to eliminate any existing depressive conditions. Of the 626 subjects initially included by the 250 general practitioners, 462 were retained for final analysis. The initial comparative status of the adrafinil groups (n=225) and the placebo group (n=237) was excellent. The improvement of the memory complaint was significantly higher (p<0.0001) in the adrafinil group (goinq from 40,5 to 26,8 over the three months) than the placebo group (from 38,1 to 31 over the same period). The subjective evaluation through analogical and visual scales carried out by the patients (memory, attention, orientation) and by the experimenting general practitioners (effectiveness and CGI) showed a very significant improvement for adrafinil across all parameters, after three months. In the absenoe of qualitative assessment of anxiety throughout the study, the modus operandi of adrafinil cannot be determined with certitude. However, the very significant improvement in memory and attention performance, evaluated by the Crocq batterie (respectively a generic word test and a dictation in morse) suggests that the action of adrafinil is not simply linked to an effect on anxiety.
Sleep Deprivation, Stimulant Medications, and Cognition provides a review, synthesis and analysis of the scientific literature concerning stimulant medications and neurobehavioral performance, with an emphasis on critically evaluating the practical utility of these agents for maintaining cognitive performance and alertness in sleep-deprived (but otherwise healthy) individuals. The book explores the nature of sleep loss-induced cognitive deficits, neurophysiologic basis of these deficits, relative efficacy and limitations of various interventions (including non-pharmacological), and implications for applying these interventions in operational environments (commercial and military). Readers of this volume will gain a working knowledge of: • Mechanisms contributing to sleep loss-induced cognitive deficits • Differential effects of stimulant compounds on various aspects of cognition • Considerations (such as abuse liability) when applying stimulant interventions in operational settings • Current state and future directions for including stimulants in comprehensive fatigue-management strategies. This text is key reading for researchers and trainees in sleep and psychopharmacology.
CNS stimulants are the most widely used drugs to treat narcolepsy which is characterized by the excessive daytime sleepiness and typically associated with cataplexy. However, a number of side effects may often arise with this therapeutic approach. Thus, investigating new drugs which are efficient but well tolerated is of utmost importance in the treatment of narcolepsy. Although modafinil, an alpha-1 adrenoreceptor agonist, has been reported to bring substantial awakening properties in animals, the studies performed in man, particularly in narcoleptic subjects, are few. In the present study, we evaluated the effects of a 300 mg daily dose of modafinil on sleepiness and psychomotor performance of 16 narcoleptic subjects. The major effect of modafinil in narcoleptic subjects was a decrease of daytime sleepiness and corresponding improvement of performances involving attentive functions. However, the learning effect in psychomotor tests may mask the drug effect.
Adrafinil is a novel drug that is not well known outside of France, where it is used primarily as a vigilance-enhancing agent. Clinical studies strongly indicate that adrafinil has efficacy in improving attention, memory, as well as other deficits resulting from decreased vigilance. Adrafinil has two metabolites, modafinil and CRL 40476. Little is known about CRL 40476. Modafinil, on the other hand, has been much more extensively studied, and the production of modafinil is likely to account for at least part of the effects of adrafinil. Thus, adrafinil has very similar pharmacological effects to modafinil. Moreover, the behavioral effects of adrafinil are more closely tied to the pharmacokinetics of its metabolite modafinil. Most researchers assume that adrafinil works as a selective α1-adrenergic receptor agonist. This belief, however, is challenged by evidence that adrafinil does not produce peripheral adrenergic effects, instances where the actions of adrafinil are not blocked by α1 blockers, and by instances where adrafinil is unable to counteract the effect of α1 blockers. Recent evidence indicates that adrafinil affects amino acid release, generally causing increased release of glutamate and decreased release of GABA. Given the effectiveness of adrafinil in improving performance on psychometric tests and motor function in people with mild cognitive impairment, it is surprising that neither adrafinil nor modafinil have been used in trials with demented patients. In fact, two possible applications deserve careful consideration. One possible application is the treatment of age-associated memory impairment (AAMI). This term was introduced to describe 'medically, neurologically, and psychiatrically healthy persons over 50 years of age who have experienced a gradual decline in the ability to perform certain tasks of daily life dependent on memory' (14,15). A second possible application for adrafinil would be in the treatment of subjects with dementing disorders, such as Alzheimer's disease. This application is not directly suggested from the studies performed thus far, which have precluded examination of severely demented patients because of the subject selection criterion used. In fact, research with canines provides limited support for this possibility. Adrafinil improved discrimination learning in a group of aged dogs; the dogs that showed the greatest improvement in cognitive functioning were those that showed the greatest overall impairment (42). The evidence that modafinil can have neuroprotective effects provides another compelling reason for testing adrafinil in patients with dementing disorders. This study raises at least the possibility that long-term treatment with adrafinil can arrest or even reverse neurodegenerative processes that contribute to dementia. Clearly, however, further preclinical studies are needed before this potential application can be evaluated. Three other therapeutic applications of adrafinil warrant further study. The first application is as a potential therapeutic drug in treatment of Parkinson's (see ref. 30) and another is as a potential treatment for deficits associated with movement disorders (8). Finally, further investigations of the antidepressive effects of adrafinil are warranted. In summary, adrafinil is a novel stimulant that lacks the adverse effects associated with other psychostimulants. It directly affects CNS function, but its mechanism of action is not completely understood. Clinical studies have demonstrated that adrafinil has efficacy as a vigilance-promoting agent. It has also cognitive enhancing potential, and trials on patients with dementing disorders appear warranted.
Die Neurotransmission (Riederer et al. 2007) ist innerhalb der biologischen Psychiatrie in zweierlei Hinsicht von Interesse: Einerseits bietet sie Zugang zu einem tieferen
Einblick in die ätiopa-thogenetischen Bedingungen, die zum Entstehen psychiatrischer Erkrankungen führen, andererseits bildet
sie einen wichtigen Ansatzpunkt für pharmakotherapeutische Maßnahmen zur Behandlung dieser Krankheiten (s. Müller et al. Kapitel
3.2).
Recent neuroimaging studies in narcolepsy discovered significant gray matter loss in the right prefrontal and frontomesial cortex, a critical region for executive processing. In the present study, event-related potential (ERP) low-resolution brain electromagnetic tomography (LORETA) was used to investigate cognition before and after modafinil as compared with placebo.
In a double-blind, placebo-controlled cross-over design, 15 patients were treated with a 3-week fixed titration scheme of modafinil and placebo. The Epworth Sleepiness Scale (ESS), Maintenance of Wakefulness Test (MWT) and auditory ERPs (odd-ball paradigm) were obtained before and after the 3 weeks of therapy. Latencies, amplitudes and LORETA sources were determined for standard (N1 and P2) and target (N2 and P300) ERP components.
The ESS score improved significantly from 15.4 (+/- 4.0) under placebo to 10.2 (+/- 4.1) under 400mg modafinil (p=0.004). In the MWT, latency to sleep increased nonsignificantly after modafinil treatment (11.9+/-6.9 versus 13.3+/-7.1 min). In the ERP, N2 and P300 latencies were shortened significantly. While ERP amplitudes showed only minor changes, LORETA revealed increased source strengths: for N1 in the left auditory cortex and for P300 in the medial and right dorsolateral prefrontal cortex.
LORETA revealed that modafinil improved information processing speed and increased energetic resources in prefrontal cortical regions, which is in agreement with other neuroimaging studies.
1. In a double-blind study forty abstinent hospitalized male patients with an alcoholic organic brain syndrome (OBS) were treated for 6 weeks with either 200 mg modafinil or placebo. 2. Modafinil (CRL 40476) is a putative central alpha-1 adrenergic agonist. It's pharmacological profile is quite different from that of amphetamine, which can be seen by the lack of peripheral sympathomimetic effects. The vigilance promoting effect of modafinil has been shown previously in pharmaco-EEG and psychometric studies as well as in clinical studies involving treatment of daytime sleepiness in idiopathic hypersomniacs and narcoleptics. 3. The present clinical investigations demonstrated that the spontaneous restitution of the alcoholic OBS was significantly augmented and accelerated by modafinil. 4. Psychometric tests did not show significant intergroup differences. Modafinil- and placebo-treated patients improved continously over the 6-week period. 5. Psychophysiological and autonomous nervous system parameters were affected neither by placebo nor by modafinil. 6. Neurophysiological investigations by means of quantitative pharmaco-EEG showed partly inconsistent findings. However, superimposed dosages of modafinil (on the top of 6 weeks chronic administration) induced a decrease of slow activity and an increase of alpha activity suggesting an improvement of vigilance after the daily drug intake. 7. Considering the beneficial effects of modafinil in abstinent chronic alcoholic patients, it may be said that activation and improvement of adaptive behaviour by an alpha-adrenergic agonist could be regarded as a therapeutic principle in the treatment of the OBS, eventually due to noradrenergic deficits.
In a double-blind, placebo-controlled study the encephalotropic and psychotropic properties of an acutely and 3-weeks subacutely administered novel drug Duxil (consisting of 30 mg of the antihypoxic almitrine which increases the oxygenation of the arterial blood by specific action on the pulmonary exchange system and of 10 mg raubasine, which potentiates this effect via increase in peripheral circulation), were investigated in 12 elderly subjects in their 70s. Each subject had a treatment of 3 weeks with Duxil and placebo (1 tablet b.i.d.) with an interval of 1 week in between (the order of drug sequence was randomized). EEG recordings, psychometric and psychophysiological tests as well as evaluation of pulse, blood pressure and side effects were carried out at 0, 2, 4, 6 and 8 h after the administration of one single dose on day 1 (acute effect), at the 0 h on day 21 (subacute effect) as well as at the 2, 4, 6, and 8 h after one additional superimposed dosage on day 21 (superimposed effect). Computer-assisted spectral analysis of the EEG demonstrated after single doses of two tablets of Duxil only subtle changes in the resting EEG, while after subacute administration and even more so after one superimposed dosage highly significant changes were observed, which were characterized by an increase of total power, alpha and alpha-adjacent beta activity, decrease in fast beta activity, and by an augmentation of absolute and relative power of the dominant frequency. These findings are indicative of an improvement in vigilance. The latter was seen also at the behavioral level, as psychometric tests showed specifically in noopsychic variables a significant improvement in intellectual, mnestic and psychomotor performance after the novel antihypoxic compound, as compared with placebo. There were practically no changes in thymopsychic variables. Evaluation of psychophysiological variables and side effects showed extremely good tolerability of the drug.
Irregular work/rest patterns frequently cause disturbed sleep and excessive sleepiness and accidents. This review is focused on four pharmacological countermeasures-the "new" drugs modafinil and pemoline, the traditional caffeine, and, as a reference, amphetamine. It is concluded that there is still too little data available to decide whether systematic use of alertness-enhancing drugs is feasible in occupational settings. D-Amphetamine is ruled out because of its abuse potential and mood effects. Modafinil and pemoline have not been tested in field situations, whereas caffeine certainly is used to improve alertness during work, but the use is spontaneous/ad hoc, and there is still a lack of data on its systematic application. Particularly, the optimal amount and pattern of administration need elucidation.
Aged beagle dogs were trained on either a size or intensity discrimination task 2 h following treatment with either 20 mg/kg of adrafinil or a placebo control. Training continued until the dogs reached a predetermined criterion level of performance, or failed to acquire the task after 40 sessions. The treatments and tasks were then reversed, with both the test order and treatment order counterbalanced. Thus, half of the animals were first tested on the intensity discrimination, and half of these were first tested under adrafinil. Treatment with adrafinil produced significant improvement in learning, as indicated by a decrease in both errors and trials to criterion. An effect of adrafinil on motivation may partially account for these findings; however, adrafinil did not significantly affect response latency. Adrafinil is believed to serve as an alpha-1 adrenoceptor agonist. The improved learning may also result from enhancement of vigilance due to facilitation of noradrenergic transmission in the central nervous system.
Adrafinil, a vigilance enhancing pharmaceutical, was administered to aged dogs for 14 consecutive days at doses of 10, 20, 30, or 40 mg/kg using a crossover design. The effects on spontaneous behavior in a 10-min canine open-field test were systematically recorded every fourth day, starting with day 1 of treatment. The open field tests were given 2 or 10 h following oral administration of capsules containing either adrafinil or lactose, the placebo control. Adrafinil caused an increase in locomotor activity at the three highest doses at both the 2- and 10-h intervals and during both the first (days 1 and 5) and second treatment week (days 9 and 13). Adrafinil also caused a transient increase in directed sniffing. At the highest dose level, adrafinil caused a decrease in urination frequency. The increased locomotion was generally unaccompanied by stereotypical behavior in the test session. There was some variability; a subpopulation of animals showed either no effect, or decreased locomotion. The individual differences were correlated with changes in serum levels of adrafinil 10 h following treatment.
In 1998, the FDA approved modafinil for treating excessive daytime sleepiness in narcoleptics, and this has raised questions about the appropriateness of this compound for enhancing alertness in sleep-deprived controls. This study explored the efficacy of modafinil for maintaining the performance of volunteers required to accomplish highly demanding tasks despite sleep loss.
The principal objective was to determine whether prophylactic doses of modafinil would attenuate decrements in aviator performance and arousal throughout 2 days and 1 night without sleep.
Six pilots were exposed to two 40-h periods of continuous wakefulness. In one, three 200-mg doses of modafinil were given and in the other, matching placebos were administered. Helicopter simulator flights, resting EEGs, and Profile of Mood States (POMS) questionnaires were evaluated.
Modafinil attenuated sleep deprivation effects on four of six flight maneuvers, reduced slow-wave EEG activity, and lessened self-reported problems with mood and alertness in comparison to placebo. The most noticeable benefits occurred between 0330 and 1130 hours, when the combined impact of sleep loss and the circadian trough was most severe. The most frequently observed drug side effects were vertigo, nausea, and dizziness. These could have been related to: 1) the motion-based testing, 2) the use of a simulator rather than an actual aircraft (i.e., "simulator sickness"), and/or 3) the administration of more than 400 mg modafinil.
Modafinil is a promising countermeasure for sleep loss in normals; however, additional studies aimed at reducing side effects are needed before it should be used in aviators.
1. Adrafmil is a novel vigilance promoting agent developed in France by Louis Lafon Laboratories. 2. Adrafinil causes increased locomotion without producing stereotypical activity in canines tested in an open field. 3. The effectiveness of a single treatment is long-lasting, and the effectiveness persists over repeated treatments. 4. Acquisition of a size discrimination problem is enhanced by adrafinil. This may be linked to performance motivation. 5. Adrafinil causes a long-lasting increase in high frequency electroencephalographic activity recorded from cortical electrodes. 6. These results indicate that adrafinil is novel behavioral stimulant with cognitive enhancing potential. The underlying mechanisms of action are still unknown.
Daytime tiredness and daytime sleepiness are frequent complaints occurring in 29% and 14% of the Austrian population. Epidemiological studies demonstrate a high comorbidity between nonorganic hypersomnia and mental disorders. Especially comorbidity with affective disorders increases steadily from the general population over primary to tertiary care settings. Diagnostic criteria of nonorganic hypersomnia have been described in the International Classification of Diseases (ICD-10). Nonorganic hypersomnia can be primary or associated with a number of psychiatric disorders such as reaction to severe stress or adjustment disorders, affective disorders, other functional disorders, tolerance to or withdrawal of CNS-stimulating substances and chronic use of CNS-sedating substances. Diagnostic procedures comprise case history and symptom evaluation, sleep-specific and supplementary investigations. Concerning the latter, this article will focus on sleep questionnaires, vigilance and psychological tests as well as CNS investigations. Therapy of nonorganic hypersomnia rests on 3 pillars: psychological, somatic and pharmacological treatment. In view of the wide variety of psychiatric causes, resulting in a number of therapeutic options, it seems desirable that apart from subjective clinical assessment also objective methods be used in diagnosis and treatment. On the neurophysiological level objective measures can be obtained by means of EEG mapping during the day and polysomnography at night. Different mental disorder patients show different brain activity patterns as compared with normal controls and different classes of psychotropic substances cause different changes in neurophysiological variables. The fact that the changes in electrophysiological brain activity caused by mental disorders are exactly opposite to those induced by the psychotropic drugs used for their treatment suggests a key-lock principle in the diagnosis and treatment of nonorganic hypersomnia.
Modafinil is a wake-promoting agent that affects hypothalamic structures involved in the homeostatic and circadian regulation of vigilance. Administered during sleep deprivation, it reduces the need for prolonged recovery sleep and decreases the rebound in EEG slow-wave activity. These diachronic effects suggest an action of modafinil on a homeostatic sleep regulatory process.
The aim of this study was to determine whether modafinil, in comparison to the d-amphetamine reference psychostimulant and to placebo, interferes with the vigilance regulatory processes reflected in the EEG during waking.
Thirty-three healthy subjects were investigated during 60 h of sustained wakefulness in a double-blind placebo-controlled parallel-design study. A 4-min maintenance-of-wakefulness test administered hourly allowed the concomitant assessment of alertness and waking EEG activity. The effects of equipotent psychostimulant dosages (modafinil 300 mg and d-amphetamine 20 mg) were evaluated at the beginning of the first sleep deprivation night, at the end of the second sleep deprivation night and in the afternoon preceding the first recovery night.
One hour following ingestion, both psychostimulants increased alertness during 10-12 h, independently of the time of administration. At the level of the waking EEG, d-amphetamine attenuated the natural circadian rhythm of the different frequency bands and suppressed the sleep deprivation-related increase in low frequency (0.5-7 Hz) powers. In contrast, modafinil, which exhibited a transient amphetamine-like effect, had slight effect on circadian rhythms. Its selective action was characterized by maintenance of the alpha(1) (8.5-11.5 Hz) EEG power, which under placebo exhibited a homeostatic decrease paralleling that of alertness with a circadian trough at night.
These findings demonstrate that the alertness-promoting effects of modafinil and d-amphetamine involve distinct EEG activities and do not reside on the same vigilance regulatory processes. While d-amphetamine inhibits the expression of a sleep-related process, probably through a direct cortical activation masking EEG circadian rhythms, modafinil, through a synchronic effect, preferentially disrupts the homeostatic down-regulation of a waking drive.
Utilizing computer-assisted quantitative analyses of human scalp-recorded electroencephalogram (EEG) in combination with certain statistical procedures (quantitative pharmaco-EEG) and mapping techniques (pharmaco-EEG mapping), it is possible to classify psychotropic substances and objectively evaluate their bioavailability at the target organ: the human brain. Specifically, one may determine at an early stage of drug development whether a drug is effective on the central nervous system (CNS) compared with placebo, what its clinical efficacy will be like, at which dosage it acts, when it acts and the equipotent dosages of different galenic formulations. Pharmaco-EEG profiles and maps of neuroleptics, antidepressants, tranquilizers, hypnotics, psychostimulants and nootropics/cognition-enhancing drugs will be described in this paper. Methodological problems, as well as the relationships between acute and chronic drug effects, alterations in normal subjects and patients, CNS effects, therapeutic efficacy and pharmacokinetic and pharmacodynamic data will be discussed. In recent times, imaging of drug effects on the regional brain electrical activity of healthy subjects by means of EEG tomography such as low-resolution electromagnetic tomography (LORETA) has been used for identifying brain areas predominantly involved in psychopharmacological action. This will be demonstrated for the representative drugs of the four main psychopharmacological classes, such as 3 mg haloperidol for neuroleptics, 20 mg citalopram for antidepressants, 2 mg lorazepam for tranquilizers and 20 mg methylphenidate for psychostimulants. LORETA demonstrates that these psychopharmacological classes affect brain structures differently.
Narcolepsy is a disorder of impaired expression of wakefulness and rapid-eye-movement (REM) sleep. This manifests as excessive daytime sleepiness and expression of individual physiological correlates of REM sleep that include cataplexy and sleep paralysis (REM sleep atonia intruding into wakefulness), impaired maintenance of REM sleep atonia (e.g. REM sleep behaviour disorder [RBD]), and dream imagery intruding into wakefulness (e.g. hypnagogic and hypnopompic hallucinations).
Excessive sleepiness typically begins in the second or third decade followed by expression of auxiliary symptoms. Only cataplexy exhibits a high specificity for diagnosis of narcolepsy. While the natural history is poorly defined, narcolepsy appears to be lifelong but not progressive. Mild disease severity, misdiagnoses or long delays in cataplexy expression often cause long intervals between symptom onset, presentation and diagnosis. Only 15–30% of narcoleptic individuals are ever diagnosed or treated, and nearly half first present for diagnosis after the age of 40 years.
Attention to periodic leg movements (PLM), sleep apnoea and RBD is particularly important in the management of the older narcoleptic patient, in whom these conditions are more likely to occur. Diagnosis requires nocturnal polysomnography (NPSG) followed by multiple sleep latency testing (MSLT). The NPSG of a narcoleptic patient may be totally normal, or demonstrate the patient has a short nocturnal REM sleep latency, exhibits unexplained arousals or PLM. The MSLT diagnostic criteria for narcolepsy include short sleep latencies (
Previous studies in humans and dogs have reported beneficial effects of adrafinil on specific cognitive functions. The effects in dogs are limited to a single study examining discrimination learning. We wanted to further explore the cognitive effects of adrafinil in dogs. The purpose of the present study was to determine the effect of oral administration of adrafinil on visuospatial function in dogs. Eighteen aged beagle dogs were tested on a delayed nonmatching-to-position (DNMP) task 2 h following one of three possible treatments; 20 mg/kg of adrafinil, 10 mg/kg of adrafinil or a placebo control. All dogs were tested under each treatment for eight test sessions. A 2-day washout period was given between treatments and the order of treatments was varied. Treatment with 20 mg/kg of adrafinil produced a significant impairment in working memory as indicated by an increase in the number of errors over the 8-day test period. The disturbance of memory functions from adrafinil could be a result of increased noradrenergic transmission in the prefrontal cortex.
In a double-blind, placebo-controlled, crossover study the encephalotropic and nootropic effects of single doses of two ergotalkaloids (30 and 60 mg nicergoline and 5 mg co-dergocrine mesylate (CDM)) were investigated in 12 elderly subjects (mean age 67 years), utilizing topographic brain mapping of the EEG. Evaluation of EEG, memory, pulse and blood pressure were carried out at 0, 2, 4, 6 and 8 h. Topographic brain maps demonstrated an augmentation of total power, an acceleration of the centroid of the total activity, a decrease of delta/theta and an increase of beta activity (mostly in the alpha-adjacent frequency bands), as well as an acceleration of the centroid of the delta/theta and a slowing of the beta centroid. These changes are indicative of improvement in vigilance of elderly subjects after ergotalkaloids, which was also reflected in the significant improvement of memory after nicergoline. Topographically, the main effect was found over the frontal, central and temporal regions. Timewise, the pharmacodynamic peak fell into the 4th h, although with 60 mg significant encephalotropic effects could be observed in the 2nd and in the 6th h. The drugs were well tolerated.
The aim of the present study was to identify brain regions associated with vigilance in untreated and modafinil-treated narcoleptic patients by means of low-resolution brain electromagnetic tomography (LORETA). 16 drug-free narcoleptics and 16 normal controls were included in the baseline investigation. Subsequently patients participated in a double-blind, placebo-controlled crossover study receiving a three-week fixed titration of modafinil (200, 300, 400 mg) and placebo. Measurements comprised LORETA, the Multiple Sleep Latency Test (MSLT) and the Epworth Sleepiness Scale (ESS) obtained before and after three weeks' therapy. Statistical overall analysis by means of the omnibus significance test demonstrated significant inter-group differences in the resting (R-EEG), but not in the vigilance-controlled recordings (V-EEG). Subsequent univariate analysis revealed a decrease in alpha-2 and beta 1-3 power in prefrontal, temporal and parietal cortices, with the right hemisphere slightly more involved in this vigilance decrement. Modafinil 400 mg/d as compared with placebo induced changes opposite to the aforementioned baseline differences (key-lock principle) with a preponderance in the left hemisphere. This increase in vigilance resulted in an improvement in the MSLT and the ESS. LORETA provided evidence of a functional deterioration of the fronto-temporo-parietal network of the right-hemispheric vigilance system in narcolepsy and a therapeutic effect of modafinil on the left hemisphere, which is less affected by the disease.
By multi-lead computer-assisted quantitative analyses of human scalp-recorded electroencephalogram (QEEG) in combination with certain statistical procedures (quantitative pharmaco-EEG) and mapping techniques (pharmaco-EEG mapping or topography), it is possible to classify psychotropic substances and objectively evaluate their bioavailability at the target organ, the human brain. Specifically, one may determine at an early stage of drug development whether a drug is effective on the central nervous system (CNS) compared with placebo, what its clinical efficacy will be like, at which dosage it acts, when it acts and the equipotent dosages of different galenic formulations. Pharmaco-EEG maps of neuroleptics, antidepressants, tranquilizers, hypnotics, psychostimulants and nootropics/cognition-enhancing drugs will be described. Methodological problems, as well as the relationships between acute and chronic drug effects, alterations in normal subjects and patients, CNS effects and therapeutic efficacy will be discussed.
Imaging of drug effects on the regional brain electrical activity of healthy subjects by means of EEG tomography such as low-resolution electromagnetic tomography (LORETA) has been used for identifying brain areas predominantly involved in psychopharmacological action. This will be shown for the representative drugs of the four main psychopharmacological classes, such as 3 mg haloperidol for neuroleptics, 20 mg citalopram for antidepressants, 2 mg lorazepam for tranquilizers and 20 mg methylphenidate for psychostimulants. LORETA demonstrates that these psychopharmacological classes affect brain structures differently.
By considering these differences between psychotropic drugs and placebo in normal subjects, as well as between mental disorder patients and normal controls, it may be possible to choose the optimum drug for a specific patient according to a key-lock principle, since the drug should normalize the deviant brain function. Thus, pharmaco-EEG topography and tomography are valuable methods in human neuropsychopharmacology, clinical psychiatry and neurology.
The performance- and alertness-sustaining/restoring effects of modafinil during sleep deprivation in normal, healthy adults were reviewed. Results indicate that modafinil is efficacious for sustaining/restoring objective performance and alertness during sleep deprivation with few adverse effects. At appropriate dosages, modafinil restores performance and alertness to non-sleep deprived levels. Modafinil also impairs post-sleep deprivation recovery sleep, but from the few studies available addressing this issue, it is unclear whether these sleep impairments translate into post-sleep performance impairments. Further research is needed to determine whether modafinil restores performance on simple cognitive tasks only or whether modafinil additionally restores executive functions (e.g., abstract thought, critical reasoning, planning, decision-making, situational awareness, and effective judgment) which are critical in most modern operational settings. In addition, studies are needed to determine whether modafinil use during sleep deprivation is preferable to that of other available controlled stimulants (such as dextroamphetamine) or non-controlled stimulants (such as caffeine). Such studies would be comprised of direct, head-to-head comparisons among various stimulants across a range of dosages.
Low-resolution brain electromagnetic tomography (LORETA) showed a functional deterioration of the fronto-temporo-parietal network of the right hemispheric vigilance system in narcolepsy and a therapeutic effect of modafinil. The aim of this study was to determine the effects of modafinil on cognitive and thymopsychic variables in patients with narcolepsy and investigate whether neurophysiological vigilance changes correlate with cognitive and subjective vigilance alterations at the behavioral level. In a double-blind, placebo-controlled crossover design, EEG-LORETA and psychometric data were obtained during midmorning hours in 15 narcoleptics before and after 3 weeks of placebo or 400 mg modafinil. Cognitive investigations included the Pauli Test and complex reaction time. Thymopsychic/psychophysiological evaluation comprised drive, mood, affectivity, wakefulness, depression, anxiety, the Symptom Checklist 90 and critical flicker frequency. The Multiple Sleep Latency Test (MSLT) and the Epworth Sleepiness Scale (ESS) were performed too. Cognitive performance (Pauli Test) was significantly better after modafinil than after placebo. Concerning reaction time and thymopsychic variables, no significant differences were observed. Correlation analyses revealed that a decrease in prefrontal delta, theta and alpha-1 power correlated with an improvement in cognitive performance. Moreover, drowsiness was positively correlated with theta power in parietal and medial prefrontal regions and beta-1 and beta-2 power in occipital regions. A less significant correlation was observed between midmorning EEG LORETA and the MSLT; between EEG LORETA and the ESS, the correlation was even weaker. In conclusion, modafinil did not influence thymopsychic variables in narcolepsy, but it significantly improved cognitive performance, which may be related to medial prefrontal activity processes identified by LORETA.
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