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PubMed1995

Effects of a vigilance-enhancing drug, modafinil, on rat brain metabolism: a 2D COSY 1H-NMR study.

The effects of modafinil, a vigilance-enhancing drug, on brain metabolism were investigated directly in situ by the 2D COSY 1H-NMR spectroscopy in anesthetized rats. Modafinil (600 mg/kg, i.p.) induced significant increases in both aspartate (72% +/- 15%) and glutamate-glutamine pool (28% +/- 8%) simultaneously with increases in inositol (51% +/- 19%) and creatine-phosphocreatine pool (47% +/- 14%) in comparison with control values (P < 0.05; n = 5). These results suggest that the awakening properties of modafinil could be mediated by metabolic activation.

Animals↗

PubMed1996

Use of modafinil in the treatment of narcolepsy: a long term follow-up study.

One hundred and forty patients (104 male and 36 female) aged 42.26 +/- 19.19 (range = 8 to 79.5 years) with narcolepsy-cataplexy were given modafinil (200 to 400 mg) at the Montpellier sleep disorders center from 1984 onwards. The follow-up focused on the reduction of excessive daytime somnolence (EDS), side effects and duration of treatment. In order to determine if any clinical aspect of narcolepsy could be involved in modafinil discontinuation, patients were divided into two groups according to continued or interrupted treatment. When modafinil effect on EDS was evaluated according to a scale varying from 0 (no effect) to 3 (excellent effect), 64.1% of the subjects, scored good or excellent. The mean duration of treatment was 22.05 months +/- 24.9, ranging from 1 to 114 months. Dependency signs were never observed.

Adolescent↗

PubMed2007

P300 and treatment effect of modafinil on fatigue in multiple sclerosis.

To evaluate the value of visual and auditory P300 for predicting the response of multiple sclerosis-related fatigue to modafinil treatment, 33 patients were treated with 100 mg modafinil once daily for 4 weeks, following a 4-week baseline phase and an optional 8-week extension phase. The main clinical outcome parameter was a decrease in the fatigue visual analogue score (VAS) before and after 4 weeks of treatment. Patients with shorter auditory P300 latency at baseline were more likely to benefit from modafinil treatment. Auditory P300 latency predicted treatment response with a specificity of 76% and a sensitivity of 75% at a cut-off latency of 350 ms. Visual P300 latency could not be used to predict treatment response. Baseline auditory P300 latency predicted treatment response, whereas visual P300 latency did not. Clinical improvement did not correlate with changes in either visual or auditory P300.

Acoustic Stimulation↗

PubMed2006

Armodafinil, the R-enantiomer of modafinil: wake-promoting effects and pharmacokinetic profile in the rat.

Modafinil reduces the excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder. In rats, modafinil promotes dose-dependent increases in wake duration. The wake-promoting activity of the R-enantiomer of modafinil (armodafinil) was evaluated in WKY rats and compared to the classical stimulant, D-methamphetamine. Electroencephalographic and electromyographic signals were assessed via a tethered cranial implant. Body temperature and locomotor activity were assessed by telemetry via intraperitoneal implant. Rats (n=60, 12 per group) were subjected to one of five parallel treatments: armodafinil at 30, 100 and 300 mg/kg i.p.; D-methamphetamine, 1 mg/kg i.p. and vehicle. Armodafinil and D-methamphetamine increased time spent awake relative to vehicle. Armodafinil-evoked increases in wake duration were dose-dependent and proportional to plasma compound exposure. Induction of wakefulness by D-methamphetamine was associated with an approximately two-fold increase in locomotor activity during the 2-h period immediately following administration relative to vehicle. D-methamphetamine also increased body temperature over the same time interval. The dose of armodafinil (100 mg/kg, i.p.) that was closest to D-methamphetamine in its wake-promoting efficacy did not produce changes in either body temperature or the intensity of locomotor activity relative to vehicle. Acute rebound hypersomnolence, characterized by increases in non-rapid eye movement sleep (NREMS) as a percentage of time and NREMS bout duration and by a decreased frequency of brief awakenings following sleep deprivation, occurred following D-methamphetamine-but not armodafinil-induced wake in this rat model which has been shown to be predictive of human drug responses.

Animals↗

PubMed2004

Concomitant use of modafinil and tranylcypromine in a patient with narcolepsy: a case report.

This is a case report of a patient with narcolepsy treated simultaneously with modafinil and tranylcypromine. The concurrent use of these two medications is normally contraindicated based on theoretical concerns. To our knowledge this is the first report of the combined use of these two medications in a patient for any reason. This combination of medications was particularly effective in the treatment of the patient's narcoleptic symptoms and was well tolerated, with no evidence of the potential cardiovascular side effects. Due to modafinil's lack of sympathomimetic activity and unique pharmacological profile, it may be well tolerated with monoamine oxidase inhibitor's (MAOI's) in humans with respect to hemodynamic parameters and concerns of hypertensive crisis. Further investigation would help clarify cardiovascular safety issues in using this combined therapy. We believe that with proper informed consent from the patient and careful monitoring, a combination of an MAOI and modafinil may be a viable treatment alternative in refractory cases of narcolepsy.

Benzhydryl Compounds↗

PubMed1993

[The effects of modafinil (300mg) on sleep, sleepiness and arousal in narcoleptic patients].

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 adreno-receptor 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.

Adolescent↗

PubMed2004

Modafinil in endozepine stupor. A case report.

BACKGROUND: Endozepine-4 stupor is a rare disorder. It presents with recurrent episodes of stupor and coma. Endozepine-4 levels are elevated during an attack with electroencephalogram showing fast activity during the ictal phase. There is no specific treatment and various drugs have been tried without long-term benefit. METHOD: We used the vigilance promoting drug modafinil to prevent such attacks in a case presented with endozepine stupor. RESULTS: The vigilance promoting drug modafinil prevented recurrent episodes of stupor and coma in this patient at a dose of 200 mg/day for a period of six months. Upon withdrawal of the drug, the patient experienced recurrent episodes and on reinstitution of modafinil she has remained asymptomatic in the following one year.

Administration, Oral↗

PubMed1999

Contrasting EEG profiles elicited by antipsychotic agents in the prefrontal cortex of the conscious rat: antagonism of the effects of clozapine by modafinil.

1. Power spectra (0-30 Hz) were recorded from transcortical electrodes implanted in prefrontal and sensorimotor cortex in conscious rats. For each animal, the spectra in the presence of a drug were divided by the spectra in the presence of vehicle to give a drug-related differential display of the power spectra, the profile of EEG effects. 2. The profiles of a range of antipsychotic agents of different classes were compared. Haloperidol (0.5 mg kg-1 and 1 mg kg-1 s.c., peak 8 - 12 Hz), chlorpromazine (0.5 mg kg-1, i. p., peak 8 Hz), levomepromazine (1 mg kg-1, i.p., peak 8 Hz), quetiapine (2.5 mg kg-1, s.c., peak 9 - 12 Hz), sertindole (2.5 mg kg-1, s.c., peak 6 - 14 Hz), risperidone (0.5 and 1 mg kg-1 i.p., peak 9 Hz), clozapine (0.1, 0.2, 0.3 and 5 mg kg-1, s.c., peak 8 Hz) and MDL100907 (0.01 mg kg-1 s.c. peak 2 Hz) synchronized the EEG, increasing the power spectra between 2 and 30 Hz, although there were marked differences between the individual profile of EEG effects for each drug. 3. In contrast, the benzamides, sulpiride (7.5 and 15 mg kg-1 i.p.), and amisulpiride (1 and 15 mg kg-1 i.p.) caused marked asynchronous changes in the EEG. Raclopride (2.5 mg kg-1 i.p.), caused an initial peak at 9 Hz, but the effects of raclopride desynchronized over a 3 h time period. 4 Modafinil and apomorphine, administered alone, decreased the power spectra at frequencies higher than 4. Hz. Modafinil (62.4 mg kg-1, i.p.) selectively antagonized the effects of clozapine, but did not antagonize the effects of raclopride. 5. Different pharmacological classes of antipsychotic show synchronization or desynchronization of the EEG in the prefrontal cortex, with the benzamides showing a distinctive spectrum. There appears to be a specific interaction between modafinil and clozapine. Thus, modulation of prefrontal cortical function, perhaps by thalamic gating, may be important for antipsychotic activity.

Animals↗

PubMed2003

Modafinil treatment of opioid-induced sedation.

STUDY OBJECTIVE: The purpose of this study was to assess the efficacy of modafinil in combating opioid-induced sedation. DESIGN: A 1-year retrospective chart review of all patients receiving modafinil, a wake-promoting agent, to treat opioid-induced sedation. Opioid-induced sedation was measured using Epworth Sleepiness Scale (ESS). SETTING: Outpatient, private practice. PATIENTS: Eleven adult patients, six female and five male, being treated with opioids for chronic, nonmalignant pain. RESULTS: A significant decrease was observed between pretreatment and posttreatment ESS measurements during modafinil treatment. CONCLUSION: The results suggest an improvement in opioid-induced sedation in patients treated for nonmalignant pain.

Adult↗

PubMed1997

The antinarcoleptic drug modafinil increases glutamate release in thalamic areas and hippocampus.

The antinarcoleptic drug modafinil [(diphenyl-methyl)-sulfinyl-2-acetamide; Modiodal] dose-dependently inhibits the activity of GABA neurons in the cerebral cortex and in the nucleus accumbens, as well as in sleep-related brain areas such as the medial preoptic area and the posterior hypothalamus. This study examined the effects of modafinil (30-300 mg/kg, i.p.) on dialysate glutamate and GABA levels in the ventromedial (VMT) and ventrolateral (VLT) thalamus and hippocampal formation (Hip) of the awake rat. The results show a maximal increase in glutamate release in these brain regions at the 100 mg/kg dose, associated with a lack of effect on GABA release. Thus modafinil may increase excitatory glutamatergic transmission in these regions, altering the balance between glutamate and GABA transmission.

Animals↗

PubMed1998

Modafinil prevents glutamate cytotoxicity in cultured cortical neurons.

The ability of modafinil (Modiodal) to protect cortical neurons from glutamate-induced degeneration was evaluated by measuring electrically evoked [3H]GABA release and [3H]GABA uptake in primary cerebral cortical cultures. In normal cells, electrical stimulation (10 Hz, 2 min) increased [3H]GABA release (FR-NER St1 = 0.77+/-0.14; St2/St1 ratio = 0.94+/-0.02). The exposure of sister cells to glutamate, reduced electrically evoked [3H]GABA release (FR-NER St1 = 0.40+/-0.05; St2/St1 ratio = 0.60+/-0.08). Modafinil (0.3-1 microM) prevented the glutamate-induced reduction of the St2/St1 ratio (0.85+/-0.11; 0.88+/-0.05, respectively). A similar protective effect was observed for [3H]GABA uptake. These findings suggest that modafinil may be neuroprotective in that it attenuates glutamate-induced excitotoxicity in cortical neurons.

Animals↗

PubMed2001

Effects of modafinil in children with attention-deficit/hyperactivity disorder: an open-label study.

OBJECTIVE: To examine the effect of once-daily dosing of modafinil, a stimulant that has a long duration of action, on clinical features of attention-deficit/hyperactivity disorder (ADHD) in children. METHOD: An open-label design was used to compare the Conners Parent and Teacher Rating Scale-Revised (L) (CPRS, CTRS), the ADHD Rating Scale-IV, and the Test of Variables of Attention (TOVA), without and with medication, in children with ADHD. Eleven children with ADHD, ranging in age from 5 to 15 years, took modafinil for an average of 4.6 weeks. RESULTS: Average TOVA ADHD scores improved by 2.43 SD (p = .0009). CTRS and CPRS ADHD index T scores improved by an average of 14.1 (p = .0009) and 17.7 points (p = .001), respectively. The mean ADHD Rating Scale-IV scores improved from the 88th percentile to the 75th percentile (p = .047). One subject withdrew from the study because of an adverse event that was resolved completely with medication withdrawal. Other side effects were mild and responded to dose adjustment. No subjects required more than one dose per day. CONCLUSIONS: Modafinil may be a useful once-daily treatment for children with ADHD. Further study using a double-blind, placebo-controlled design is needed.

Adolescent↗

PubMed2006

Modafinil for atypical depression: effects of open-label and double-blind discontinuation treatment.

Atypical depression, with features of hypersomnia, hyperphagia, anergia, and rejection sensitivity, is a common presentation of major depressive disorder. There are few available effective therapies for this disorder. We test modafinil, a novel wake-promoting agent, as monotherapy for atypical depression in a double-blind, placebo-controlled, relapse prevention trial after open-label treatment. We found that modafinil significantly improved atypical depression symptoms during 12 weeks of open-label treatment (mean +/- SD Hamilton Depression Scale (29-item version) score changed from 34 +/- 8.2 at baseline to 9.7 +/- 9.3, P < 0.0001), and that benefits were maintained alike in both the continuation and placebo arms during the double-blind treatment phase (P = 0.92). Modafinil was well tolerated and the drug was associated with significant weight loss compared with placebo (P = 0.01).

Adult↗

PubMed1997

Self-monitoring cognitive performance during sleep deprivation: effects of modafinil, d-amphetamine and placebo.

Self-monitoring refers to the ability to assess accurately one's own performance in a specific environment. The present study investigated the effects of the stimulating drugs modafinil (300 mg) and d-amphetamine (20 mg) on the ability to self-monitor cognitive performance during 64 h of sleep deprivation (SD) and sustained mental work. Two cognitive tasks were investigated: a visual (perceptual) judgement task and a complex mental addition task. Subjects in the placebo condition displayed marked circadian and SD effects on cognitive task performance but their self-monitoring was substantively undisturbed by SD. Subjects performing under the influence of d-amphetamine likewise displayed highly proficient self-monitoring throughout the SD period. In contrast, modafinil had a disruptive effect on self-monitoring, inducing a reliable 'overconfidence' effect (i.e. an overestimation of actual cognitive performance), which was particularly marked 2-4 h post-dose. Although modafinil has proven to be a safe and effective countermeasure to the effects of extensive SD on cognitive task performance, we encourage a more comprehensive understanding of the relation between its subjective and performance enhancing effects before the drug is recommended as a viable fatigue countermeasure.

Adult↗

PubMed1996

Analysis of stimulant locomotor effects of modafinil in various strains of mice and rats.

Locomotor effects of modafinil were analysed and compared in various strains of mice and rats. A stimulation of locomotor activity was evidenced in all tested strains of mice: Swiss CD1, BALB/c, DBA2, C3H, B6CBAF1/JICO, Nude CD1 and in all tested strains of rats: Long Evans, Sprague Dawley, Wistar. In mice, from 10 mg/kg intraperitoneal, a precocious stimulant effect was observed. The drug seems to operate in its native form on the mouse brain since its intracerebroventricular administration (from 15 micrograms/mouse) elicited a stimulation of locomotion. In rats, the effective doses were higher (from 40 mg/kg ip); the effects of modafinil mainly oppose to the decrease in locomotion (habituation) which normally occurs in control animals. In addition, it was observed that administration of modafinil in rats habituated to their environment induced a recovery of locomotor activity.

Analysis of Variance↗

PubMed1997

Modafinil in obstructive sleep apnea-hypopnea syndrome: a pilot study in 6 patients.

We studied the effects of modafinil, a vigilance-enhancing drug, on excessive daytime sleepiness, memory, night sleep and respiration in 6 patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) using a double-blind random cross-over design with 24-hour polysomnography, verbal memory test and a 5-week sleep-wake diary kept by the patients. There were two 2-week treatment periods in which either modafinil or placebo was used; they were separated by a 1-week wash-out period. Our results show that modafinil reduces daytime sleep duration, lengthens the duration of subjective daytime vigilance and improves long-term memory in patients with OSAHS without modifying night sleep and respiration events.

Aged↗

PubMed2002

Effect of modafinil at steady state on the single-dose pharmacokinetic profile of warfarin in healthy volunteers.

Modafinil has been reported to produce a concentration-related suppression of CYP2C9 activity in vitro in primary cultures of human hepatocytes. To determine whether this effect occurs in vivo, the pharmacokinetics of (S)-warfarin was investigated after single oral doses of racemic warfarin (5 mg; COUMADIN) in a placebo-controlled, single-blind, single-period study in 28 volunteers. Subjects received an oral dose of warfarin prior to administration of modafinil (200 mg for 7 days, followed by 400 mg for 21 days) or placebo and they received another after 4 weeks of treatment. Treatment with modafinil did not significantly alter the pharmacokinetics of (S)- or (R)-warfarin relative to placebo. Since (S)-warfarin is predominantly metabolized via CYP2C9, the results indicate that the marked suppression of CYP2C9 activity in vitro does not translate into a similar effect clinically. However, limitations arising from investigation of single doses of warfarin preclude global conclusions about the potential for more subtle interactions after chronic warfarin administration.

Adult↗

PubMed2005

Chronic treatment with modafinil may not be beneficial in patients with chronic fatigue syndrome.

Fourteen patients (7 male, 7 female, 22-63 years), classified as having chronic fatigue syndrome (CFS), but without concurrent major depression, significant sleepiness or use of psychoactive medication, completed a double-blind, placebo-controlled, crossover study of the effects of the selective wakefulness-promoting agent, modafinil (200 and 400mg/day). The treatment periods were each 20 days, with washout periods of 2 weeks. The primary aim was to determine effects on cognition and the secondary aim was to determine effects on self-ratings of fatigue, quality of life and mood. Modafinil had mixed effects in two cognitive tasks. In a test of sustained attention, treatment with 200mg reduced the latency to correctly detect sequences, but 400mg increased the number of missed targets. In a test of spatial planning, the 200mg dose resulted in a slower initial thinking time for the easiest part of the task, whereas 400mg reduced the initial thinking time for the hardest part of the test. Lastly, in a test of mental flexibility and one of motor speed, patients performed worse whilst on modafinil (400mg), compared with the placebo period. No effects were observed on the performance of other psychometric tests or on self-ratings of fatigue, quality of life or mood, but this may have been due to insufficient statistical power. It is discussed whether the limited and mixed cognitive effects that we observed could have occurred by chance, or whether a subgroup of CFS patients with daytime sleepiness would have shown greater benefits.

Adult↗